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WHO guidelines for the treatment of Treponema pallidum (syphilis)

24 août 2016 Organisation mondiale de la santé

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WHO GUIDELINES FOR THE

Treatment of Treponema pallidum (syphilis)

WHO GUIDELINES FOR THE

Treatment of Treponema pallidum (syphilis)

WHO Library Cataloguing-in-Publication Data WHO guidelines for the treatment of Treponema pallidum (syphilis). Contents: Web annex D: Evidence profiles and evidence-to-decision frameworks - Web annex E: Systematic reviews for syphilis guidelines Web annex F: Summary of conflicts of interest 1.Syphilis – drug therapy. 2.Treponema pallidum. 3.Sexually Transmitted Diseases. 4.Guideline. I.World Health Organization. ISBN 978 92 4 154980 6 (NLM classification: WC 170)

© World Health Organization 2016 All rights reserved. Publications of the World Health Organization are available on the WHO website (http://www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; email: bookorders@who.int). Requests for permission to reproduce or translate WHO publications – whether for sale or for non-commercial distribution– should be addressed to WHO Press through the WHO website (http://www.who.int/about/licensing/ copyright_form/index.html). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. Printed by the WHO Document Production Services, Geneva, Switzerland

CONTENTS

Acknowledgements iii Abbreviations and acronyms Executive summary iv 1

Overview of the guidelines for the prevention, treatment and management of STIs 6 STI epidemiology and burden 6 Why new guidelines for the prevention, treatment and management of STIs? 6 Approach to the revision of STI guidelines 8 References 9 WHO guidelines for the treatment of Treponema pallidum (syphilis) 1. 1.1 1.2 1.3 1.4 1.5 2. 2.1 2.2 2.3 2.4 2.5 3. 3.1 3.2 3.3 4. 4.1 4.2 Introduction Epidemiology, burden and clinical considerations Clinical presentation Laboratory diagnosis Rationale for new recommendations Objectives Target audience Structure of the guidelines Methods Guideline Development Group (GDG) Questions and outcomes Reviews of the evidence Making recommendations Management of conflicts of interest Dissemination, updating and implementation of the guidelines Dissemination Updating the STI guidelines and user feedback Implementation of the WHO guidelines for the treatment of T. pallidum (syphilis) Adaptation, implementation and monitoring Identifying and procuring STI medicines Recommendations for treatment of syphilis Early syphilis Recommendation 1 Recommendation 2 Recommendation 3 Recommendation 4 Late syphilis Recommendation 5 Recommendation 6 Recommendation 7 Recommendation 8 10 10 10 10 11 13 14 14 14 15 15 15 15 16 17 18 18 18 18 18 19 20 20 20 20 21 21 22 22 22 22 22

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

CONTENTS (CONTINUED)

4.3 Congenital syphilis Recommendation 9 Recommendation 10 5. Research implications

23 23 23 25

References 26 Annex A: STI guideline development teams Annex B: Detailed methods for guidelines development Questions and outcomes Review of the evidence Applying the GRADE approach to making the recommendations Annex C: Lists of references for reviewed evidence Recommendation 1 and 2 Recommendation 3 and 4 Recommendation 5 and 6 Recommendation 7 and 8 Recommendation 9 Recommendation 10 27 36 36 42 44 45 45 46 47 48 48 48

Web annexes available at: www.who.int/reproductivehealth/publications/rtis/syphilis-treatment-guidelines/en/ Web annex D: Evidence profiles and evidence-to-decision frameworks Web annex E: Systematic reviews for syphilis guidelines Web annex F: Summary of conflicts of interest

ACKNOWLEDGEMENTS

iii

ACKNOWLEDGEMENTS

The Department of Reproductive Health and Research at the World Health Organization (WHO) would like to thank the members of the STI Guideline Development Group for their consistent availability and commitment to making these guidelines possible. The Department is also grateful to the STI External Review Group for peer reviewing these guidelines, and appreciates the contribution of the WHO Steering Committee. The names of the members of each group are listed below, with full details provided in Annex A. Special thanks to Dr Nancy Santesso, the guideline methodologist who also led the systematic review process, for her hard work and firm commitment of the guideline development process. We also thank the members of the Systematic Review Team from McMaster University. We appreciate the overall support of the WHO Guideline Review Committee Secretariat during the guideline development process, with grateful thanks to Dr Susan Norris. We thank Theresa Ryle for the administrative support, and 400 Communication for assistance with the guideline design and layout. This guideline document was edited by Ms Jane Patten, of Green Ink, United Kingdom. Dr Teodora Wi led the guideline development process and Dr Nathalie Broutet co-led the process under the supervision of Dr James Kiarie and leadership of Dr Ian Askew. Lee Sharkey provided support during the guideline development process.

Members: Yaw (Sax) Adu-Sarkodie, Andrew Amato, Gail Bolan, John Changalucha, Xiang-Sheng Chen, Harrel Chesson, Craig Cohen, Francisco Garcia, Suzanne Garland, Sarah Hawkes, Mary Higgins, King Holmes, Jeffrey Klausner, David Lewis, Nicola Low, David Mabey, Angelica Espinosa Miranda, Nelly Mugo, Saiqa Mullick, Francis Ndowa, Joel Palefsky, Keith Radcliffe, Ulugbek Sabirov, Judith Stephenson, Richard Steen, Magnus Unemo, Bea Vuylsteke, Anna Wald, Thomas Wong and Kimberly A. Workowski STI GDG working group for syphilis: Gail Bolan, John Changalucha, Xiang-Sheng Chen, Patricia Garcia, Suzanne Garland, Antonio Gerbase, Jeffrey Klausner, Ornella Lincetto, David Mabey, Saiqa Mullick, Joel Palefsky, Ulugbek Sabirov, Richard Steen STI External Review Group: Laith Abu-Raddad, Chris Akolo, Adele Benaken-Schwarts, Mircea Betiu, Anupong Chitwarakorn, Carolyn Deal, Margaret Gale-Rowe, William M. Geisler, Mary Kamb, Amina El Kettani, Mizan Kiros, Ahmed Latif, Philippe Mayaud, David McCartney, Ali M. Mir, Nuriye Ortayli, Pablo Sanchez, Khantanouvieng Sayabounthavong and Aman Kumar Singh WHO Steering Committee: WHO regional offices: Massimo Ghidinelli, Hamida Khattabi, Lali Khotenashvili, Ornella Lincetto Ying-Ru Lo, Frank Lule and Razia Pendse WHO headquarters: Moazzam Ali, Avni Amin, Rachel Baggaley, Venkatraman Chandra-Mouli, Jane Ferguson, Mario Festin, Mary Lyn Gaffield, Antonio Gerbase, Sami Gottlieb, Frances McConville, Lori Newman, Annette Mwansa Nkowane, Anita Sands, Igor Toskin and Marco Vitoria WHO STI Secretariat: Ian Askew, Teodora Elvira Wi (lead, development of the guidelines), Nathalie Broutet (co-lead, development of the guidelines), James Kiarie and Lee Sharkey Systematic Review Team: Nancy Santesso (lead), Housne Begum, Janna-Lina Kerth, Gian Paolo Morgano, Kristie Poole, John Riva, Nicole Schwab, Matthew Ventresca, Yuan Zhang and Andrew Zikic (members) Methodologist: Nancy Santesso.

FUNDING The preparation and printing of the guidelines were funded exclusively by the UNDP/UNFPA/UNICEF/ WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP). No external source of funding was solicited or utilized.

CONTRIBUTORS TO WHO GUIDELINES ON THE TREATMENT OF TREPONEMA PALLIDUM STI Guideline Development Group (GDG): Chairpersons: Judith Wasserheit, Holger Schünemann and Patricia Garcia

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

ABBREVIATIONS AND ACRONYMS

AIDS acquired immune deficiency syndrome AMR CI DFA DNA DOI antimicrobial resistance confidence interval direct fluorescent antibody deoxyribonucleic acid declaration of interests

NAAT PCR

nucleic acid amplification test polymerase chain reaction

PICO population, intervention, comparator, outcome PMTCT prevention of mother-to-child transmission RDT RPR STI rapid diagnostic tests rapid plasma reagin sexually transmitted infection

FTA-ABS fluorescent treponemal antibody absorbed GDG Guideline Development Group

GRADE Grading of Recommendations Assessment, Development and Evaluation GUD HIV HPV HSV HSV-1 HSV-2 genital ulcer disease human immunodeficiency virus human papillomavirus herpes simplex virus herpes simplex virus type 1 herpes simplex virus type 2

TPHA Treponema pallidum haemagglutination assay TPPA Treponema pallidum particle agglutination assay TRUST Toluidine Red Unheated Serum Test

VDRL Venereal Diseases Research Laboratory

ICT immunochromatographic IM intramuscular

IV intravenous MSH MSM MU Management Sciences for Health men who have sex with men million units

EXECUTIVE SUMMARY

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS) EXECUTIVE SUMMARY

Sexually transmitted infections (STIs) are a major public health problem worldwide, affecting quality of life and causing serious morbidity and mortality. STIs have a direct impact on reproductive and child health through infertility, cancers and pregnancy complications, and they have an indirect impact through their role in facilitating sexual transmission of human immunodeficiency virus (HIV) and thus they also have an impact on national and individual economies. More than a million STIs are acquired every day. In 2012, an estimated 357 million new cases of curable STIs (gonorrhoea, chlamydia, syphilis and trichomoniasis) occurred among 15- to 49-year-olds worldwide, including 5.6 million cases of syphilis. There are an estimated 18 million prevalent cases of syphilis.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Syphilis is a bacterial STI caused by Treponema pallidum that results in substantial morbidity and mortality. Syphilis is transmitted through sexual contact with infectious lesions of the mucous membranes or abraded skin, via blood transfusion, or transplacentally from a pregnant woman to her fetus. Untreated, the disease lasts many years and is divided into stages. Early syphilis consists of primary syphilis, secondary syphilis and early latent syphilis, while late syphilis consists of late latent syphilis and tertiary syphilis (neurosyphilis, cardiosyphilis and gumma). Primary syphilis classically presents as a solitary, painless chancre at the site of inoculation. However, the primary chancre may go unnoticed by patients. If untreated, the disease progresses to the secondary stage, characterized by generalized mucocutaneous lesions affecting both skin, mucous membranes and lymphnodes. The rash of secondary syphilis can vary widely and mimic other infectious and non-infectious conditions, but characteristically affects the palms and soles. The symptoms and signs of secondary syphilis spontaneously resolve, even without treatment, and if left untreated, the patient enters the latent stage. Latent syphilis is asymptomatic, characterized by positive syphilis serology with no clinical manifestations. Latent syphilis is often divided into two phases: early latent syphilis is defined as infection for less than two years while late latent syphilis is the presence of the disease for two years or more. Sexual transmission typically occurs during primary, secondary or early latent stage infections; however, mother-to-child transmission has been documented to occur in untreated cases several years after initial maternal infection. Mother-to-child transmission of syphilis (congenital syphilis) is usually devastating to the fetus if maternal infection is not detected and treated sufficiently early in pregnancy. The burden of morbidity and mortality due to congenital syphilis is high. In 2012, an estimated 350 000 adverse pregnancy outcomes worldwide were attributed to syphilis, including 143 000 early fetal deaths/stillbirths, 62 000 neonatal deaths, 44 000 preterm/low-birth-weight babies and 102 000 infected infants. Most untreated primary and secondary syphilis infections in pregnancy result in severe adverse pregnancy outcomes. Latent (asymptomatic) syphilis infections in pregnancy also cause serious adverse pregnancy outcomes in more than half of cases. Mother-to-child transmission of syphilis is declining globally due to increased efforts to screen and treat pregnant women for syphilis.

Syphilis diagnosis is usually based on clinical history, physical examination, laboratory testing and sometimes radiology. In most laboratory settings, the diagnosis is based upon serologic tests. These include treponemal tests that measure antibodies to infection (including Treponema pallidum haemagglutination assay [TPHA], Treponema pallidum particle agglutination assay [TPPA], fluorescent treponemal antibody absorbed [FTA-ABS]) and non-treponemal tests that are indirect markers measuring host immune response to infections (including rapid plasma reagin [RPR], Venereal Diseases Research Laboratory [VDRL], Toluidine Red Unheated Serum Test [TRUST]). Rapid treponemal tests for syphilis and dual HIV and syphilis tests are now available. These tests will increase coverage for diagnosing syphilis.

RATIONALE FOR THE GUIDELINES Since the publication of the WHO Guidelines for the management of sexually transmitted infections in 2003, changes in the epidemiology of STIs and advancements in prevention, diagnosis and treatment necessitate changes in STI management. These guidelines provide updated treatment recommendations for treatment of Treponema pallidum (syphilis) based on the most recent evidence. They form one of several modules of guidelines for specific STIs. Other modules will focus on treatments for Chlamydia trachomatis (chlamydia), Neisseria gonorrhoeae (gonorrhoea) and genital herpes simplex virus (genital HSV). In addition, future work will provide guidance for syphilis screening and treatment of pregnant women, STI syndromic approach, clinical management, STI prevention, and treatments of other STIs. It is strongly recommended that countries take updated global guidance into account as they establish standardized national protocols and adapt it to the local epidemiological situation and antimicrobial susceptibility data.

OBJECTIVES The objectives of these guidelines are: • t o provide evidence-based guidance on treatment of Treponema pallidum; and • t o support countries to update their national guidelines for treatment of Treponema pallidum.

EXECUTIVE SUMMARY

METHODS These guidelines were developed following the methods outlined in the 2014 WHO handbook for guideline development. The Guideline Development Group (GDG) included international STI experts, clinicians, researchers and programme managers. The GDG prioritized questions and outcomes related to treatment of syphilis and congenital syphilis infections to include in this update, and a methodologist and a team of systematic reviewers from McMaster University, the WHO Collaborating Centre for Evidence-Informed Policy, independently conducted systematic reviews of the effectiveness of different treatments for syphilis and congenital syphilis. The evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach and presented to the GDG. Conflicts of interest were managed according to WHO guidelines and declared before the recommendations were discussed and finalized. Research implications were also developed by the GDG.

RECOMMENDATIONS The current guidelines provide treatment recommendations for Treponema pallidum and congenital syphilis. The recommendations summarized in Table 1 apply to all adults and adolescents (10–19 years of age), including pregnant women, people living with HIV, people who are immunocompromised and key populations, including sex workers, men who have sex with men (MSM) and transgender persons.

Table 1. Summary of recommendations for treatment of Treponema pallidum and congenital syphilis Recommendations Strength of recommendation and quality of evidence

Early syphilis (primary, secondary and early latent syphilis of not more than two years’ duration) Adults and adolescents Recommendation 1 In adults and adolescents with early syphilis, the WHO STI guideline recommends benzathine penicillin G 2.4 million units once intramuscularly over no treatment. Recommendation 2 In adults and adolescents with early syphilis, the WHO STI guideline suggests using benzathine penicillin G 2.4 million units once intramuscularly over procaine penicillin G 1.2 million units 10–14 days intramuscularly. When benzathine or procaine penicillin cannot be used (e.g. due to penicillin allergy) or are not available (e.g. due to stock-outs), the WHO STI guideline suggests using doxycycline 100 mg twice daily orally for 14 days or ceftriaxone 1 g intramuscularly once daily for 10–14 days, or, in special circumstances, azithromycin 2 g once orally. Remarks: Doxycycline is preferred over ceftriaxone due to its lower cost and oral administration. Doxycycline should not be used in pregnant women (see recommendations 3 and 4 for pregnant women). Azithromycin is an option in special circumstances only when local susceptibility to azithromycin is likely. If the stage of syphilis is unknown, follow recommendations for people with late syphilis. Strong recommendation, very low quality evidence

Conditional recommendation, very low quality evidence

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Pregnant women Recommendation 3 In pregnant women with early syphilis, the WHO STI guideline recommends benzathine penicillin G 2.4 million units once intramuscularly over no treatment. Recommendation 4 In pregnant women with early syphilis, the WHO STI guideline suggests using benzathine penicillin G 2.4 million units once intramuscularly over procaine penicillin 1.2 million units intramuscularly once daily for 10 days. When benzathine or procaine penicillin cannot be used (e.g. due to penicillin allergy where penicillin desensitization is not possible) or are not available (e.g. due to stock-outs), the WHO STI guideline suggests using, with caution, erythromycin 500 mg orally four times daily for 14 days or ceftriaxone 1 g intramuscularly once daily for 10–14 days or azithromycin 2 g once orally. Remarks: Although erythromycin and azithromycin treat the pregnant women, they do not cross the placental barrier completely and as a result the fetus is not treated. It is therefore necessary to treat the newborn infant soon after delivery (see recommendations 9 and 10 for congenital syphilis). Ceftriaxone is an expensive option and is injectable. Doxycycline should not be used in pregnant women. Because syphilis during pregnancy can lead to severe adverse complications to the fetus or newborn, stock-outs of benzathine penicillin for use in antenatal care should be avoided. Late syphilis (infection of more than two years’ duration without evidence of treponemal infection) Adults and adolescents Recommendation 5 In adults and adolescents with late syphilis or unknown stage of syphilis, the WHO STI guideline recommends benzathine penicillin G 2.4 million units intramuscularly once weekly for three consecutive weeks over no treatment. Remarks: The interval between consecutive doses of benzathine penicillin should not exceed 14 days. Recommendation 6 In adults and adolescents with late syphilis or unknown stage of syphilis, the WHO STI guideline suggests benzathine penicillin G 2.4 million units intramuscularly once weekly for three consecutive weeks over procaine penicillin 1.2 million units once daily for 20 days. When benzathine or procaine penicillin cannot be used (e.g. due to penicillin allergy where penicillin desensitization is not possible) or are not available (e.g. due to stock-outs), the WHO STI guideline suggests using doxycycline 100 mg twice daily orally for 30 days. Remarks: Doxycycline should not be used in pregnant women (see recommendations 7 and 8 for pregnant women). Conditional recommendation, very low quality evidence Strong recommendation, very low quality evidence Strong recommendation, very low quality evidence

Conditional recommendation, very low quality evidence

EXECUTIVE SUMMARY

Pregnant women Recommendation 7 In pregnant women with late syphilis or unknown stage of syphilis, the WHO STI guideline recommends benzathine penicillin G 2.4 million units intramuscularly once weekly for three consecutive weeks over no treatment. Remarks: The interval between consecutive doses of benzathine penicillin should not exceed 14 days. Recommendation 8 In pregnant women with late syphilis or unknown stage of syphilis, the WHO STI guideline suggests benzathine penicillin G 2.4 million units intramuscularly once weekly for three consecutive weeks over procaine penicillin 1.2 million units intramuscularly once a day for 20 days When benzathine or procaine penicillin cannot be used (e.g. due to penicillin allergy where penicillin desensitization is not possible) or are not available (e.g. due to stock-outs), the WHO STI guideline suggests using, with caution, erythromycin 500 mg orally four times daily for 30 days. Remarks: Although erythromycin treats the pregnant women, it does not cross the placental barrier completely and as a result the fetus is not treated. It is therefore necessary to treat the newborn infant soon after delivery (see recommendations 9 and 10 for congenital syphilis). Doxycycline should not be used in pregnant women. Because syphilis during pregnancy can lead to severe adverse complications to the fetus or newborn, stock-outs of benzathine penicillin for use in antenatal care should be avoided. Congenital syphilis Infants Recommendation 9 In infants with confirmed congenital syphilis or infants who are clinically normal, but whose mothers had untreated syphilis, inadequately treated syphilis (including treatment within 30 days of delivery) or syphilis that was treated with non-penicillin regimens, the WHO STI guideline suggests aqueous benzyl penicillin or procaine penicillin. Dosages: • Aqueous benzyl penicillin 100 000–150 000 U/kg/day intravenously for 10–15 days • Procaine penicillin 50 000 U/kg/day single dose intramuscularly for 10–15 days Remarks: If an experienced venipuncturist is available, aqueous benzyl penicillin may be preferred instead of intramuscular injections of procaine penicillin. Recommendation 10 In infants who are clinically normal and whose mothers had syphilis that was adequately treated with no signs of reinfection, the WHO STI guideline suggests close monitoring of the infants. Remarks: The risk of transmission of syphilis to the fetus depends on a number of factors, including maternal titres from non-treponemal tests (e.g. RPR), timing of maternal treatment and stage of maternal infection, and therefore this recommendation is conditional. If treatment is provided, benzathine penicillin G 50 000 U/kg/day single dose intramuscularly is an option. Conditional recommendation, very low quality evidence Conditional recommendation, very low quality evidence Conditional recommendation, very low quality evidence Strong recommendation, very low quality evidence

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

OVERVIEW OF THE GUIDELINES FOR THE PREVENTION, TREATMENT AND MANAGEMENT OF STIs STI EPIDEMIOLOGY AND BURDEN Sexually transmitted infections (STIs) are a major public health problem worldwide, affecting quality of life and causing serious morbidity and mortality. STIs have a direct impact on reproductive and child health through infertility, cancers and pregnancy complications, and they have an indirect impact through their role in facilitating sexual transmission of human immunodeficiency virus (HIV) and thus they also have an impact on national and individual economies. The prevention and control of STIs is an integral component of comprehensive sexual and reproductive health services that are needed to attain the related targets under Sustainable Development Goal (SDG) No. 3 (Ensure healthy lives and promote well-being for all at all ages), including: target 3.2 – to end preventable deaths of newborns and children under 5 years of age; target 3.3 – to end the epidemics of AIDS and other communicable diseases; target 3.4 – to reduce premature mortality from noncommunicable diseases and promote mental health and well-being; target 3.7 – to ensure universal access to sexual and reproductive health-care services; and target 3.8 – to achieve universal health coverage. Worldwide, more than a million curable STIs are acquired every day. In 2012, there were an estimated 357 million new cases of curable STIs among adults aged 15–49 years worldwide: 131 million cases of chlamydia, 78 million cases of gonorrhoea, 6 million cases of syphilis and 142 million cases of trichomoniasis (1). The prevalence of some viral STIs is similarly high, with an estimated 417 million people infected with herpes simplex virus type 2 (HSV-2) (2), and approximately 291 million women harbouring human papillomavirus (HPV) at any point in time (3). The burden of STIs varies by region and gender, and is greatest in resource-poor countries. When left undiagnosed and untreated, curable STIs can result in serious complications and sequelae, such as pelvic inflammatory disease, infertility, ectopic pregnancy, miscarriage, fetal loss and congenital infections. In 2012, an estimated 930 000 maternal syphilis infections resulted in 350 000 adverse pregnancy outcomes, including stillbirths, neonatal deaths, preterm births and infected infants (4). Curable STIs accounted for the loss of nearly 11 million disability-adjusted life years (DALYs) in 2010 (5). The psychological consequences of STIs include stigma, shame and loss of self-worth. STIs have also been associated with relationship disruption and gender-based violence (6). Both ulcerative and non-ulcerative STIs are associated with a several-fold increased risk of transmitting or acquiring HIV (7, 8). Infections causing genital ulcers are associated with the highest HIV transmission risk; in addition to curable ulcer-causing STIs (e.g. syphilis and chancroid), highly prevalent HSV-2 infections substantially increase that risk (9). Non-ulcerative STIs, such as gonorrhoea, chlamydia and trichomoniasis, have been shown to increase HIV transmission through genital shedding of HIV (10). Treating STIs with the right medicines at the right time is necessary to reduce HIV transmission and improve sexual and reproductive health (11). Efforts should therefore be taken to strengthen STI diagnosis and treatment.

WHY NEW GUIDELINES FOR THE PREVENTION, TREATMENT AND MANAGEMENT OF STIs? Since the publication of the World Health Organization (WHO) Guidelines for the management of sexually transmitted infections in 2003, changes in the epidemiology of STIs and advancements in prevention, diagnosis and treatment necessitate changes in STI management. Indeed, 88% of countries have updated their national STI guidelines or recommendations since 2006 (12). Updated global guidance reflecting the most recent evidence and expert opinion is therefore needed to assist countries to incorporate new developments into an effective national approach to the prevention and treatment of STIs. There is an urgent need to update global treatment recommendations to effectively respond to the changing antimicrobial resistance (AMR) patterns of STIs, especially for Neisseria gonorrhoeae. Effective treatment protocols that take into account global and local resistance patterns are essential to reduce the risk of further development of AMR. High-level gonococcal resistance to quinolones, a previously recommended first-line treatment, is widespread and decreased susceptibility to the extended-spectrum (third-generation) cephalosporins, another first-line treatment for gonorrhoea, is on the rise (13). Low-level resistance to Trichomonas vaginalis has also been reported for nitroimidazoles, the only available treatment. Resistance to azithromycin has been reported in some strains of Treponema pallidum and treatment failures have been reported for tetracyclines and macrolides in the treatment of Chlamydia trachomatis (14, 15). A WHO STI expert consultation recommended updating the WHO 2003

OVERVIEW OF THE GUIDELINES FOR THE PREVENTION, TREATMENT AND MANAGEMENT OF STIs

guidelines for the first- and second-line treatments for C. trachomatis, increasing the dosage of ceftriaxone to 250 mg for treatment of N. gonorrhoeae with continued monitoring of antimicrobial susceptibility, and consideration of whether azithromycin (2 g, single dose) should be recommended in early syphilis (16). The epidemiology of STIs is changing, with viral pathogens becoming more prevalent than bacterial etiologies for some conditions; this means that updated information is required to inform locally appropriate prevention and treatment strategies. An increasing proportion of genital ulcers are now due to viral infections as previously common bacterial infections, such as chancroid, approach elimination in many countries (16, 17). As recommended during the STI expert consultation, treatment guidelines for genital ulcer disease (GUD) should be updated to include HSV-2 treatment and a longer treatment duration for HSV-2 should be explored. In addition, suppressive therapy for HSV-2 should be considered in areas with high HIV prevalence (16). The chronic, lifelong nature of viral infections also requires that renewed attention be paid to developing effective prevention strategies, including expanding accessibility to available vaccines for HPV and development of new vaccines for HSV-2. In the 2003 WHO guidelines, a syndromic approach was recommended for the management of STIs. The approach guides the diagnosis of STIs based on identification of consistent groups of symptoms and easily recognized signs and indicates treatment for the majority of organisms that may be responsible for producing the syndrome. The syndromic management algorithms need to be updated in response to the changing situation. In addition to changes to the GUD algorithm, other syndromes need to be reevaluated, particularly vaginal discharge. The approach to syndromes for key populations also needs to be updated. For example, addition of a syndromic management algorithm for anorectal infections in men who have sex with men (MSM) and sex workers is urgently needed since a substantial number of these infections go unrecognized and untreated in the absence of guidelines (16). New rapid, point-of-care diagnostic tests (POCTs) are changing STI management. Rapid syphilis diagnostic tests are now widely available, making syphilis screening more widely accessible and allowing for earlier initiation of treatment for those who test positive. Efforts are under way to develop POCTs for other STIs that will augment syndromic management of symptomatic cases and increase the ability to identify asymptomatic infections (12). Updated guidelines are needed that incorporate rapid tests into syndromic management of STIs and provide algorithms for testing and screening (16).

Although recent technological advances in diagnostics, therapeutics, vaccines and barrier methods offer better opportunities for the prevention and care of STIs, access to these technologies is still limited, particularly in areas where the burden of infection is highest. For optimal effectiveness, global guidelines for the management of STIs need to include approaches for settings with limited access to modern technologies, as well as for settings in which these technologies are available. It is strongly recommended that countries take updated global guidance into account as they establish standardized national protocols, adapting this guidance to the local epidemiological situation and antimicrobial susceptibility data. Standardization ensures that all patients receive adequate treatment at every level of health-care services, optimizes the training and supervision of health-care providers and facilitates procurement of medicines. It is recommended that national guidelines for the effective management of STIs be developed in close consultation with local STI, public health and laboratory experts.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

APPROACH TO THE REVISION OF STI GUIDELINES To ensure effective treatment for all STIs, WHO plans a phased approach to updating the STI guidelines to address a range of infections and issues. Four phases have been proposed by the WHO STI Secretariat and agreed upon by the STI Guideline Development Group (GDG) members (see Annex A for members of these groups). Table 2 summarizes the proposed phases and timeline.

Table 2: Phases for development of the STI guidelines Phases Phase 1 Topics Treatment of specific STIs: Chlamydia trachomatis (chlamydia), Neisseria gonorrhoeae (gonorrhoea), HSV-2 (genital herpes) and Treponema pallidum (syphilis) Syphilis screening and treatment of pregnant women Timeframe November 2013 – April 2016

STI syndromic approach Clinical management package Phase 2 Phase 3 STI prevention: condoms, behaviour change communication, biomedical interventions and vaccines Treatment of specific STIs and reproductive tract infections (RTIs) not addressed in Phase 1: Trichomonas vaginalis (trichomoniasis), bacterial vaginosis, Candida albicans (candidiasis), Hemophilus ducrey i (chancroid), Klebsiella granulomatis (donovanosis), human papillomavirus (HPV; genital warts/cervical cancer), Sarcoptes scabiei (scabies) and Phthirus pubis (pubic lice) STI laboratory diagnosis and screening

May 2016 – December 2017 2017–2018 2017–2018

Phase 4

2017–2018

Phase 1 will focus on treatment recommendations for specific STIs as well as other important and urgent STI issues. Recommendations for the treatment of specific infections will be developed and published as independent modules: • Chlamydia trachomatis (chlamydia) • Neisseria gonorrhoeae (gonorrhoea) • HSV-2 (genital herpes) • Treponema pallidum (syphilis) • Syphilis screening and treatment of pregnant women.

In addition, guidelines for the STI syndromic approach and a clinical management package will be developed later in Phase 1. Phase 2 will focus on guidelines for STI prevention. The independent Phase 1 and 2 modules will later be consolidated into one document and published as comprehensive WHO guidelines on STI case management. Phase 3 will address treatment of additional infections, including Trichomonas vaginalis (trichomoniasis), bacterial vaginosis, Candida albicans (candidiasis), Hemophilus ducreyi (chancroid), Klebsiella granulomatis (donovanosis), HPV (genital warts/cervical cancer), Sarcoptes scabiei (scabies) and Phthirus pubis (pubic lice). Phase 4 will provide guidance on laboratory diagnosis and screening of STIs.

OVERVIEW OF THE GUIDELINES FOR THE PREVENTION, TREATMENT AND MANAGEMENT OF STIs

REFERENCES

1. Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One. 2015;10(12):e0143304. doi:10.1371/journal.pone.0143304. 2. Looker KJ, Magaret AS, Turner KME, Vickerman P, Gottlieb SL, Newman LM. Global estimates of prevalent and incident herpes simplex virus type 2 infections in 2012. PLoS One. 2015;10(1):e114989. doi:10.1371/journal.pone.0114989. 3. De Sanjosé S, Diaz M, Castellsagué X, Clifford G, Bruni L, Muñoz N, Bosch FX. Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. Lancet Infect Dis. 2007;7(7):453–9. 4. Wijesooriya NS, Rochat RW, Kamb ML, Turlapati P, Temmerman M, Broutet N, Newman LM. Global burden of maternal and congenital syphilis in 2008 and 2012: a health systems modelling study. Lancet Global Health. 2016;4(8):e525–e533. doi:10.1016/S2214-109X(16)30135-8. 5. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2197–223. doi:10.1016/S01406736(12)61689-4. 6. Gottlieb SL, Low N, Newman LM, Bolan G, Kamb M, Broutet N. Toward global prevention of sexually transmitted infections (STIs): the need for STI vaccines. Vaccine. 2014;32(14):1527–35. doi:10.1016/j. vaccine.2013.07.087. 7. Wasserheit JN. Epidemiological synergy: interrelationships between human immunodeficiency virus infections and other sexually transmitted diseases. Sex Transm Dis. 1992;19(2):61–77. 8. Sexton J, Garnett G, Røttingen J-A. Metaanalysis and metaregression in interpreting study variability in the impact of sexually transmitted diseases on susceptibility to HIV infection. Sex Transm Dis. 2005;32(6):351–7. 9. Glynn JR, Biraro S, Weiss HA. Herpes simplex virus type 2: a key role in HIV incidence. AIDS. 2009;23(12):1595–8. doi:10.1097/QAD.0b013e32832e15e8. 10. Johnson LF, Lewis DA. The effect of genital tract infections on HIV-1 shedding in the genital tract: a systematic review and meta-analysis. Sex Transm Dis. 2008;35(11):946–59. doi:10.1097/ OLQ.0b013e3181812d15. 11. Cohen MS. Classical sexually transmitted diseases drive the spread of HIV-1: back to the future. J Infect Dis. 2012;206(1):1–2. doi:10.1093/infdis/jis303. 12. Progress report of the implementation of the global strategy for prevention and control of sexually transmitted infections: 2006–2015. Geneva: World Health Organization; 2015 (http://apps.who.int/ iris/bitstream/10665/183117/1/9789241508841_eng.pdf, accessed 24 May 2016). 13. Ndowa FJ, Ison CA, Lusti-Narasimhan M. Gonococcal antimicrobial resistance: the implications for public health control. Sex Transm Infect. 2013;89(Suppl 4):iv1–2. doi:10.1136/sextrans-2013-051394. 14. Gottlieb SL, Low N, Newman LM, Bolan G, Kamb M, Broutet N. Toward global prevention of sexually transmitted infections (STIs): the need for STI vaccines. Vaccine. 2014;32(14):1527–35. doi:10.1016/j. vaccine.2013.07.087. 15. Mabey D. Epidemiology of sexually transmitted infections: worldwide. Medicine. 2014;42(6):287–90. doi:10.1016/j.mpmed.2014.03.004. 16. Report of the expert consultation and review of the latest evidence to update guidelines for the management of sexually transmitted infections. Geneva: World Health Organization; 2011 (WHO/ RHR/11.37; http://apps.who.int/iris/bitstream/10665/75194/1/WHO_RHR_11.37_eng.pdf, accessed 24 May 2016). 17. Steen R. Eradicating chancroid. Bull World Health Organ. 2001;79(9):818–26.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

01 INTRODUCTION 1.1 EPIDEMIOLOGY, BURDEN AND CLINICAL CONSIDERATIONS Syphilis is a bacterial sexually transmitted infection (STI) caused by Treponema pallidum. It results in substantial morbidity and mortality. WHO estimates that 5.6 million new cases of syphilis occurred among adolescents and adults aged 15–49 years worldwide in 2012 with a global incidence rate of 1.5 cases per 1000 females and 1.5 per 1000 males. The estimated 18 million prevalent cases of syphilis in 2012 translates to a global prevalence of 0.5% among females and 0.5% among males aged 15–49 years, with the highest prevalence in the WHO African Region (1). Mother-to-child transmission may occur if the expectant mother has syphilis. Mother-to-child transmission of syphilis (congenital syphilis) is usually devastating to the fetus in cases where maternal infection is not detected and treated sufficiently early in pregnancy. The burden of morbidity and mortality due to congenital syphilis is high. In 2012, an estimated 350 000 adverse pregnancy outcomes worldwide were attributed to syphilis, including 143 000 early fetal deaths/stillbirths, 62 000 neonatal deaths, 44 000 preterm/low-birth-weight babies and 102 000 infected infants. There is also an increase in mother-to-child transmission of HIV among pregnant women co-

infected with syphilis and HIV. Untreated primary and secondary syphilis infections in pregnancy typically result in severely adverse pregnancy outcomes, including fetal deaths in a substantial proportion of cases. Latent syphilis infections in pregnancy result in serious adverse pregnancy outcomes in more than half of cases. The burden of disease is highest in low- and middle-income countries, particularly in the WHO African Region (2). Congenital syphilis is preventable, however, and elimination of mother-to-child transmission of syphilis can be achieved through implementation of effective early screening and treatment strategies for syphilis in pregnant women (3). The fetus can be easily cured with treatment, and the risk of adverse outcomes to the fetus is minimal if the mother receives adequate treatment during early pregnancy – ideally before the second trimester. There are indications that mother-to-child transmission of syphilis is beginning to decline globally due to increased efforts to screen and treat pregnant women for syphilis. CLINICAL PRESENTATION Syphilis is transmitted through sexual contact with infectious lesions of the mucous membranes or abraded skin, via blood transfusion, or transplacentally from a pregnant woman to her fetus. Untreated, the disease lasts many years and is divided into stages. Early syphilis consists of primary syphilis, secondary syphilis and early latent syphilis, while late syphilis consists of late latent syphilis and tertiary syphilis. Primary syphilis classically presents as a solitary, painless chancre at the site of inoculation, usually in the vagina, penis or anus (but it may be extra-genital), after a mean incubation period of 21 days (range: 9–90 days). The primary lesion begins as a raised papule and ulcerates before healing within 3 to 10 weeks, with or without treatment. The primary chancre may go unnoticed by patients. If untreated, the disease progresses to the secondary stage, four to eight weeks after the appearance of the primary lesion. Secondary syphilis is characterized by generalized mucocutaneous lesions affecting both skin and mucous membranes. The rash of secondary syphilis can vary widely and mimic other infectious or non-infectious conditions, but characteristically affects the palms and soles. The rash is often symmetrical and non-itchy, but may have several manifestations and can be minimal enough to be overlooked. In warm and moist areas of the body, such as the anus and labia, large white or grey raised lesions develop as a result of the spread of the treponemes from the primary lesion.

INTRODUCTION

These are known as condylomata lata. The lesions of the skin and mucous membranes may be associated with non-specific constitutional symptoms of malaise, fever and lymphadenopathy. The symptoms and signs of secondary syphilis spontaneously resolve, even without treatment, and if left untreated, the patient enters the latent stage. Latent syphilis is characterized by positive syphilis serology with no clinical symptoms or signs. Latent syphilis is often categorized in two phases: early latent syphilis is defined as infection for less than two years and late latent syphilis is the presence of the disease for two years or more. The treatment of latent syphilis is different for the early and late phases. Patients with unknown duration of infection should be treated for late latent syphilis. Sexual transmission typically occurs only during primary, secondary and early latent infection. Mother-to-child transmission, however, has been documented to occur up to several years after initial infection. If left untreated, most patients will remain in the latent stage. Approximately 25% will develop the late clinical sequelae of tertiary syphilis (4), which can affect any organ system up to 30 years or more after infection. The main manifestations of tertiary syphilis are neurological disease (neurosyphilis), cardiovascular disease (cardiosyphilis) and gummatous lesions (gumma). Neurosyphilis can occur at any stage of syphilis infection, even in the first few months. Early neurological manifestations include acute changes in mental status, meningitis, stroke, cranial nerve dysfunction and auditory or ophthalmic and ocular abnormalities. Late neurosyphilis occurs 10–30 years or more after infection and is characterized by tabes dorsalis and general paresis. The most common manifestation of congenital syphilis is second or third trimester fetal loss or premature labour. Thus, serologic testing for syphilis should be performed for all mothers with stillborn infants, to document evidence of syphilis. In most countries, it is estimated that the majority of congenital syphilis cases result in syphilitic stillbirths, and these cases are often not recognized as having been caused by syphilis. Infants born to mothers with positive syphilis serology should be examined for signs and symptoms of early congenital syphilis, including bullous rash, rhinitis, laryngitis, lymphadenopathy, hepatosplenomegaly, osteochrondritis, periostitis, meningitis and chorioretinitis. The signs of late congenital syphilis infection in children over the age of 2 years include inflammatory manifestations affecting the eyes, ears and joints, as well as skeletal malformations and

stigmata resulting from developmental damage during the early stages of syphilis. However, it is important to keep in mind that many infants with syphilis infection will not have obvious clinical signs or symptoms. BOX 1. THE WHO GLOBAL SURVEILLANCE CASE DEFINITION FOR CONGENITAL SYPHILIS • A stillbirth, live birth or fetal loss at greater than 20 weeks of gestation or more than 500 g to a syphilis seropositive mother without adequate syphilis treatment; or • A stillbirth, live birth or child under 2 years of age with clinical (as above) or microbiological evidence of syphilis infection. The microbiological evidence of congenital syphilis includes any one of the following: −− d emonstration by dark-field microscopy or direct fluorescent antibody test of the presence of T. pallidum in the umbilical cord, the placenta, nasal discharge or skin lesion materials; −− detection of T. pallidum-specific IgM; −− i nfant with a positive non-treponemal serology titre at least four-fold higher than the mother’s titre. Source: Global guidance on criteria and processes for validation: elimination of mother-to-child transmission (EMTCT) of HIV and syphilis. Geneva: World Health Organization; 2014 (5).

LABORATORY DIAGNOSIS Syphilis diagnosis is based on the patient’s history, physical examination, laboratory testing and sometimes radiology. The available laboratory tests for diagnosis of syphilis include direct detection methods (i.e. darkfield microscopy, direct fluorescent antibody test and nucleic acid amplification test), serology (treponemal and non-treponemal tests), and examination of cerebrospinal fluids (6).

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

DIRECT DETECTION METHODS Direct detection methods require exudates from lesions of primary, secondary or early congenital syphilis, and need careful collection of samples. Dark-field microscopy demonstrating treponemes with characteristic morphology and motility in lesion exudate or tissue is the most specific method for diagnosis of the early stages of syphilis. The dark-field examination must be performed immediately after specimen collection from primary chancres, moist secondary lesions or lymph nodes or from mucocutaneous lesions in newborns. Dark-field microscopy requires specialized equipment and a trained, experienced microscopist, and is therefore usually limited to specialized laboratories. Dark-field microscopy is highly specific, therefore the presence of characteristic spirochetes is diagnostic of an active infection. Its sensitivity, however, is less than 50%, so a negative result does not exclude syphilis. Although dark-field microscopy is one of the simplest and most reliable methods for the direct detection of T. pallidum, its availability is increasingly limited. The direct fluorescent antibody (DFA) test uses a fluorescence microscope to detect spirochetes that have been stained with fluorescein-labelled antiT. pallidum globulin. Specimens are obtained in the same way as for dark-field microscopy, but the fluorescein-stained organisms are easier to detect and are not likely to be confused with other organisms, leading to a higher sensitivity and specificity for the DFA test. However, specialized equipment is required and the specific fluorescein conjugate is not commercially available in most countries. Nucleic acid amplification tests (NAATs) directly detect T. pallidum DNA by polymerase chain reaction (PCR) from specimens of any lesion exudate, tissue or body fluid. The sensitivity varies according to the specific PCR assay; most assays can detect approximately 10 organism equivalents, although some can detect one organism per PCR reaction. Commercial PCR tests for T. pallidum are not yet commercially available and therefore are relatively costly compared with other tests used to diagnose syphilis. For studies with testing done in well-equipped laboratories, multiplex PCR assays have been developed for detection of the most common causes of genital ulcers, including syphilis, herpes simplex virus and H. ducreyi (chancroid).

SYPHILIS SEROLOGY There are two types of serological tests for syphilis: non-treponemal and treponemal. A presumptive diagnosis of syphilis requires a positive result from at least one of these types of tests. A confirmed diagnosis requires positive results from both types of serologic tests. Serum is the specimen of choice for serological testing, although plasma can be used in some non-treponemal serological tests. Cerebrospinal fluid is used to diagnose congenital and tertiary syphilis and when neurological symptoms are present. The most widely available non-treponemal tests are the microscopic Venereal Diseases Research Laboratory (VDRL) and the macroscopic rapid plasma reagin (RPR) tests. These tests detect anti-lipid immunoglobin M or G (IgM or IgG) antibodies. Since these antibodies can also be produced in other diseases, non-treponemal tests are not highly specific for syphilis and can give false-positive results in conditions such as acute febrile viral infections and some chronic autoimmune diseases. Most false-positive results have low titres of less then 1 : 4. Non-treponemal tests may be negative for up to four weeks after the lesion of primary syphilis first appears and can be negative in late latent syphilis; additionally in primary and secondary syphilis, these tests may be false negative due to a prozone reaction (i.e. interference by high concentrations of antibodies in a specimen, which can be uncovered with dilution and retesting). In primary syphilis, repeated testing at two and four weeks may be required to exclude syphilis when suspect lesions are present. A negative non-treponemal test at three months after onset of the primary chancre virtually excludes the diagnosis of syphilis. Non-treponemal tests may be qualitative or quantitative. Quantitative non-treponemal test titres can be used to monitor response to treatment. Titres are expected to decrease following effective treatment and increase in untreated active infection. A four-fold change or higher in titre, equivalent to a change of at least two dilutions (e.g. from 1 : 16 to 1 : 4 for effective positive response to treatment, or from 1 : 8 to 1 : 32 for continued active infection) is considered a significant difference between two sequential tests using the same method (e.g. VDRL or RPR) and preferably by the same laboratory. Titres that differ by only one dilution (e.g. 1 : 8 versus 1 : 4 or 1 : 2 versus 1 : 1) are not considered significant and may only represent differences in laboratory interpretation).

INTRODUCTION

Treponemal tests include the Treponema pallidum haemagglutination assay (TPHA), the Treponema pallidum particle agglutination assay (TPPA) and the fluorescent treponemal antibody absorbed (FTA-ABS) tests. These tests are highly specific because they detect antibodies against treponemal-specific antigens; however, they do not differentiate venereal syphilis from endemic syphilis (the latter includes yaws and pinta). Classically, one of these tests is used as a confirmatory test following a positive non-treponemal test. Treponemal tests usually remain positive (85%) for the patient’s lifetime, regardless of treatment. Thus, a positive treponemal test does not distinguish between active infection and infection that has been previously treated. All live or stillborn infants of seropositive mothers should be examined for evidence of congenital syphilis. Live-born infants should be examined and tested at birth and at monthly intervals for three months until it is confirmed that serological tests in the infant are, and remain, negative. Antibodies can be passively transmitted from the mother, complicating the interpretation of laboratory results in neonates, but usually disappear within three to four months after birth. However, maternal antibodies can sometimes persist for up to 18 months. In such cases, repeat testing with titration should be carried out and if a four-fold or greater increase in titre of a non-treponemal or treponemal test is detected, the baby should be treated for congenital syphilis. RAPID DIAGNOSTIC TESTS In the past decade, a number of point-of-care rapid diagnostic tests (RDTs) for treponemal antibodies in syphilis infection have been developed. RDTs provide treponemal antibody results in 10–15 minutes and can be performed in any setting since they do not require refrigerated storage or laboratory equipment. The sensitivity of the RDTs ranges from 85% to 98% and the specificity from 93% to 98%, compared to the TPHA or TPPA as reference standards. In general, RDTs with higher sensitivities tend to have lower specificities and vice versa. Most of the initial range of RDTs use T. pallidum antigens to detect treponema-specific antibodies. Many of the tests use immunochromatographic strips, which work by having a test strip impregnated with treponemal antigens that react with antibodies to syphilis in whole blood or serum. The tests work on the same principle as the specific treponemal tests described above, thus a positive result does not distinguish between active and previously treated infections.

More recently, tests that can detect antibodies against cardiolipin-like materials have been developed that work on the same principle as other non-treponemal tests. They are available in combination with the treponemal RDTs, providing both a screening (RPR/VDRL equivalent) and confirmatory (TPHA/TPPA equivalent) component. However, these dual RDTs have not yet been sufficiently evaluated or field-tested to be recommended.

1.2 RATIONALE FOR NEW RECOMMENDATIONS Review and reassessment of the guidelines for treatment of syphilis is needed, taking into account recent evidence on the effectiveness and antimicrobial susceptibility patterns of azithromycin. Benzathine penicillin has been the recommended treatment for syphilis for more than 70 years. Doxycycline is recommended as an alternative treatment for penicillin-allergic, non-pregnant patients. Some studies suggest that azithromycin may be equivalent to benzathine penicillin for treatment of early syphilis. Azithromycin has the added advantage of single-dose oral administration and should be assessed as a possible alternative treatment for penicillin-allergic pregnant patients. However, those advantages need to be weighed against the increasing number of reports of T. pallidum azithromycin resistance. Other options for treating penicillin-allergic patients should also be explored, such as desensitization and injectable daily ceftriaxone. The WHO Guidelines for the management of sexually transmitted infections, published in 2003 (7), recommend early screening and treatment of pregnant women with syphilis, ideally prior to the second trimester of pregnancy, to avoid any fetal complications. In addition, the 2003 WHO STI guidelines recommended treatment for early and late congenital syphilis. Based on this recommendation, it is important for the health-care provider to make a diagnosis and to differentiate early and late congenital syphilis. Diagnosis of congenital syphilis remains a challenge because it requires clinical acumen and availability of laboratory tests. Given these challenges, countries have expressed the need for diagnostic guidelines and treatment recommendations based not only on clinical signs and laboratory tests for congenital syphilis, but also on maternal syphilis serostatus and treatment.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

1.3 OBJECTIVES The objectives of these guidelines are: • t o provide evidence-based guidance on treatment of infection with Treponema pallidum; and • t o support countries to update their national guidelines for treatment of Treponema pallidum.

1.5 STRUCTURE OF THE GUIDELINES These guidelines provide evidence-based recommendations for the treatment of specific clinical conditions caused by T. pallidum. These guidelines provide direction for countries as they develop national treatment recommendations; however, national guidelines should also take into account the local pattern of antimicrobial resistance (AMR), as well as heath service capacity and resources. Updated treatment recommendations based on the most recent evidence are included for the most important common conditions caused by T. pallidum. Recommendations were not updated for rare conditions including neurosyphilis and tertiary syphilis (gumma and cardiovascular syphilis) for which no new information became available since the 2003 WHO STI guidelines were issued. Treatment recommendations for the following conditions caused by T. pallidum are included in these guideline: • early latent syphilis • late latent syphilis • congenital syphilis.

1.4 TARGET AUDIENCE These guidelines are primarily intended for health-care providers at all levels (primary, secondary and tertiary) of the health-care system involved in the treatment and management of people with STIs in low-, middleand high-income countries. They are also intended for individuals working in sexual and reproductive health programmes, such as HIV/AIDS, family planning, maternal and child health and adolescent health, to ensure appropriate STI diagnosis and management. The guidelines are also useful for policy-makers, managers, programme officers and other professionals in the health sector who are responsible for implementing STI management interventions at regional, national and subnational levels.

METHODS

02 METHODS These guidelines were developed following the methods outlined in the 2014 edition of the WHO handbook for guideline development (8) (see Annex B for a detailed description). 2.1 GUIDELINE DEVELOPMENT GROUP (GDG) To update the WHO guidelines for the prevention, treatment and management of STIs, a GDG was established, comprising 33 international STI experts, including clinicians, researchers and programme managers (Annex A). A core subgroup to focus on the guidelines related to syphilis was created within the GDG, to provide more intensive feedback throughout the process (Annex A). The GDG participated in meetings and teleconferences to prioritize the questions to be addressed, discuss the evidence reviews and finalize the recommendations. Additional sub-working group teleconferences were organized to review the methodology and results of systematic reviews and to discuss and finalize the evidence reviews and recommendations. The GDG reviewed and approved the final version of the guidelines.

2.2 QUESTIONS AND OUTCOMES In December 2013, the first GDG meeting was held to identify and agree on the key PICO (population, intervention, comparator, outcome) questions that formed the basis for the systematic reviews and the recommendations. Following this meeting, a survey of GDG members was conducted to prioritize the questions and outcomes according to clinical relevance and importance. Nine PICO questions were identified for the update on the treatment of early and late syphilis and congenital syphilis (see Annex B). These questions pertained to adults and other special populations, namely: adolescents; pregnant women; people living with HIV; populations at high risk of acquiring and transmitting STIs, such as men who have sex with men (MSM), transgender persons and sex workers; and infants and children below the age of 2 years (i.e. the questions on congenital syphilis). Only outcomes that were ranked as critical or important to patients and decision-making were included: serological response and clinical cure, transmission to partner, antimicrobial resistance (AMR), compliance, HIV transmission or acquisition, STI complications and adverse effects (including maternal and fetal effects in pregnant women) (see Annex B).

2.3 REVIEWS OF THE EVIDENCE The systematic reviews for each priority question were conducted by McMaster University, the WHO Collaborating Centre for Evidence-Informed Policy. Evidence for desirable and undesirable outcomes, patient values and preferences, resources, acceptability, equity and feasibility were reviewed from published and unpublished literature. Comprehensive searches for previously conducted systematic reviews, randomized controlled trials and non-randomized studies were performed up to April 2015. Additional searches were conducted to identify studies on patient values and preferences (e.g. qualitative research designs) and resources (e.g. cost-effectiveness studies). Two members of the Systematic Review Team screened studies, extracted and analysed the data, and assessed the quality/certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.1

For more information, see: http://www.gradeworkinggroup.org/

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

The quality/certainty of the evidence was assessed at four levels: • H igh – We are very confident that the true effect lies close to that of the estimate of the effect. • M oderate – We are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. • L ow – Our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. • V ery low – We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect. In addition, the direct costs of medicines were estimated using the 2014 edition of the Management Sciences for Health (MSH) International drug price indicator guide (9). References for all the reviewed evidence are listed in Annex C. All evidence was summarized in GRADE evidence profiles and in evidence-to-decision frameworks (see Web annexes D and E).

2.4 MAKING RECOMMENDATIONS Recommendations were developed during a second meeting of the GDG in October 2015, which was facilitated by two co-chairs, one with expertise in GRADE and the other with clinical STI expertise. The methodologist presented the GRADE evidence profiles and evidence-to-decision frameworks at the meeting. When formulating the recommendations, the GDG considered and discussed the desirable and undesirable effects of the interventions, the value placed on the outcomes, the associated costs and use of resources, the acceptability of the interventions to all stakeholders (including people affected by STIs), the impact on health equity and the feasibility of implementation. Treatments were judged according to the above criteria and final decisions and guideline recommendations were agreed. The discussion was facilitated by the co-chairs with the goal of reaching consensus across the GDG. Disagreements among the GDG members were noted in the evidence-to-decision framework for each judgement. In the case of failure to reach consensus for a recommendation, the planned procedure was for the GDG to take a vote and record the results. However, no votes were taken because the GDG reached consensus during discussion for all of the recommendations. Following the meeting, the recommendations were finalized via teleconference and final approval was obtained from all GDG members electronically. These guidelines were subsequently written up in full and then peer reviewed. The External Review Group approved the methods and agreed with the recommendations made by the GDG (members are listed in Annex A). According to the GRADE approach, the strength of each recommendation was rated as either strong or conditional. Strong recommendations are presented using the wording “The WHO STI guideline recommends…”, while conditional recommendations are worded as “The WHO STI guideline suggests…” throughout the guidelines. The implications of the differing strengths of recommendations for patients, clinicians and policy-makers are explained in detail in Table 3.

METHODS

Table 3. Implications of strong and conditional recommendations using the GRADE approach Implications Strong recommendation “The WHO STI guideline recommends… ” For patients Most individuals in this situation would want the recommended course of action, and only a small proportion would not. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. For clinicians Most individuals should receive the recommended course of action. Adherence to this recommendation according to the guidelines could be used as a quality criterion or performance indicator. Clinicians should recognize that different choices will be appropriate for each individual and that clinicians must help each individual arrive at a management decision consistent with the individual’s values and preferences. Decision aids may be useful to help individuals make decisions consistent with their values and preferences. For policymakers The recommendation can be adopted as policy in most situations. Policy-making will require substantial debate and involvement of various stakeholders. Conditional recommendation “The WHO STI guideline suggests… ” The majority of individuals in this situation would want the suggested course of action, but many would not.

2.5 MANAGEMENT OF CONFLICTS OF INTEREST Management of conflicts of interest was a key priority throughout the process of guideline development. WHO guidelines for declaration of interests (DOI) for WHO experts were implemented (10). DOI statements were obtained from all GDG members prior to assuming their roles in the group. At the GDG meetings (December 2013 and October 2015), the members disclosed their interests, if any, at the beginning of the meetings. The DOI statements are summarized in Web annex F. After analysing each DOI, the STI team concluded that no member had financial or commercial interests related to STI treatment. Other notified interests were minor; they were either not related to STI or were noncommercial grants or interests. The STI team concluded that there were no significant conflicts of interest that would exclude any member from participating fully in the guideline development process. Therefore, options for conditional participation, partial or total exclusion of any GDG member were no discussed.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

03 3.1 DISSEMINATION

DISSEMINATION, UPDATING AND IMPLEMENTATION OF THE GUIDELINES

United Nations Programme on HIV/AIDS (UNAIDS), nongovernmental organizations (NGOs) and other agencies implementing sexual and reproductive health and STI services – to ensure that the new recommendations are integrated and implemented in sexual and reproductive health, family planning, and maternal, neonatal, child and adolescent health services. Reference to this document will be made within other relevant WHO guidelines. These guidelines will also be disseminated at major conferences related to STIs and HIV and the aforementioned programme areas.

3.2 UPDATING THE STI GUIDELINES AND USER FEEDBACK A system of monitoring relevant new evidence and updating the recommendations as new findings become available will be established within a year of implementing the guidelines. An electronic follow-up survey of key end-users of the STI guidelines will be conducted after the release of the guidelines. The results of the survey will be used to identify challenges and barriers to the uptake of the guidelines, to evaluate their usefulness for improving service delivery, and to identify topics or gaps in treatment that need to be addressed in future editions.

The guidelines will be made available as a printed publication, as a download on the website of the WHO Department of Reproductive Health and Research (where there will also be links to all supporting documentation)2, and in the WHO Reproductive Health Library (RHL)3. The recommendations will also be available in a guideline application (“app”) created with the GRADEpro GDT software. The guidelines will be announced in the next edition of the RHL newsletter and in the Reproductive Health and Research departmental newsletter, and other relevant organizations will be requested to copy the announcement in their respective newsletters. WHO headquarters will work with WHO’s regional offices and country offices to ensure that countries receive support in the adaptation, implementation and monitoring of these guidelines using the WHO Department of Reproductive Health and Research guidance on Introducing reproductive health guidelines and tools into national programmes (11). All levels of WHO (headquarters, regional offices and countries) will work with regional and national partners – including the United Nations Population Fund (UNFPA), the United Nations Children’s Fund (UNICEF), the Joint

3.3 IMPLEMENTATION OF THE WHO GUIDELINES FOR THE TREATMENT OF T. PALLIDUM (SYPHILIS) ADAPTATION, IMPLEMENTATION AND MONITORING These guidelines provide recommendations for treatment of syphilis based on the best global evidence available at the time of compilation. However, the epidemiology and AMR of STIs vary by geographical location and are constantly changing, sometimes rapidly. It is recommended that countries conduct good quality studies to gather the information needed to adapt these guidelines to the local STI situation as they update their national guidelines. In areas lacking local data as a basis for adaptation, the recommendations in these guidelines can be adopted as presented. For further guidance on adaptation, implementation and monitoring of national guidelines please refer to Introducing WHO’s reproductive health guidelines and tools into national programmes: principles and processes of adaptation and implementation (11).

2 These guidelines and all supporting documents will be available at: www.who.int/reproductivehealth/publications/ rtis/syphilis-treatment-guidelines/en/ 3 RHL is available at: http://apps.who.int/rhl/en/

DISSEMINATION, UPDATING AND IMPLEMENTATION OF THE GUIDELINES

In adapting the guidelines for national use, recommended treatments should have an efficacy of at least 95%. The criteria to be considered for the selection of medicines are listed in Box 2. Recommended medicines should meet as many of the criteria as possible, taking into account local availability, efficacy, route and frequency of administration.

BOX 2. CRITERIA FOR THE SELECTION OF MEDICINES FOR THE TREATMENT OF STIS • High efficacy (at least 95% cure rate) • High quality (potent active ingredient) • Low cost • Low toxicity levels • O rganism resistance unlikely to develop or likely to be delayed • Single dose • Oral administration • N ot contraindicated for pregnant or lactating women Appropriate medicines should be included in the national essential medicines lists. When selecting medicines, consideration should be given to the competencies and experience of health-care providers.

Budgeting for medicines is critical. If the national ministry of health does not provide medicines for free and the patient cannot afford to buy the medicines, then there will essentially be no possibility of curtailing the spread of infection and the occurrence of complications. At the national level it is important that decision-makers, politicians and fiscal controllers understand the need to subsidize STI medicines. Low-cost STI medicines can be obtained through international vendors of generic products, nonprofit organizations with procurement schemes such UNICEF, UNFPA and UNHCR, and through joint medicine procurement schemes. By way of such schemes, national programmes can join other national programmes to jointly procure medicines, thus reducing the overall costs by sharing the overhead costs and taking advantage of discounts for purchasing in bulk. Placing STI medicines on national lists of essential medicines increases the likelihood of achieving a supply of these medicines at low cost.

IDENTIFYING AND PROCURING STI MEDICINES It is important not only to identify medicines that will be recommended as first-line treatment for STIs but also the estimated quantities of medicines that will be required. Quantifying medication needs is important in order to estimate costs, to reconcile financial requirements with available budget, and to make orders in advance so that the unit and freight costs can be minimized. In order to estimate the quantity of medicines needed, it will be necessary to review the medicines that are recommended for treatment, their unit prices, the quantity required per treatment and the epidemiological information on the prevalence of infection. One can estimate medicine needs by multiplying the estimated number of cases by the total quantity of medicine specified for treatment of one case. These figures can be derived from health centres providing care but they must be verified to avoid wasteful over-ordering.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

04 RECOMMENDATIONS FOR TREATMENT OF SYPHILIS The first eight recommendations (in sections 4.1 and 4.2) apply to adults and adolescents (10–19 years of age), including people living with HIV, key populations (including sex workers, men who have sex with men and transgender persons), and pregnant women. Specific recommendations have also been developed for congenital syphilis caused by T. pallidum – recommendations 9 and 10 apply to infants (see section 4.3). 4.1 EARLY SYPHILIS (PRIMARY, SECONDARY AND EARLY LATENT SYPHILIS OF NOT MORE THAN TWO YEARS’ DURATION) ADULTS AND ADOLESCENTS RECOMMENDATION 1 In adults and adolescents with early syphilis, the WHO STI guideline recommends benzathine penicillin G 2.4 million units once intramuscularly over no treatment. Strong recommendation, very low quality evidence RECOMMENDATION 2 In adults and adolescents with early syphilis, the WHO STI guideline suggests using benzathine penicillin G 2.4 million units once intramuscularly over procaine penicillin G 1.2 million units 10–14 days intramuscularly. Conditional recommendation, very low quality evidence

When benzathine or procaine penicillin cannot be used (e.g. due to penicillin allergy) or are not available (e.g. due to stock-outs), the WHO STI guideline suggests using doxycycline 100 mg twice daily orally for 14 days or ceftriaxone 1 g intramuscularly once daily for 10–14 days, or, in special circumstances, azithromycin 2 g once orally. Conditional recommendation, very low quality evidence Remarks: Doxycycline is preferred over ceftriaxone due to its lower cost and oral administration. Doxycycline should not be used in pregnant women (see recommendations 3 and 4 for pregnant women). Azithromycin is an option in special circumstances only when local susceptibility to azithromycin is likely. If the stage of syphilis is unknown, recommendations for people with late syphilis should be followed. SUMMARY OF THE EVIDENCE Overall, there was very low quality evidence for outcomes after treatment of early syphilis. Evidence was gathered from 7 randomized and 18 non-randomized studies, each of which included one or two groups evaluating benzathine penicillin G, procaine penicillin, ceftriaxone, azithromycin and doxycycline (with or without tetracycline). Although not captured in published studies, most treatments today are based on historical and successful use of benzathine penicillin G and procaine penicillin. The number of serological cures achieved with benzathine penicillin G 2.4 million units (MU) provided as a single dose intramuscularly (IM) was estimated on average as 840 per 1000 people with early syphilis. When compared to this single dose of benzathine penicillin G, the evidence suggests little to no difference in the numbers of serological cures achieved with a double dose of benzathine penicillin G; lower numbers cured with a triple dose of benzathine penicillin G; similar numbers cured when treated with ceftriaxone, azithromycin or doxycycline; and slightly lower numbers cured with doxycycline and tetracycline together. Evidence also suggests that there may be little to no difference in the effects of different medicines in people living with HIV and those not living with HIV. Transmission to partners, HIV transmission and acquisition, and STI complications were not measured. Few studies provided data for adverse events. Azithromycin may increase gastrointestinal side-effects and dizziness or headache (3–4 times greater than with benzathine penicillin G), but it may reduce rash (65% reduction), fever (50–65% reduction) and serious adverse events (30% reduction). Ceftriaxone may be less likely to cause diarrhoea and rash, but this evidence is uncertain. Data were not available on resistance to azithromycin for treating syphilis in specific settings,

RECOMMENDATIONS FOR TREATMENT OF SYPHILIS

and this will likely remain unknown in many places as the capacity to monitor AMR in T. pallidum is not available in many settings. Resistance to azithromycin for other conditions is spreading, and therefore the Guideline Development Group (GDG) was concerned about the risk of azithromycin resistance in T. pallidum. There was some research evidence relating to overall acceptability of injections versus medicines taken orally in people with syphilis: approximately 10–20% of people refused injections. The GDG noted that in practice some health-care providers are averse to providing injections, and there are additional staff time and equipment costs with IM administration. The GDG raised concerns about the impending global shortage of benzathine penicillin; a shortage would reduce health equity and it would not be feasible to apply the treatment recommendation. The GDG judged the benefits of treatment with benzathine penicillin G versus no treatment as large based on the historically successful treatment of syphilis over the past 70 years. It was also judged that the differences in benefits between medicines used for treatment are likely to be trivial. There were inconsistent results for greater benefit with higher doses of benzathine penicillin G. The differences in the undesirable anticipated effects (side-effects) were judged to be small. Because the benefits probably outweigh the harms, and because of the potential for resistance to azithromycin and greater cost, benzathine penicillin G was suggested. Benzathine penicillin G was also suggested over ceftriaxone and doxycycline due to the unknown side-effects and benefits of the latter two medicines, and the higher costs of ceftriaxone. The GDG also judged the administration of benzathine and procaine penicillins by injection as being acceptable to most people. PREGNANT WOMEN RECOMMENDATION 3 In pregnant women with early syphilis, the WHO STI guideline recommends benzathine penicillin G 2.4 million units once intramuscularly over no treatment. Strong recommendation, very low quality evidence RECOMMENDATION 4 In pregnant women with early syphilis, the WHO STI guideline suggests using benzathine penicillin G 2.4 million units once intramuscularly over procaine penicillin 1.2 million units intramuscularly once daily for 10 days. Conditional recommendation, very low quality evidence

When benzathine or procaine penicillin cannot be used (e.g. due to penicillin allergy where penicillin desensitization is not possible) or are not available (e.g. due to stock-outs), the WHO STI guideline suggests using, with caution, erythromycin 500 mg orally four times daily for 14 days or ceftriaxone 1 g intramuscularly once daily for 10–14 days or azithromycin 2 g once orally. Conditional recommendation, very low quality evidence Remarks: Although erythromycin and azithromycin treat the pregnant women, they do not cross the placental barrier completely and as a result the fetus is not treated. It is therefore necessary to treat the newborn infant soon after delivery (see recommendations 9 and 10 for congenital syphilis). Ceftriaxone is an expensive option and is injectable. Doxycycline should not be used in pregnant women. Because syphilis during pregnancy can lead to severe adverse complications to the fetus or newborn, stock-outs of benzathine penicillin for use in antenatal care should be avoided. SUMMARY OF THE EVIDENCE The overall quality of the evidence for treatments used for pregnant women was very low. There were few studies (10 non-randomized studies) and very few pregnant women included in the studies. In most studies, the stage of syphilis (early or late) was unknown. The evidence in adults and adolescents, and the evidence from successful historical use of benzathine and procaine penicillins and erythromycin, was used to inform the judgements about the benefits of different medicines. The benefits were large for the use of benzathine penicillin compared to no treatment. The differences in medicines in terms of benefits and harms were trivial. Prevention of mother-to-child transmission (PMTCT) was a critical outcome. Penicillins cross the placental barrier, while azithromycin and erythromycin do not, meaning there is an increased chance of mother-to-child transmission of syphilis with the use of the latter medicines. There was no evidence for adverse effects, transmission to partner, antimicrobial resistance (AMR), HIV transmission or acquisition, or STI complications. Research evidence for the other factors (acceptability, feasibility, equity and costs) was not specific to pregnant women. Therefore, evidence for non-pregnant adults was used to inform this recommendation. Overall, the recommendations for non-pregnant women with early syphilis were used to inform the recommendations for pregnant women with early syphilis, with the exception of the use of doxycycline which cannot be used in pregnant women. Erythromycin was added as an alternative based on successful historical use.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

4.2 LATE SYPHILIS (INFECTION OF MORE THAN TWO YEARS’ DURATION WITHOUT EVIDENCE OF TREPONEMAL INFECTION) ADULTS AND ADOLESCENTS RECOMMENDATION 5 In adults and adolescents with late syphilis or unknown stage of syphilis, the WHO STI guideline recommends benzathine penicillin G 2.4 million units intramuscularly once weekly for three consecutive weeks over no treatment. Strong recommendation, very low quality evidence Remarks: The interval between consecutive doses of benzathine penicillin should not exceed 14 days. RECOMMENDATION 6 In adults and adolescents with late syphilis or unknown stage of syphilis, the WHO STI guideline suggests benzathine penicillin G 2.4 million units intramuscularly once weekly for three consecutive weeks over procaine penicillin 1.2 million units once daily for 20 days. Conditional recommendation, very low quality evidence When benzathine or procaine penicillin cannot be used (e.g. due to penicillin allergy where penicillin desensitization is not possible) or are not available (e.g. due to stock-outs), the WHO STI guideline suggests using doxycycline 100 mg twice daily orally for 30 days. Conditional recommendation, very low quality evidence Remarks: Doxycycline should not be used in pregnant women (see recommendations 7 and 8 for pregnant women). PREGNANT WOMEN RECOMMENDATION 7 In pregnant women with late syphilis or unknown stage of syphilis, the WHO STI guideline recommends benzathine penicillin G 2.4 million units intramuscularly once weekly for three consecutive weeks over no treatment. Strong recommendation, very low quality evidence Remarks: The interval between consecutive doses of benzathine penicillin should not exceed 14 days. RECOMMENDATION 8 In pregnant women with late syphilis or unknown stage of syphilis, the WHO STI guideline suggests benzathine penicillin G 2.4 million units intramuscularly once weekly for three consecutive weeks over procaine penicillin 1.2 million units intramuscularly once daily for 20 days. Conditional recommendation, very low quality evidence

When benzathine or procaine penicillin cannot be used (e.g. due to penicillin allergy where penicillin desensitization is not possible) or are not available (e.g. due to stock-outs), the WHO STI guideline suggests using, with caution, erythromycin 500 mg orally four times daily for 30 days. Conditional recommendation, very low quality evidence Remarks: Although erythromycin treats the pregnant women, it does not cross the placental barrier completely and as a result the fetus is not treated. It is therefore necessary to treat the newborn infant soon after delivery (see recommendations 9 and 10 for congenital syphilis). Doxycycline should not be used in pregnant women. Because syphilis during pregnancy can lead to severe adverse complications to the fetus or newborn, stock-outs of benzathine penicillin for use in antenatal care should be avoided. SUMMARY OF THE EVIDENCE Overall, the quality of the evidence was very low. Most studies typically include people with early or late syphilis and don’t distinguish between the stage of syphilis when reporting the results. However, one study included over 300 people diagnosed with late syphilis. It evaluated benzathine penicillin G 2.4 MU given once IM and azithromycin 2 g given once orally. Serological cure was low (33–39%); these doses are typically provided for early syphilis. Another study included 135 pregnant women treated for late syphilis. This study found that 99% of women with the double dose of benzathine penicillin G were cured. Historically, multiple doses of benzathine penicillin G (once a week for three weeks) or procaine penicillin 1.2 MU (once daily for 20 days) have been successful for serological and clinical cure of syphilis. For pregnant women, PMTCT is a critical outcome. Penicillins cross the placental barrier, while azithromycin and erythromycin do not, meaning that there is an increased chance of mother-to-child transmission of syphilis with the use of the latter medicines. There has been some successful historical use of doxycycline 100 mg twice daily for 30 days, but not in pregnant women. There were no data for adverse events, transmission to partners, HIV transmission and acquisition, or STI complications. There are no reported data on resistance to azithromycin for treating syphilis in specific settings, and this will likely remain unknown in many places as the capacity to monitor AMR in T. pallidum is not available in many settings. Resistance to azithromycin for other conditions is spreading, and therefore the STI GDG was concerned about the risk of azithromycin resistance in T. pallidum.

RECOMMENDATIONS FOR TREATMENT OF SYPHILIS

Evidence used for making recommendations for treatment in early syphilis was used to inform this recommendation for late syphilis. There was some research evidence relating to overall acceptability of injections versus medicines taken orally in people with syphilis: approximately 10–20% of people refused injections. The GDG noted that in practice some healthcare providers are averse to providing injections, and there are additional staff time and equipment costs with IM administration. The GDG raised concerns about the impending global shortage of benzathine penicillin; a shortage would reduce health equity and it would not be feasible to apply the treatment recommendation. The GDG judged the benefits of treatment with benzathine penicillin G versus no treatment as large based on the historically successful treatment of syphilis over the past 70 years. It was also judged that the differences in benefits between medicines used for treatment are likely to be trivial. The differences in the undesirable anticipated effects (side-effects) were judged to be small. Because the benefits probably outweigh the harms, and because of the potential for resistance to azithromycin, greater cost and lack of historical data for azithromycin, benzathine penicillin G and procaine penicillin were suggested. The penicillins were suggested over doxycycline due to the lack of historical data in late syphilis and unknown side-effects and benefits of doxycycline. For pregnant women, the penicillins were also suggested over erythromycin since erythromycin does not cross the placental barrier. The GDG also judged the administration of benzathine and procaine penicillins by injection as being acceptable to most people.

4.3 CONGENITAL SYPHILIS INFANTS RECOMMENDATION 9 In infants with confirmed congenital syphilis or infants who are clinically normal, but whose mothers had untreated syphilis, inadequately treated syphilis (including treatment within 30 days of delivery) or syphilis that was treated with non-penicillin regimens, the WHO STI guideline suggests aqueous benzyl penicillin or procaine penicillin. Conditional recommendation, very low quality evidence Dosages: • A queous benzyl penicillin 100 000–150 000 U/kg/day intravenously for 10–15 days • P rocaine penicillin 50 000 U/kg/day single dose intramuscularly for 10–15 days Remarks: If an experienced venipuncturist is available, aqueous benzyl penicillin may be preferred instead of intramuscular injections of procaine penicillin. RECOMMENDATION 10 In infants who are clinically normal and whose mothers had syphilis that was adequately treated with no signs of reinfection, the WHO STI guideline suggests close monitoring of the infants. Conditional recommendation, very low quality evidence Remarks: The risk of transmission of syphilis to the fetus depends on a number of factors, including maternal titres from non-treponemal tests (e.g. RPR), timing of maternal treatment and stage of maternal infection, and therefore this recommendation is conditional. If treatment is provided, benzathine penicillin G 50 000 U/kg/day single dose intramuscularly is an option.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

SUMMARY OF THE EVIDENCE The overall quality of the evidence was very low. Nine non-randomized studies informed this recommendation, as well as historical use of the medicines to treat and prevent confirmed or suspected congenital syphilis. The sample sizes of most studies was small, and rates of follow-up of babies achieved after treatment were very low. When there was follow-up, it ranged from six months to one year. Treatments provided included aqueous benzyl penicillin, procaine penicillin and benzathine penicillin G; ceftriaxone was not assessed. In most studies of infants with confirmed congenital syphilis or infants whose mothers received inadequate or no treatment, treatment of infants resulted in 100% cures with no adverse effects. Aqueous benzyl penicillin or procaine penicillin were favoured over ceftriaxone due to little or no data, and known potential for side-effects and contraindications with the use of ceftriaxone to treat other conditions. There were some historical data (but no other data) indicating that benzathine penicillin G may have benefit and few adverse effects, but this is uncertain. There were no follow-up data for untreated infants who were clinically normal and born to mothers who had received adequate treatment. From global estimates, the risk of congenital syphilis for infants born alive to mothers with untreated syphilis is approximately 16 per 100 mothers. A systematic review found that when mothers are treated, the risk of congenital syphilis is 0.03 times the risk in infants born to untreated mothers; from this it can be roughly estimated that there would be 4.8 births with congenital syphilis per 1000 treated mothers. Only half of these infants (2.4 per 1000) would be expected to show signs or symptoms of congenital syphilis. Therefore, in 1000 treated mothers, there would be a risk of two to three infants born with congenital syphilis who are clinically normal.

There was little cost difference between aqueous benzyl penicillin or procaine penicillin, but ceftriaxone was more expensive. The GDG agreed that the medicines are available and thus availability would likely not have an impact on equity. However, for people who need to travel for treatment, health equity may be reduced. The GDG agreed that IM injections would be acceptable, given that finding a vein for intravenous (IV) administration is often very difficult for infants. However, if an experienced venupuncturist is present and willing, benzyl penicillin could be administered IV. Overall, historical data show benefits of treatment with aqueous benzyl penicillin and procaine penicillin with few to no adverse effects, and similar costs. There are little to no data for benzathine penicillin G, but there may be no adverse effects; there are also little to no data for ceftriaxone but adverse effects may occur and it is more expensive than the other medicines. A preference for IM injections or IV administration was not determined, but these options are available with either medication. Overall, the risk of congenital syphilis in infants born to mothers who have received adequate treatment was judged to be very low and therefore, monitoring of these infants is suggested over treatment.

RESEARCH IMPLICATIONS

05 RESEARCH IMPLICATIONS The Guideline Development Group (GDG) discussed the need to develop a new treatment. Ideally the new treatment should be a short course administered orally which can treat pregnant women with syphilis and cross the blood–brain and placental barriers to prevent transmission to the fetus. Cephalosporins could be potential options. Trials investigating appropriate dosages and effectiveness of ceftriaxone use for early and late syphilis should be conducted. The trials should compare ceftriaxone with benzathine penicillin G and doxycycline. To what extent the medicines cross the blood–brain and placental barriers should also be investigated. More research should also be conducted into medicines that are taken orally for a few days, such as cephalosporins. Since benzathine penicillin G and other penicillins require injection by health workers, it was suggested that the safety of self-injection be investigated. There was little data for ceftriaxone use in infants with confirmed congenital syphilis and therefore research is needed, in particular comparing ceftriaxone to procaine penicillin.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

REFERENCES 1. Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N et. al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One. 2015;10(12):e0143304. 2. Wijesooriya NS, Rochat RW, Kamb ML, Turlapati P, Temmerman M. Broutet N, Newman L. Global burden of maternal and congenital syphilis in 2008 and 2012: a health systems modelling study. Lancet Global Health. 2016 ; 4(8): e525–-e533. doi:10.1016/S2214-109X(16)30135. 3. Technical consultation on the elimination of mother-to-child transmission of HIV: final meeting report. Geneva: World Health Organization; 2011 (http://apps.who.int/iris/ bitstream/10665/44638/1/9789241501910_eng.pdf, accessed 1 July 2016). 4. Clark EG, Danbolt N. The Oslo study of the natural course of untreated syphilis: an epidemiologic investigation based on re-study of the BoeckBruusgaard material. Med Clin North Am. 1964;48:613– 23. 5. Global guidance on criteria and processes for validation: elimination of mother-to-child transmission (EMTCT) of HIV and syphilis. Geneva: World Health Organization; 2014 (http://apps.who.int/iris/ bitstream/10665/112858/1/9789241505888_eng.pdf, accessed 1 July 2016). 6. Unemo M, Ballard R, Ison C, Lewis D, Ndowa F, Peeling R, editors. Laboratory diagnosis of sexually transmitted infections including human immunodeficiency virus. Geneva: World Health Organization; 2013 (http://apps.who.int/iris/bitstream/10665/85343/1/9789241505840_eng.pdf, accessed 1 July 2016 7. Guidelines for the management of sexually transmitted infections. Geneva: World Health Organization; 2003 (http://www.who.int/hiv/pub/sti/en/STIGuidelines2003.pdf, accessed 25 May 2016). 8. WHO handbook for guideline development, 2nd edition. Geneva: World Health Organization; 2014 (http://www.who.int/kms/handbook_2nd_ed.pdf, accessed 25 May 2016). 9. International drug price indicator guide, 2014 edition (updated annually). Medford (MA): Management Sciences for Health; 2015 (http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2014.pdf, accessed 6 June 2016). 10. WHO guidelines for declaration of interests (WHO experts). Geneva: World Health Organization; 2014. 11. Introducing WHO’s reproductive health guidelines and tools into national programmes: principles and processes of adaptation and implementation. Geneva: World Health Organization; 2007. (http://whqlibdoc.who.int/hq/2007/WHO_RHR_07.9_eng.pdf, accessed 25 May 2016).

ANNEX A: STI GUIDELINE DEVELOPMENT TEAMS

ANNEX A: STI GUIDELINE DEVELOPMENT TEAMS WHO STI STEERING COMMITTEE WHO regional STI focal points 1. 2. 3. 4. 5. Massimo Ghidinelli Lali Khotenashvili Ying-Ru Lo Frank Lule Razia Pendse and Ornella Lincetto Hamida Khattabi and Gabriela Reidner Region Region of the Americas (AMR) Washington, DC – United States of America (USA) European Region (EUR) Copenhagen – Denmark Western Pacific Region (WPR) Manila – Philippines African Region (AFR) Brazzaville – Congo South-East Asia Region (SEAR) New Delhi – India WHO Country Representative, Bhutan Eastern Mediterranean Region (EMR) Cairo – Egypt Department and Team Department of Reproductive Health and Research Human Reproduction Team Department of Reproductive Health and Research Adolescents and at-Risk Populations Department of HIV/AIDS Key Populations and Innovative Prevention Department of Reproductive Health and Research Adolescents and at-Risk Populations Department of Maternal, Newborn, Child and Adolescent Health; Research and Development Department of Reproductive Health and Research Human Reproduction Team Department of Reproductive Health and Research Human Reproduction Team Department of HIV/AIDS Key populations and Innovative Prevention Department of Reproductive Health and Research Human Reproduction Team Department of Maternal, Newborn, Child and Adolescent Health Department of Reproductive Health and Research Human Reproduction Team Department of Health Workforce Essential Medicines and Health Products, Prequalification Team

WHO headquarters 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. Moazzam Ali Avni Amin Rachel Baggaley Venkatraman Chandra-Mouli Jane Ferguson Mario Festin Mary Lyn Gaffield Antonio Gerbase Sami Gottlieb Frances McConville Lori Newman Annette Mwansa Nkowane Anita Sands

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

20. 21.

Igor Toskin Marco Vitoria

Department of Reproductive Health and Research Human Reproduction Team Department of HIV/AIDS Treatment and Care Department and Team Department of Reproductive Health and Research Human Reproduction Team Department of Reproductive Health and Research Human Reproduction Team Department of Reproductive Health and Research Human Reproduction Team Department of Reproductive Health and Research Human Reproduction Team Department of Reproductive Health and Research Human Reproduction Team

WHO STI Secretariat 22. 23. 24. 25. 26. Ian Askew Nathalie Broutet (co-lead of the development process) James Kiarie Lee Sharkey Teodora Elvira Wi (lead of the development process)

METHODOLOGIST Nancy Santesso Department of Clinical Epidemiology McMaster University 1200 Main Street West Hamilton, Ontario L8N 3Z5 Canada

SYSTEMATIC REVIEW TEAM: MCMASTER UNIVERSITY Team lead: Nancy Santesso Team members: Housne Begum, Janna-Lina Kerth, Gian Paolo Morgano, Kristie Poole, John Riva, Nicole Schwab, Matthew Ventresca, Yuan Zhang, Andrew Zikic

ANNEX A: STI GUIDELINE DEVELOPMENT TEAMS

STI GUIDELINE DEVELOPMENT GROUP Chairpersons: Judith Wasserheit, Holger Schünemann, Patricia Garcia

Name and address 1. Yaw (Sax) Adu-Sarkodie School of Medical Sciences Kwame Nkrumah University of Science and Technology (KNUST) PO Box 1934, Bantama Kumasi Ghana Andrew Amato European Centre for Disease Prevention and Control Tomtebodavägen 11a 171 83 Stockholm Sweden Gail Bolan Centers for Disease Control and Prevention 1600 Clifton Rd. Atlanta, GA 30333 USA John Changalucha National Institute for Medical Research Mwanza Medical Research Centre PO Box 1462 Mwanza Tanzania Xiang-Sheng Chen National Center for STD Control Chinese Academy of Medical Sciences and Peking Union Medical College 12 Jiangwangmiao Street Nanjing 210042 China Harrel Chesson Division of STI Prevention Centers for Disease Control and Prevention 1600 Clifton Rd. Atlanta, GA 30333 USA Craig Cohen University of California, San Francisco 50 Beale Street, Suite 1200 San Francisco, CA 94117 USA Francisco Garcia Pima County Health Department 3950 S. Country Club Road Suite 100 Tucson, AZ 85714 USA

Region AFR

Sex M

EUR

AMR

AFR

WPR

AMR

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Patricia Garcia (Co-Chair) School of Public Health and Administration Universidad Peruana Cayetano Heredia Ave Honorio Delgado 430 31 AP, 4314 Lima Peru Suzanne Garland Royal Women’s Hospital, Level 1 Bldg 404, Bio 21 Institute 30 Flemington Road, Parkville Victoria Australia Sarah Hawkes University College London Institute for Global Health London United Kingdom Mary Higgins International Confederation of Midwives Laan van Meerdervoort 70 2517 AN The Hague The Netherlands King Holmes Department of Global Health and Department of Medicine University of Washington Harborview Medical Center 325 9th Ave., Box 359931 Seattle, WA 98104 USA Jeffrey Klausner Division of Infectious Diseases and Program in Global Health David Geffen School of Medicine and Fielding School of Public Health University of California, Los Angeles USA David Lewis Western Sydney Sexual Health Centre Marie Bashir Institute for Infectious Diseases and Biosecurity Sydney Medical School Westmead, University of Sydney Sydney Australia Nicola Low Epidemiology and Public Health University of Bern Institute of Social and Preventive Medicine Finkenhubelweg 11 3012 Bern Switzerland David Mabey Communicable Diseases London School of Hygiene and Tropical Medicine (LSHTM) Keppel Street London WC1E 7HT United Kingdom

AMR

10.

WPR

11.

EUR

12.

EUR

13.

AMR

14.

AMR

15.

WPR

16.

EUR

17.

EUR

ANNEX A: STI GUIDELINE DEVELOPMENT TEAMS

18.

Angelica Espinosa Miranda Núcleo de Doenças Infecciosas Universidade Federal do Espirito Santo Av. Marechal Campos 1468 Maruípe Vitória – ES CEP 29040-091 Brazil Nelly Mugo Kenya Medical Research Institute Mbagathi Rd. PO Box 54840 - 00200 Nairobi Kenya Saiqa Mullick Implementation Science University of the Witwatersrand Hillbrow Health Precinct Hillbrow, Johannesburg South Africa Francis Ndowa 6 Thames Road Vainona, Harare Zimbabwe Joel Palefsky Division of Infectious Diseases Box 0654 513 Parnassus Ave, Room S420 University of California, San Francisco San Francisco, CA 94143 USA Keith Radcliffe European STI Guidelines Project International Union against Sexually Transmitted Infections (IUSTI) Royal Society of Medicine 1 Wimpole Street London W1G 0AE United Kingdom Ulugbek Sabirov National STI Program Republican Center for Dermato-Venereology Tashkent Uzbekistan Holger Schünemann (Co-Chair) Department of Clinical Epidemiology and Biostatistics McMaster University 1200 Main Street West Hamilton, Ontario L8N 3Z5 Canada Richard Steen Localitá Cassaluvo Diano San Pietro Imperia 18013 Italy

AMR

19.

AFR

20.

AFR

21.

AFR

22.

AMR

23.

EUR

24.

EUR

25.

AMR

26.

EUR

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

27.

Judith Stephenson University College London Gower Street London United Kingdom Magnus Unemo Department of Laboratory Medicine Microbiology Örebro University Hospital SE-701 85 Örebro Sweden Bea Vuylsteke Institute of Tropical Medicine Nationalestraat 155 2000 Antwerp Belgium Anna Wald University of Washington Virology Research Clinic Harborview Medical Center 325 9th Ave, Box 359928 Seattle, WA 98104 USA Judith Wasserheit (Co-Chair) Department of Global Health Professor of Global Health and Medicine Adjunct Professor of Epidemiology University of Washington Harris Hydraulics Building, Room 309D 1705 NE Pacific Street Box 357965 Seattle, WA 98195-7965 USA Thomas Wong Division of Community Acquired Infections Centre for Communicable Diseases and Infection Control Public Health Agency of Canada Room 2391, 100 Eglantine Driveway Tunney’s Pasture, AL 0602C Ottawa, Ontario K1A 0L2 Canada Kimberly A. Workowski Centers for Disease Control and Prevention (CDC) Division of Infectious Diseases Emory University School of Medicine 1600 Clifton Rd. Atlanta, GA 30333 USA

EUR

28.

EUR

29.

EUR

30.

AMR

31.

AMR

32.

AMR

33.

AMR

AFR: WHO African Region; AMR: WHO Region of the Americas; EMR: WHO Eastern Mediterranean Region; EUR: WHO European Region; SEAR: WHO South-East Asia Region; WPR: WHO Western Pacific Region

ANNEX A: STI GUIDELINE DEVELOPMENT TEAMS

STI Guideline Development Group: Working group for syphilis 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Gail Bolan John Changalucha Xiang-Sheng Chen Patricia Garcia Suzanne Garland Antonio Gerbase Jeffrey Klausner Ornella Lincetto David Mabey Saiqa Mullick Joel Palefsky Ulugbek Sabirov Richard Steen

STI External Review Group: Working group for syphilis Name and address 1. Laith Abu-Raddad Biostatistics, Epidemiology and Biomathematics Research Core Infectious Disease Epidemiology Group Department of Public Health Weill Cornell Medical College Cornell University Qatar Foundation – Education City Qatar Chris Akolo FHI 360 224 Chapel Hill, Nelson Highway Durham, NC 277712 USA Adele Benaken-Schwartz Ministry of Health STI, AIDS and Viral Hepatitis Department SAF Sul Trecho 2, Ed. Premium Torre I, Térreo, Sala 12 70.070-600 – Brasília – DF Brasil Mircea Betiu Nicolae Testemițanu State University of Medicine and Pharmacy Republic of Maldova Region EMR Sex M

AMR

EUR

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Anupong Chitwarakorn Department of Diseases Control Bureau of AIDS, TB and STIs Ministry of Public Health Nonthaburi Thailand Carolyn Deal National Institute of Allergy and Infectious Diseases (NIAID) United States Department of Health and Human Services National Institutes of Health Washington, DC USA Margaret Gale-Rowe Professional Guidelines and Public Health Practice Division Centre for Communicable Diseases and Infection Control Public Health Agency of Canada Ottawa, Ontario Canada William M. Geisler Medicine and Epidemiology University of Alabama at Birmingham Division of Infectious Diseases 703 19th Street South Zeigler Research Building, Room 242 Birmingham, AL 35294-0007 USA Amina El Kettani Direction de l’Epidémiologie Service des MST-sida Ministry of Health 71 Avenue Ibn Sinaa, Agdal Rabat Morocco Ahmed Latif Public Health Consultant Zimbabwe Mary Kamb Centers for Disease Control and Prevention 1600 Clifton Rd. Atlanta, GA 30333 USA Mizan Kiros Disease Prevention and Control Directorate Federal Ministry of Health Ethiopia Philippe Mayaud Clinical Research Department Faculty of Infectious and Tropical Diseases London School of Hygiene and Tropical Medicine Keppel Street London WC1E 7HT United Kingdom

SEAR

AMR

EMR

10.

AFR

11.

AMR

12.

AFR

13.

EUR

ANNEX A: STI GUIDELINE DEVELOPMENT TEAMS

14.

David McCartney Research and Technical Support International Planned Parenthood Federation (IPPF) 4 Newhams Row, London SE1 3UZ United Kingdom Ali M. Mir Population Council No. 7 Street 62, Sector F/6-3 Islamabad Pakistan Nuriye Ortayli United Nations Population Fund (UNFPA) 605 Third Avenue, 4th floor New York, NY 10158 USA Pablo Sanchez The Ohio State University Nationwide Children’s Hospital Clinical and Translational Research (Neonatology) Center for Perinatal Research 700 Children’s Drive Columbus, OH 43205-2664 USA Khantanouvieng Sayabounthavong Ministry of Health Lao People’s Democratic Republic Aman Kumar Singh Department of AIDS Control (National AIDS Control Organization) Ministry of Health and Family Welfare Government of India Chandralok Building, 9th Floor, 36, Janpath New Delhi 110001 India

EUR

15.

SEAR

16.

AMR

17.

AMR

18.

WPR

19.

SEAR

AFR: WHO African Region; AMR: WHO Region of the Americas; EMR: WHO Eastern Mediterranean Region; EUR: WHO European Region; SEAR: WHO South-East Asia Region; WPR: WHO Western Pacific Region

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

ANNEX B: DETAILED METHODS FOR GUIDELINES DEVELOPMENT QUESTIONS AND OUTCOMES To determine which recommendations to update, in December 2013 the World Health Organization (WHO) Department of Reproductive Health and Research reviewed current recommendations of key international guidelines: • S exually transmitted diseases treatment guidelines, 2010, Department of Health and Human Services, United States Centers for Disease Control and Prevention (CDC)4; • U nited Kingdom national guidelines for the management of sexually transmitted infections, British Association for Sexual Health and HIV (BASHH), 2006–2011;5 • C anadian guidelines on sexually transmitted infections, Public Health Agency of Canada, 2013–2014;6 • E uropean sexually transmitted infections guidelines, International Union of Sexually Transmitted Infections (IUSTI);7 • N ational management guidelines for sexually transmissible infections, Sexual Health Society of Victoria, Australia, 2008;8 • N ational guideline for the management and control of sexually transmitted infections (STIs), National Department of Health, South Africa, 2009;9 and • N ational guidelines on prevention, management and control of reproductive tract infections including sexually transmitted infections, Ministry of Health and Family Welfare, Government of India, August 2007.10 Based on the review, four proposed categories of sexually transmitted infection (STI) conditions were prioritized: a. STI conditions included in the 2003 WHO STI guidelines11 that were selected by the GDG to be reviewed and updated in the new WHO STI guidelines. These are important and common conditions. b. STI conditions not included in the 2003 WHO STI guidelines that were selected by the GDG to be reviewed and added in the new WHO STI guidelines. These are important and common conditions. c. STI conditions included in the 2003 WHO STI guidelines that were not updated but were selected by the GDG to be included in the new WHO STI guidelines. These STI conditions are rare and diagnosis is not often made in the majority of settings, or it is unlikely that there is new information available as a basis for making any changes to the 2003 WHO STI recommendations. d. STI conditions not included in the 2003 WHO STI guidelines that are part of other national guidelines, but were not selected by the GDG to be included in the new WHO STI guidelines. These conditions are rare and difficult to diagnose in the majority of settings, or it is unlikely that new research or information has become available; there are existing recommendations for these conditions that can be applied in other settings (e.g. reference hospitals that manage complicated conditions).

Available at: http://www.cdc.gov/std/treatment/2010/std-treatment-2010-rr5912.pdf

5 Available at: http://www.bashh.org/BASHH/Guidelines/Guidelines/BASHH/Guidelines/Guidelines. aspx?hkey=072c83ed-0e9b-44b2-a989-7c84e4fbd9de 6 7 Available at: http://www.phac-aspc.gc.ca/std-mts/sti-its/cgsti-ldcits/index-eng.php Available at: http://www.iusti.org/regions/europe/euroguidelines.htm

8 Melbourne Sexual Health Centre Treatment Guidelines, available at: http://mshc.org.au/HealthProfessional/ MSHCTreatmentGuidelines/tabid/116/Default 9 DA Lewis, E Maruma. Revision of the national guideline for first-line comprehensive management and control of sexually transmitted infections: what’s new and why? South Afr J Epidemiol Infect. 2009;24(2):6–9 (http://apps.who. int/medicinedocs/documents/s18369en/s18369en.pdf). 10 Available at: http://www.ilo.org/wcmsp5/groups/public/---ed_protect/---protrav/---ilo_aids/documents/ legaldocument/wcms_117313.pdf 11 Guidelines for the management of sexually transmitted infections. Geneva: World Health Organization; 2003 (http:// www.who.int/hiv/pub/sti/en/STIGuidelines2003.pdf, accessed 30 May 2016).

ANNEX B: DETAILED METHODS FOR GUIDELINES DEVELOPMENT

A meeting was held in December 2013, at which the Guideline Development Group (GDG) discussed and decided on the initial list of population, intervention, comparator and outcome (PICO) questions identified by WHO. After the meeting, surveys pertaining to each of the four STI topic areas (i.e. gonorrhoea, chlamydia, syphilis and genital herpes simplex virus were administered among subgroups of the GDG members with expertise relating to the relevant STIs. The goal of the surveys was to rank the population, interventions and outcomes for each specific STI condition by importance. The surveys required the members of the STI subgroups to rank the population, interventions and outcomes on a scale of 1 to 9, from lowest to highest priority. Four different priority STI surveys were conducted, and each survey attained a 90–100% response rate from the STI subgroup members. The survey results for priority populations, interventions and outcomes were analysed. Populations, interventions and outcomes with an average rating of 7 to 9 were considered “critical”; those with an average rating of 4 to 6 were considered “important”; and those with an average rating of 1 to 3 were considered “not important” and were thus not covered in the guidelines. Some questions that scored less than 7 were kept for consistency.

The number of comparisons in each question was also reduced; only “critical” interventions were compared with each other and with important interventions. Thus, “important” interventions were not compared to each other. A revised list of questions was then compiled and all members of the full STI GDG were requested to review the priority questions. The priority questions were then revised based on this feedback. Nine questions were identified for the update of the syphilis guidelines and used to inform the recommendations. Each question is framed using the PICO format (population, intervention, comparison, and outcomes).

PRIORITY QUESTIONS AND OUTCOMES FOR TREPONEMA PALLIDUM (SYPHILIS) EARLY SYPHILIS: ADULTS AND ADOLESCENTS (RECOMMENDATIONS 1 AND 2) Question 1: Should benzathine penicillin G 2.4 million units (MU) x 1 compared with other treatments be used for treating adults and adolescents, including people living with HIV, with early syphilis? Early syphilis (primary, secondary or latent < 2 years) in adults and adolescents and people living with HIV Population Adults and adolescents and people living with HIV with early syphilis (primary, secondary or latent < 2 years) Intervention Benzathine PCN 2.4 MU x 1 Comparator Ceftriaxone 1 g IM qd x 10–14 days Azithromycin 2 g x 1 Benzathine PCN 2.4 MU x 3 doses Benzathine PCN 2.4 MU x 2 doses Doxycycline 100 mg po bid x 14 days Erythromycin 500 mg po qid x 14 days Outcome Critical: Serological response, clinical cure Important: Transmission to partner, antimicrobial resistance, compliance, side-effects (including allergy, toxicity), HIV transmission or acquisition, STI complications

bid: twice daily; IM: intramuscular; MU: million units; PCN: penicillin; po: by mouth (orally); qd: daily; qid: four times daily

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Question 2: Should benzathine penicillin G 2.4 MU x 1 compared with other treatments be used for treating adults and adolescents, including people living with HIV, with early syphilis with penicillin allergy? Early syphilis (primary, secondary or latent < 2 years) in patients with penicillin allergy Population Patients with penicillin allergy with early syphilis (primary, secondary or latent < 2 years) Intervention PCN desensitization and PCN Comparator Ceftriaxone 1 g IM qd x 10–14 days Azithromycin 2 g x 1 Doxycycline 100 mg po bid x 14 days Erythromycin 500 mg po qid x 14 days Outcome Critical: Serological response, clinical cure, allergic reaction/ anaphylactic shock Important: Transmission to partner, antimicrobial resistance, compliance, side-effects (including allergy, toxicity), HIV transmission or acquisition, STI complications

bid: twice daily; IM: intramuscular; PCN: penicillin; po: by mouth (orally); qd: daily; qid: four times daily

EARLY SYPHILIS: PREGNANT WOMEN (RECOMMENDATIONS 3 AND 4) Question 3: Should benzathine penicillin G 2.4 MU x 1 compared with other treatments be used for treating pregnant women with early syphilis? Early syphilis (primary, secondary or latent < 2 years) in pregnant women Population Pregnant women with early syphilis (primary, secondary or latent < 2 years) Intervention Benzathine PCN 2.4 MU x 1 Comparator Ceftriaxone 1 g IM qd x 10–14 days Azithromycin 2 g x 1 dose Benzathine PCN 2.4 MU x 3 doses Benzathine PCN 2.4 MU x 2 doses Erythromycin 500 mg po qid x 14 days Outcome Critical: Mother-to-child transmission, serological response, low birth weight/ preterm, stillbirth/neonatal death, clinical cure, congenital deformities, side-effects (including allergy, toxicity) Important: Compliance, antimicrobial resistance, STI complications, transmission to partner, HIV transmission or acquisition IM: intramuscular; MU: million units; PCN: penicillin; po: by mouth (orally); qd: daily; qid: four times daily

ANNEX B: DETAILED METHODS FOR GUIDELINES DEVELOPMENT

Question 4: Should benzathine penicillin G 2.4 MU x 1 compared with other treatments be used for treating pregnant women with early syphilis with penicillin allergy? Early syphilis (primary, secondary or latent < 2 years) in pregnant women with penicillin allergy Population Pregnant women with penicillin allergy with early syphilis (primary, secondary or latent < 2 years) Intervention PCN desensitization and PCN Comparator Ceftriaxone 1 g IM qd x 10–14 days Azithromycin 2 g x 1 Erythromycin 500 mg po qid x 14 days Outcome Critical: Mother-to-child transmission, serological response, low birth weight/ preterm, stillbirth/neonatal death, clinical cure, congenital deformities, side-effects (Including allergy, toxicity), anaphylaxis Important: Compliance, antimicrobial resistance, STI complications, transmission to partner, HIV transmission or acquisition

IM: intramuscular; PCN: penicillin; po: by mouth (orally); qd: daily; qid: four times daily

LATE SYPHILIS: ADULTS AND ADOLESCENTS (RECOMMENDATIONS 5 AND 6) Question 5: Should benzathine penicillin G 2.4 MU x 1 dose weekly x 3 weeks compared with other treatments be used in adults and adolescents, including people living with HIV, with late syphilis? Late syphilis (latent syphilis or syphilis of unknown duration) in adults and adolescents and people living with HIV Population Adults and adolescents and people living with HIV with latent syphilis > 2 years or syphilis of unknown duration Intervention Benzathine PCN 2.4 MU IM 3 doses (1 dose per week x 3 weeks) Comparator Azithromycin Ceftriaxone 1 g IM or IV qd x 10 days Benzathine PCN 2.4 MU x 1, 2 doses over 2 weeks Doxycycline 100 mg po bid x 30 days Erythromycin 500 mg po qid x 30 days Outcome Critical: Serological response, compliance Important: Transmission to partner, antimicrobial resistance, side-effects (including allergy, toxicity), HIV transmission or acquisition, STI complications

bid: twice daily; IM: intramuscular; IV: intravenous; MU: million units; PCN: penicillin; po: by mouth (orally); qd: daily; qid: four times daily

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

LATE SYPHILIS: PREGNANT WOMEN (RECOMMENDATIONS 7 AND 8) Question 6: Should benzathine penicillin G 2.4 MU x 1 dose weekly x 3 weeks compared with other treatments be used for treating pregnant women with late syphilis? Late syphilis (latent syphilis or syphilis of unknown duration) in pregnant women Population Pregnant women with latent syphilis > 2 years or syphilis of unknown duration Intervention Benzathine PCN 2.4 MU IM 3 doses (1 dose per week x 3 weeks) Comparator Azithromycin Ceftriaxone 1 g IM or IV qd x 10 days Benzathine PCN 2.4 MU x 1, 2 doses over 2 weeks Erythromycin 500 mg po qid x 30 days Outcome Critical: Mother-to-child transmission, serological response, low birth weight/ preterm, stillbirth/neonatal death, congenital deformities, compliance Important: Antimicrobial resistance, STI complications, transmission to partner, HIV transmission or acquisition, sideeffects (including allergy, toxicity)

IM: intramuscular; IV: intravenous; MU: million units; PCN: penicillin; po: by mouth (orally); qd: daily; qid: four times daily

CONGENITAL SYPHILIS: INFANTS (RECOMMENDATIONS 9 AND 10) Question 7: In infants with congenital syphilis, or in infants whose mothers had untreated syphilis, inadequately treated syphilis or adequately treated syphilis, what are the treatment options? Multiple scenarios of proven or possible infection: Scenario 1: Infants with congenital syphilis Population Infants with congenital syphilis Intervention Benzyl penicillin 100 000– 150 000 U/kg/ day x 10–15 days Procaine penicillin 50 000 U/kg/ day x 10–15 days Comparator Ceftriaxone: • I nfants < 30 days: Ceftriaxone 75 mg/ kg BW IM/IV single dose x 10–14 days • I nfants ≥ 30 days: Ceftriaxone 100 mg/kg BW IM/IV single dose x 10–14 days Outcome Critical: Clinical cure, serologic response, congenital syphilis manifestation

BW: body weight; IM: intramuscular; IV: intravenous

ANNEX B: DETAILED METHODS FOR GUIDELINES DEVELOPMENT

Question 8: In infants who are clinically normal but whose mothers had untreated syphilis, inadequately treated syphilis or syphilis that was treated with non-penicillin regimens, what are the treatment options? Scenario 2: Infants who are clinically normal but whose mothers had untreated syphilis, inadequately treated syphilis or syphilis that was treated with non-penicillin regimens

Population Infants clinically normal, but mother with syphilis not treated, inadequately treated or treated with non-penicillin

Intervention Benzyl penicillin 100 000– 150 000 U/kg/ day x 10 days to 15 days Procaine penicillin 50 000 U/kg/ day x 10–15 days

Comparator Benzathine penicillin 50 000 U/kg IM single dose Ceftriaxone: • I nfants < 30 days: Ceftriaxone 75 mg/ kg BW IM/IV single dose x 10–14 days • I nfants ≥ 30 days: Ceftriaxone 100 mg/kg BW IM/IV single dose x 10–14 days No treatment

Outcome Critical: Clinical cure, serologic response, congenital syphilis manifestation

BW: body weight; IM: intramuscular; IV: intravenous

Question 9: In infants who are clinically normal and whose mothers had syphilis that was adequately treated with no signs of reinfection, what is the recommended course of action? Scenario 3: Infants who are clinically normal and whose mothers had syphilis that was adequately treated with no signs of reinfection Population Infants clinically normal, but mother treated, no signs of reinfection Intervention Benzathine penicillin 50 000 U/kg IM single dose Comparator No treatment Ceftriaxone: • I nfants < 30 days: Ceftriaxone 75 mg/ kg BW IM/IV single dose x 1 day • I nfants ≥ 30 days: Ceftriaxone 100 mg/kg BW IM/IV single dose x 1 day Outcome Critical: Clinical cure, serologic response, congenital syphilis manifestation

BW: body weight; IM: intramuscular; IV: intravenous

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

REVIEW OF THE EVIDENCE

SEARCH FOR EVIDENCE FOR EFFECTS OF INTERVENTIONS To avoid duplication of reviews that have been previously published, evidence was searched using a hierarchical approach. The team first searched for synthesized evidence then searched the primary studies for all the factors needed to complete the evidence-to-decision framework for each question (i.e. benefits and harms, patient values, acceptability, feasibility, equity and costs). The hierarchical approach consisted of identifying pre-existing synthesized evidence, including from previously published guidelines that included systematic reviews of the literature. When synthesized evidence about benefits and harms for an intervention was not available or the synthesized evidence was not up to date, a new systematic review of randomized controlled trials (RCTs) and non-randomized studies was conducted. The search strategies were developed by an information specialist trained in systematic reviews. The strategies included the use of keywords from the controlled vocabulary of the database and text words based on the PICO questions. There were no restrictions based on language, publication status or study design. RCTs were included for critical and important outcomes, and non-randomized studies for critical outcomes when no evidence was available from RCTs. Additional strategies included contacting Cochrane review groups and authors of study protocols. The Cochrane Library suite of databases (Cochrane Database of Systematic Reviews [CDSR], Database of Abstracts of Reviews of Effects [DARE], Health Technology Assessment [HTA] database and the American College of Physicians [ACP] Journal Club) was searched for published systematic reviews and protocols up to January 2014. Search strategy: 1. treponema.mp. 2. pallidum.mp. 3. syphilis.mp. 4. chancre*.mp. 5. or/1-4 Primary studies were searched for in the Cochrane Central Register of Controlled Trials (CENTRAL) (up to March 2015), MEDLINE and Embase databases (up to 26 February 2015) and LILACS (up to 19 April 2015).

The strategies included searching for subject headings and text words related to syphilis and specific interventions (e.g. medication names and classes). Additional strategies included checking reference lists and consulting with the GDG for any missed articles.

SCREENING STUDIES, DATA EXTRACTION AND ANALYSIS Two researchers independently screened titles and abstracts of systematic reviews identified through database searching to determine studies eligible for inclusion in the analysis. Disagreements were resolved by discussing study inclusion with a third member of the research team. Data were extracted using a pilottested form for patient characteristics (including the subgroups identified by the GDG), diagnosis, treatment (dose, schedule, etc.), setting, follow-up and outcomes. Two investigators independently abstracted data. Risk of bias of each study was also assessed using risk of bias tools appropriate for RCTs (http://handbook. cochrane.org/chapter_8/8_assessing_risk_of_bias_ in_included_studies.htm) and using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I; previously called ACROBAT) tool to assess nonrandomized studies (www.riskofbias.info). To measure the treatment effect, the data were analysed using RevMan 5.2.12 For dichotomous outcomes, we calculated relative risks with 95% confidence intervals (e.g. risk ratios and odds ratios) by pooling results from RCTs and pooling results from non-randomized studies using the random effects model. Moderate to high heterogeneity (I2 > 50%) was explored. Effects were converted to absolute effects using the calculated relative effect and a representative baseline risk (agreed upon by the GDG). When nonrandomized studies with one group were included, a pooled proportion of an event (and confidence intervals) were calculated across the studies using the generic inverse variance. For continuous outcomes, a mean difference or a standardized mean difference (when studies used different scales to measure an outcome) was calculated. When possible, the forest plots of the meta-analyses were made available to the GDG. When data could not be pooled across studies, narrative synthesis methods were used (see http://methods. cochrane.org/sites/methods.cochrane.org/files/ Mckenzie.pdf). Results were presented in tables (e.g. median effects with interquartile ranges), or were narratively described by direction of the effect or by statistical significance as reported in the primary study.

12 RevMan (Computer Program). Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration; 2012.

ANNEX B: DETAILED METHODS FOR GUIDELINES DEVELOPMENT

PATIENT VALUES AND PREFERENCES, ACCEPTABILITY, EQUITY AND FEASIBILITY Studies on patient values and preferences, acceptability, equity and feasibility were searched for and screened using two methods. First, while screening studies for the effects of treatments and costs, two investigators identified studies of potential relevance in these areas. Secondly, a separate search was conducted in MEDLINE, Embase and PsycINFO from January 2000 to July 2015. Text words and keywords for the different STIs were used in combination with words such as “preference”, “adherence”, “satisfaction”, “attitudes”, “health utilities” and “value”, “equity” and “feasibility”. The results included 2563 unique references. Two investigators screened the studies, and 162 studies were identified for full text retrieval. Any study design was included that addressed equity or feasibility. In addition, when adherence was measured in RCTs or nonrandomized studies, the data were collected, synthesized and presented in the evidence profiles for each PICO question. The following study designs were included: a. Patient utilities and health status values studies: These studies examine how patients value alternative health states and their experiences with treatment. The measurement techniques used can include: standard gamble, time trade-off, visual analogue scale, or mapping results based on generic surveys (EuroQol five dimensions health questionnaire [EQ5D] or the 36-Item Short Form Health Survey [SF-36]) or specific measurement (e.g. St George Respiratory Questionnaire) of health-related quality of life. b. Studies of patients’ direct choices when presented with decision aids: These studies examine the choices patients make when presented with decision aids for management options (i.e. probabilistic trade-off techniques). c. Studies on non-utility measurement of health states: These studies quantitatively examine patients’ views, attitudes, satisfaction or preferences through questionnaires or scales; these are neither utility studies nor studies of patients’ responses to decision aids. Patients are asked about how desirable or aversive a particular outcome is for them. This category includes some studies that use questionnaires or scales. d. Qualitative studies: These studies explore patients’ views, attitudes, satisfactions or preferences related to different treatment options based on qualitative research methods including focus group discussions, interviews, etc.

From the search, we included 17 studies reporting information relating to different STIs. In many instances, data for all infections informed the evidence for syphilis specifically.

RESOURCES We searched the published literature for evidence on use of resources and obtained data on direct costs of medicines. Based on the list of possible treatments identified by the GDG, an estimate of the cost associated with each alternative was calculated. This costing estimate refers only to the actual market price of the medication and does not include the costs of other resources that could be involved, such as syringes, injection time or needle disposal. Data were presented in a table and included: treatment, dose per day, treatment duration, days, medicine cost per dose, medicine cost per full course of treatment, and 25% of procurement costs (as defined in the 2014 Management Sciences for Health (MSH) International drug price indicator guide)13. A final price for a full course of treatment for each medicine by dosage was calculated as the number of doses per day, multiplied by the number of days of the treatment, plus 25% of the procurement costs for the medicines used. The unit price of the medicine was obtained from the median prices provided in the 2014 MSH International drug price indicator guide and information available on the Internet. In order to determine a precise and reliable estimate, the price per unit (all expressed in US dollars) was provided only when the information available matched the dosage of interest (grams per pill or 1000 units per vial). No calculations were made based on assumptions about the cost per unit of hypothetical packaging not listed in the directory. The major medical databases were also searched (MEDLINE, Embase and the Cochrane Library for Economic Evaluation and Technology Assessment reports) from January 2005 to July 2015. In addition, while screening studies for the effects of treatments, two investigators also identified studies of potential relevance for costs. No studies were identified for resource use relating to treatment of syphilis.

13 International drug price indicator guide, 2014 edition (updated annually). Medford (MA): Management Sciences for Health; 2015 (http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2014.pdf, accessed 6 June 2016).

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

APPLYING THE GRADE APPROACH TO MAKING THE RECOMMENDATIONS EVIDENCE PROFILES An evidence profile was made for each PICO question using the GRADEpro software (www.gradepro.org). Each profile included the critical and important outcomes, the relative and absolute effects, and the quality of evidence according to the GRADE domains (see the GRADE handbook)14. Briefly, the GRADE approach assesses the quality of evidence for treatment interventions using well-established criteria for the design, risk of bias, inconsistency, indirectness, imprecision, effect size, dose–response curve and other considerations that may affect the quality of the evidence. Two investigators used the GRADE approach to assess the quality and level of certainty of the evidence. The evidence profiles for each recommendation are available in Web annex D.

MAKING THE RECOMMENDATIONS In October 2015, the GDG met to make the recommendations. This meeting was facilitated by two co-chairs – one with expertise in GRADE and the other with clinical expertise of syphilis. During the meeting, the evidence profiles and evidence-to-decision frameworks were presented by the methodologists. The GDG discussed each GRADE criterion and judged which intervention was favoured. Then a final decision and guideline recommendation was developed. The goal was to arrive at agreement across all members of the GDG and this was facilitated by the chairpersons through discussion. When there was disagreement for a criterion, it was noted in the evidence-to-decision framework for the relevant judgement. If there was disagreement for any of the final recommendations, the plan was for the GDG to vote and the numbers to be recorded. Because there was no disagreement for any of the final recommendations, however, votes were not taken or reported in these guidelines. The GDG made a strong or conditional recommendation for or against each intervention and described special circumstances in the remarks. Research implications were also developed and presented, based on the gaps identified in the evidence. Following the meeting, the recommendations were finalized via teleconference, and final approval was obtained from the GDG members electronically. All decisions and discussions from the GDG for each recommendation are available in the evidence-to-decision frameworks in Web annex D.

EVIDENCE-TO-DECISION FRAMEWORKS Evidence-to-decision frameworks were also developed using GRADEpro software (www.gradepro.org). Evidence-to-decision frameworks present the desirable and undesirable effects of the interventions, the value of the outcomes, the costs and resource use, the acceptability of the interventions to all stakeholders, the impact on health equity, and the feasibility of implementation (i.e. the GRADE criteria for making decisions). The evidence-to-decision frameworks are based on a population perspective for these recommendations. All GRADE criteria were considered from this perspective.

14 Schünemann H, Brożek J, Guyatt G, Oxman A, editors. GRADE handbook. Hamilton, Ontario: McMaster University and Evidence Prime Inc.; 2013 (http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/ handbook.html, accessed 31 May 2016).

ANNEX C: LISTS OF REFERENCES FOR REVIEWED EVIDENCE

ANNEX C: LISTS OF REFERENCES FOR REVIEWED EVIDENCE RECOMMENDATION 1 AND 2 Question 1: Should benzathine penicillin G 2.4 million units (MU) x 1 compared with other treatments be used for treating adults and adolescents including people living with HIV with early syphilis? Question 2: Should benzathine penicillin G 2.4 MU x 1 compared with other treatments be used for treating adults and adolescents, including people living with HIV, with early syphilis with penicillin allergy? Systematic reviews 1. Bai ZG, Wang B, Yang K, Tian JH, Ma B, Liu Y, Jiang L, Gai QY, He X, Li Y. Azithromycin versus penicillin G benzathine for early syphilis. Cochrane Database Syst Rev. 2012;(6):CD007270. 2. Blank LJ, Rompalo AM, Erbelding EJ, Zenilman JM, Ghanem KG. Treatment of syphilis in HIV-infected subjects: a systematic review of the literature. Sex Transm Infect. 2011;87:9e16. 3. Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives Saved Tool supplement detection and treatment of syphilis in pregnancy to reduce syphilis related stillbirths and neonatal mortality. BMC Public Health. 2011;11(Suppl 3):S9. 4. Clement ME, Lance NO, Hicks CB. Treatment of syphilis: a systematic review. JAMA. 2014;312(18):1905-17. 5. Galvao TF, Silva MT, Serruya SJ, Newman LM, Klausner JD, Pereira MG, Fescina R. Safety of benzathine penicillin for preventing congenital syphilis: a systematic review. PLoS One. 2013;8(2):e56463. doi:10.1371/journal.pone.0056463. Included studies 1. Agmon-Levin N, Elbirt D, Asher I, Gradestein S, Werner B, Sthoeger Z. Syphilis and HIV co-infection in an Israeli HIV clinic: incidence and outcome. Int J STD AIDS. 2010;21(4):249-52. 2. Dionne-Odom J, Karita E, Kilembe W, Henderson F, Vwalika B, Bayingana R et al. Syphilis treatment response among HIVdiscordant couples in Zambia and Rwanda. Clin Infect Dis. 2013;56(12):1829-37. 3. Fiumara NJ. Treatment of primary and secondary syphilis: serologic response. J Am Acad Dermatol. 1986;14(3):487-91. 4. Ghanem KG, Erbelding EJ, Cheng WW, Rompalo AM. Doxycycline compared with benzathine penicillin for the treatment of early syphilis. Clinical Infect Dis. 2006;42(6):e45-9. doi:10.1086/500406. 5. González-López JJ, Fernández Guerrero ML, Luján R, Fernandez Tostado S, de Górgolas M, Requena L. Factors determining serologic response to treatment in patients with syphilis. Clin Infect Dis. 2009;49(10):1505–11. doi:10.1086/644618. 6. Hook IEW, Martin DH, Stephens J, Smith BS, Smith K. A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis. Sex Transm Dis. 2002;29(8):486-90. 7. Hook IEW, Behets F, Van Damme K, Ravelomanana N, Leone P, Sena AC et al. A Phase III equivalence trial of azithromycin versus benzathine penicillin for treatment of early syphilis. J Infect Dis. 2010;201(11):1729-35. 8. Jinno S, Anker B, Kaur P, Bristow CC, Klausner JD. Predictors of serological failure after treatment in HIV-infected patients with early syphilis in the emerging era of universal antiretroviral therapy use. BMC Infect Dis. 2013;13:605. 9. Katsambas A, Adoniou C, Katsarou A, Kerkidou A, Stratigos J. Comparative study of ceftriaxone and benzathine penicillin G in the treatment of primary and secondary syphilis. Chemioterapia. 1987;6(2 Suppl): 549-50. 10. Knaute DF, Graf N, Lautenschlager S, Weber R, Bosshard PP. Serological response to treatment of syphilis according to disease stage and HIV status. Clin Infect Dis. 2012;55(12):161522. doi:10.1093/cid/cis757. 11. Kiddugavu Mg, Kiwanuka N, Wawer MJ, Serwadda D, Sewankambo NK, Wabwire-Mangen F et al.; Rakai Study Group.. Effectiveness of syphilis treatment using azithromycin and/ or benzathine penicillin in Rakai, Uganda. Sex Transm Dis. 2005;32(1):1-6. 12. Li J, Zheng HY. Early syphilis: serological treatment response to doxycycline/tetracycline versus benzathine penicillin. J Infect Dev Ctries. 2014;8(2):228-32. doi:10.3855/jidc.3013. 13. Long CM, Klausner JD, Leon S, Jones FR, Giron M, Cuadros J et al. Syphilis treatment and HIV infection in a population-based study of persons at high risk for sexually transmitted disease/ HIV infection in Lima, Peru. Sex Transm Dis. 2006;33(3):151-5. 14. Moorthy TT, Lee CT, Lim KB, Tan T. Ceftriaxone for treatment of primary syphilis in men: a preliminary study. Sex Transm Dis. 1987;14(2):116-8. 15. Petersen CS, Jorgensen BB, Pedersen NS. Treatment of early infectious syphilis in Denmark. A retrospective serological study. Dan Med Bull. 1984;31(1):70-2. 16. Psomas KC, Brun M, Causse A, Atoui N, Reynes J, Le Moing V. Efficacy of ceftriaxone and doxycycline in the treatment of early syphilis. Med Mal Infect. 2012;42(1):15-9. doi:10.1016/j. medmal.2011.10.003. 17. Riedner G, Rusizoka M, Todd J, Maboko L, Hoelscher M, Mmbando D et al. Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N Engl J Med. 2005;353(12):1236-44. 18. Rolfs RT, Joesoef MR, Hendershot EF, Rompalo AM, Augenbraun MH, Chiu M et al. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. N Engl J Med. 1997;337(5):307-14. 19. Sena AC, Wolff M, Martin DH, Behets F, Van Damme K, Leone P et al. Predictors of serological cure and serofast state after treatment in HIV-negative persons with early syphilis. Clin Infect Dis. 2011;53(11):1092-9. 20. Talwar S, Tutakne MA, Tiwari VD. VDRL titres in early syphilis before and after treatment. Genitourin Med. 1992;68(2):120-2. 21. Tittes J, Aichelburg MC, Antoniewicz L, Geusau A. Enhanced therapy for primary and secondary syphilis: a longitudinal retrospective analysis of cure rates and associated factors. Int J STD AIDS. 2013;24(9):703-11. 22. Tong ML, Lin LR, Liu GL, Zhang HL, Zeng YL, Zheng WH et al. Factors associated with serological cure and the serofast state of HIV-negative patients with primary, secondary, latent, and tertiary syphilis. PLoS One. 2013;8(7):e70102.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

23. Wong T, Singh AE, De P. Primary syphilis: serological treatment response to doxycycline/tetracycline versus benzathine penicillin. Am J Med. 2008;121(10):903-8. 24. Yinnon AM, Coury-Doniger P, Polito R, Reichman RC. Serologic response to treatment of syphilis in patients with HIV infection. Arch Int Med. 1996;156(3):321-5. 25. Yang CJ, Lee NY, Chen TC, Lin YH, Liang SH, Lu PL. One dose versus three weekly doses of benzathine penicillin G for patients co-infected with HIV and early syphilis: a multicenter, prospective observational study. PLoS One. 2012;9(10). Patient values and preferences, acceptability and cost: specific to syphilis infections 1. Chauhan M, Serisha B, Sankar KN, Pattman RS, Schmid ML. Audit of the use of benzathine penicillin, post-treatment syphilis serology and partner notification of patients with early infectious syphilis. Int J STD AIDS. 2006;17(3):200-2 2. Crowe G, Theodore C, Forster GE, Goh BT. Acceptability and compliance with daily injections of procaine penicillin in the outpatient treatment of syphilis-treponemal infection. Sex Transm Dis. 1997;24(3):127-30. 3. Kingston MA, Higgins SP. Audit of the management of early syphilis at North Manchester General Hospital. Int J STD AIDS. 2004;15(5):352-4. 4. Owusu-Edusei K, Gift TL, Ballard RC. Cost-effectiveness of a dual non-treponemal/treponemal syphilis point-of-care test to prevent adverse pregnancy outcomes in sub-Saharan Africa (Provisional abstract). Sex Transm Dis. 2011;38:997-1003. 5. Tayal S, Ahmed MS, Hanif U. Audit of early syphilis: Teesside experience 2005–2007. Int J STD AIDS. 2009;20(9):647-9. Penicillin allergy Systematic review 1. Salkind AR, Cuddy PG, Foxworth JW. The rational clinical examination. Is this patient allergic to penicillin? An evidencebased analysis of the likelihood of penicillin allergy. JAMA. 2001;285(19):2498-505. Included studies 1. You might be allergic to penicillin. Then again, you might not. In: ACAAI.org [website]. Arlington Heights (IL): American College of Allergy, Asthma and Immunology (ACAAI); 2014 (http://acaai. org/news/you-might-be-allergic-penicillin-then-again-youmight-not, accessed 30 June 2016). 2. Co Minh HB, Bousquet PJ, Fontaine C, Kvedariene V, Demoly P. Systemic reactions during skin tests with beta-lactams: a risk factor analysis. J Allergy Clin Immunol. 2006;117:466–8. 3. Lockey RF, Benedict LM, Turkeltaub PC, Bukantz SC. Fatalities from immunotherapy (IT) and skin testing (ST). J Allergy Clin Immunol. 1987;79:660–77. 4. Nolan RC, Puy R, Deckert K, O’Hehir RE, Douglass JA. Experience with a new commercial skin testing kit to identify IgE-mediated penicillin allergy. Intern Med J. 2008;38:357–61. 5. Riezzo I, Bello S, Neri M, Turillazzi E, Fineschi V. Ceftriaxone intradermal test-related fatal anaphylactic shock: a medico-legal nightmare. Allergy. 2010;65:130–1.

6. Sogn DD, Evans R 3rd, Shepherd GM, Casale TB, Condemi J, Greenberger PA et al. Results of the National Institute of Allergy and Infectious Diseases Collaborative Clinical Trial to test the predictive value of skin testing with major and minor penicillin derivatives in hospitalized adults. Arch Intern Med. 1992;152(5):1025-32. 7. Van Dellen RG. Skin testing for penicillin allergy. J Allergy Clin Immunol. 1981;68:169-70.

RECOMMENDATION 3 AND 4 Question 3: Should benzathine penicillin G 2.4 MU x 1 compared with other treatments be used for treating pregnant women with early syphilis? Question 4: Should benzathine penicillin G 2.4 MU x 1 compared with other treatments be used for treating pregnant women with early syphilis with penicillin allergy? Systematic review 1. Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives Saved Tool supplement detection and treatment of syphilis in pregnancy to reduce syphilis related stillbirths and neonatal mortality. BMC Public Health. 2011;11(Suppl 3):S9. Included studies 1. Alexander JM, Sheffield JS, Sanchez PJ, Mayfield J, Wendel Jr GD. Efficacy of treatment for syphilis in pregnancy. Obstet Gynecol. 1999;93(1):5-8. 2. Chang SN, Chung KY, Lee MG, Lee JB. Seroreversion of the serological tests for syphilis in the newborns born to treated syphilitic mothers. Genitourin Med. 1995;71(2):68-70. 3. Donders GGG, Desmyter J, Hooft P, Dewet GH. Apparent failure of one injection of benzathine penicillin G for syphilis during pregnancy in human immunodeficiency virus-seronegative African women. Sex Transm Dis. 1997;24(2):94-101. 4. Klein VR, Cox SM, Mitchell MD, Wendel GD Jr. The JarischHerxheimer reaction complicating syphilotherapy in pregnancy. Obstet Gynecol. 1990;75(3 Pt I):375-80. 5. Lu J, Huang C, Zeng Y. Syphilis in pregnancy women. Zhonghua fu chan ke za zhi 2001;36(8):456-9 (in Chinese). 6. Mullick S, Beksinksa M, Msomi S. Treatment for syphilis in antenatal care: compliance with the three dose standard treatment regimen. Sex Transm Infect. 2005;81(3):220-2. 7. Myer L, Karim SSA, Lombard C, Wilkinson D. Treatment of maternal syphilis in rural South Africa: effect of multiple doses of benzathine penicillin on pregnancy loss. Trop Med Int Health. 2004;9(11):1216-21. 8. Myles TD, Elam G, Park-Hwang E, Nguyen T. The JarischHerxheimer reaction and fetal monitoring changes in pregnant women. Obstet Gynecol. 1998;92(5):859-64. 9. Phaosavasdi S, Snidvongs W, Thasanapradit P, Ungthavorn P, Bhongsvej S, Jongpiputvanich S et al. Effectiveness of benzathine penicillin regimen in the treatment of syphilis in pregnancy. J Med Assoc Thai. 1989;72(2):101-8.

ANNEX C: LISTS OF REFERENCES FOR REVIEWED EVIDENCE

10. Watson-Jones D, Gumodoka B, Weiss H, Changalucha J, Todd J, Mugeye K et al. Syphilis in pregnancy in Tanzania. II. The effectiveness of antenatal syphilis screening and single-dose benzathine penicillin treatment for the prevention of adverse pregnancy outcomes. J Infect Dis. 2002;186(7):948-57. 11. Wendel GD Jr., Stark BJ, Jamison RB, Molina RD, Sullivan TJ. Penicillin allergy and desensitization in serious infections during pregnancy. N Engl J Med. 1985;312(19):1229-32. 12. Zhang XM, Zhang RN, Lin SQ, Chen SX, Zheng LY. Clinical analysis of 192 pregnant women infected by syphilis. Zhonghua fu chan ke za zhi. 2004;39(10):682-6. 13. Zhou P, Gu Z, Xu J, Wang X, Liao K. A study evaluating ceftriaxone as a treatment agent for primary and secondary syphilis in pregnancy. Sex Transm Dis. 2005;32(8):495-8. Patient values and preferences, acceptability and cost: specific to syphilis infections 1. Chauhan M, Serisha B, Sankar KN, Pattman RS, Schmid ML. Audit of the use of benzathine penicillin, post-treatment syphilis serology and partner notification of patients with early infectious syphilis. Int J STD AIDS. 2006;17(3):200-2. 2. Crowe G, Theodore C, Forster GE, Goh BT. Acceptability and compliance with daily injections of procaine penicillin in the outpatient treatment of syphilis-treponemal infection. Sex Transm Dis. 1997;24(3):127-30. 3. Kingston MA, Higgins SP. Audit of the management of early syphilis at North Manchester General Hospital. Int J STD AIDS. 2004;15(5):352-4. 4. Owusu-Edusei K, Gift TL, Ballard RC. Cost-effectiveness of a dual non-treponemal/treponemal syphilis point-of-care test to prevent adverse pregnancy outcomes in sub-Saharan Africa (Provisional abstract). Sex Transm Dis. 2011;38:997-1003. 5. Tayal S, Ahmed MS, Hanif U. Audit of early syphilis: Teesside experience 2005–2007. Int J STD and AIDS. 2009;20(9):647-9.

Included studies 1. Kiddugavu MG. Effectiveness of syphilis treatment using azithromycin and/or benzathine penicillin in Rakai, Uganda. Sex Transm Dis. 2005;32(1):1-6. Patient values and preferences, acceptability and cost: specific to syphilis infections 1. Chauhan M, Serisha B, Sankar KN, Pattman RS, Schmid ML. Audit of the use of benzathine penicillin, post-treatment syphilis serology and partner notification of patients with early infectious syphilis. Int J STD AIDS. 2006; 17(3):200-2 2. Crowe G, Theodore C, Forster GE, Goh BT. Acceptability and compliance with daily injections of procaine penicillin in the outpatient treatment of syphilis-treponemal infection. Sex Transm Dis. 1997;24(3):127-30. 3. Kingston MA, Higgins SP. Audit of the management of early syphilis at North Manchester General Hospital. Int J STD AIDS. 2004; 15(5):352-4. 4. Owusu-Edusei K, Gift TL, Ballard RC: Cost-effectiveness of a dual non-treponemal/treponemal syphilis point-of-care test to prevent adverse pregnancy outcomes in sub-Saharan Africa (Provisional abstract). Sex Transm Dis. 2011;38:997-1003. 5. Tayal S, Ahmed MS, Hanif U. Audit of early syphilis: Teesside experience 2005–2007. Int J STD AIDS. 2009;20(9):647-9. RECOMMENDATION 7 AND 8

Question 6: Should benzathine penicillin G 2.4 MU x 1 dose weekly x 3 weeks compared with other treatments be used for treating pregnant women with late syphilis? Systematic review 1. Bai ZG, Wang B, Yang K, Tian JH, Ma B, Liu Y et al. Azithromycin versus penicillin G benzathine for early syphilis. Cochrane Database Syst Rev. 2012;(6):CD007270. 2. Blank LJ, Rompalo AM, Erbelding EJ, Zenilman JM, Ghanem KG. Treatment of syphilis in HIV-infected subjects: a systematic review of the literature. Sex Transm Infect. 2011;87:9e16. 3. Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives Saved Tool supplement detection and treatment of syphilis in pregnancy to reduce syphilis related stillbirths and neonatal mortality. BMC Public Health. 2011;11(Suppl 3):S9. 4. Clement ME, Lance NO, Hicks CB. Treatment of syphilis: a systematic review. JAMA. 2014;312(18):1905-17. 5. Galvao TF, Silva MT, Serruya SJ, Newman LM, Klausner JD, Pereira MG, Fescina R. Safety of benzathine penicillin for preventing congenital syphilis: a systematic review. PLoS One. 2012;8(2):e56463. doi:10.1371/journal.pone.0056463. Included studies 1. Alexander JM, Sheffield JS, Sanchez PJ, Mayfield J, Wendel Jr GD. Efficacy of treatment for syphilis in pregnancy. Obstet Gynecol. 1999;93(1):5-8.

RECOMMENDATION 5 AND 6 Question 5: Should benzathine penicillin G 2.4 MU x 1 dose weekly x 3 weeks compared with other treatments be used in adults and adolescents including people living with HIV with late syphilis? Systematic review 1. Bai ZG, Wang B, Yang K, Tian JH, Ma B, Liu Y et al. Azithromycin versus penicillin G benzathine for early syphilis. Cochrane Database Syst Rev. 2012;(6):CD007270. 2. Blank LJ, Rompalo AM, Erbelding EJ, Zenilman JM, Ghanem KG. Treatment of syphilis in HIV-infected subjects: a systematic review of the literature. Sex Transm Infect. 2011;87:9e16. 3. Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives Saved Tool supplement detection and treatment of syphilis in pregnancy to reduce syphilis related stillbirths and neonatal mortality. BMC Public Health. 2011;11(Suppl 3):S9. 4. Clement ME, Lance NO, Hicks CB. Treatment of syphilis: a systematic review. JAMA. 2014;312(18):1905-17. 5. Galvao TF, Silva MT, Serruya SJ, Newman LM, Klausner JD, Pereira MG, Fescina R. Safety of benzathine penicillin for preventing congenital syphilis: a systematic review. PLoS One. 2013;8(2):e56463. doi:10.1371/journal.pone.0056463.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

RECOMMENDATION 9 Question 7: In infants with congenital syphilis or in infants whose mothers had untreated syphilis, inadequately treated syphilis or adequately treated syphilis, what are the treatment options? Question 8: In infants who are clinically normal but whose mothers had untreated syphilis, inadequately treated syphilis or syphilis that was treated with nonpenicillin regimens, what are the treatment options?

RECOMMENDATION 10 Question 9: In infants who are clinically normal and whose mothers had syphilis that was adequately treated with no signs of reinfection, what is the recommended course of action? Systematic review 1. Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives Saved Tool supplement detection and treatment of syphilis in pregnancy to reduce syphilis related stillbirths and neonatal mortality. BMC Public Health. 2011;11(Suppl 3):S9. 2. Gomez GB, Kamb ML, Newman LM, Mark J, Broutet N, Hawkes SJ. Untreated maternal syphilis and adverse outcomes of pregnancy: a systematic review and meta-analysis. Bull World Health Organ. 2013;91(3):217-26. doi:10.2471/BLT.12.107623. 3. Newman L, Kamb M, Hawkes S, Gomez G, Say L, Seuc A, Broutet N. Global estimates of syphilis in pregnancy and associated adverse outcomes: analysis of multinational antenatal surveillance data. PLoS Med. 2013;10(2):e1001396. Included studies 1. Fujii R, Hashira S, Sakata H, Inyaku F, Fujita K, Maruyama S et al. [Pharmacokinetics and clinical evaluation of ceftriaxone in neonates]. Jpn J Antibiot. 1988;41(9):1237-50. 2. Lago EG, Vaccari A, Fiori RM. Clinical features and follow-up of congenital syphilis. Sex Transm Dis. 2013;40(2):85-94. 3. Paryani SG, Vaughn AJ, Crosby M, Lawrence S. Treatment of asymptomatic congenital syphilis: Benzathine versus rocaine penicillin G therapy. J Pediatr. 1994;125(3):471-5. 4. Pfizer. Product monograph PrBICILLIN® L-A (penicillin G benzathine) Sterile injection (for deep intramuscular injection only) antibiotic. Quebec: Pfizer Canada Inc.; 2011. 5. Radcliffe M. Single-dose benzathine penicillin in infants at risk of congenital syphilis – results of a randomised study. South African Med J. 1997;87(1):62-5. 6. Roerig. Buffered PFIZERPEN (penicillin G potassium) for injection. New York (NY): Pfizer Inc.; 2005 (https://www.pfizer. com/files/products/uspi_pfizerpen.pdf, accessed 15 July 2016). 7. Sangtawesin V, Lertsutthiwong W, Kanjanapattanakul W, Khorana M, Horpaopan S. Outcome of maternal syphilis at Rajavithi Hospital on offsprings. J Med Assoc Thai. 2005;88(11):1519-25.

ANNEX C: LISTS OF REFERENCES FOR REVIEWED EVIDENCE

8. Valentini P, Speziale D, Grillo RL, D'Apolito A, Angelone DF, Ngalikpima CJ et al. Congenital syphilis: still an open question. Ital J Pediatr. 2004;30(5):312-9. 9. WHO ceftriaxone safety. Second Meeting of the Subcommittee of the Expert Committee on the Selection and Use of Essential Medicines. Geneva: World Health Organization; 29 September to 3 October 2008. Patient values and preferences, acceptability and cost: specific to syphilis infections 1. Owusu-Edusei K, Gift TL, Ballard RC: Cost-effectiveness of a dual non-treponemal/treponemal syphilis point-of-care test to prevent adverse pregnancy outcomes in sub-Saharan Africa (Provisional abstract). Sex Transm Dis. 2011;38:997-1003. 2. International drug price indicator guide, 2014 edition (updated annually). Medford (MA): Management Sciences for Health; 2015 (http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2014.pdf, accessed 6 June 2016).

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

For more information, contact: Department of Reproductive Health and Research World Health Organization Avenue Appia 20, CH-1211 Geneva 27 Switzerland Phone +41 22 791 3264 Fax +41 22 791 4171 E-mail: reproductivehealth@who.int www.who.int/reproductive health

WHO GUIDELINES FOR THE

Treatment of Treponema pallidum (syphilis) Web annex D: Evidence profiles and evidence-to-decision frameworks

July 2016 The full guidelines are available at: www.who.int/reproductivehealth/publications/rtis/syphilis-treatment-guidelines/en/

WHO GUIDELINES FOR THE

Treatment of Treponema pallidum (syphilis) Web annex D: Evidence profiles and evidence-to-decision frameworks

CONTENTS

Recommendations 1 and 2 2 Assessment 3 Summary of judgements 7 Conclusions 8 Evidence profile 10 Supplementary table of adverse events 12 References 14 Recommendations 3 and 4 16 Assessment 17 Summary of judgements 20 Conclusions 21 Evidence profile 23 References 25 Recommendations 5, 6, 7 and 8 26 Assessment 27 Summary of judgements 30 Conclusions 31 Evidence profile 34 Evidence profile 35 References 36 Recommendations 9 and 10 37 Assessment 38 Summary of judgements 42 Conclusions 43 Evidence profile 46 Evidence profile 47 References 50

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

RECOMMENDATIONS 1 AND 2: EARLY SYPHILIS – ADULTS AND ADOLESCENTS Treatments for adults with early syphilis (primary, secondary, or early latent syphilis of not more than 2 years’ duration) Population: Intervention: Comparison: Main outcomes: Adults with early syphilis Ceftriaxone, azithromycin, doxycycline, erythromycin Benzathine penicillin G 2.4 MU × 1 Critical: serological response, clinical cure

Important: transmission to partner, antimicrobial resistance, compliance, side-effects (including allergy, toxicity), HIV transmission or acquisition, STI complications Setting: Perspective: Background: All settings Population level Syphilis is a systemic disease from the outset and is caused by the spirochaete Treponema pallidum. The infection can be classified as congenital (transmitted from mother to child in utero) or acquired (through sex or blood transfusion). Acquired syphilis is divided into early and late syphilis. Early syphilis comprises the primary, secondary and early latent stages. Late syphilis refers to late latent syphilis, gummatous, neurological and cardiovascular syphilis. Primary syphilis is characterized by an ulcer or chancre at the site of infection or inoculation. Secondary syphilis manifestations include a skin rash, condylomata lata, mucocutaneous lesions and generalized lymphadenopathy. The 2003 World Health Organization (WHO) STI guidelines recommend treatment of early syphilis in adults with benzathine benzyl penicillin, 2.4 million IU by intramuscular injection, at a single session. Because of the volume involved, this dose is usually given as two injections at separate sites. An alternative regimen for penicillin-allergic pregnant patients is erythromycin, 500 mg orally, four times daily for 14 days.

RECOMMENDATIONS 1 AND 2: ASSESSMENT EARLY SYPHILIS – ADULTS AND ADOLESCENTS

ASSESSMENT Judgement Is the problem a priority? Problem Desirable Effects Undesirable Effects Research evidence Research evidence: WHO estimates that 5.6 million new cases of syphilis occurred among adolescents and adults aged 15–49 years worldwide in 2012 and there are an estimated 18 million prevalent cases of syphilis. Untreated, up to one third of patients progress to later stages of disease. Late syphilis can cause irreversible damage to the cardiovascular and central nervous systems, resulting in profound morbidity and even death. Additional considerations: None How substantial are the desirable anticipated effects? Research evidence: We included 7 randomized and 18 non-randomized studies with one or two groups. Many studies did not indicate whether people had early or late syphilis. When indicated, we included studies when over 90% of patients were defined as “early”. Serological cures: when compared to single dose benzathine penicillin G, the evidence suggested little to no difference for a double dose of benzathine penicillin G, but fewer cures for a triple dose; similar cure rates with ceftriaxone, azithromycin and doxycycline; fewer cures with doxycycline and tetracycline together. Transmission to partners, HIV transmission and acquisition, and STI complications were not measured. Few studies provided data for adverse events. Azithromycin may increase gastrointestinal side-effects and dizziness or headache, but may reduce rash, fever and serious adverse events. Ceftriaxone may lead to fewer people with diarrhoea and rash, but this evidence is uncertain. A systematic review (Blank, 2011) reported on the effects in people living with HIV. This review was updated. Results suggest that there is little to no difference in the effects in treatments in people living or not living with HIV. See Evidence profiles for the detailed summary of the findings. Additional considerations: The Guideline Development Group (GDG) noted that there are few studies conducted and most treatment is based on historical use of benzathine penicillin G and procaine penicillin. Data were not available for resistance to azithromycin for syphilis in specific settings and will probably be unknown in many places. Resistance to azithromycin for other conditions is spreading, therefore there was concern for the risk of azithromycin resistance to syphilis.

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

• • • •

Trivial Small Moderate Large

• Varies • Don’t know How substantial are the undesirable anticipated effects?

• • • •

Large Moderate Small Trivial

• Varies • Don’t know

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

What is the overall certainty of the evidence of effects?

Certainty of evidence Values Balance of effects Resources required

• • • •

Very low Low Moderate High

• No included studies Is there important uncertainty about or variability in how much people value the main outcomes? Research evidence: According to economic evaluation studies, the disability weights due to syphilis (utility loss due to the disease) are as follows: early syphilis: 0.0072–0.015 secondary syphilis: 0.041 tertiary (neurological): 0.094–0.283 death: 1 Additional considerations: The GDG noted that there may be variability in outcome values depending on stages of syphilis.

• I mportant uncertainty or variability • Possibly important uncertainty or variability • Probably no important uncertainty or variability • No important uncertainty or variability • N o known undesirable outcomes Does the balance between desirable and undesirable effects favour the intervention or the comparison?

Research evidence: No research evidence Additional considerations: The GDG decided that there was little agreement with the evidence for higher doses (given two or three times) providing greater benefit (probably due to study methodology). When compared with azithromycin, benzathine penicillin G was probably favoured due to side-effects. Because there was little evidence for the effects and side-effects for ceftriaxone and doxycycline, benzathine penicillin G was favoured.

• Favours the comparison • Probably favours the comparison

• Does not favour either the intervention or the comparison • Probably favours the intervention • Favours the intervention

• Varies • Don’t know How large are the resource requirements (costs)? Research evidence: No research evidence Additional considerations: Benzathine penicillin G requires local preparation, making cost heavily dependent on local labour costs. Benzathine penicillin G without preparation costs $0.28 per dose. For three doses, $3.72 was the average price. Azithromycin cost $1.56. Ceftriaxone has greater costs (data not available).

• • • • •

Large costs Moderate costs Negligible costs and savings Moderate savings Large savings

• Varies • Don’t know

RECOMMENDATIONS 1 AND 2: ASSESSMENT EARLY SYPHILIS – ADULTS AND ADOLESCENTS

What is the certainty of the evidence of resource requirements (costs)?

Research evidence: No research evidence Additional considerations: None

Certainty of evidence of required resources Cost–effectiveness Equity

• • • •

Very low Low Moderate High

• No included studies

Does the cost-effectiveness of the intervention favour the intervention or the comparison?

Research evidence: No research evidence available published since 2005. Additional considerations: The benefits are similar between the different medicines, but costs are probably higher with ceftriaxone and azithromycin compared to benzathine penicillin.

• Favours the comparison • Probably favours the comparison

• Does not favour either the intervention or the comparison • Probably favours the intervention • Favours the intervention

• Varies • No included studies What would be the impact on health equity? Research evidence: No research evidence Additional considerations: The GDG considered that health equity could be reduced, if benzathine penicillin is not available, but other medicines should be included in the recommendations.

• • • • •

Reduced Probably reduced Probably no impact Probably increased Increased

• Varies • Don’t know

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Is the intervention acceptable to key stakeholders?

• • • • • •

No Probably no Probably yes Yes Varies Don’t know

Research evidence: We found four studies that addressed acceptability of injections (daily or weekly) versus oral medicines in people with various stages of syphilis. Studies were from 1997 to 2006 and indicated that ~80% or more people accepted injections, but weekly injections were preferred. The others refused injections and took oral medicines. Additional considerations: The GDG reported that in practice, there seemed to be variation in acceptability to key stakeholders. In different countries, health workers were averse to giving injections for this infection, and in others they wanted to give the injections (instead of giving oral treatment). Regarding acceptability to patients, some were averse to injections, and in other settings patients preferred injections. Some suggested that part of this variability could be explained by the varying fear of allergic reaction among both patients and health workers. Research evidence: No research evidence Additional considerations: Currently, azithromycin and doxycycline are considered more widely available than benzathine penicillin G.

Acceptability Feasibility

Is the intervention feasible to implement?

• • • • • •

No Probably no Probably yes Yes Varies Don’t know

RECOMMENDATIONS 1 AND 2: ASSESSMENT EARLY SYPHILIS – ADULTS AND ADOLESCENTS

SUMMARY OF JUDGEMENTS Judgement Problem Desirable Effects Undesirable Effects Certainty of evidence Values No Trivial Large Very low Important uncertainty or variability Favours the comparison Probably no Small Moderate Low Possibly important uncertainty or variability Probably favours the comparison Probably yes Moderate Small Moderate Probably no important uncertainty or variability Does not favour either the intervention or the comparison Negligible costs and savings Moderate Yes Large Trivial High No important uncertainty or variability Probably favours the intervention Favours the intervention Varies Varies Varies Varies Don’t know Don’t know Don’t know No included studies No known undesirable outcomes Don’t know

Balance of effects

Resources required Certainty of evidence of required resources Cost– effectiveness

Large costs

Moderate costs Low

Moderate savings High

Large savings

Varies

Don’t know

Very low

No included studies

Favours the comparison

Probably favours the comparison

Does not favour either the intervention or the comparison Probably no impact Probably yes Probably yes

Probably favours the intervention

Favours the intervention

Varies

No included studies

Equity Acceptability Feasibility

Reduced No No

Probably reduced Probably no Probably no

Probably increased Yes Yes

Increased

Varies Varies Varies

Don’t know Don’t know Don’t know

CONCLUSIONS

Treatments for adults with early syphilis Conditional recommendation against the intervention • • • Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention

Type of recommendation

Strong recommendation against the intervention

•

Recommendation

Recommendation 1 In adults and adolescents with early syphilis, the WHO STI guideline recommends benzathine penicillin G 2.4 million units (MU) once intramuscularly over no treatment. Strong recommendation, very low quality evidence

Recommendation 2 In adults and adolescents with early syphilis, the WHO STI guideline suggests using benzathine penicillin G 2.4 MU once intramuscularly over procaine penicillin G 1.2 MU 10–14 days intramuscularly. Conditional recommendation, very low quality evidence

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

When benzathine or procaine penicillin cannot be used (e.g. due to penicillin allergy) or is not available, the WHO STI guideline suggests using doxycycline 100 mg twice daily orally for 14 days or ceftriaxone, 1 g intramuscularly once daily for 10–14 days, or in special circumstances azithromycin 2 g once orally. Conditional recommendation, very low quality evidence

Remarks: Doxycycline is preferred over ceftriaxone due to its lower cost and oral administration. Doxycycline should not be used in pregnant women (see recommendations for pregnant women). Azithromycin is an option in special circumstances only when local susceptibility to azithromycin is likely. If the stage of syphilis is unknown, follow recommendations for people with late syphilis.

Justification

Overall, there was very low quality evidence for outcomes from treatment of early syphilis. Evidence was from seven randomized and 18 nonrandomized studies including one or two groups evaluating benzathine penicillin G, procaine penicillin, ceftriaxone, azithromycin and doxycycline (with or without tetracycline). Although not captured in published studies, most treatments today are based on historical and successful use of benzathine penicillin G and procaine penicillin. Serological cure with benzathine penicillin G 2.4 MU provided once intramuscularly was estimated on average as 840 per 1000 people with early syphilis. When compared to single dose benzathine penicillin G, the evidence suggested little to no difference in serological cures with a double dose of benzathine penicillin G, but fewer cures for a triple dose; similar cure rates with ceftriaxone, azithromycin and doxycycline; and slightly fewer cures with doxycycline and tetracycline together. A systematic review that was updated in the course of preparations for these guidelines (Blank, 2011) suggests that there may be little to no difference in the effects of different medicines in people living with HIV and those not living with HIV. Transmission to partners, HIV transmission and acquisition, and STI complications were not measured.

Few studies provided data for adverse events. Azithromycin may increase gastrointestinal side-effects and dizziness or headache (3–4 times greater than with benzathine penicillin G), but it may reduce rash (65% reduction), fever (50–65% reduction) and serious adverse events (30% reduction). Ceftriaxone may lead to fewer people with diarrhoea and rash, but this evidence is uncertain. Data were not available on resistance to azithromycin for treating syphilis in specific settings, and this will likely remain unknown in many places as the capacity to monitor antimicrobial resistance (AMR) in T. pallidum is not available in many settings. Resistance to azithromycin for other conditions is spreading, and therefore there was concern for the risk of azithromycin resistance to syphilis.

Justification

There was some research evidence for overall acceptability of injections versus oral medicines in people with syphilis, but approximately 10–20% of people refused injections. The GDG noted that in practice, some health-care providers are averse to providing injections, and there are additional staff time and equipment costs with intramuscular administration. The GDG raised concerns about the impending global shortage of benzathine penicillin; a shortage would reduce health equity and it would not be feasible to apply the treatment recommendation.

The GDG judged the benefits of treatment with benzathine penicillin G versus no treatment as large based on the historical successful treatment of syphilis over the past 70 years. It was also judged that the differences in benefits between medicines are likely trivial. There were inconsistent results for greater benefit with higher doses of benzathine penicillin G. The differences in the undesirable anticipated effects (side-effects) were judged as small. Because the benefits probably outweigh the harms, and because of the potential for resistance to azithromycin and greater cost, benzathine penicillin G was suggested. Benzathine penicillin G was also suggested over ceftriaxone and doxycycline due to the unknown side-effects and benefits of the latter two medicines, and the higher costs of ceftriaxone. The GDG also judged the administration benzathine and procaine penicillins by injection as being acceptable to most people.

Subgroup considerations

The recommendation for adults and adolescents with early syphilis applies to people living with HIV, people who are immunocompromised, or people at high risk of transmitting and acquiring STIs. If the stage of syphilis is unknown, follow recommendations for people with late syphilis.

Implementation considerations

Monitoring and evaluation

Resistance to azithromycin should be monitored.

RECOMMENDATIONS 1 AND 2: ASSESSMENT EARLY SYPHILIS – ADULTS AND ADOLESCENTS

Research priorities

Trials investigating appropriate dosages and effectiveness of ceftriaxone use for early and late syphilis should be conducted. The trials should compare ceftriaxone with benzathine penicillin G and doxycycline. More research should also be conducted into medicines that are taken orally for a few days, such as cephalosporins. Since benzathine penicillin G and other penicillins require injection by health workers, it was suggested that the safety of selfinjection be investigated.

EVIDENCE PROFILE

Other treatments compared to benzathine penicillin G 2.4 MU × 1 for treatment of adults and adolescents with early syphilis Ceftriaxone 1 g IM qd × 10–14 days Benzathine penicillin G 2.4 MU × 1 dose Azithromycin 1-2 g × 1 dose Doxycycline 100 mg po bid × 14 days Doxycycline 100 mg po bid × 14 days/tetracycline 500 mg po qid × 14 days RR 0.96 (0.81–1.14) 34 fewer per 1000 (from 118 more to 160 fewer) 1086 participants, 2 non-RCT very low Imprecision1,3 Overall/average risk 948 serological cures per 10006 patients Overall/average risk 840 serological cures per 10002 patients

Outcomes

Benzathine penicillin 2.4 MU × 2 doses

Benzathine penicillin 2.4 MU × 3 doses

Serological cure 8 more per 1000 (from 76 fewer to 92 more) 155 participants, 2 RCTs and 1 nonRCT4 125 participants, 3 non-RCT very low Imprecision1,3 RR 0.96 (0.88–1.05) 38 fewer per 1000 (from 48 more to 115 fewer) 125 participants, 1 non-RCT very low Imprecision1,3 RR 1.00 (0.90 to 1.12) 0 fewer per 1000 (from 55 fewer to 807 more) 34 participants, 1 RCT very low Imprecision1,3 642 participants, 2 RCTs high Not estimable7 very low Imprecision1,3 very low Imprecision1 1742 participants, 3 RCTs and 2 nonRCT 4 0 fewer per 1000 (from 42 fewer to 50 more) 17 more per 1000 (from 8 fewer to 42 more)

RR 1.02 (0.96–1.08)

RR 0.92 (0.65–1.30)

RR 1.01 (0.91–1.11)

RR 1.00 (0.95–1.06)

RR 1.02 (0.99–1.05)

17 more per 1000 (58 fewer to 391 more)

67 fewer per 1000 (from 252 more to 294 fewer)

1654 participants, 3 non-RCT

287 participants, 2 non-RCT

very low Imprecision1

very low Imprecision3

Serological cure HIV-positive adults

RR 1.04 (0.88–1.23)

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

29 more per 1000 (from 86 fewer to 165 more)

1138 participants, 3 non-RCT

very low Inconsistency5 and imprecision1

Clinical cure

Overall risk 1000 clinical cures per 1000 patients

Adverse events

See supplementary table

Transmission to partner

Not measured

Antimicrobial resistance

Not measured

HIV transmission or acquisition

Not measured

STI complications

Not measured

IM: intramuscular; MU: million units; po: by mouth (orally); qd: daily; qid: 4 times daily

1. The 95% CI is inconclusive, suggesting “other treatment” as more effective treatment in one extreme, and benzathine penicillin G × 1 dose in the other extreme.

2. The baseline risk represents the average risk (range 65.4–99.4%) of the control group patients (treated with benzathine penicillin G × 1 dose) through all the different comparisons.

3. The total number of events does not meet the optimal information size (OIS).

4. 50% of studies RCT and 50% non-RCT.

RECOMMENDATIONS 1 AND 2: ASSESSMENT EARLY SYPHILIS – ADULTS AND ADOLESCENTS

5. The point estimates of the included studies suggest different magnitude of effects; I2 > 70%.

6. Baseline risk represents the average risk (range 93.8–94.7%) of the control groups in studies on HIV patients.

7. All patients were clinically cured in both benzathine penicillin G × 1 dose and azithromycin treatment groups.

SUPPLEMENTARY TABLE OF ADVERSE EVENTS

Azithromycin 2 g × 1 dose compared to benzathine penicillin G 2.4 MU × 1 for treatment of adults with early syphilis3 Quality of the evidence (GRADE) Risk with benzathine penicillin G 2.4 MU × 1 LOW 1 2 LOW 1 2 LOW 1 2 1 per 1000 25 per 1000 42 per 1000 98 per 1000 25 per 1000 74 per 1000 LOW 1 2

Outcomes Risk difference with azithromycin 2 g × 1 69 fewer per 1000 (174 fewer to 210 more) 84 more per 1000 (30 fewer to 961 more) 2 more per 1000 (1 fewer to 26 more) 3 more per 1000 (1 fewer to 77 more)

Number of participants (studies)

Relative effect (95% CI)

Anticipated absolute effects

Jarisch–Herxheimer reaction 238 per 1000 48 per 1000 1 per 1000 RR 2.77 (0.36–21.19) RR 3.11 (0.36–26.99) RR 4.48 (0.26–77.65)

74 (1 RCT)

RR 0.71 (0.27–1.88)

Nausea

74 (1 RCT)

Vomiting < 2 h after administration

642 (2 RCT s)

Diarrhoea

74 (1 RCT)

Serious adverse events (excluding deaths) LOW 1 2

568 (1 RCT)

RR 0.72 (0.23–2.24)

7 fewer per 1000 (19 fewer to 30 more)

Cutaneous (rash, fever) LOW 1 2

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

568 (1 RCT) RR 0.50 (0.27–0.94) RR 2.73 (1.17–6.40) RR 3.31 (2.09–5.24)

RR 0.34 (0.11–1.03)

28 fewer per 1000 (37 fewer to 1 more) 49 fewer per 1000 (72 fewer to 6 fewer) 42 more per 1000 (4 more to 133 more) 170 more per 1000 (80 more to 312 more)

Administration-related (pain, fever) LOW 1 2 LOW 1 2 LOW 1 2

568 (1 RCT)

Central nervous system (dizziness, headache)

568 (1 RCT)

Gastrointestinal (diarrhoea, nausea)

568 (1 RCT)

Ceftriaxone 1 g IM or IV × 10–14 days vs benzathine penicillin 4 MU × 1 in adults with early syphilis Quality of the evidence (GRADE) Risk with benzathine penicillin G 2.4 MU × 1 dose RR 1.00 (0.07–14.72) 59 per 1000 59 per 1000 59 per 1000 RR 0.33 (0.01–7.65) 0 fewer per 1000 (55 fewer to 807 more) 39 fewer per 1000 (58 fewer to 391 more) Risk difference with ceftriaxone 1 g IM or IV × 10–14 days Relative effect (95% CI) Anticipated absolute effects

Outcomes

Number of participants (studies)

Jarisch–Herxheimer reaction VERY LOW 1,2 VERY LOW 1,2 VERY LOW 1,2

34 (1 RCT)

Mild transient macular rash RR 0.33 (0.01–7.65)

34 (1 RCT)

Mild diarrhoea

34 (1 RCT)

39 fewer per 1000 (58 fewer to 391 more)

RECOMMENDATIONS 1 AND 2: ASSESSMENT EARLY SYPHILIS – ADULTS AND ADOLESCENTS

95% CI includes potential for fewer or greater “adverse events”

The total number of events does not meet the optimal information size (OIS).

None of the patients treated with benzathine penicillin × 1 had vomiting or diarrhoea events.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

REFERENCES

Systematic reviews 1. Bai ZG, Wang B, Yang K, Tian JH, Ma B, Liu Y, Jiang L, Gai QY, He X, Li Y. Azithromycin versus penicillin G benzathine for early syphilis. Cochrane Database Syst Rev. 2012;(6):CD007270. 2. Blank LJ, Rompalo AM, Erbelding EJ, Zenilman JM, Ghanem KG. Treatment of syphilis in HIV-infected subjects: a systematic review of the literature. Sex Transm Infect. 2011;87:9e16. 3. Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives Saved Tool supplement detection and treatment of syphilis in pregnancy to reduce syphilis related stillbirths and neonatal mortality. BMC Public Health. 2011;11(Suppl 3):S9. 4. Clement ME, Lance NO, Hicks CB. Treatment of syphilis: a systematic review. JAMA. 2014;312(18):1905-17. 5. Galvao TF, Silva MT, Serruya SJ, Newman LM, Klausner JD, Pereira MG, Fescina R. Safety of benzathine penicillin for preventing congenital syphilis: a systematic review. PLoS One. 2013;8(2):e56463. doi:10.1371/journal.pone.0056463. Included studies 1. Agmon-Levin N, Elbirt D, Asher I, Gradestein S, Werner B, Sthoeger Z. Syphilis and HIV co-infection in an Israeli HIV clinic: incidence and outcome. Int J STD AIDS. 2010;21(4):249-52. 2. Dionne-Odom J, Karita E, Kilembe W, Henderson F, Vwalika B, Bayingana R et al. Syphilis treatment response among HIVdiscordant couples in Zambia and Rwanda. Clin Infect Dis. 2013;56(12):1829-37. 3. Fiumara NJ. Treatment of primary and secondary syphilis: serologic response. J Am Acad Dermatol. 1986;14(3):487-91. 4. Ghanem KG, Erbelding EJ, Cheng WW, Rompalo AM. Doxycycline compared with benzathine penicillin for the treatment of early syphilis. Clinical Infect Dis. 2006;42(6):e45-9. doi:10.1086/500406. 5. González-López JJ, Fernández Guerrero ML, Luján R, Fernandez Tostado S, de Górgolas M, Requena L. Factors determining serologic response to treatment in patients with syphilis. Clin Infect Dis. 2009;49(10):1505–11. doi:10.1086/644618. 6. Hook IEW, Martin DH, Stephens J, Smith BS, Smith K. A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis. Sex Transm Dis. 2002;29(8):486-90. 7. Hook IEW, Behets F, Van Damme K, Ravelomanana N, Leone P, Sena AC et al. A Phase III equivalence trial of azithromycin versus benzathine penicillin for treatment of early syphilis. J Infect Dis. 2010;201(11):1729-35. 8. Jinno S, Anker B, Kaur P, Bristow CC, Klausner JD. Predictors of serological failure after treatment in HIV-infected patients with early syphilis in the emerging era of universal antiretroviral therapy use. BMC Infect Dis. 2013;13:605. 9. Katsambas A, Adoniou C, Katsarou A, Kerkidou A, Stratigos J. Comparative study of ceftriaxone and benzathine penicillin G in the treatment of primary and secondary syphilis. Chemioterapia. 1987;6(2 Suppl):549-50. 10. Knaute DF, Graf N, Lautenschlager S, Weber R, Bosshard PP. Serological response to treatment of syphilis according to disease stage and HIV status. Clin Infect Dis. 2012;55(12):161522. doi:10.1093/cid/cis757.

11. Kiddugavu Mg, Kiwanuka N, Wawer MJ, Serwadda D, Sewankambo NK, Wabwire-Mangen F et al.; Rakai Study Group. Effectiveness of syphilis treatment using azithromycin and/ or benzathine penicillin in Rakai, Uganda. Sex Transm Dis. 2005;32(1):1-6. 12. Li J, Zheng HY. Early syphilis: serological treatment response to doxycycline/tetracycline versus benzathine penicillin. J Infect Dev Ctries. 2014;8(2):228-32. doi:10.3855/jidc.3013. 13. Long CM, Klausner JD, Leon S, Jones FR, Giron M, Cuadros J et al. Syphilis treatment and HIV infection in a population-based study of persons at high risk for sexually transmitted disease/ HIV infection in Lima, Peru. Sex Transm Dis. 2006;33(3):151-5. 14. Moorthy TT, Lee CT, Lim KB, Tan T. Ceftriaxone for treatment of primary syphilis in men: a preliminary study. Sex Transm Dis. 1987;14(2):116-8. 15. Petersen CS, Jorgensen BB, Pedersen NS. Treatment of early infectious syphilis in Denmark. A retrospective serological study. Dan Med Bull. 1984;31(1):70-2. 16. Psomas KC, Brun M, Causse A, Atoui N, Reynes J, Le Moing V. Efficacy of ceftriaxone and doxycycline in the treatment of early syphilis. Med Mal Infect. 2012;42(1):15-9. doi:10.1016/j. medmal.2011.10.003. 17. Riedner G, Rusizoka M, Todd J, Maboko L, Hoelscher M, Mmbando D et al. Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N Engl J Med. 2005;353(12):1236-44. 18. Rolfs RT, Joesoef MR, Hendershot EF, Rompalo AM, Augenbraun MH, Chiu M et al. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. N Engl J Med. 1997;337(5):307-14. 19. Sena AC, Wolff M, Martin DH, Behets F, Van Damme K, Leone P, et al. Predictors of serological cure and serofast state after treatment in HIV-negative persons with early syphilis. Clin Infect Dis. 2011;53(11):1092-9. 20. Talwar S, Tutakne MA, Tiwari VD. VDRL titres in early syphilis before and after treatment. Genitourin Med. 1992;68(2):120-2. 21. Tittes J, Aichelburg MC, Antoniewicz L, Geusau A. Enhanced therapy for primary and secondary syphilis: a longitudinal retrospective analysis of cure rates and associated factors. Int J STD AIDS. 2013;24(9):703-11. 22. Tong ML, Lin LR, Liu GL, Zhang HL, Zeng YL, Zheng WH et al. Factors associated with serological cure and the serofast state of HIV-negative patients with primary, secondary, latent, and tertiary syphilis. PLoS One. 2013;8(7):e70102. 23. Wong T, Singh AE, De P. Primary syphilis: serological treatment response to doxycycline/tetracycline versus benzathine penicillin. Am J Med. 2008;121(10):903-8. 24. Yinnon AM, Coury-Doniger P, Polito R, Reichman RC. Serologic response to treatment of syphilis in patients with HIV infection. Arch Int Med. 1996;156(3):321-5. 25. Yang CJ, Lee NY, Chen TC, Lin YH, Liang SH, Lu PL. One dose versus three weekly doses of benzathine penicillin G for patients co-infected with HIV and early syphilis: a multicenter, prospective observational study. PLoS One. 2012;9(10).

RECOMMENDATIONS 1 AND 2: ASSESSMENT EARLY SYPHILIS – ADULTS AND ADOLESCENTS

Patient values and preferences, acceptability and cost: specific to syphilis infections 1. Chauhan M, Serisha B, Sankar KN, Pattman RS, Schmid ML. Audit of the use of benzathine penicillin, post-treatment syphilis serology and partner notification of patients with early infectious syphilis. Int J STD AIDS. 2006;17(3):200-2 2. Crowe G, Theodore C, Forster GE, Goh BT. Acceptability and compliance with daily injections of procaine penicillin in the outpatient treatment of syphilis-treponemal infection. Sex Transm Dis. 1997;24(3):127-30. 3. Kingston MA, Higgins SP. Audit of the management of early syphilis at North Manchester General Hospital. Int J STD AIDS. 2004;15(5):352-4. 4. Owusu-Edusei K, Gift TL, Ballard RC. Cost–effectiveness of a dual non-treponemal/treponemal syphilis point-of-care test to prevent adverse pregnancy outcomes in sub-Saharan Africa (Provisional abstract). Sex Transm Dis. 2011;38:997-1003. 5. Tayal S, Ahmed MS, Hanif U. Audit of early syphilis: Teesside experience 2005–2007. Int J STD AIDS. 2009;20(9):647-9. Penicillin allergy Systematic review 1. Salkind AR, Cuddy PG, Foxworth JW. The rational clinical examination. Is this patient allergic to penicillin? An evidencebased analysis of the likelihood of penicillin allergy. JAMA. 2001;285(19):2498-505. Included studies 1. You might be allergic to penicillin. Then again, you might not. In: ACAAI.org [website]. Arlington Heights (IL): American College of Allergy, Asthma and Immunology (ACAAI); 2014 (http://acaai. org/news/you-might-be-allergic-penicillin-then-again-youmight-not, accessed 30 June 2016). 2. Co Minh HB, Bousquet PJ, Fontaine C, Kvedariene V, Demoly P. Systemic reactions during skin tests with beta-lactams: a risk factor analysis. J Allergy Clin Immunol. 2006;117:466–8. 3. Lockey RF, Benedict LM, Turkeltaub PC, Bukantz SC. Fatalities from immunotherapy (IT) and skin testing (ST). J Allergy Clin Immunol. 1987;79:660–77. 4. Nolan RC, Puy R, Deckert K, O’Hehir RE, Douglass JA. Experience with a new commercial skin testing kit to identify IgE-mediated penicillin allergy. Intern Med J. 2008;38:357–61. 5. Riezzo I, Bello S, Neri M, Turillazzi E, Fineschi V. Ceftriaxone intradermal test-related fatal anaphylactic shock: a medico-legal nightmare. Allergy. 2010;65:130–1. 6. Sogn DD, Evans R 3rd, Shepherd GM, Casale TB, Condemi J, Greenberger PA et al. Results of the National Institute of Allergy and Infectious Diseases Collaborative Clinical Trial to test the predictive value of skin testing with major and minor penicillin derivatives in hospitalized adults. Arch Intern Med. 1992;152(5):1025-32. 7. Van Dellen RG. Skin testing for penicillin allergy. J Allergy Clin Immunol. 1981;68:169-70.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

RECOMMENDATIONS 3 AND 4: EARLY SYPHILIS – PREGNANT WOMEN Treatments for pregnant women with early syphilis (primary, secondary or early latent syphilis of not more than 2 years’ duration) Population: Intervention: Comparison: Main outcomes: Pregnant with early syphilis Ceftriaxone, azithromycin, erythromycin Benzathine penicillin G 2.4 MU × 1 Critical: mother-to-child transmission, serological response, low birth weight/preterm, stillbirth/ neonatal death, clinical cure, congenital deformities, side-effects (including allergy, toxicity) Important: compliance, antimicrobial resistance, STI complications, transmission to partner, HIV transmission or acquisition Setting: Perspective: Background: All settings Population level Syphilis is a systemic disease from the outset and is caused by the spirochaete Treponema pallidum. The infection can be classified as congenital (transmitted from mother to child in utero) or acquired (through sex or blood transfusion). Acquired syphilis is divided into early and late syphilis. Early syphilis comprises the primary, secondary and early latent stages. Late syphilis refers to late latent syphilis, gummatous, neurological and cardiovascular syphilis. Primary syphilis is characterized by an ulcer or chancre at the site of infection or inoculation. Secondary syphilis manifestations include a skin rash, condylomata lata, mucocutaneous lesions and generalized lymphadenopathy. The 2003 WHO STI guidelines recommended treatment of early syphilis in adults is benzathine benzyl penicillin, 2.4 MU by intramuscular injection, at a single session. Because of the volume involved, this dose is usually given as two injections at separate sites. An alternative regimen for penicillin-allergic pregnant patients is erythromycin, 500 mg orally, four times daily for 14 days.

RECOMMENDATIONS 3 AND 4: EARLY SYPHILIS – PREGNANT WOMEN

ASSESSMENT Judgement Is the problem a priority? Problem Desirable Effects Undesirable Effects Certainty of evidence Research evidence Research evidence: WHO estimates that 5.6 million new cases of syphilis occurred among adolescents and adults aged 15–49 years worldwide in 2012 and there are an estimated 18 million prevalent cases of syphilis. Mother-to-child transmission of syphilis is declining globally due to increased efforts to screen and treat pregnant women for syphilis. However, the burden of morbidity and mortality due to congenital syphilis remains high. In 2012, there were an estimated 350 000 adverse pregnancy outcomes worldwide attributed to syphilis, including 143 000 early fetal deaths/stillbirths, 62 000 neonatal deaths, 44 000 preterm/low weight births, and 102 000 infected infants. Additional considerations: None How substantial are the desirable anticipated effects? Research evidence: We found 10 non-randomized studies including pregnant women with early and/or late syphilis, and with or without allergy to penicillin. The data suggested that a single dose of penicillin was better than a triple dose for achieving serological cure, but the evidence is uncertain. Mother-to-child transmission was greater with two doses than one dose of benzathine penicillin G, although this again was uncertain. Evidence was also used from adults and adolescents to inform judgements about the benefits of treatments. The benefits were large for benzathine penicillin compared to no treatment, but differences between medicines for benefits and harms were trivial. Additional considerations: In the studies it was often unclear if pregnant women had early or late syphilis. The GDG reported that this is common in practice. The GDG decided that there should be a recommendation in pregnancy generally (similar recommendations for early or late), and also a recommendation if early syphilis was suspected. The GDG noted that azithromycin is also ineffective for reducing mother-to-child transmission as it does not cross the placental barrier. Procaine penicillin crosses the placental barrier (and additionally the blood–brain barrier, thus treating neurosyphilis); it was proposed that should be the second-line treatment in pregnant women, not azithromycin. Research evidence: No research evidence was identified. Additional considerations: None

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

• • • •

Trivial Small Moderate Large

• Varies • Don’t know How substantial are the undesirable anticipated effects?

• • • •

Large Moderate Small Trivial

• Varies • Don’t know

What is the overall certainty of the evidence of effects?

• • • •

Very low Low Moderate High

• No included studies

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Is there important uncertainty about or variability in how much people value the main outcomes?

Research evidence: According to economic evaluation studies, the disability weights due to syphilis (utility loss due to the disease) are as follows: early syphilis: 0.0072–0.015 secondary syphilis: 0.041 tertiary (neurological): 0.094–0.283 death: 1 For neonatal, the disutilities are as follows: congenital syphilis: 0.315 low birth weight: 0.106 neonatal death: 1 stillbirth: 1 miscarriage: 1 Additional considerations: None

Values Balance of effects Resources required Certainty of evidence of required resources

• Important uncertainty or variability

• Possibly important uncertainty or variability

• Probably no important uncertainty or variability

• No important uncertainty or variability

• No known undesirable outcomes

Does the balance between desirable and undesirable effects favour the intervention or the comparison?

• Favours the comparison • Probably favours the comparison

Research evidence: The benefits of benzathine penicillin and procaine penicillin were large and outweighed undesirable effects. When comparing these medicines (Ceftriaxone, azithromycin and erythromycin to benzathine penicillin and procaine penicillin (in pregnant women and non-pregnant adults) by the desirable and undesirable effects, these medicines were not favoured over others. Additional considerations: None

• Does not favour either the intervention or the comparison • Probably favours the intervention • Favours the intervention

• Varies • Don’t know How large are the resource requirements (costs)? Research evidence: No research evidence. Benzathine penicillin G requires local preparation, making cost heavily dependent on local labour costs. Benzathine penicillin G without preparation costs $0.28 per dose. For three doses, $3.72 was the average price. Azithromycin cost $1.56. Ceftriaxone has greater costs (data not available). Additional considerations: None Research evidence: No research evidence was identified. Additional considerations: None

• • • • •

Large costs Moderate costs Negligible costs and savings Moderate savings Large savings

• Varies • Don’t know

What is the certainty of the evidence of resource requirements (costs)?

• • • •

Very low Low Moderate High

• No included studies

RECOMMENDATIONS 3 AND 4: EARLY SYPHILIS – PREGNANT WOMEN

Does the cost-effectiveness of the intervention favour the intervention or the comparison?

Research evidence: Cost–effectiveness studies assessed costs of screening and treatment, and data could not be separated for treatment. Most comments in published literature addressed the usefulness of screening only if treatment is provided. Additional considerations: The GDG indicated that treatment versus no treatment was favoured. The benefits are similar between the different medicines, but costs are probably higher with ceftriaxone and azithromycin compared to benzathine penicillin.

Cost–effectiveness Equity Acceptability Feasibility

• Favours the comparison • Probably favours the comparison

• Does not favour either • • • • the intervention or the comparison Probably favours the intervention Favours the intervention Varies No included studies

What would be the impact on health equity?

Research evidence: No research evidence. Additional considerations: The GDG considered that health equity could be reduced if benzathine penicillin is not available, but other medicines should be included in the recommendations.

• • • • • • •

Reduced Probably reduced Probably no impact Probably increased Increased Varies Don’t know

Is the intervention acceptable to key stakeholders?

• • • • • •

No Probably no Probably yes Yes Varies Don’t know

Research evidence: We found four studies that addressed acceptability of injections (daily or weekly) versus oral medicines in people with various stages of syphilis. Studies were from 1997 to 2006 and indicated that ~80% or more people accepted injections, but weekly injections were preferred. The others refused injections and took oral medicines. Additional considerations: The GDG reported that in practice there seemed to be variation in acceptability to key stakeholders. In different countries, health workers were averse to giving injections for this infection, and in others they wanted to give the injections (instead of giving oral treatment). Regarding acceptability to patients, some were averse to injections, and in other settings patients preferred injections. Some suggested that part of this variability could be explained by the varying fear of allergic reaction among both patients and health workers. Research evidence: No research evidence. Additional considerations: Currently azithromycin and doxycycline are considered more widely available than benzathine penicillin G.

Is the intervention feasible to implement?

• • • • • •

No Probably no Probably yes Yes Varies Don’t know

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Balance of effects

Resources required Certainty of evidence of required resources Cost– effectiveness

Large costs

Moderate costs Low

Moderate savings High

Large savings

Varies

Don’t know

Very low

No included studies

Favours the comparison

Probably favours the comparison

Does not favour either the intervention or the comparison Probably no impact Probably yes Probably yes

Probably favours the intervention

Favours the intervention

Varies

No included studies

Equity Acceptability Feasibility

Reduced No No

Probably reduced Probably no Probably no

Probably increased Yes Yes

Increased

Varies Varies Varies

Don’t know Don’t know Don’t know

CONCLUSIONS

Treatments for pregnant women with early syphilis Conditional recommendation against the intervention • • Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention

Type of recommendation

Strong recommendation against the intervention

•

• •

Recommendation

Recommendation 3 In pregnant women with early syphilis, the WHO STI guideline recommends benzathine penicillin G 2.4 MU once intramuscularly over no treatment. Strong recommendation, very low quality evidence

Recommendation 4 In pregnant women with early syphilis, the WHO STI guideline suggests using benzathine penicillin G 2.4 MU once intramuscularly over procaine penicillin 1.2 MU intramuscularly once a day for 10 days. Conditional recommendation, very low quality evidence

When benzathine or procaine penicillin cannot be used (e.g. due to penicillin allergy where penicillin desensitization is not possible) or is not available (e.g. due to stock-outs), the WHO STI guideline suggests using, with caution, erythromycin 500 mg orally four times daily for 14 days, or ceftriaxone 1 g intramuscularly once daily for 10–14 days, or azithromycin 2 g once orally. Conditional recommendation, very low quality evidence

Remarks: Although erythromycin and azithromycin treat pregnant women, they do not cross the placental barrier completely and as a result the fetus is not treated. It is therefore necessary to treat the newborn infant soon after delivery (see recommendations for congenital syphilis). Ceftriaxone is an expensive option and is injectable. Doxycycline should not be used in pregnant women. Because syphilis during pregnancy can lead to severe adverse complications to the fetus or newborn, stock-outs of benzathine penicillin for use in antenatal care should be avoided.

Justification

The overall quality of the evidence for treatments used for pregnant women was very low. There were few studies (10 non-randomized studies) and very few pregnant women were included in the studies. In most studies, the stage of syphilis (early or late) was unknown. The evidence in adults and adolescents was used to inform judgements about the benefits of different medicines. Similar to that evidence, the benefits were large for the use of benzathine penicillin compared to no treatment, and based on successful historical use of benzathine and procaine penicillins, and erythromycin. The differences in medicines for benefits and harms were trivial. Prevention of mother-to-child transmission was a critical outcome. The penicillins cross the placental barrier; however, azithromycin and erythromycin do not. Therefore there is an increased chance of transmission with the use of these latter medicines.

RECOMMENDATIONS 3 AND 4: EARLY SYPHILIS – PREGNANT WOMEN

There was no evidence for adverse effects, transmission to partner, antimicrobial resistance, HIV transmission or acquisition, or STI complications. Research evidence for the other factors (acceptability, feasibility, equity and costs) was not specific to pregnant women. Therefore evidence for nonpregnant adults was used to inform this recommendation.

Overall, the recommendations for non-pregnant women with early syphilis were used to inform the recommendations for pregnant women with early syphilis, with the exception of the use of doxycycline, which cannot be used in pregnant women. Erythromycin was added as an alternative based on successful historical use.

Type of recommendation

Strong recommendation against the intervention

Conditional recommendation against the intervention • •

Conditional recommendation for either the intervention or the comparison

Conditional recommendation for the intervention

Strong recommendation for the intervention

•

• •

Subgroup considerations

Implementation considerations

Monitoring and evaluation

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Research priorities

The GDG discussed the possibility of developing a new treatment. An oral therapy is needed that can treat syphilis in pregnant women, cross the blood– brain and placental barriers, and involve only a short course of therapy. Cephalosporins could be potential options. Trials investigating appropriate dosages and effectiveness of ceftriaxone use for early and late syphilis should be established. The trials should compare ceftriaxone with benzathine penicillin G. The extent to which the medicines cross the blood–brain and placental barriers should also be investigated.

EVIDENCE PROFILE

Other treatments compared to benzathine penicillin G 2.4 MU × 1 dose for treatment of pregnant women with early syphilis Benzathine penicillin 2.4 MU × 3 doses 810 people per 1000 (0.7– 0.87) 197 participants, 1 non-RCT (one arm) very low Risk of bias1 890 people per 1000 (0.86–0.87) 383 participants, 2 non-RCT (one arm) very low Risk of bias1, inconsistency2 970 people per 1000 (0.95–1.00) 204 participants, one-arm observational study low Risk of bias1 and strong association OR 0.72 (0.28–1.82) 16 fewer per 1000 (43 fewer to 44 more) 507 participants, 2 non-RCT very low Imprecision3 OR 0.19 (0.62–2.31) 11 more per 1000 (22 fewer to 69 more) 593 participants, 2 observational studies very low Imprecision3 Overall risk 60 stillbirth/neonatal death per 1000 patients 1000 people per 1000 (0.99–1.01) 204 participants, one-arm observational study low Risk of bias1 and strong association No treatment Benzathine penicillin G 2.4 MU × 1 dose

Outcomes (IMPORTANCE)

Benzathine penicillin 2.4 MU × 2 doses

Serological cure CRITICAL)

Compliance (IMPORTANT)

Prevention of mother-to-child transmission (CRITICAL)

1000 people per 1000 (0.99–1.01)

250 participants, 2 non-RCT (one arm) very low Risk of bias1 and strong association

Stillbirth/neonatal death (CRITICAL)

OR 0.42 (0.20–0.80)

34 fewer per 1000 (7 fewer to 48 fewer)

RECOMMENDATIONS 3 AND 4: EARLY SYPHILIS – PREGNANT WOMEN

785 participants, 2 non-RCT very low Imprecision3

Other treatments compared to benzathine penicillin G 2.4 MU × 1 dose for treatment of pregnant women with early syphilis Benzathine penicillin 2.4 MU × 3 doses OR 0.13 (0.04–0.42) 335 fewer per 1000 (187 fewer to 393 more) 101 participants, 1 non-RCT very low Imprecision3 74 participants, 1 non-RCT very low Imprecision3 74 fewer per 1000 (184 more to 267 fewer) 421 preterm delivery/low birth weight per 1000 patients OR 0.73 (0.25–2.11) Overall risk No treatment Benzathine penicillin G 2.4 MU × 1 dose

Outcomes (IMPORTANCE)

Benzathine penicillin 2.4 MU × 2 doses

Preterm delivery/low birth weight (CRITICAL)

OR 0.13 (0.02–0.69)

335 fewer per 1000 (87 fewer to 407 fewer)

63 participants, 1 non-RCT very low Imprecision3

Clinical cure

Not measured

Adverse events

Not measured

Transmission to partner

Not measured

Antimicrobial resistance

Not measured

HIV transmission or acquisition

Not measured

STI complications

Not measured

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

MU: million units; OR: odds ratio; RCT: randomized controlled trial

1. One-arm study; authors did not mention any information related to the use of an appropriate analysis method that adjusted for all the critically important confounding domains.

2. Small sample size, the total number of events does not meet the optimal information size (OIS) and/or the 95% confidence interval is inconclusive.

RECOMMENDATIONS 3 AND 4: EARLY SYPHILIS – PREGNANT WOMEN

REFERENCES

Systematic review 1. Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives Saved Tool supplement detection and treatment of syphilis in pregnancy to reduce syphilis related stillbirths and neonatal mortality. BMC Public Health. 2011;11(Suppl 3):S9. Included studies 2. Alexander JM, Sheffield JS, Sanchez PJ, Mayfield J, Wendel Jr GD. Efficacy of treatment for syphilis in pregnancy. Obstet Gynecol. 1999;93(1):5-8. 3. Chang SN, Chung KY, Lee MG, Lee JB. Seroreversion of the serological tests for syphilis in the newborns born to treated syphilitic mothers. Genitourin Med. 1995;71(2):68-70. 4. Donders GGG, Desmyter J, Hooft P, Dewet GH. Apparent failure of one injection of benzathine penicillin G for syphilis during pregnancy in human immunodeficiency virus-seronegative African women. Sex Transm Dis. 1997;24(2):94-101. 5. Klein VR, Cox SM, Mitchell MD, Wendel GD Jr. The JarischHerxheimer reaction complicating syphilotherapy in pregnancy. Obstet Gynecol. 1990;75(3 Pt I):375-80. 6. Lu J, Huang C, Zeng Y. Syphilis in pregnancy women. Zhonghua fu chan ke za zhi 2001;36(8):456-9 (in Chinese). 7. Mullick S, Beksinksa M, Msomi S. Treatment for syphilis in antenatal care: compliance with the three dose standard treatment regimen. Sex Transm Infect. 2005;81(3):220-2. 8. Myer L, Karim SSA, Lombard C, Wilkinson D. Treatment of maternal syphilis in rural South Africa: effect of multiple doses of benzathine penicillin on pregnancy loss. Trop Med Int Health. 2004;9(11):1216-21. 9. Myles TD, Elam G, Park-Hwang E, Nguyen T. The JarischHerxheimer reaction and fetal monitoring changes in pregnant women. Obstet Gynecol. 1998;92(5):859-64. 10. Phaosavasdi S, Snidvongs W, Thasanapradit P, Ungthavorn P, Bhongsvej S, Jongpiputvanich S et al. Effectiveness of benzathine penicillin regimen in the treatment of syphilis in pregnancy. J Med Assoc Thai. 1989;72(2):101-8. 11. Watson-Jones D, Gumodoka B, Weiss H, Changalucha J, Todd J, Mugeye K et al. Syphilis in pregnancy in Tanzania. II. The effectiveness of antenatal syphilis screening and single-dose benzathine penicillin treatment for the prevention of adverse pregnancy outcomes. J Infect Dis. 2002;186(7):948-57. 12. Wendel GD Jr., Stark BJ, Jamison RB, Molina RD, Sullivan TJ. Penicillin allergy and desensitization in serious infections during pregnancy. N Engl J Med. 1985;312(19):1229-32. 13. Zhang XM, Zhang RN, Lin SQ, Chen SX, Zheng LY. Clinical analysis of 192 pregnant women infected by syphilis. Zhonghua fu chan ke za zhi. 2004;39(10):682-6. 14. Zhou P, Gu Z, Xu J, Wang X, Liao K. A study evaluating ceftriaxone as a treatment agent for primary and secondary syphilis in pregnancy. Sex Transm Dis. 2005;32(8):495-8.

Patient values and preferences, acceptability and cost: Specific to syphilis infections 1. Chauhan M, Serisha B, Sankar KN, Pattman RS, Schmid ML. Audit of the use of benzathine penicillin, post-treatment syphilis serology and partner notification of patients with early infectious syphilis. Int J STD AIDS. 2006;17(3):200-2. 2. Crowe G, Theodore C, Forster GE, Goh BT. Acceptability and compliance with daily injections of procaine penicillin in the outpatient treatment of syphilis-treponemal infection. Sex Transm Dis. 1997;24(3):127-30. 3. Kingston MA, Higgins SP. Audit of the management of early syphilis at North Manchester General Hospital. Int J STD AIDS. 2004;15(5):352-4. 4. Owusu-Edusei K, Gift TL, Ballard RC. Cost-effectiveness of a dual non-treponemal/treponemal syphilis point-of-care test to prevent adverse pregnancy outcomes in sub-Saharan Africa (Provisional abstract). Sex Transm Dis. 2011;38:997-1003. 5. Tayal S, Ahmed MS, Hanif U. Audit of early syphilis: Teesside experience 2005–2007. Int J STD and AIDS. 2009;20(9):647-9.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

RECOMMENDATIONS 5, 6, 7 AND 8: LATE SYPHILIS – ADULTS, ADOLESCENTS AND PREGNANT WOMEN

Treatments for adults and adolescents, and pregnant women with late syphilis (infection of more than 2 years’ duration without evidence of treponemal infection) Population: Intervention: Comparison: Main outcomes: Adults and adolescents, and pregnant women with late syphilis Azithromycin, ceftriaxone, doxycycline, erythromycin Benzathine penicillin G 2.4 MU × 1 Critical: Serological response, compliance Important: Transmission to partner, antimicrobial resistance, side-effects (including allergy, toxicity), HIV transmission or acquisition, STI complications Setting: Perspective: Background: All settings Population Syphilis is a systemic disease from the outset and is caused by the spirochaete Treponema pallidum. The infection can be classified as congenital (transmitted from mother to child in utero) or acquired (through sex or blood transfusion). Acquired syphilis is divided into early and late syphilis. Early syphilis comprises the primary, secondary and early latent stages. Late syphilis refers to late latent syphilis, gummatous, neurological and cardiovascular syphilis. Primary syphilis is characterized by an ulcer or chancre at the site of infection or inoculation. Secondary syphilis manifestations include a skin rash, condylomata lata, mucocutaneous lesions and generalized lymphadenopathy. The 2003 WHO STI guidelines recommended treatment of late syphilis in adults was benzathine penicillin G 2.4 MU by intramuscular injection, once weekly for 3 consecutive weeks. An alternative regimen is procaine penicillin 1.2 MU by intramuscular injection, once daily for 20 consecutive days. Alternative regimen for penicillin-allergic non-pregnant patients is doxycycline 100 mg orally twice daily for 30 days, or tetracycline 500 mg orally four times daily for 30 days.

RECOMMENDATIONS 5, 6, 7 AND 8: LATE SYPHILIS – ADULTS, ADOLESCENTS AND PREGNANT WOMEN

ASSESSMENT

Judgement Is the problem a priority? Problem Desirable Effects Undesirable Effects Certainty of evidence

Research evidence Research evidence: WHO estimates that 5.6 million new cases of syphilis occurred among adolescents and adults aged 15–49 years worldwide in 2012 with a global incidence rate of 1.5 cases per 1000 females (regional range: 0.9–4.4) and 1.5 per 1000 males (regional range: 0.9–4.4). The estimated 18 million prevalent cases of syphilis in 2012 translates to a global prevalence of 0.5% (0.4–0.6%) among females and 0.5% (0.3–0.7%) among males aged 15–49 years, with the highest prevalence in the African region. Mother-to-child transmission of syphilis is declining globally due to increased efforts to screen and treat pregnant women for syphilis. However, the burden of morbidity and mortality due to congenital syphilis remains high. In 2012 there were an estimated 350 000 adverse pregnancy outcomes worldwide attributed to syphilis, including 143 000 early fetal deaths/stillbirths, 62 000 neonatal deaths, 44 000 preterm/low weight births, and 102 000 infected infants. The burden of disease is highest in low- and middle-income countries, particularly in the African region. Untreated, up to one-third of patients progress to later stages of disease. Late syphilis can cause irreversible damage to the cardiovascular and central nervous systems, resulting in profound morbidity and even death. Additional considerations: None

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

How substantial are the desirable anticipated effects?

• • • •

Trivial Small Moderate Large

Research evidence: Two non-randomized studies were found which assessed treatment for late syphilis: one comparative study in adults (non-pregnant) and one single-arm (non-comparative) study in pregnant women. In non-pregnant adults, benzathine penicillin G 2.4 MU given once intramuscularly and azithromycin 2 g given once were evaluated. The study in pregnant women evaluated benzathine penicillin G 2.4 MU given once a week intramuscularly for 2 weeks. Serological cure rates were low in non-pregnant adults for both medicines (33–39%), but higher for the double dose in pregnant women (99%). Additional considerations: The GDG noted that there are few studies conducted in people with late syphilis and most treatment is based on historical use of benzathine penicillin G and procaine penicillin, and in addition, some use of doxycycline at higher and longer doses than treatments for early syphilis. Data were not available for resistance to azithromycin for syphilis in specific settings and will probably be unknown in many places. Resistance to azithromycin for other conditions is spreading, and therefore there was concern for the risk of azithromycin resistance to syphilis. Research evidence: No research evidence was identified. Additional considerations: None

• Varies • Don’t know How substantial are the undesirable anticipated effects?

• • • •

Large Moderate Small Trivial

• Varies • Don’t know What is the overall certainty of the evidence of effects?

• • • • •

Very low Low Moderate High No included studies

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Is there important uncertainty about or variability in how much people value the main outcomes?

• Important uncertainty or variability

• Possibly important uncertainty or variability

Research evidence: According to economic evaluation studies, the disability weights due to syphilis (utility loss due to the disease) are as follows: early syphilis: 0.0072–0.015 secondary syphilis: 0.041 tertiary (neurological): 0.094–0.283 death: 1 Additional considerations: The GDG noted that there may be variability in outcome values depending on stages of syphilis.

Values Balance of effects Resources required Certainty of evidence of required resources

• Probably no important uncertainty or variability

• No important uncertainty or variability

• No known undesirable outcomes Does the balance between desirable and undesirable effects favour the intervention or the comparison? Research evidence: No research evidence. Additional considerations: The GDG agreed that the benefits with penicillins seen historically are large and favour their use. These benefits are similar for pregnant women. However, although there are limited historical data for doxycycline and erythromycin (for pregnant women), the benefits probably favour the use of these medicines.

• F avours the comparison • Probably favours the comparison

• Does not favour either the intervention or the comparison • Probably favours the intervention • Favours the intervention

• Varies • Don’t know How large are the resource requirements (costs)? Research evidence: Benzathine penicillin G requires local preparation, making cost heavily dependent on local labour costs. Benzathine penicillin G without preparation costs $0.28 per dose. For three doses, $3.72 was the average price. Azithromycin cost $1.56. Ceftriaxone has greater costs (data not available). Additional considerations: None Research evidence: No research evidence was identified. Additional considerations: None

• • • • •

Large costs Moderate costs Negligible costs and savings Moderate savings Large savings

• Varies • Don’t know What is the certainty of the evidence of resource requirements (costs)?

• • • •

Very low Low Moderate High

• No included studies

RECOMMENDATIONS 5, 6, 7 AND 8: LATE SYPHILIS – ADULTS, ADOLESCENTS AND PREGNANT WOMEN

Does the cost-effectiveness of the intervention favour the intervention or the comparison?

Cost–effectiveness Equity Acceptability Feasibility

• Favours the comparison • Probably favours the comparison

• Does not favour either the intervention or the comparison • Probably favours the intervention • Favours the intervention

• Varies • No included studies What would be the impact on health equity? Research evidence: No research evidence. Additional considerations: The GDG considered that health equity could be reduced if benzathine penicillin is not available, but other medicines should be included in the recommendations.

• • • • •

Reduced Probably reduced Probably no impact Probably increased Increased

• Varies • Don’t know Is the intervention acceptable to key stakeholders? Research evidence: We found four studies that addressed the acceptability of injections (daily versus weekly) versus oral treatments in people with various stages of syphilis. Studies were from 1997 to 2006. Results indicated that approximately 80% or more of people accepted injections, but that weekly injections were preferred. The other people had refused injections and took oral medicines. Additional considerations: The GDG reported that in practice, there seemed to be variation in acceptability to key stakeholders. In different countries, health workers were averse to giving injections for this infection, and in others they wanted to give the injections (instead of giving oral treatment). Regarding acceptability to patients, some were averse to injections, and in other settings patients preferred injections. Some suggested that part of this variability could be explained by the varying fear of allergic reaction among both patients and health workers. Research evidence: No research evidence. Additional considerations: Currently, azithromycin and doxycycline are considered more widely available than benzathine penicillin G.

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

Is the intervention feasible to implement?

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Balance of effects

Resources required Certainty of evidence of required resources Cost– effectiveness

Large costs

Moderate costs Low

Moderate savings High

Large savings

Varies

Don’t know

Very low

No included studies

Favours the comparison

Probably favours the comparison

Does not favour either the intervention or the comparison Probably no impact Probably yes Probably yes

Probably favours the intervention

Favours the intervention

Varies

No included studies

Equity Acceptability Feasibility

Reduced No No

Probably reduced Probably no Probably no

Probably increased Yes Yes

Increased

Varies Varies Varies

Don’t know Don’t know Don’t know

CONCLUSIONS

Treatments for adults and adolescents, and pregnant women with late syphilis Conditional recommendation against the intervention • • • Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention

Type of recommendation

Strong recommendation against the intervention

•

Recommendation

Adults and adolescents

Recommendation 5

In adults and adolescents with late syphilis or unknown stage of syphilis, the WHO STI guideline recommends benzathine penicillin G 2.4 MU intramuscularly once weekly for three consecutive weeks over no treatment. Strong recommendation, very low quality evidence

Remarks: The interval between consecutive doses of benzathine penicillin should not exceed 14 days.

Recommendation 6 In adults and adolescents with late syphilis or unknown stage of syphilis, the WHO STI guideline suggests benzathine penicillin G 2.4 MU intramuscularly once weekly for three consecutive weeks over procaine penicillin 1.2 MU once a day for 20 days. Conditional recommendation, very low quality evidence

When benzathine or procaine penicillin cannot be used (e.g. due to penicillin allergy where penicillin desensitization is not possible) or are not available (due to stock-outs), the WHO STI guideline suggests using doxycycline 100 mg twice daily orally for 30 days. Conditional recommendation, very low quality evidence

Remarks: Doxycycline should not be used in pregnant women (see recommendation for pregnant women).

Pregnant women

Recommendation 7 In pregnant women with late syphilis or unknown stage of syphilis, the WHO STI guideline recommends benzathine penicillin G 2.4 MU intramuscularly once weekly for three consecutive weeks over no treatment. Strong recommendation, very low quality evidence

RECOMMENDATIONS 5, 6, 7 AND 8: LATE SYPHILIS – ADULTS, ADOLESCENTS AND PREGNANT WOMEN

Remarks: The interval between consecutive doses of benzathine penicillin should not exceed 14 days.

Type of recommendation

Strong recommendation against the intervention

Conditional recommendation against the intervention • •

Conditional recommendation for either the intervention or the comparison

Conditional recommendation for the intervention

Strong recommendation for the intervention

•

• •

Recommendation

Recommendation 8 In pregnant women with late syphilis or unknown stage of syphilis, the WHO STI guideline suggests benzathine penicillin G 2.4 MU intramuscularly once weekly for three consecutive weeks over procaine penicillin 1.2 MU intramuscularly once a day for 20 days. Conditional recommendation, very low quality evidence

When benzathine or procaine penicillin cannot be used (e.g. due to penicillin allergy where penicillin desensitization is not possible) or are not available (due to stock-outs), the WHO STI guideline suggests using erythromycin 500 mg orally four times daily for 30 days. Conditional recommendation, very low quality evidence

Remarks: Although erythromycin treats the pregnant women, it does not cross the placental barrier completely and as a result the fetus is not treated. It is therefore necessary to treat the newborn infant soon after delivery (see recommendations for congenital syphilis). Doxycycline should not be used in pregnant women. Erythromycin treats the mother but is not known to be effective for preventing mother-to-child transmission of syphilis. Because syphilis during pregnancy can lead to severe adverse complications to the fetus or newborn, stock-outs of benzathine penicillin for use in antenatal care should be avoided.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Justification

Overall, the quality of the evidence was very low. Most studies typically report results for people with late or early syphilis and do not distinguish between the stage of syphilis in the results. However, one study included over 300 people identified with late syphilis. It evaluated benzathine penicillin G 2.4 MU given once intramuscularly and azithromycin 2 g given once. Serological cure was low with these doses, which are typically provided for early syphilis (33–39%). One study was also found for treatment for pregnant women with late syphilis. This study found a cure rate of 99% in 135 women with the double dose of benzathine penicillin G. Historically, multiple doses of benzathine penicillin G provided once a week for 3 weeks and procaine penicillin 1.2 MU provided once daily for 20 days, have been successful for serological and clinical cure of syphilis. For pregnant women, prevention of mother-tochild transmission is a critical outcome. The penicillins cross the placental barrier; however, azithromycin and erythromycin do not. Therefore there is an increased chance of transmission with the use of the latter medicines.

There is some historical use of doxycycline 100 mg twice daily for 30 days with success (but not in pregnant women). There were no data for adverse events, transmission to partners, HIV transmission and acquisition, and STI complications. There are no reported data available on resistance to azithromycin for treating syphilis in specific settings, and this will likely remain unknown in many places as the capacity to monitor antimicrobial resistance (AMR) in T. pallidum is not available in many settings. Resistance to azithromycin for other conditions is spreading, and therefore the GDG was concerned about the risk of azithromycin resistance in T. pallidum.

Evidence used for making recommendations in early syphilis was used to inform this recommendation for late syphilis. There was some research evidence for overall acceptability of injections versus oral medicines in people with syphilis, but approximately 10–20% of people refused injections. The GDG noted that in practice, some health-care providers are averse to providing injections, and there is additional staff time and equipment costs with intramuscular administration. The GDG raised concern about the impending global shortage of benzathine penicillin; a shortage would reduce health equity and it would not be feasible to apply the treatment recommendation.

Justification

The GDG judged the benefits of treatment with benzathine penicillin G versus no treatment as large, based on the historically successful treatment of syphilis over the past 70 years. It was also judged that the differences in benefits between medicines used for treatment are likely to be trivial. The differences in the undesirable anticipated effects (side-effects) were judged to be small. Because the benefits probably outweigh the harms, and because of the potential for resistance to azithromycin, greater cost and lack of historical data for azithromycin, benzathine penicillin G and procaine penicillin were suggested. The penicillins were suggested over doxycycline due to the lack of historical data in late syphilis and unknown side-effects and benefits of doxycycline. For pregnant women, the penicillins were also suggested over erythromycin since erythromycin does not cross the placental barrier. The GDG also judged administration of benzathine and procaine penicillins by injection as being acceptable to most people.

Subgroup considerations

Implementation considerations

Monitoring and evaluation

RECOMMENDATIONS 5, 6, 7 AND 8: LATE SYPHILIS – ADULTS, ADOLESCENTS AND PREGNANT WOMEN

Research priorities

More clinical research is needed into the treatment of adults and HIV-positive patients with late syphilis with benzathine penicillin G (including different dosing regimens) and other treatments such as doxycycline and azithromycin.

EVIDENCE PROFILE

Benzathine penicillin G 2.4 MU weekly × 3 or azithromycin 2 grams for treatment of adults and adolescents, including HIV-positive patients, with late syphilis Number of patients Indirectness Imprecision Other considerations Azithromycin 2 g × 1 dose Benzathine penicillin G 2.4 MU ×1 Relative (95% CI) Absolute (95% CI) Effect with azithromycin Quality of evidence (GRADE) Importance

Quality assessment

Number of studies

Study design

Risk of bias

Inconsistency

Serological cure Serious1 Serious2 None 55/165 (33.3%) 66/168 (39.3%) OR 0.77 (0.49– 1.21) 60 fewer per 1000 (from 46 more to 152 fewer) CRITICAL VERY LOW1

Observational studies

Not serious

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

CI: confidence interval; MU: million units; OR: odds ratio

The data compare benzathine penicillin G given once, not three times.

2. The 95% CI is inconclusive, suggesting azithromycin as more effective treatment in one extreme, and benzathine penicillin G × 1 dose in the other extreme.

RECOMMENDATIONS 5, 6, 7 AND 8: LATE SYPHILIS – ADULTS, ADOLESCENTS AND PREGNANT WOMEN

EVIDENCE PROFILE Benzathine penicillin G 2.4 MU × 3 for treatment of pregnant women with late syphilis Effects and quality of the evidence Outcomes (IMPORTANCE) Serological cure (CRITICAL) Benzathine penicillin 2.4 MU × 2 doses 990 people per 1000 (970 to 1010) 135 participants, 1 non-RCT Very low Risk of bias and indirectness1 Prevention of mother-to-child transmission (CRITICAL) 1000 people per 1000 (1 to 1) 136 participants, 1 non-RCT Very low Risk of Bias and indirectness1 Stillbirth/neonatal death (CRITICAL) 1 people per 1000 (–0.0137 to 0.0157) 136 participants, 1 non-RCT Very low Risk of bias and indirectness1 Clinical cure Compliance Adverse events Transmission to partner Antimicrobial resistance HIV transmission or acquisition STI complications Not measured Not measured Not measured Not measured Not measured Not measured Not measured

1. Results from single-arm non-randomized studies evaluating 1 dose for 2 weeks, not 3 weeks.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

REFERENCES

RECOMMENDATION 5 AND 6 Systematic reviews 1. Bai ZG, Wang B, Yang K, Tian JH, Ma B, Liu Y, Jiang L, Gai QY, He X, Li Y. Azithromycin versus penicillin G benzathine for early syphilis. Cochrane Database Syst Rev. 2012;(6):CD007270. 2. Blank LJ, Rompalo AM, Erbelding EJ, Zenilman JM, Ghanem KG. Treatment of syphilis in HIV-infected subjects: a systematic review of the literature. Sex Transm Infect. 2011;87:9e16. 3. Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives Saved Tool supplement detection and treatment of syphilis in pregnancy to reduce syphilis related stillbirths and neonatal mortality. BMC Public Health. 2011;11(Suppl 3):S9. 4. Clement ME, Lance NO, Hicks CB. Treatment of syphilis: a systematic review. JAMA. 2014;312(18):1905-17. 5. Galvao TF, Silva MT, Serruya SJ, Newman LM, Klausner JD, Pereira MG, Fescina R. Safety of benzathine penicillin for preventing congenital syphilis: a systematic review. PLoS One. 2013;8(2):e56463. doi:10.1371/journal.pone.0056463. Included studies 1. Kiddugavu MG. Effectiveness of syphilis treatment using azithromycin and/or benzathine penicillin in Rakai, Uganda. Sex Transm Dis. 2005;32(1):1-6. Patient values and preferences, acceptability and cost: specific to syphilis infections 1. Chauhan M, Serisha B, Sankar KN, Pattman RS, Schmid ML. Audit of the use of benzathine penicillin, post-treatment syphilis serology and partner notification of patients with early infectious syphilis. Int J STD AIDS. 2006; 17(3):200-2 2. Crowe G, Theodore C, Forster GE, Goh BT. Acceptability and compliance with daily injections of procaine penicillin in the outpatient treatment of syphilis-treponemal infection. Sex Transm Dis. 1997;24(3):127-30. 3. Kingston MA, Higgins SP. Audit of the management of early syphilis at North Manchester General Hospital. Int J STD AIDS. 2004; 15(5):352-4. 4. Owusu-Edusei K, Gift TL, Ballard RC: Cost-effectiveness of a dual non-treponemal/treponemal syphilis point-of-care test to prevent adverse pregnancy outcomes in sub-Saharan Africa (Provisional abstract). Sex Transm Dis. 2011;38:997-1003. 5. Tayal S, Ahmed MS, Hanif U. Audit of early syphilis: Teesside experience 2005–2007. Int J STD AIDS. 2009;20(9):647-9.

3. Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives Saved Tool supplement detection and treatment of syphilis in pregnancy to reduce syphilis related stillbirths and neonatal mortality. BMC Public Health. 2011;11(Suppl 3):S9. 4. Clement ME, Lance NO, Hicks CB. Treatment of syphilis: a systematic review. JAMA. 2014;312(18):1905-17. 5. Galvao TF, Silva MT, Serruya SJ, Newman LM, Klausner JD, Pereira MG, Fescina R. Safety of benzathine penicillin for preventing congenital syphilis: a systematic review. PLoS One. 2012;8(2):e56463. doi:10.1371/journal.pone.0056463. Included studies 1. Alexander JM, Sheffield JS, Sanchez PJ, Mayfield J, Wendel Jr GD. Efficacy of treatment for syphilis in pregnancy. Obstet Gynecol. 1999;93(1):5-8. Patient values and preferences, acceptability and cost: specific to syphilis infections 1. Chauhan M, Serisha B, Sankar KN, Pattman RS, Schmid ML. Audit of the use of benzathine penicillin, post-treatment syphilis serology and partner notification of patients with early infectious syphilis. Int J STD AIDS. 2006;17(3):200-2. 2. Crowe G, Theodore C, Forster GE, Goh BT. Acceptability and compliance with daily injections of procaine penicillin in the outpatient treatment of syphilis-treponemal infection. Sex Transm Dis. 1997;24(3):127-30. 3. Kingston MA, Higgins SP. Audit of the management of early syphilis at North Manchester General Hospital. Int J STD AIDS. 2004;15(5):352-4. 4. Owusu-Edusei K, Gift TL, Ballard RC. Cost-effectiveness of a dual non-treponemal/treponemal syphilis point-of-care test to prevent adverse pregnancy outcomes in sub-Saharan Africa (Provisional abstract). Sex Transm Dis. 2011;38:997-1003. 5. Tayal S, Ahmed MS, Hanif U. Audit of early syphilis: Teesside experience 2005–2007. Int J STD AIDS. 2009;20(9):647-9. Additional references 1. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743-800. doi:10.1016/S0140-6736(15)60692-4. 2. Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One. 2015;10(12):e0143304. doi:10.1371/journal.pone.0143304.

RECOMMENDATION 7 AND 8 Systematic review 1. Bai ZG, Wang B, Yang K, Tian JH, Ma B, Liu Y et al. Azithromycin versus penicillin G benzathine for early syphilis. Cochrane Database Syst Rev. 2012;(6):CD007270. 2. Blank LJ, Rompalo AM, Erbelding EJ, Zenilman JM, Ghanem KG. Treatment of syphilis in HIV-infected subjects: a systematic review of the literature. Sex Transm Infect. 2011;87:9e16.

RECOMMENDATIONS 9 AND 10: CONGENITAL SYPHILIS – INFANTS

RECOMMENDATIONS 9 AND 10: CONGENITAL SYPHILIS – INFANTS Treatments for infants with confirmed congenital syphilis or infants who are clinically normal, but whose mothers had untreated syphilis, inadequately treated syphilis or syphilis that was treated with non-penicillin regimens Treatments for infants who are clinically normal and whose mothers had syphilis that was adequately treated with no signs of reinfection Population: Infants with confirmed congenital syphilis or infants who are clinically normal, but whose mothers had untreated syphilis, inadequately treated syphilis or syphilis that was treated with non-penicillin regimens Infants who are clinically normal and whose mothers had syphilis that was adequately treated with no signs of reinfection Intervention: Comparison: Main outcomes: Aqueous crystalline/procaine penicillin Ceftriaxone Critical: – clinical cure – serological response – congenital syphilis manifestation All settings Population WHO definition of confirmed congenital syphilis: Microbiological evidence of congenital syphilis includes any one of the following:

Setting: Perspective: Background:

• demonstration by dark-field microscopy or fluorescent antibody detection of T. pallidum in the umbilical cord, the placenta, a nasal discharge or skin lesion material

• detection of T. pallidum-specific IgM • infant with a positive non-treponemal serology titre ≥ fourfold above that of the mother Also defined as live birth to a syphilis seropositive mother without adequate syphilis treatment (from Global guidance on criteria and processes for validation: elimination of mother-to-child transmission (EMTCT) of HIV and syphilis)1. The GDG identified the following for review: Aqueous crystalline penicillin 100 000–150 000 U/kg IM single dose OR procaine penicillin 50 000 U/kg/day IM × 10–15 days OR ceftriaxone in infants (< 30 days) 75 mg/kg BW IM/IV single dose × 1 day, infants (≥ 30 days) 100 mg/kg BW IM/IV single dose × 1 day. BW: body weight; IgM: immunoglobulin M; IM: intramuscular; IV: intravenous

1. Global guidance on criteria and processes for validation: elimination of mother-to-child transmission (EMTCT) of HIV and syphilis. Geneva: World Health Organization; 2014 (http://www.who.int/reproductivehealth/publications/ rtis/9789241505888/en/).

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

ASSESSMENT Judgement Is the problem a priority? Problem Desirable Effects Undesirable Effects Research evidence Research evidence: Global estimates published in 2013 (Newman) indicated that there were 217 678 live births with syphilis per 1 360 485 women with syphilis not treated. This would mean approximately 16 live births with syphilis per 100 women with syphilis not treated, therefore there would have been other stillbirths or neonatal deaths, or premature births. A systematic review found that when mothers are treated, the risk of congenital syphilis is 0.03 times the risk in infants born to untreated mothers; from this it can be roughly estimated that there would be 4.8 births with congenital syphilis per 1000 treated mothers. Only half of these infants (2.4 per 1000) would be expected to show signs or symptoms of congenital syphilis. Therefore in 1000 treated mothers there would be a risk of 2–3 infants born with congenital syphilis who are clinically normal. The resource implications of hospitalization for infants with congenital syphilis is > 3 times higher versus infants without the disease. At one South African hospital, 57% of symptomatic infants required neonatal intensive care unit (NICU) admission, and 52% of those infants died. On average, almost one NICU bed (in a 12-bed unit with 600 admissions annually) was always occupied by an infant with syphilis (Bateman, 1997). Also, it has been reported that in developed countries neonates with congenital syphilis are more likely to be admitted to the NICU and stay longer in hospital. Additional considerations: None How substantial are the desirable anticipated effects? Research evidence: We found nine non-randomized studies. Most studies included very few babies and there was very low follow-up of babies after treatment was provided. When there was follow-up, it ranged from 6 months to 1 year. Treatments provided included aqueous benzyl penicillin and procaine penicillin; ceftriaxone was not assessed. In most studies, treatment resulted in 100% cures with no adverse effects. However, ceftriaxone was known to interact with calcium in neonates and is contraindicated in infants before 41 weeks. Historical experience is available. Historically, benzathine penicillin dosing consists of scaling down doses by body weight, and there is little data obtained about success. Additional considerations: None

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

• • • •

Trivial Small Moderate Large

• Varies • Don’t know How substantial are the undesirable anticipated effects?

• • • •

Large Moderate Small Trivial

• Varies • Don’t know

RECOMMENDATIONS 9 AND 10: CONGENITAL SYPHILIS – INFANTS

What is the overall certainty of the evidence of effects?

Research evidence: No research evidence was identified. Additional considerations: None

Certainty of evidence Values Balance of effects

• • • •

Very low Low Moderate High

• No included studies Is there important uncertainty about or variability in how much people value the main outcomes? Research evidence: According to economic evaluation studies, the disability weights due to syphilis (utility loss due to the disease) are as follows: congenital syphilis: 0.315 low birth weight: 0.106 neonatal death: 1 stillbirth: 1 miscarriage: 1 Additional considerations: A high value was placed on treatment and avoidance of congenital syphilis.

• Important uncertainty or variability

• Possibly important uncertainty or variability

• Probably no important uncertainty or variability • No important uncertainty or variability • No known undesirable outcomes Does the balance between desirable and undesirable effects favour the intervention or the comparison?

Research evidence: Aqueous benzyl penicillin or procaine penicillin was favoured over ceftriaxone, for which there was little to no data and potential for side-effects and contraindications. Additional considerations: None

• Favours the comparison • Probably favours the comparison

• Does not favour either the intervention or the comparison • Probably favours the intervention • Favours the intervention

• Varies • Don’t know

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

How large are the resource requirements (costs)?

Resources required Certainty of evidence of required resources

Treatment

• Large costs • Moderate costs • Negligible costs and savings • Moderate savings • Large savings

Administer in dose(s) across day 2

Treatment duration (days) 10–15

Cost, per dose ($) * 0.23

Cost per full-course treatment ($) 2.30–3.45

25% procurement ($) 2.88–4.31

• Varies • Don’t know

Aqueous crystalline penicillin G, benzyl 100 000150 000 U/ kg (5 MU INJ IV) ~10 kg Procaine penicillin 50 000 U/ kg (1 MU powder INJ) ~10 kg Ceftriaxone 75 mg/kg (250 mg vial INJ) ~4 kg Ceftriaxone 100 mg/kg (1 g vial INJ) ~12 kg

10–15

0.18

1.80–2.70

2.25–3.38

10–14

0.52

5.20–7.28

6.50–9.10

10–14

0.75

7.50–10.50

9.38–13.13

* Sources: International drug price indicator guide, 2014 editions (Management Sciences for Health, 2015) and www.drugs.com

Additional considerations: Costs for therapy would be increased if the infant had to stay in hospital. The GDG agreed that there was little cost difference between aqueous benzyl penicillin or procaine penicillin, but that ceftriaxone was more expensive. What is the certainty of the evidence of resource requirements (costs)? Research evidence: No research evidence was identified. Additional considerations: None

• • • •

Very low Low Moderate High

• No included studies

RECOMMENDATIONS 9 AND 10: CONGENITAL SYPHILIS – INFANTS

Does the cost-effectiveness of the intervention favour the intervention or the comparison?

Research evidence: No research evidence was identified. Additional considerations: None

Cost–effectiveness Equity Acceptability Feasibility

• Favours the comparison • Probably favours the comparison

• Does not favour either the intervention or the comparison • Probably favours the intervention • Favours the intervention

• Varies • No included studies What would be the impact on health equity? Research evidence: No research evidence Additional considerations: The GDG agreed that the medicines are available and probably would not have an impact on equity. However, for people who need to travel for treatment, health equity may be reduced.

• • • • • • •

Reduced Probably reduced Probably no impact Probably increased Increased Varies Don’t know

Is the intervention acceptable to key stakeholders?

Research evidence: No research evidence. Additional considerations: There were concerns that 10–15 days of injections would not be acceptable or feasible if patients had to travel, but for infants born in hospital this regimen was deemed appropriate. The GDG agreed that intramuscular injections would be acceptable, given that finding a vein for intravenous administration is often very difficult for infants. However, if an experienced venipuncturist is present and willing, intravenous benzyl penicillin could be administered. Research evidence: The infant will already be hospitalized in a confirmed case so implementing a strategy in this population is likely to be feasible. All medicines are feasible to acquire in various settings. In addition to these considerations, it was noted that opened containers of benzathine penicillin G need to be refrigerated. Additional considerations: None

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

Is the intervention feasible to implement?

• • • • • •

No Probably no Probably yes Yes Varies Don’t know

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Balance of effects

Resources required Certainty of evidence of required resources Cost– effectiveness

Large costs

Moderate costs Low

Moderate savings High

Large savings

Varies

Don’t know

Very low

No included studies

Favours the comparison

Probably favours the comparison

Does not favour either the intervention or the comparison Probably no impact Probably yes Probably yes

Probably favours the intervention

Favours the intervention

Varies

No included studies

Equity Acceptability Feasibility

Reduced No No

Probably reduced Probably no Probably no

Probably increased Yes Yes

Increased

Varies Varies Varies

Don’t know Don’t know Don’t know

CONCLUSIONS

Treatments for infants with confirmed or suspected congenital syphilis Conditional recommendation against the intervention • • Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention

Type of recommendation

Strong recommendation against the intervention

•

• •

Recommendation

Infants

Recommendation 9 In infants with confirmed congenital syphilis or infants who are clinically normal, but whose mothers had untreated syphilis, inadequately treated syphilis (including treatment within 30 days of delivery) or syphilis that was treated with non-penicillin regimens, the WHO STI guideline suggests aqueous benzyl penicillin or procaine penicillin. Conditional recommendation, very low quality evidence

Dosages: · Aqueous benzyl penicillin 100 000–150 000 U/kg/day intravenously for 10–15 days · Procaine penicillin 50 000 U/kg/day single dose intramuscularly for 10–15 days

Remarks: If an experienced venipuncturist is available, aqueous benzyl penicillin may be preferred instead of intramuscular injections of procaine penicillin.

Recommendation 10 In infants who are clinically normal and whose mothers had syphilis that was adequately treated with no signs of reinfection, the WHO STI guideline suggests close monitoring of the infants. Conditional recommendation, very low quality evidence

RECOMMENDATIONS 9 AND 10: CONGENITAL SYPHILIS – INFANTS

Remarks: The risk of transmission of syphilis to the fetus depends on a number of factors, including maternal titres from non-treponemal tests (e.g. rapid plasma reagin, RPR), timing of maternal treatment and stage of maternal infection, and therefore this recommendation is conditional. If treatment is provided, benzathine penicillin G 50 000 U/kg/day single dose intramuscularly is an option.

Type of recommendation

Strong recommendation against the intervention

Conditional recommendation against the intervention • •

Conditional recommendation for either the intervention or the comparison

Conditional recommendation for the intervention

Strong recommendation for the intervention

•

• •

Justification

The overall quality of the evidence was very low. Nine non-randomized studies informed this recommendation, as well as historical use of the medicines to treat and prevent confirmed or suspected congenital syphilis. The sample size of most studies was low and rates of follow-up of babies after treatment was very low. When there was follow-up, it ranged from 6 months to 1 year. Treatments provided included aqueous benzyl penicillin and procaine penicillin and benzathine penicillin G; ceftriaxone was not assessed. In most studies of infants with confirmed congenital syphilis or infants with mothers who had inadequate or no treatment, treatment of infants resulted in 100% cures with no adverse effects. Aqueous benzyl penicillin or procaine penicillin was favoured over ceftriaxone due to little or no data and potential for side-effects and contraindications with ceftriaxone. There were very few data; some historical data indicate that benzathine penicillin G may have benefit and few adverse effects, but this is uncertain. There were no followup data for untreated infants who were clinically normal and born to mothers who had received adequate treatment. From global estimates, the risk of congenital syphilis for infants born alive to untreated mothers is approximately 16 per 100 mothers. A systematic review found that when mothers are treated, the risk of congenital syphilis is 0.03 times the risk in infants born to untreated mothers; from this it can be roughly estimated that there would be 4.8 births with congenital syphilis per 1000 treated mothers. Only half of these infants (2.4 per 1000) would be expected to show signs or symptoms of congenital syphilis. Therefore in 1000 treated mothers there would be a risk of 2–3 infants born with congenital syphilis who are clinically normal.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Overall, historical data show benefits of treatment with aqueous benzyl penicillin and procaine penicillin with little to no adverse effects, and the costs are similar. There are few to no data for benzathine penicillin G, but there may be no adverse effects; and few to no data for ceftriaxone, but adverse effects may occur and it is more expensive than the other medicines. A preference for intramuscular injections or intravenous administration was not determined, but there is an option with either medicine. Overall, the risk for congenital syphilis for infants born to mothers who have received adequate treatment was very low and therefore monitoring was suggested over treatment of these infants.

Subgroup considerations

Implementation considerations

Injection is more painful to babies but is probably more practical as it is administered once per day. With intravenous administration it is often difficult for the clinician to insert the line, and it is administered multiple times per day. Same day diagnosis and treatment is ideal as high loss to follow-up after testing is likely.

Monitoring and evaluation

Research priorities

Trials investigating appropriate dosages and effectiveness of ceftriaxone use for early and late syphilis should be conducted. The trials should compare ceftriaxone with benzathine penicillin G and doxycycline. More research should be conducted into medicines taken orally for a few days, such as cephalosporins. Since benzathine penicillin G and other penicillins require injection by health workers, it was suggested that the safety of self-injection be investigated.

The GDG discussed the need to develop new treatment. Ideally the new treatment should be a short course administered orally and that can treat pregnant women with syphilis and cross the blood–brain and placental barriers to prevent transmission to the fetus. Cephalosporins could be potential options. Trials investigating appropriate dosages and effectiveness of ceftriaxone use for early and late syphilis should be established. The trials should compare ceftriaxone with benzathine penicillin G. The extent to which the medicines cross the blood–brain and placental barriers should also be investigated.

There were few data for ceftriaxone use in infants with confirmed congenital syphilis and therefore research is needed, in particular in comparison to procaine penicillin.

RECOMMENDATIONS 9 AND 10: CONGENITAL SYPHILIS – INFANTS 45

EVIDENCE PROFILE

Aqueous crystalline/procaine penicillin compared to ceftriaxone for infants with confirmed congenital syphilis Number of patients Aqueous crystalline/ procaine penicillin Ceftriaxone Relative (95% CI) Absolute (95% CI) Effect Quality Importance

Quality assessment

Number of studies

Study design

Risk of bias

Inconsistency Indirectness Imprecision Other considerations

Infants with negative tests after treatment with aqueous crystalline penicillin (follow up: 3–6 months)1 Not serious Serious3 None 9/9 (100%) VERY LOW

Observational studies

Serious2

Not serious

Aqueous crystalline penicillin adverse events4 Pharmaceutical label information described skin rashes ranging from maculopapular eruptions to exfoliative dermatitis; urticaria; and reactions resembling serum sickness, including chills, fever, edema, arthralgia and prostration and Jarisch– Herxheimer reaction; but without frequencies. – CRITICAL

Procaine adverse events5 Pharmaceutical label information described diarrhoea, candidiasis and skin rash; but without frequencies. – CRITICAL

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Ceftriaxone adverse events (e.g. diarrhoea, vomiting, exanthema) in neonates (early unspecified follow-up) Not serious Not serious None 14/161 (8.7%) Not estimable CRITICAL LOW

Observational studies

Not serious

Ceftriaxone causing fatalities in neonates (calcium interaction)5 Caution for use in neonates because of “interaction with calcium”. Most parenteral nutrition formulations and many IV solutions used contain calcium. – CRITICAL

1. 2. 3. 4. 5. 6.

Sangtawesin, 2005 Limited follow-up Few neonates Roerig, 2005 WHO, 2008 Fujii, 1988

EVIDENCE PROFILE

Benzathine penicillin compared to no treatment/ceftriaxone for infants who are clinically normal and whose mothers had syphilis that was adequately treated with no signs of reinfection Number of patients Indirectness Imprecision Other considerations Benzathine penicillin No treatment/ ceftriaxone Relative (95% CI) Absolute (95% CI) Effect Quality Importance

Quality assessment

Number of studies

Study design

Risk of bias

Inconsistency

Infants: sequelae (follow-up: at least 8 months) Not serious Serious2 None 0/27 (0.0%) VERY LOW CRITICAL

Observational studies

Serious2

Not serious

Infants: very low birth weight (not included in sequelae) (follow-up: at least 8 months) Not serious Serious2 None 1/27 (3.7%) VERY LOW CRITICAL

Observational studies

Serious2

Not serious

Infants: non infected (follow-up: 1 year) Not serious Serious4 None 1/1 (100.0%) VERY LOW CRITICAL

Observational studies

Serious4

Not serious

Benzathine adverse events5 Hypersensitivity reactions included the following: skin eruptions (maculopapular to exfoliative dermatitis), erythema, cellulitis, paresthesia, urticaria, laryngeal edema, fever, eosinophilia; other serum sickness-like reactions (including chills, fever, edema, arthralgia and prostration) and Jarisch– Herzheimer reaction; but without frequencies. CRITICAL

Ceftriaxone adverse events (e.g. diarrhoea, vomiting, exanthema) in neonates (early unspecified follow-up) Not serious Not serious None 14/161 (8.7%) Not estimable CRITICAL LOW

Observational studies

Not serious

Ceftriaxone: adverse event frequencies7 Caution for use in neonates because of “interaction with calcium”. Most parenteral nutrition formulations and many IV solutions used contain calcium. CRITICAL

RECOMMENDATIONS 9 AND 10: CONGENITAL SYPHILIS – INFANTS 47

Lago, 2013;

2. 27 followed up from 120 total population with mother who were adequately treated;

3. Valentini, 2004;

4. One treated out of 13 and 8 followed up;

5. Pfizer, 2011;

6. Fujii, 1988;

7. WHO, 2008.

EVIDENCE PROFILE

Aqueous crystalline/procaine penicillin compared to benzathine penicillin/ceftriaxone/no treatment for clinically normal infants whose mothers had untreated syphilis, inadequately treated syphilis or syphilis that was treated with non-penicillin regimens Number of patients Indirectness Benzathine Relative penicillin/ (95% CI) ceftriaxone/ no treatment Absolute (95% CI) Imprecision Other considerations Aqueous crystalline/ procaine penicillin Effect Quality Importance

Quality assessment

Number Study design of studies

Risk of bias

Inconsistency

Negative tests and normal growth aqueous crystalline (follow-up: 3–6 months) Not serious Serious3 None 25/25 (100.0%) VERY LOW CRITICAL

Observational studies

Serious2

Not serious

Infants: non infected (follow-up: 1 years) treated with crystalline penicillin Not serious Serious3 None 5/5 (100.0%) VERY LOW

Observational studies

Serious2

Not serious

Aqueous crystalline penicillin adverse events5 Pharmaceutical label information described skin rashes ranging from maculopapular eruptions to exfoliative dermatitis; urticaria; and reactions resembling serum sickness, including chills, fever, edema, arthralgia and prostration and Jarisch– Herxheimer reaction; but without frequencies. CRITICAL

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Procaine AND Benzathine Penicillin: non-reactive RPR titres (follow-up: 12 months) Not serious Not serious None 68/68 (100.0%) 84/84 (100.0%) Not estimable CRITICAL LOW

Observational studies

Not serious

Procaine adverse events

Pharmaceutical label information described diarrhoea, candidiasis and skin rash; but without frequencies.

CRITICAL

Benzathine: no immunoglobulin M (IgM) reactivity (follow-up: up to 6 months) Not serious Serious 10 None 10/10 (100.0%) Not estimable CRITICAL VERY LOW

Observational studies

Serious9

Not serious

Quality assessment Indirectness Benzathine Relative penicillin/ (95% CI) ceftriaxone/ no treatment Absolute (95% CI) Imprecision Other considerations Aqueous crystalline/ procaine penicillin

Number of patients

Effect

Quality

Importance

Number Study design of studies

Risk of bias

Inconsistency

Benzathine adverse events11 Hypersensitivity reactions included the following: skin eruptions (maculopapular to exfoliative dermatitis), erythema, cellulitis, paresthesia, urticaria, laryngeal edema, fever, eosinophilia; other serum sickness-like reactions (including chills, fever, edema, arthralgia and prostration) and Jarisch– Herzheimer reaction; but without frequencies. CRITICAL

Ceftriaxone adverse events (e.g. diarrhoea, vomiting, exanthema) in neonates (early unspecified follow-up) Not serious Not serious None 14/161 (8.7%) Not estimable CRITICAL LOW

1 12

Observational studies

Not serious

Ceftriaxone: adverse event frequencies7 RECOMMENDATIONS 9 AND 10: CONGENITAL SYPHILIS – INFANTS

Caution for use in neonates because of “interaction with calcium”. Most parenteral nutrition formulations and many IV solutions used contain calcium.

CRITICAL

1. Sangtawesin, 2005 2. High loss to follow-up. 3. Few neonates. 4. Valentini, 2004 5. Roerig, 2005 6. Paryani, 1994 7. WHO, 2008 8. Radcliffe, 1997 9. No description of allocation process described. 10. 28% loss to follow up. 11. Pfizer, 2011 12. Fujii, 1988.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

REFERENCES

Systematic review 1. Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives Saved Tool supplement detection and treatment of syphilis in pregnancy to reduce syphilis related stillbirths and neonatal mortality. BMC Public Health. 2011;11(Suppl 3):S9. 2. Gomez GB, Kamb ML, Newman LM, Mark J, Broutet N, Hawkes SJ. Untreated maternal syphilis and adverse outcomes of pregnancy: a systematic review and meta-analysis. Bull World Health Organ. 2013;91(3):217-26. doi:10.2471/BLT.12.107623. 3. Newman L, Kamb M, Hawkes S, Gomez G, Say L, Seuc A, Broutet N. Global estimates of syphilis in pregnancy and associated adverse outcomes: analysis of multinational antenatal surveillance data. PLoS Med. 2013;10(2):e1001396. Included studies 1. Fujii R, Hashira S, Sakata H, Inyaku F, Fujita K, Maruyama S et al. [Pharmacokinetics and clinical evaluation of ceftriaxone in neonates]. Jpn J Antibiot. 1988;41(9):1237-50. 2. Lago EG, Vaccari A, Fiori RM. Clinical features and follow-up of congenital syphilis. Sex Transm Dis. 2013;40(2):85-94. 3. Paryani SG, Vaughn AJ, Crosby M, Lawrence S. Treatment of asymptomatic congenital syphilis: Benzathine versus rocaine penicillin G therapy. J Pediatr. 1994;125(3):471-5. 4. Pfizer. Product monograph PrBICILLIN® L-A (penicillin G benzathine) Sterile injection (for deep intramuscular injection only) antibiotic. Quebec: Pfizer Canada Inc.; 2011. 5. Radcliffe M. Single-dose benzathine penicillin in infants at risk of congenital syphilis – results of a randomised study. South African Med J. 1997;87(1):62-5. 6. Roerig. Buffered PFIZERPEN (penicillin G potassium) for injection. New York (NY): Pfizer Inc.; 2005 (https://www.pfizer. com/files/products/uspi_pfizerpen.pdf, accessed 15 July 2016). 7. Sangtawesin V, Lertsutthiwong W, Kanjanapattanakul W, Khorana M, Horpaopan S. Outcome of maternal syphilis at Rajavithi Hospital on offsprings. J Med Assoc Thai. 2005;88(11):1519-25. 8. Valentini P, Speziale D, Grillo RL, D'Apolito A, Angelone DF, Ngalikpima CJ et al. Congenital syphilis: still an open question. Ital J Pediatr. 2004;30(5):312-9. 9. WHO ceftriaxone safety. Second Meeting of the Subcommittee of the Expert Committee on the Selection and Use of Essential Medicines. Geneva: World Health Organization; 29 September to 3 October 2008.

Patient values and preferences, acceptability and cost: specific to syphilis infections 1. Owusu-Edusei K, Gift TL, Ballard RC: Cost-effectiveness of a dual non-treponemal/treponemal syphilis point-of-care test to prevent adverse pregnancy outcomes in sub-Saharan Africa (Provisional abstract). Sex Transm Dis. 2011;38:997-1003. 2. nternational drug price indicator guide, 2014 edition (updated I annually). Medford (MA): Management Sciences for Health; 2015 (http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2014.pdf, accessed 6 June 2016).

For more information, contact: Department of Reproductive Health and Research World Health Organization Avenue Appia 20, CH-1211 Geneva 27 Switzerland Fax +41 22 791 4171 E-mail: reproductivehealth@who.int www.who.int/reproductive health

WHO GUIDELINES FOR THE

Treatment of Treponema pallidum (syphilis) Web annex F: Summary of conflicts of interest

WHO GUIDELINES FOR THE

Treatment of Treponema pallidum (syphilis)* Web annex F: Summary of conflicts of interest

*Full guidelines available at: www.who.int/reproductivehealth/publications/rtis/syphilis-treatment-guidelines/en/ WHO Library Cataloguing-in-Publication Data

WHO guidelines for the treatment of Treponema pallidum (syphilis). Contents: Web annex D: Evidence profiles and evidence-to-decision frameworks - Web annex E: Systematic reviews for syphilis guidelines - Web annex F: Summary of conflicts of interest 1.Syphilis – drug therapy. 2.Treponema pallidum. 3.Sexually Transmitted Diseases. 4.Guideline. I.World Health Organization. ISBN 978 92 4 154980 6 © World Health Organization 2016

(NLM classification: WC 170)

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Web annex F- Summary of conflict of interest

Name

Members of the STI Guideline Development Group (GDG) Region Country Institution

Adu-Sarkodie, Yaw (Sax)

AFR

Ghana

Amato, Andrew

EUR

Sweden

Bolan, Gail Changalucha, John

AMR AFR

USA United Republic of Tanzania

School of Medical Sciences, Kwame Nkrumah University of Science and Technology (KNUST) European Centre for Disease Prevention and Control Centers for Disease Control and Prevention (CDC) National Institute for Medical Research, Mwanza Medical Research Centre

Declarations of conflicts of interest (i.e. related to the topic of the meeting/guideline) Involved in Declared Declared any related any related indirectly related academic commercial commercial work financial financial interest interest No No No

Meeting restriction Declared related noncommercial interest or grants No

No No

No Yes: GSK – research support to evaluate the safety and immunogenicity of the GSK HPV vaccines (ended 2011); HPV not part of STI guidelines

No No

WHO guidelines for the treatment of Treponema pallidum (syphilis).

Name

Region

Country

Institution

Chen, XiangSheng

WPR

China

Chesson, Harrel

AMR

USA

Cohen, Craig

AMR

USA

National Center for STD Control, Chinese Academy of Medical Sciences and Peking Union Medical College Division of STI Prevention, Centers for Disease Control and Prevention (CDC) University of California, San Francisco

Meeting restriction Declared related noncommercial interest or grants No

Yes: Consulted in the development of new drugs for bacterial vaginosis – Symbiomix Inc. (US$ 8000)

Garcia, Francisco

AMR

USA

Pima County Health Department

Yes: Grants not related to STI studies (National Institutes of Health [NIH], CDC and the Bill & Melinda Gates Foundation) No

Web annex F- Summary of conflict of interest

Name

Region

Country

Institution

Garcia, Patricia

AMR

Peru

Garland, Suzanne

WPR

Australia

School of Public Health and Administration, Universidad Peruana Cayetano Heredia Royal Women’s Hospital

Meeting restriction Declared related noncommercial interest or grants No

Yes: Merck – award for HPV (US $5,500) Japan Ministry of Health – surveillance of recurrent respiratory papillomatosis (US$ 50 382); speaker at HPV symposiums GSK – vaccine trial (US$ 98 000) CSLbio – cervical cancer genotypes (US$ 210 000) No

Yes: IARC – support work in HPV vaccine trials

Hawkes, Sarah

EUR

United Kingdom

University College London

WHO guidelines for the treatment of Treponema pallidum (syphilis).

Name

Region

Country

Institution

Higgins, Mary Holmes, King

EUR AMR

Netherlands USA

Klausner, Jeffrey

AMR

USA

International Confederation of Midwives Department of Global Health and Department of Medicine, University of Washington, Harborview Medical Center Division of Infectious Diseases and Program in Global Health, David Geffen School of Medicine and Fielding School of Public Health, University of California, Los Angeles

Meeting restriction Declared related noncommercial interest or grants No No

No No

Yes: Standard Diagnostic – syphilis test provided, travel support (US$ 2000)

Yes: Hologic, Cepheid, Standard Diagnostics, ALere, MedMira, Chembio – free STI tests provided, not related to STI treatment (US$ 5000) Flora Bioscience – candidiasis

No Syphilis test being discussed, but no commercial recommendati ons being made. Other STI diagnostics not part of the recommendati ons being discussed.

Web annex F- Summary of conflict of interest

Name

Region

Country

Institution

Lewis, David

AFR

South Africa

Low, Nicola

EUR

Switzerland

Mabey, David

EUR

United Kingdom Brazil

Miranda, Angelica Espinosa

AMR

Mullick, Saiqa

AFR

South Africa

Western Sydney Sexual Health Centre, Marie Bashir Institute for Infectious Diseases and Biosecurity, Sydney Medical School Epidemiology and Public Health, University of Bern, Institute of Social and Preventive Medicine London School of Hygiene and Tropical Medicine (LSHTM) Núcleo de Doenças Infecciosas, Universidade Federal do Espirito Santo University of the Witwatersrand, Hillbrow Health Precinct

Meeting restriction Declared related noncommercial interest or grants No

WHO guidelines for the treatment of Treponema pallidum (syphilis).

Name

Region

Country

Institution

Palefsky, Joel

AMR

USA

Radcliffe, Keith

EUR

United Kingdom

Sabirov, Ulugbek

EUR

Uzbekistan

Schünemann, Holger

AMR

Canada

Steen, Richard Stephenson, Judith

EUR EUR

Italy United Kingdom

Division of Infectious Diseases, University of California, San Francisco European STI Guidelines Project, International Union against Sexually Transmitted Infections (IUSTI), Royal Society of Medicine National STI Program, Republican Center for DermatoVenereology Department of Clinical Epidemiology and Biostatistics, McMaster University Erasmus University University College London

Meeting restriction Declared related noncommercial interest or grants No

No No

Web annex F- Summary of conflict of interest

Name

Region

Country

Institution

Unemo, Magnus

EUR

Sweden

Vuylsteke, Bea Wald, Anna

EUR AMR

Belgium USA

Wasserheit, Judith

AMR

USA

Wong, Thomas

AMR

Canada

Department of Laboratory Medicine, Microbiology, Örebro University Hospital Institute of Tropical Medicine University of Washington, Virology Research Clinic, Harborview Medical Center Department of Global Health and Medicine, University of Washington Division of Community Acquired Infections, Centre for Communicable Diseases and Infection Control, Public Health Agency of Canada

Meeting restriction Declared related noncommercial interest or grants No

No No

No Yes: Involved in the development of herpes simplex virus (HSV) vaccination No

No No

WHO guidelines for the treatment of Treponema pallidum (syphilis).

Name

Region

Country

Institution

Workowski, Kimberly A.

AMR

USA

Centers for Disease Control and Prevention, Division of Infectious Diseases, Emory University School of Medicine

Meeting restriction Declared related noncommercial interest or grants No

WHO regions: AFR: African Region; AMR: Region of the Americas; EMR: Eastern Mediterranean Region; EUR: European Region; SEAR: South-East Asia Region; WPR: Western Pacific Region

Web annex F- Summary of conflict of interest

Name

Methodologist

Region

Country

Institution

Santesso, Nancy

AMR

Canada

Department of Clinical Epidemiology and Biostatistics, McMaster University

Declarations of conflicts of interest (i.e. related to the topic of the meeting/guideline) Involved in Declared any Declared any related related indirectly academic work commercial related financial commercial interest financial interest No No No

Meeting restriction Declared related noncommercial interest or grants No No

AMR: WHO Region of the Americas

WHO guidelines for the treatment of Treponema pallidum (syphilis).

Name

Members of the External Review Group Region Country

Institution

Abu-Raddad, Laith

EMR

Qatar

Akolo, Chris Benaken-Schwartz, Adele Betiu, Mircea

AMR AMR EUR

USA Brazil Republic of Moldova Thailand

Chitwarakorn, Anupong

SEAR

Department of Public Health, Weill Cornell Medical College, Cornell University, Qatar Foundation – Education City FHI 360 STI, AIDS and Viral Hepatitis Department, Ministry of Health Nicolae Testemițanu State University of Medicine and Pharmacy Department of Diseases Control, Bureau of AIDS, TB and STIs, Ministry of Public Health

Meeting restriction

No No No

Web annex F- Summary of conflict of interest

Name

Region

Country

Institution

Deal, Carolyn

AMR

USA

Gale-Row, Margaret

AMR

Canada

National Institute of Allergy and Infectious Diseases (NIAID), United States Department of Health and Human Services, National Institutes of Health Professional Guidelines and Public Health Practice Division, Centre for Communicable Diseases and Infection Control, Public Health Agency of Canada

Meeting restriction

WHO guidelines for the treatment of Treponema pallidum (syphilis).

Name

Region

Country

Institution

Geisler, William

AMR

USA

University of Alabama at Birmingham

Declarations of conflicts of interest (i.e. related to the topic of the meeting/guideline) Involved Declared any Declared Declared in related commercial any related nonrelated financial interest indirectl commercial academi y related interest or c work commerc grants ial financial interest No Yes: No No Activbiotics Pharma, LLC – involved in protocol development of phase 2 clinical trial of rifalazil for chlamydia treatment (US$ 4987) Warner Chilcott LLC – review efficacy data for clinical trial of a chlamydia drug – FDA discussion (US$ 10 640) No

Meeting restriction

Kamb, Mary

AMR

USA

Centers for Disease Control and Prevention

Web annex F- Summary of conflict of interest

Name

Region

Country

Institution

Kettani, Amina

EMR

Morocco

Direction de l’Epidemiologie, Service des MST-sida, Ministry of Health Disease Prevention and Control Directorate Federal Ministry of Health Public Health Consultant Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine Research and Technical Support, International Planned Parenthood Federation Population Council

Meeting restriction

Kiros, Mizan

AFR

Ethiopia

Latif, Ahmed Mayaud, Philippe

AFR EUR

Zimbabwe United Kingdom

No No

McCartney, David

EUR

United Kingdom Pakistan

Mir, Ali M.

EMR

WHO guidelines for the treatment of Treponema pallidum (syphilis).

Name

Region

Country

Institution

Ortayli, Nuriya

EMR

Turkey

United Nations Population Fund (UNFPA) The Ohio State University Nationwide Children's Hospital Clinical & Translational Research (Neonatology) Center for Perinatal Research Center for HIV/AIDS and STIs, Ministry of Health National AIDS Control Organization, Ministry of Health and Family Welfare

Meeting restriction

Sanchez, Pablo

AMR

USA

Sayabounthavong, Khantanouvieng Singh, Aman Kumar

WPR SEAR

Lao People’s Democratic Republic India

No No

WHO regions: AFR: African Region; AMR: Region of the Americas; EMR: Eastern Mediterranean Region; EUR: European Region; SEAR: South-East Asia Region; WPR: Western Pacific Region

Informations clés

Organisation Organisation mondiale de la santé (OMS)

Type de document Publications

Date d'adoption 24 août 2016

Source Organisation mondiale de la santé