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Treatment and care for HIV-positive injecting drug users: Module 9 - Management of coinfections in HIV-positive drug users

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Participant Manual

Module 9

Management of Coinfections in HIV-Positive Injecting Drug Users Treatment and Care for HIV-Positive Injecting Drug Users

Regional Office for South-East Asia

Family Health International

Module 9

Management of coinfections in HIV-positive injecting drug users Participant Manual

2007

The Association of Southeast Asian Nations (ASEAN) was established on 8 August 1967. The Member States of theAssociation are Brunei Darussalam, Cambodia, Indonesia, Lao PDR, Malaysia, Myanmar, Philippines, Singapore, Thailand and Viet Nam. The ASEAN Secretariat is based in Jakarta, Indonesia. For inquiries, contact The Public Affairs Office, The ASEAN Secretariat, 70A Jalan Sisingamangaraja, Jakarta 12110, Indonesia, Phone: (62 21) 724-3372, 726-2991, Fax: (62 21) 739-8234, 724-3504. E-mail: public@aseansec.org. General information on ASEAN appears on-line at the ASEAN Website: www.aseansec.org. Catalogue-in-Publication Data Treatment and Care for HIV-Positive Injecting Drug Users Jakarta: ASEAN Secretariat, December 2007 616.9792 1. ASEAN – USAID 2. HIV – Drugs – Modules ISBN 978-979-3496-63-4 (NLM classification: 503.6)

This publication is available on the internet at www.aseansec.org, www.fhi.org and www.searo.who.int/hiv-aids publications. Copies may be requested from: The ASEAN Secretariat, 70A, Jl. Sisingamangaraja, Jakarta 12110, Indonesia. e-mail: public@aseansec.org and Family Health International, Asia/Pacific Regional Office, 19th Floor, Tower 3, Sindhorn Building, 130–132 Wireless Road, Lumpini, Phatumwan, Bangkok 10330, Thailand, e-mail: sunee@fhibkk.org and HIV Unit, Department of Communicable Diseases, World Health Organization, Regional Office for South-East Asia, Indraprastha Estate, Mahatma Gandhi Marg, New Delhi-110 002, India, e-mail: hiv@searo.who.int Module 1: Drug use and HIV in Asia: participant manual Module 2: Comprehensive services for injecting drug users – participant manual Module 3: Initial patient assessment – participant manual Module 4: Managing opioid dependence – participant manual Module 5: Managing non-opioid drug dependence – participant manual Module 6: Managing ART in injecting drug users – participant manual Module 7: Adherence counselling for injecting drug users – participant manual Module 8: Drug interactions – participant manual Module 10: Managing pain in HIV-infected injecting drug users – participant manual Module 11: Psychiatric illness, psychosocial care and sexual health – participant manual Module 12: Continuing medical education – participant manual Trainer manual: Treatment and care for HIV-positive injecting drug users © ASEAN Secretariat 2007

Typesetting and Design: Macro Graphics Pvt. Ltd. Printed in India

Contents Abbreviations and acronyms.......................................................................................................................................iv Sub-module 9.1: HIV/HCV and HIV/HBV coinfections..........................................................................................1 Overview................................................................................................................................................................................ 1 Hepatitis C coinfection...................................................................................................................................................... 2 Natural history..................................................................................................................................................................... 4 Effect of HCV on HIV progression.................................................................................................................................. 5 Effect of HIV on HCV progression.................................................................................................................................. 5 Treatment of HCV in HIV coinfection........................................................................................................................... 6 Treatment of HIV in HCV coinfection........................................................................................................................... 9 Conclusion...........................................................................................................................................................................10 Hepatitis B coinfection....................................................................................................................................................10 Natural history...................................................................................................................................................................12 Effect of HBV on HIV progression................................................................................................................................14 Effect of HIV on HBV progression................................................................................................................................14 Treatment of HBV in HIV coinfection.........................................................................................................................14 Treatment of HIV in HBV coinfection.........................................................................................................................16 Conclusion...........................................................................................................................................................................17 References and recommended reading...................................................................................................................17

Sub-module 9.2: Management of HIV/TB coinfection in IDUs.......................................................................19 Overview..............................................................................................................................................................................19 Care and support for HIV-infected individuals with active TB..........................................................................20 Co-trimoxazole preventive treatment and HIV-associated active TB. ............................................................21 Principles of antiretroviral therapy (ART).................................................................................................................22 References and recommended reading...................................................................................................................26 Exercise 9.2.1: Case studies............................................................................................................................................29

Annex 1: PowerPoint presentation 9.1: HIV/HCV and HIV/HBV coinfections............................................ 35 Annex 2: PowerPoint presentation 9.2: Management of HIV/TB coinfection in IDUs ........................... 45

Abbreviations and acronyms 3TC ABC AFB AIDS ALT ART ARV ASEAN AST AZT CBC CCC CDC CNS CPT CTX d4T DNA DOTS EFV ESLD ETR EVR FHI FTC GFATM HBcAb HBeAb HBeAg HBsAg HBV HCC HCV lamivudine abacavir acid-fast bacilli acquired immunodeficiency syndrome alanine aminotransferase (liver enzyme) antiretroviral therapy antiretroviral Association of Southeast Asian Nations aspartate aminotransferase (liver enzyme) zidovudine (also ZDV) complete blood count comprehensive continuum of care Centers for Disease Control and Prevention (US Government) central nervous system co-trimoxazole preventive treatment co-trimoxazole stavudine deoxyribonucleic acid directly observed treatment, short course efavirenz end-stage liver disease end-of-treatment response early virological response Family Health International emtricitabine Global Fund to Fight AIDS, Tuberculosis and Malaria hepatitis B core antibody hepatitis B e antibody hepatitis B e antigen hepatitis B surface antigen hepatitis B virus hepatocellular cancer hepatitis C virus

HEENT HIV IDUs IFN IRIS LFT MAC NGO NNRTI NR NRTI NSAID NVP OI OST PCP PEG-IFN PI PLWHA RBV RCT RHZE RNA SS SSRI SVR TB TDF TST ULN USAID VCT VL WCC WHO ZDV

head eye ear nose and throat human immunodeficiency virus injecting drug users interferon immune reconstitution inflammatory syndrome liver function tests Mycobacterium avium complex nongovernmental organization non-nucleoside reverse transcriptase inhibitors non-responder nucleoside reverse transcriptase inhibitors non-steroidal anti-inflammatory drug nevirapine opportunistic infection opioid substitution therapy Pneumocystis jiroveci pneumonia pegylated interferon protease inhibitor people living with HIV and AIDS ribavirin randomized control trial TB drug treatment regimen involving 4 drugs (H=isoniazid, R=rifampicin, E=ethambutol, Z=pyrazinamide) ribonucleic acid sputum smear selective serotonin reuptake inhibitor sustained virological response tuberculosis tenofovir tuberculin skin test upper limit of normal United States Agency for International Development voluntary counselling and testing viral load while cell count World Health Organization zidovudine (also AZT)

TNP-plus Thai Network for People Living with HIV/AIDS

Sub-module

9.1 Overview

HIV/HCV and HIV/HBV coinfections

Objectives: By the end of the session the participants will:  Understand the epidemiology of viral hepatitis/HIV coinfection  Understand the influence of viral hepatitis on progression of HIV  Understand the influence of HIV on progression of viral hepatitis  Understand the approach to HCV and HBV treatment in the context of HIV infection  Understand the approach to HIV treatment in the context of viral hepatitis, including how to choose an appropriate ART regimen and monitor liver function  Understand the importance of preventing bloodborne virus transmission in coinfection  Understand the limitations of hepatitis management in resource-limited settings Time to complete session: 1 hour 45 minutes Session content: Consider both HCV/HIV and HBV/HIV coinfection:  Epidemiology  Natural history  Effect of HCV on HIV progression  Effect of HIV on HCV progression  Treatment of HCV in HIV coinfection  Treatment of HIV in HCV coinfection  Summary Training materials:  PowerPoint presentation 9.1: HIV/HCV and HIV/HBV coinfections in HIV-infected IDUs  Sub-module 9.1: HIV/HCV and HIV/HBV coinfections

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Management of coinfections in HIV-positive injecting drug users

Hepatitis C coinfection Epidemiology There are 170 million individuals living with hepatitis C in the world. Most are from developing countries. There are a number of reasons for this which include unsterile medical injections, transfusions, cultural practices where blood is potentially exchanged between individuals, and injecting drug use. The prevalence by country is shown in Figure 1: Figure 1. Prevalence of hepatitis C across the world, 2005

<1.00% 1.0% - 1.9% 2.0 - 2.9% >2.9% Not included in WHO Region

Source: Shepard CW, Finelli L, Alter MJ. Lancet Infectious Diseases, 2005

WHO Region

Total population (millions) 602 785 466 858 1500 1600 5811

HCV prevalence (%)

Infected population (millions) 31.9 13.1 21.3 8.98 32.3 62.2 169.7

Africa Americas Eastern Mediterranean Europe South-East Asia Western Pacific Total

5.3 1.7 4.6 1.03 2.15 3.9 3.1

Number of countries by WHO Region where data are not available 12 7 7 19 3 11 59

Source: Shepard CW, Finelli L, Alter MJ. Lancet Infectious Diseases, 2005

Although injecting drug use is a very common way of acquiring HCV, the proportion of HCV cases attributable to injecting drug use is lower in developing than developed countries. Screening of blood and blood products for HCV is an effective way to reduce transmission. This was first introduced in the late 1980s in Australia, Europe and the USA, but is now common in many countries. The country with the highest population prevalence of HCV is Egypt, a consequence of unsterile injections during a schistosomiasis treatment programme in the second half of the last century.

Participant Manual

Management of coinfections in HIV-positive injecting drug users

Within IDU populations, sharing of contaminated injecting equipment such as needles and syringes is the most common mode of HCV acquisition. Sharing of other equipment such as spoons and filters has also been associated with the transmission of HCV, though this is less common. HCV appears easier to transmit than HIV, and therefore the prevalence of HCV in an injecting drug user (IDU) population is often much higher than the HIV prevalence. HCV is difficult to transmit by unprotected sexual intercourse, though recent studies suggest that traumatic sexual practices are associated with HCV transmission. The epidemiology of HCV/HIV coinfection is less well understood. Generally speaking, this coinfection, by the nature of the shared transmission routes, is transmitted by injecting drug use; however, transmission can also be sexual. Thus, coinfection is more common in IDUs than in the general population. HCV is more difficult to clear spontaneously in the presence of HIV; therefore, HIV-positive IDUs are much more likely to have HCV than their HIV-negative counterparts. In a number of countries in Asia, the prevalence of HIV/HCV coinfection among HIV-positive IDUs is >95% (parts of China, Thailand, Viet Nam). By contrast, most HIV-positive individuals are not HCVpositive in those countries when injecting drug use is not a major transmission route for HIV (see Figure 2; note Italy and Spain have a greater proportion of HIV infection attributable to injecting drug use). Figure 2. Prevalence of HCV coinfection in HIV-positive individuals by country: CAESAR study 60

0 Holland South Africa Sweden Germany Portugal France Spain Switzerland Denmark Austria Belgium Canada Italy UK

Source: Amin J et al. HIV Medicine, 2004.

The virus Hepatitis C was formerly known as non-A non-B hepatitis. It was named hepatitis C in 1989 when the virus was discovered. It is a member of the Flaviviridae family. Other viruses of this family include Japanese encephalitis, dengue and West Nile virus. It is unrelated to the other hepatitis viruses, except that they all cause inflammation of the liver. It is an RNA virus, and is therefore highly variable in its expression (many mutations during replication similar to HIV). This is one reason why it is able to evade the immune system. During infection, HCV exists as many similar, but not identical, species (quasispecies) generally within the same genotype. There are nine genotypes (numbers 1–9), within which there are subtypes (letters a, b, c), so a viral infection is known as, for

Sub-module 9.1

Management of coinfections in HIV-positive injecting drug users

example, 1a or 3a or 2b, etc.). Genotypes 1, 2, and 3 are widely distributed throughout the West and in East Asia (Japan, China, Taiwan, Thailand). Types 5 and 6 are mainly confined to South Africa and South-East Asia, respectively, in contrast to type 4, which is predominant in the Middle East and Central Africa. HCV is transmitted primarily by blood-to-blood contact. Sharing injecting equipment and blood transfusion are the most efficient mechanisms of transmission. The rate of vertical transmission (mother to child) is low (<5%). The most important factor in vertical transmission is the level of virus in the mother (high level relates to a high chance of transmission). Sexual transmission is remote in mono-infection due to HCV. In HCV/HIV coinfection, sexual transmission is more common, though still very low. Hepatitis C viral load can be substantially higher in the presence of co-morbid HIV infection. Factors increasing the sexual transmission of hepatitis C in coinfection are high hepatitis C viral load, trauma during sex and possibly the presence of a sexually transmitted infection (STI).

Natural history The natural history of HCV infection is relatively benign, at least in the first few years of infection. Once transmitted, a viraemia develops. This is followed by seroconversion (development of antibodies to hepatitis C), which takes between six weeks and six months to occur. Acute infection is asymptomatic in 60% of individuals. Common symptoms include fatigue, lethargy, nausea and other constitutional symptoms. Jaundice is uncommon and occurs in <25% of individuals. Acute infection spontaneously clears in about 15% of individuals. This generally occurs within the first three to six months of treatment. There is no relationship between the genotype of HCV infection and the likelihood of clearance. The presence of HIV or other immunosuppression markedly reduces the likelihood of viral clearance. The rate of clearance among HIV-positive individuals is between 5% and 8%. If the virus is not cleared within the first few months of treatment, it is very unlikely that viral clearance will occur. Individuals with HIV coinfection generally have substantially higher viral loads than HCV mono-infected individuals. Chronic HCV infection has an indolent course. Around one third of individuals with chronic hepatitis C infection have mild hepatitis with normal liver function tests (LFT). The other two third have abnormal LFT with moderate to severe inflammation. The rate of cirrhosis (significant liver scarring resulting in impaired liver function) is around 20% in those with chronic hepatitis after 20 years of infection. Figure 3. Typical serological course of hepatitis C Typical serological course Symptoms antiHCV

Titre

ALT

Normal 0 1 2 3 4 Months 5 6 1 2 3 Years 4

Time after exposure

Participant Manual

Management of coinfections in HIV-positive injecting drug users

Figure 4. The course of HCV infection

Acute HCV infection

Viral clearance (15%)

Chronic HCV infection Mild 30–40% Normal LFT Moderate – severe 60–70% Abnormal LFT

Chronic hepatitis

Cirrhosis (20% @ 40 years)

End-stage liver diseas e

Hepatocellular cancer (HCC)

Effect of HCV on HIV progression The effect of HCV on HIV progression is somewhat controversial. A number of studies have demonstrated that HCV may accelerate the course of HIV infection. The mechanism is not well known, although HCV is known to have immunomodulatory effects. A number of studies have also demonstrated that when controlled for influencing variables such as CD4 count, age and whether or not on antiretroviral therapy (ART), there is no difference in the progression of HIV between HCV/HIV coinfected and HIV mono-infected individuals. The latter variable (ART) is probably the most important factor. Coinfection is much more common in IDUs, who often have reduced access to effective HIV treatment, thus differences in disease outcome may be attributable to differences in HIV treatment access.

Effect of HIV on HCV progression HIV does influence the progression of HCV in coinfection. Infection with HIV has been shown to result in a higher hepatitis C viral load, liver fibrosis, progression to cirrhosis, liver failure and hepatocellular carcinoma (HCC). Factors associated with an increased risk of liver disease progression in people with HIV/HCV coinfection include heavy alcohol (ethanol) intake (>50 g/day), older age at HCV acquisition, low CD4 count, increased quasispecies variability and occult hepatitis B virus (HBV) infection.

Sub-module 9.1

Management of coinfections in HIV-positive injecting drug users

Despite this, adequate immune reconstitution with ART has been shown to modify the course of HCV in HIV infection including slowing the rate of progression of liver fibrosis and reducing complications from HCV. Better survival rates among individuals with HIV treated with effective ART have also increased the proportion of liver-related mortality and morbidity in developed countries.

Hepatitis C information: do and avoid DO   



  

Vaccinate against hepatitis B and A if required Go for regular health check-ups Stop or reduce alcohol intake: alcohol use significantly increases the risk of developing cirrhosis and liver cancer Protect from reinfection: the presence of hepatitis C antibodies will not protect one from getting infected again Eat a balanced diet of fresh vegetables, fruits, beans, whole grains and lean meats; a healthy balance of protein in the diet Drink lots of fluids Exercise regularly Follow a stress reduction plan Drinking alcohol; even one drink a day can accelerate the progression of liver disease Taking large amounts of acetaminophen (paracetamol) as it is toxic to the liver Taking acetaminophen and alcohol as together they can cause severe liver damage Breathing in pollutants, chemicals, cleaning products, fumes from paint, paint thinners, chemical solvents, spray adhesives, insect sprays and cleaners as these can be harmful to the liver Foods with high salt, sugar or fat content Too much fried foods High doses of vitamins A, D, E or K Taking iron supplements unless advised by the doctor

AVOID    

   

Treatment of HCV in HIV coinfection Hepatitis C treatment is expensive and this limits access to treatment in Asia. Treatment regimen Standard treatment is a subcutaneous injection of pegylated interferon (PEG–IFN) weekly in combination with ribavirin (RBV) tablets or capsules (dose depending on weight and genotype) twice daily. The duration of treatment for HIV/HCV coinfection is 48 weeks for all genotypes. In HCV mono-infection, the treatment length can vary, depending on the genotype. There are two companies that manufacture PEG-IFN, and the dosage will vary depending on the brand used. Pegasys (Roche) is PEG-IFN α2a and is a standard dose for all weights; Pegintron (Schering Plough) is PEG-IFN α2b and the dose varies depending on the weight of the individual. Standard IFN was used in the past, but needs to be administered three times a week and is much less effective.

Participant Manual

Management of coinfections in HIV-positive injecting drug users

Effectiveness (sustained virological response) It is necessary to understand the HCV treatment terminology of HCV infection.

Early virological response (EVR) End-of-treatment response (ETR) Sustained virological response (SVR)

Usually a reduction in viral load 12 weeks into treatment, though this varies by level of reduction and timing Undetectable HCV RNA at the end of treatment

Undetectable HCV RNA at 24 weeks after completion of treatment. Obtaining a sustained virological response is often referred to as a “cure” Non-responder (NR) No significant reduction in HCV RNA levels (<2 log ) after a specified interval of treatment (usually 24 weeks), or no significant decrease in HCV RNA, but HCV RNA never becomes undetectable during treatment. Some non-responders may have improved liver histology after treatment For further information go to www.fda.gov/ohrms/dockets/ac/06/slides/2006-4250s105-FDATauber.ppt 10

Combination PEG-IFN and RBV treatment is effective, with sustained virological response (SVR) rates of between 27% and 40% overall, and up to 73% in genotypes 2 and 3. The treatment of acute hepatitis C in the context of HIV coinfection may be more effective, with an SVR of just over 70% regardless of genotype. A number of studies have shown that it is possible to treat active IDUs for HCV mono-infection and achieve good outcomes. However, few studies have looked at HCV treatment in HIV-coinfected active IDUs. HCV treatment is more effective with better immune function and treatment is most effective with adequate immune function. It is recommended that ART be commenced in individuals with a CD4 count of less than 200 cells/mm3 prior to initiation of treatment for HCV. As a consequence, appropriate ART regimens and effective ART for IDUs in Asia will facilitate effective HCV treatment when this becomes more widely available. If the CD4 count is <200 cells/mm3 then treat HIV first; once a CD4 count >350 cells/mm3 is reached treat HCV. If the CD4 count is >200 cells/mm3, then it is reasonable to treat hepatitis C first.

Reinfection and relapse There are limited data on reinfection and relapse in HIV/HCV coinfection though it appears that reinfection rates are low. Necessary precautions are advised if injecting continues during and after completion of hepatitis C treatment (e.g. the use of clean needles and syringes, and sterile injection techniques). Reinfection refers to infection with a new HCV. The reinfection rate in coinfection is unknown. In HCV mono-infection it is less than 5%. Relapse refers to a re-emergence of the same virus strain, usually relating to viral suppression during treatment beyond the detectable limit and increasing replication post-treatment, bringing the viral load back into the detectable range. The likelihood of relapse is reduced with combination treatment (PEG-IFN and RBV) compared with monotherapy

Sub-module 9.1

Management of coinfections in HIV-positive injecting drug users

(PEG-IFN only). With combination treatment, the relapse rate is around 10% in genotype 1 and 2% in genotypes 2 and 3. This means that between treatment completion and six months after treatment completion, about 10% of genotype 1 HCV moves from being undetectable to becoming detectable, while only 2% of genotypes 2 and 3 do. Information on other genotypes is not available.

Feasibility Interferon-based hepatitis C treatment regimens are difficult to tolerate. Side-effects are many and varied, and patients may need significant psychosocial and medical support. Depression is a very common side-effect and many IDUs may require antidepressant medication by the end of treatment. Selective serotonin reuptake inhibitors (SSRIs) are the first line of therapy in the management of depression during IFN treatment. There is currently no consensus on the use of prophylactic SSRI. Combination PEG-IFN and RBV therapy: Contraindications: Severe cardiac disease (<6 months prior); haemoglobinopathies (e.g. thalassaemia, sickle cell anaemia); creatinine clearance <50 ml/min; decompensated liver cirrhosis; recent, current immunosuppressive therapy (except short-term steroid); autoimmune disease; immunosuppressed transplant patients; uncontrolled thyroid disease; pregnancy, male partners of pregnant women (use contraception for longer than or for 6 months after treatment conclusion), lactation Cardiac, renal disease (monitor); ensure adequate hydration; severe hepatic dysfunction; initial, ongoing laboratory test monitoring (see full product information); diabetes, hypertension (monitor visual function); severe psychiatric conditions (including history); psoriasis; sarcoidosis; the elderly; children <18 years Possibly teratogenic; bone marrow suppression; haemolysis; fever; ocular, pulmonary, cardiovascular effects; local reactions; fatigue; flu-like symptoms; infection; headache; rigors; gastrointestinal upset; anorexia; arthralgia, myalgia; psychiatric, CNS disturbance; insomnia; alopecia; pruritus; dry skin; dental, periodontal disorders; kidney, liver graft rejection (possible); hypertriglyceridaemia; thyroid dysfunction; autoantibody development; autoimmune disorders including thrombocytopenic purpura; gout; others, see full product information Nucleoside analogues including didanosine (ddI), stavudine (d4T), zidovudine (AZT); CYP1A2, CYP2C8/9, CYP2D6 metabolized drugs; shosaikoto (Chinese herb)

Precautions:

Adverse reactions:

Drug interactions:

Particular attention should be paid to patients with cirrhosis. There is a higher risk of liver decompensation during anti-HCV treatment in those with cirrhosis. These individuals should be managed in collaboration with a gastroenterologist or hepatologist. Alcohol use should be discouraged during treatment. This impairs the effectiveness of treatment, particularly when drinking is above 10 g ethanol equivalent per day (1 small beer). Substance use should ideally be treated and stabilized prior to initiation of treatment, with continued management during treatment. Opiate dependence is ideally managed with opioid substitution therapy (OST). Clean injecting equipment should be accessible in case of relapse or continued heroin or other injecting drug use.

Participant Manual

Management of coinfections in HIV-positive injecting drug users

Treatment of HIV in HCV coinfection It has become clear that effective HIV treatment (ART) reduces the progression of liver disease in HIV/HCV coinfected individuals. Despite this, there are a number of precautions that need to be taken.

Hepatotoxicity Abnormal liver function tests are common in HIV/HCV coinfected individuals on ART. Severe dysfunction can lead to hepatotoxicity (markedly abnormal liver function, alanine aminotransferase [ALT] >5x upper limit of normal [ULN]). The mechanism is unclear but may be a combination of the direct effect of medication on the liver cells or a hypersensitivity reaction. Additionally, restoration of immune function with ART may induce immune reactions against the liver cells, causing liver damage – this is known as IRIS (see Sub-module 6.5).

NNTRI-based regimens The WHO 2006 guidelines recommend that efavirenz (EFN) is the preferred non-nucleoside reverse transcriptase inhibitor (NNRTI) option wherever possible in patients who have HIV and hepatitis C coinfection. It is recommended that nevirapine (NVP) be used with care and regular monitoring done in patients who have known HIV/HCV coinfection and grade 3 or lower elevation of ALT. NVP is not recommended for those with ALT elevations of grade 4 or higher.

NTRIs Nucleoside reverse transcriptase inhibitors (NTRIs) have been associated with hepatic steatosis leading to some hepatic dysfunction. Only limited data are available, and generally NTRIs are well tolerated during HIV treatment in coinfection.

PI-based regimens Protease inhibitors (PIs) affect the liver either directly or by affecting the metabolism of other drugs to hepatotoxic ranges. Ritonavir (RTV), particularly at higher doses, has been associated with increased liver function abnormalities and hepatotoxicity. The risk of hepatotoxicity is more than doubled in HIV/HCV coinfection compared with HIV monoinfection.

Choice of ART regimen The decision as to what ART regimen should be used in the treatment of HIV/HCV coinfection depends on the individual. NVP should possibly be avoided in moderate to severe liver dysfunction. Liver function should be monitored at treatment initiation and throughout treatment.

Monitoring during initiation and treatment IDUs with HIV should be tested for HCV antibody prior to HIV treatment initiation. A positive test in the presence of abnormal liver function tests (particularly ALT) should indicate HCV infection. Individuals should be vaccinated against HBV if necessary and if the CD4 count >200 cells/mm3, and asked to avoid alcohol. The LFT should be monitored.

Sub-module 9.1

Management of coinfections in HIV-positive injecting drug users

Conclusion       

HIV/HCV coinfection is very common in HIV-positive IDUs. Test for HCV-Ab + LFT prior to initiating ART. Treat HIV first if CD4 count <200 cells/mm3, then HCV if drugs are available. Avoid alcohol, treat substance use. Advise use of sterile injecting equipment. Use EFV instead of NVP for those with HIV/HCV coinfection. It is possible to use NVP in individuals with <grade 3 elevation of ALT if LFT can be monitored regularly. Do not use NVP if there is grade 4 elevation of ALT.



Hepatitis B coinfection Epidemiology There are over 400 million people living with chronic hepatitis B worldwide, although it is estimated that one third of the world’s population has – at some stage – had HBV infection. The vast majority are in developing countries, including Asia where infection is endemic among neonates and infants. Indeed, hepatitis B is endemic in all of Africa, some parts of South America, Alaska, northern Canada and parts of Greenland, eastern Europe, the eastern Mediterranean area, South-East Asia, China and the Pacific Islands, except Australia, New Zealand and Japan. In most of these areas, 5–15% of the population are chronically infected carriers of HBV. HBV is also more common in IDUs in both developing and developed countries. In western Europe, North America and Australia the prevalence of HBV infection is less than 0.5%. Figure 5. Geographical distribution of chronic HBV infection

HBsAg prevalence >8% - High 2 - 7% - Intermediate <2% - Low

Source: Epidemiology and prevention of viral hepatitis A to E: hepatitis B virus. Division of viral hepatitis, CDC slide set found at: http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/index.htm

Hepatitis B is transmitted vertically (mother to child) in about 5% of pregnancies among hepatitis B

Participant Manual

Management of coinfections in HIV-positive injecting drug users

carriers, and horizontally through unprotected sex, sharing of injecting equipment and importantly through close contact particularly between infants and neonates (perinatal transmission). It is also transmitted through unsterile medical injections and unscreened blood products. It is important to know how HBV is not transmitted. HBV is NOT transmitted through food or water, casual contact, such as hugging or shaking hands, or through kissing, sneezing or coughing. It is not transmitted through breastfeeding. Vaccination does not help individuals who are already infected with HBV. Chronic infection with HBV occurs in 90% of individuals infected in the first six months of life, while if acute infection occurs in adults, >95% clear the virus completely. The global epidemiology of HBV/HIV coinfection is less well understood. Due to the common pathways of transmission and endemic HBV infection in Asia, the prevalence of past exposure in IDUs is extremely high. Figure 6. Prevalence of chronic HBV virus and HCV infection in HIV-positive populations by HIV risk group 80 70 Median percentage positive 60 50 40 30 20 10 0 Total Injection drug use Heterosexual Homosexual Anti-HCV HBsAg

HIV risk group Source: Nakata S et al. Journal of Gastroenterology and Hepatology, 1994

The virus and testing Hepatitis B is a DNA virus of the Hepadnavirus family. It infects and replicates within the hepatocytes (liver cells) though it causes little or no damage to the cells. Liver damage is caused by the immune response to the virus and hence chronic infection results in greater hepatic dysfunction from a chronic immune response. There are seven hepatitis B genotypes. A is pandemic, B and C are found in Asia, D in southern Europe, E in Africa, F in the USA, and G in the USA and France. There appears to be little difference in the extent of disease caused by the different genotypes, although genotype C has been associated with more severe and prolonged disease and may be more difficult to treat. There are a number of different components of the virus that have been identified, which are useful in assessing an individual’s state of infection.

Sub-module 9.1

Management of coinfections in HIV-positive injecting drug users

Table 1. Markers of hepatitis B disease Marker HBsAg HBsAb HBcAb HBeAg HBeAb HBV DNA Source: WHO, 2002.

Full form Hepatitis B surface antigen Hepatitis B surface antibody Hepatitis B core antibody Hepatitis B e antigen Hepatitis B e antibody Hepatitis B DNA

Indicates Current infection with hepatitis B (a carrier) Immunoprotection against hepatitis from either vaccination or previous exposure Previous exposure to hepatitis B Marker of active replication/active disease Marker of inactive disease, so called “e seroconversion” Presence indicates active replication and disease. Amount of DNA is “HBV viral load”

Table 2. Interpretation of hepatitis B tests Test combination HBsAg HBcAb HBsAb HBsAg HBcAb HBsAb HBsAg HBcAb HBsAb HBsAg HBcAb HBsAb Source: WHO, 2002.

Results – – – – + + – – + – + –

Interpretation Susceptible to hepatitis B Past history of HBV with current immunoprotection

Immune due to hepatitis B vaccination

Past history of HBV infection

All IDUs should be tested for hepatitis B, especially if treatment for HIV is to begin. Testing in HIVpositive individuals is more difficult, as markers of the disease may not always be present. Initial tests should include HBsAg and if possible HBsAb and HBcAb. In HIV-positive individuals, HBsAg may be negative although the virus is present and therefore, if available, HBV DNA should be done for confirmation of the disease (occult HBV infection).

Natural history In infancy and early childhood (<2 years old) acute infection is usually asymptomatic but much more likely to result in chronic infection (>90% of individuals <6 months). In adulthood, acute infection is usually symptomatic with jaundice, nausea, fatigue and lethargy in 75% of people, but only <5% go on to have chronic infection. The presence of HIV is more likely to result in chronic infection. In the presence of HIV, HBV viral replication and therefore its viral load are higher. Liver injury is usually reduced with immunosuppression such as in HIV infection. In some people with very high viral loads, HBV can directly cause injury to the liver cells (known as fibrosing cholestatic hepatitis).

Participant Manual

Management of coinfections in HIV-positive injecting drug users

Figure 7. Natural history of hepatitis B Jaundice ALT HBeAg Anti-HBe IgG Anti-HBc HBsAg

Anti-HBs IgM Anti-HBc

100

Weeks after exposure

Symptoms HBeAg anti-HBe

Total anti-HBc

Titre HBsAg IgM anti-HBc Anti-HBs

100

Weeks after exposure

Acute (6 months) HBeAg

Chronic (years) Anti-HBe HBsAg Total anti-HBc

Titre

IgM anti-HBc

12 16 20 24 28 32 36

Year

Weeks after exposure

Source: World Health Organization. Hepatitis B. Geneva, WHO, Department of Communicable Diseases Surveillance and Response, 2002. http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf

Sub-module 9.1

Management of coinfections in HIV-positive injecting drug users

Effect of HBV on HIV progression Early studies in the pre-ART era suggested that HBV infection could be a cofactor in HIV disease; however, more recently it has become clear that this is not the case when other factors are taken into consideration. Evidence from the ART era has suggested that HBV does not appear to alter the course of HIV.

Effect of HIV on HBV progression HIV coinfection influences the course and natural history of HBV infection by impairing the quantity and quality of the innate and adaptive immune response. The rates of spontaneous resolution after acute infection and spontaneous anti-HBe and anti-HBs seroconversion are decreased, and levels of HBV replication are increased in HIV-infected patients. A more rapid progression of liver fibrosis and a higher rate of cirrhosis leading to decompensation (but not HCC) have been demonstrated in coinfected patients. The risk of HBV-associated end-stage liver disease (ESLD) and liver-related mortality may be increased by HIV coinfection. ART can have a major impact on HBV coinfection because of the restoration of immune responses and improved regulation of the immune system. In addition, at least three ARVs (3TC, TDF and FTC) are potent inhibitors of HBV replication. There is also some evidence that 3TC may prevent acute hepatitis B infection in HIV-positive individuals exposed to hepatitis on an ART regimen that contains 3TC.

Treatment of HBV in HIV coinfection Prevention There is an effective vaccine available for the prevention of hepatitis B. All at-risk individuals who are not immunoprotected (no HBsAb nor HBcAb) should be vaccinated. Those who are HIVpositive are less likely to respond to HBV vaccine (especially if the CD4 count is <200 cells/mm3), have lower mean antibody titres (by a factor of about 30), and lose protective antibody levels more quickly. The vaccination regimen in coinfection should be 0, 1, 6 months or 0, 1, 2, 12 months. Nonresponders should have a further three shots at double the dose.

Treatment regimen Treatment of hepatitis B in HIV coinfection is complex. HIV coinfected individuals are less likely to respond to treatment, yet a number of agents used to treat hepatitis B are also used to treat HIV. There are a number of drugs registered to treat hepatitis B: 3TC (a nucleoside analogue), adefovir, dipivoxil (nucleotide analogue reverse transcriptase inhibitor), entecavir (a purine-derived nucleoside analogue) and PEG-IFN a2a; TDF (a nucleotide reverse transcriptase inhibitor) and FTC are also effective in suppressing HBV. 3TC inhibits HBV replication in up to 87% of HIV/HBV coinfected patients, while anti-HBe seroconversion occurs in up to 11% of patients. Mutations in the replication mechanism of HBV lead to resistance to 3TC in 47% of patients at two years and 90% at four years of treatment. Adefovir dipivoxil taken 10 mg PO daily has been shown to reduce the viral load though resistance does develop. In combination with 3TC, resistance is less likely.

Participant Manual

Management of coinfections in HIV-positive injecting drug users

TDF has been shown to be effective in treating hepatitis B in coinfected individuals and there is no evidence of resistance developing. It is also effective against 3TC resistant hepatitis B. Entecavir has been shown to reduce the hepatitis B viral load in coinfected individuals with a low risk of development of resistance by HBV and by HIV to ART. Its suggested use is in people not requiring ART. PEG-IFN (48 weeks of weekly 180 log subcutaneous injection) has been shown to be more effective than 3TC in inducing HBeAg seroconversion, reducing the viral load and in normalizing liver function. Side-effects: 3TC is well tolerated and safe; however, development of HBV resistance is frequent. Adefovir has a nephrotoxic potential and may at least theoretically induce ARV resistance in HBV/HIV patients treated with it. TDF has gastrointestinal side-effects, is associated with hypophosphataemia that has not been known to induce serious osteopenia so far, and may have a nephrotoxic potential. The following treatment is recommended (Australasian Society for HIV Medicine 2003): In individuals requiring HBV treatment but not HIV treatment: It is reasonable to delay treatment for hepatitis B. If treatment is desired then use PEG-IFN or a non-ART agent to avoid the development of resistance to the agent (e.g. entecavir or adefovir dipivoxil). In individuals requiring both HBV treatment and HIV treatment: ARVs with HBV activity should be included in the regimen. If a single agent is used, TDF has a better resistance profile. If two agents can be used then 3TC and TDF should be used. 3TC can be used alone but HBV resistance will eventually occur. In individuals not requiring HBV treatment, but requiring HIV treatment: If hepatitis B replication is under control (HBV DNA <4 log10 copies/ml), ART need not contain agents with dual activity. The type of ART regimen should be determined as per usual indications. In individuals with resistance to 3TC: Suspect if the HBV viral load increases by 1 log10 copies/ml. Add TDF to the regimen if only 3TC is being used. Switching to adefovir or entecavir can also be dose. In individuals with cirrhosis: These patients are at risk for hepatic decompensation (failure) when ART is initiated, particularly if the CD4 count is low and viral load of HBV is high. Therefore, use a combination (e.g. 3TC + TDF) initially to reduce the viral load before commencing full ART.

Treatment of HBV is expensive, and therefore inaccessible to many people. In resource-poor settings, the key issues are:    

Vaccination for hepatitis B Stabilization of drug use with appropriate treatment (e.g. OST) Reduction and ideally cessation of alcohol use Use of ARVs in the treatment of HIV with activity against HBV.

Sub-module 9.1

Management of coinfections in HIV-positive injecting drug users

Effectiveness Limited data are available on the effectiveness of HBV treatment in HBV/HIV coinfection. Effectiveness of HBV treatment can be measured by: HBV DNA level:  This is called the HBV viral load and is the best way to monitor the effectiveness of  treatment. It is also the most expensive. 3TC reduces the viral load by almost 3 log10 copies/ml after 1 year of treatment.  Adefovir dipiroxil reduces viral load by 4 log10 copies/ml after 1 year of treatment.  TDF reduces the viral load by 4 log10 copies/ml regardless of resistance to 3TC.   HBeAg seroconversion: This signifies the development of HBeAb as a result of treatment and indicates control  of replication.  Only a minority of individuals on treatment will have HBeAg seroconversion.  ALT levels:  ALT levels are an inexpensive way to monitor therapy, but can be difficult to interpret.  There is a clear correlation between the decrease in viral load and reduction in ALT levels.  There is also a clear correlation between improvement in ALT levels and that of liver histology scores during therapy.  ALT can rise during:  Control of viral replication (due to restoration of immune function)  Liver toxicity from drug therapy.

Resistance Resistance is more common with 3TC therapy and less so with adefovir dipivoxil or TDF. Mutations that explain resistance have been identified, but resistance testing is expensive and often unavailable. It is important to remember that TDF is active against 3TC-resistant HBV.

Treatment of HIV in HBV coinfection This is discussed above, but the important aspects are: 

It is usually unnecessary to treat HBV infection when there is no indication for HIV treatment. Additionally exposing the individual to the development of resistance to ARVs is unwise. When HIV treatment is indicated, use a regimen with agents such as 3TC and/or TDF, which also have activity against HBV. In individuals with cirrhosis, low CD4 counts and high HBV viral load, control HBV replication prior to starting ART. EFV is the preferred NNRTI option in individuals with HBV/HIV coinfection. NVP may be used with care and regular monitoring in patients who have known HBV/HIV coinfection and ≤grade 3 elevation of ALT. NVP is not recommended for those with ≥grade 4 ALT elevation.

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Management of coinfections in HIV-positive injecting drug users

HBV flares on ART HBV flares may occur during ART in HBV/HIV coinfection as a presentation of the immune reconstitution inflammatory syndrome (IRIS). Flares are characterized by an acute rise in hepatic transaminases accompanied by symptoms of acute hepatitis (fatigue, abdominal pain and jaundice). These reactions generally occur during the first few months of treatment and may be difficult to distinguish from ART-induced hepatic toxicity. Drugs active against HBV should preferably be continued during a suspected flare, and, if the patient is receiving 3TC monotherapy, consideration should be given to the addition of TDF if available. If it is not possible to distinguish a serious hepatitis B flare from a grade 4 ART toxicity, all ARV drugs should be withheld until the clinical condition improves.

HBV flares when ART is stopped There is also a risk of a flare of HBV when HBV-active drugs are stopped. Fatal cases of acute HBV infection have been documented in HBV/HIV coinfected patients who discontinue 3TC monotherapy. Patients with coinfection who need to stop the HBV-active drugs in the HIV treatment regimen (3TC, FTC or TDF) should be closely monitored. If a patient is known to have chronic HBV, it is recommended that 3TC be continued as part of second-line ART following initial ART failure, even if it has been used in first-line treatment.

Conclusion          

Hepatitis B is very common in HIV-positive IDUs. All HIV-positive IDUs should be screened for HBV. All HIV-positive IDUs should be vaccinated against HBV if not already immunoprotected. Treatment for hepatitis B should generally be withheld until there is an indication to treat HIV. HIV treatment regimens in the context of hepatitis B should incorporate agents that have activity against hepatitis B. ALT should be monitored during HBV treatment. TDF should be used in case of 3TC resistance. EFV is the preferred NNRTI option in individuals with HBV/HIV coinfection. NVP may be used with care and regular monitoring in patients who have known HBV/HIV coinfection and ≤grade 3 elevation of ALT. NVP is not recommended for those with ≥grade 4 ALT elevation.

References and recommended reading Aceijas C, Rhodes T. Global estimates of prevalence of HCV infection among injecting drug users. International Journal on Drug Policy, 2007, 18:352–358. Amin J et al. HIV and hepatitis C coinfection within the CAESAR study. HIV Medicine, 2004, 5:174–179. Benhamou Y et al. Factors affecting liver fibrosis in human immunodeficiency virus-and hepatitis C virus-coinfected patients: impact of protease inhibitor therapy. Hepatology, 2001, 34:283–287. Dore G, Sasadeusz J (eds), Co-infection with HIV and viral hepatitis: a guide for clinical management. Sydney, Australasian Society of HIV Medicine, 2003 (http://www.ashm.org.au/coinfectionmanagement/). Epidemiology and prevention of viral hepatitis A to E: hepatitis B virus. Division of viral hepatitis, CDC slide set found at: http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/index.htm

Sub-module 9.1

Management of coinfections in HIV-positive injecting drug users

Fattovich G et al. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis. Hepatology, 1995, 21:77–82. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology, 2004, 127(5 Suppl 1):S35–S50. HIVandhepatitis.com web site (http://www.hivandhepatitis.com/). Ikeda K et al. Interferon decreases hepatocellular carcinogenesis in patients with cirrhosis caused by the hepatitis B virus: a pilot study. Cancer, 1998, 82:827–835. Lai C et al. Viral hepatitis B. Lancet, 2003, 362:2089–2094. Lai CL et al. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clinical Infectious Diseases, 2003, 36:687–696. Epub 2003 Mar 5. Locarnini S et al. Management of antiviral resistance in patients with chronic hepatitis B. Antiviral Therapy, 2004, 9:679–693. Mocroft A et al; EuroSIDA Study Group. Reasons for stopping antiretrovirals used in an initial highly active antiretroviral regimen: increased incidence of stopping due to toxicity or patient/ physician choice in patients with hepatitis C coinfection. AIDS Research and Human Retroviruses, 2005, 21:743–752. Nakata S et al. Hepatitis C and virus infections in populations at low or high risk in Ho Chi Minh and Hanoi, Vietnam. Journal of Gastroenterology and Hepatology, 1994, 9:416–419. Poynard T et al. Viral hepatitis C. Lancet, 2003, 362:2095–2100. Proceedings of the 1st European consensus conference on the treatment of chronic hepatitis B and C in HIV co-infected patients. Journal of Hepatology, 2006, 44(Supplement 1):S1–S152. Rockstroh JK et al; EuroSIDA Study Group. Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy. Journal of Infectious Diseases, 2005, 192:992–1002. Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infectious Diseases, 2005, 5:558–567 Swan T, Raymond D. Hepatitis C virus (HCV) and HIV/HCV co-infection: a critical review of research and treatment. New York, Treatment Action Group (TAG), 2004 (http://www.aidsinfonyc.org/tag/coinf/ hcv2004/). Torriani FJ et al.; APRICOT Study Group. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. New England Journal of Medicine, 2004, 351:438–450. University of California, San Francisco. HIV insite website. University of California, San Francisco http://hivinsite.ucsf.edu/accessed 2006. Wong JB. Costs of antiviral therapy of chronic hepatitis B. NIH meeting “Management of Hepatitis B,” 7 April 2006. World Health Organization. Hepatitis B. Geneva, World Health Organization, Department of Communicable Diseases Surveillance and Response, 2002 (http://www.who.int/csr/disease/ hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf ). Yim HJ, Lok AS. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology, 2006, 43(2 Suppl 1):S173–S181.

Participant Manual

Sub-module

9.2 Overview

Management of HIV/TB coinfection in IDUs

F º  4

Objectives: By the end of the session participants will be able:  To describe the epidemiology of TB among IDUs and PLWHA  To use the WHO guidelines to prescribe co-trimoxazole prophylaxis in HIV-infected patients  To describe care and treatment interventions for HIV-infected IDUs with active TB  To appropriately use ART in HIV-infected IDUs with active TB

Time to complete session: 1 hour 15 minutes Session content:  Care and support for HIV-infected individuals with active TB  Co-trimoxazole preventive treatment and hiv-associated active tb  Principles of antiretroviral therapy Training materials:  PowerPoint presentation 9.2: Management of HIV/TB coinfection in IDUs  Sub-module 9.2: Management of HIV/TB coinfection in IDUs  Exercise 9.2.1: Case studies 1, 2, 3

Management of coinfections in HIV-positive injecting drug users

care and support for HIV-infected individuals with active TB Background The public health approach to decrease the burden of TB/HIV requires more effective delivery of the available interventions for HIV-infected individuals including those with TB/HIV coinfection or active TB disease by health service providers. Increased population coverage by these interventions is also needed. HIV-infected patients, including those with active TB, should benefit from HIV/AIDS care, treatment and support. Whereas previous national TB and AIDS programmes have largely pursued separate courses, they need to look for synergy in supporting health service providers to deliver care and treatment for HIV-infected individuals with TB. A key operational issue is that HIV programmes are largely vertical, with care centred in a small number of tertiary referral centres or specialized clinics in most countries. TB programmes are administratively vertical, but services are disseminated and integrated into the primary health-care systems down to the sub-district/health centre level. Other issues remain in determining optimal cross-referral procedures, care integration and patient monitoring. Significant administrative, social, stigma-related and ethical barriers to successful collaboration remain to be addressed. Thailand is the only country in the Region, and one of the few in the world, where TB and HIV services are equally decentralized down to the sub-district level.

Concept of comprehensive HIV/AIDS care Comprehensive HIV/AIDS care is a holistic approach to meeting the needs of HIV-infected individuals. Several studies have been conducted in the Asia-Pacific Region to assess the needs of persons living with HIV (PLWHA). The following needs were identified (WHO SEARO, 2002a). Providing comprehensive HIV care includes:      

Clinical and nursing care for those affected to alleviate the symptoms of HIV disease Psychosocial support and ongoing counselling Financial support or employment opportunities for PLWHA Housing and legal assistance Care and support for orphans and widows Information and training of caregivers and affected people.

Comprehensive care should link the formal (health facilities including health centres) and informal (family and community care) sections of the health system in a cohesive network of services. The success of a comprehensive continuum of care model depends on the cooperation and collaboration of health-care workers at all levels (primary, secondary and tertiary) and the active involvement of communities at risk, PLWHA and their families and caregivers. The “continuum of care” stands for the seamless movement of PLWHA to and from the formal to the informal health services. If comprehensive care across the continuum operates successfully, then it will facilitate:  

An improvement in the duration and quality of life of PLWHA A reduction in the level of stigma and discrimination in clinical and community care settings Alleviation of the impact of HIV and AIDS

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Management of coinfections in HIV-positive injecting drug users

The comprehensive care model builds on the existing health system. Strategies to provide comprehensive care include:  Involving formal and informal health-care services at the district and sub-district levels in the national scale-up plan  Defining the roles of each institution and health cadre at all levels of care including monitoring and supervision  Defining and/or establishing referral networks so that PLWHA can access appropriate services when they are needed  Establishing formal linkages between community-based and facility-based services to regularly exchange information and strengthen partnerships between care providers  Capacity building including at the district and sub-district levels and developing appropriate training tools and methodologies  Providing appropriate opportunities for health-care workers and care providers (both formal and informal) to identify gaps in skills and services. The full involvement of PLWHA peers in HIV services such as in day-care centres or centres for comprehensive and continuous care is a key approach for ensuring treatment adherence and facilitating follow up of people.

experience from thailand The consortium of Thai Network for People Living with HIV/AIDS (TNP-plus) and other NGOs received support from the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) in 2003 to strengthen PLWHA involvement in the comprehensive continuum of care (CCC) centres. As of October 2004 the programme had been expanded to 114 hospitals and one women’s prison covering nearly 10 000 PLWHA on care and treatment. The number of PLWHA followed in each CCC centre ranged from 6 to 350. PLWHA support groups provide education on ART literacy and peer counselling including for treatment adherence. They also work as volunteers for providing logistic support to health-care workers and patients such as filling in forms, transporting files, problem-solving, conducting inpatient visits, providing outreach for home care and support, and tracing of defaulters. PLWHA disclose their HIV status upon entering the PLWHA group. At the district level this implies disclosure of the HIV status to the family and community. These groups allow PLWHA to address factors that may affect their adherence to ART, such as side-effects, lack of family and emotional support, lack of treatment information and advice on taking pills regularly and on time. PLWHA groups and NGOs also support and encourage enrolment in the national ART programme (Kumphitak et al. 2004).

Models for the delivery of HIV/AIDS care and treatment for HIV-infected TB patients, in particular during TB treatment, are less well described. Collaboration between the TB and HIV programmes is essential for the delivery of an integrated package of HIV and TB services for HIV-infected TB patients (WHO, 2004).

CO-trImOxAZOle preVentIVe treAtment And HIV-ASSOCIAted ACtIVe tB Co-trimoxazole (CTX) preventive treatment is the gold standard in developed countries for HIVinfected individuals with CD4+ T-cell counts <200 cells/mm3 to prevent Pneumocystis jiroveci pneumonia (PCP) , a common opportunistic infection (OI) with a high mortality (USPHA/IDSA, 2001). This common OI and other bacterial infections cause considerable morbidity during the treatment of HIV-infected TB cases. Studies have shown that preventive treatment with CTX against

Sub-module 9.2

Management of coinfections in HIV-positive injecting drug users

these infections decreased morbidity and mortality in HIV-infected patients with TB disease in Africa. A study conducted in Côte d’Ivoire (Africa) showed a significant benefit of CTX prophylaxis against some bacterial causes of pneumonia and diarrhoea and their complications (Wiktor, 1999; Wagner, 2001; Havlir, 1999). A cohort study conducted in Malawi compared an HIV-seropositive TB cohort receiving CTX for 12 months with a historical comparison group who were not receiving CTX. Both cohorts received TB treatment as per the national directly observed treatment, shortcourse (DOTS) strategy. Survival of HIV-positive TB patients improved dramatically with the addition of CTX prophylaxis to the treatment regimen (Mwaungulu, 2004). Data on the prevalence of OIs and the use of CTX are less well documented in Asian countries. PCP is the second most commonly reported OI in Thailand and India after TB (MOPH Thailand, 2003; Hira, 1998). The Thai HIV/AIDS clinical management guidelines recommend the use of CTX (MOPH, 2000). All HIV-infected patients with a CD4+ T-cell count <200 cells/mm3 are offered CTX in Thai health facilities. Further studies are necessary to evaluate the best models for the use of CTX in HIVinfected TB patients in Asia and the Pacific. While all HIV-exposed infants and children should benefit from CTX preventive therapy, this intervention is particularly important in children coinfected with TB and HIV. WHO recommends the use of CTX preventive treatment in HIV-infected individuals as part of a minimum package of care for PLWHA (World Health Organization. Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents and adults: recommendations for a public health approach. Geneva, Switzerland, WHO, 2006.).

Principles of antiretroviral therapy (ART) Antiretroviral treatment and TB Due to the high prevalence of TB among HIV-infected individuals living in the Asia–Pacific Region, many patients who are candidates for ART will have active TB (Narain, 2002). HIV-infected persons with active TB will often be offered ART because those with pulmonary TB meet the criteria for WHO stage 3 disease and those with extrapulmonary TB for WHO stage 4. ART may be highly beneficial in reducing case-fatality rates in these persons (Girardi, 2001; Badri, 2002). In addition, patients already receiving ART may develop clinical TB. ART in individuals undergoing treatment for TB merits special consideration because co-management of HIV and TB is complicated by:     

Drug interactions between rifampicin and several classes of ARVs High pill burden Difficulties in adherence to treatment Drug toxicity Immune reconstitution inflammatory syndrome (IRIS) (Kwara, 2005)

The treatment of TB remains a central priority for patient care. TB treatment following the DOTS strategy should be initiated promptly in diagnosed cases of TB regardless of the HIV serostatus (Santoro-Lopes, 2002). Other guidelines and materials should be consulted for more guidance on ART. In this rapidly evolving field, it is highly recommended to consult regularly updated treatment guidelines and the literature. The WHO websites are useful sources of up-to-date guidance (http://www.who.int/HIV, http://www. searo.who.int/aids, http://www.wpro.who.int). They also provide links to treatment-related websites.

Participant Manual

Management of coinfections in HIV-positive injecting drug users

Antiretroviral drugs in adults and adolescents When to start ART in adults and adolescents WHO recommends that in resource-limited settings, HIV-infected adolescents and adults should start ART when they have confirmed HIV infection and one of the conditions shown in Tables 3 and 4. When to start ART in adults and adolescents with active TB disease In HIV-infected persons being treated for TB, the optimal timing of initiation of ART is not known. On the one hand, case-fatality rates in patients with TB during the first two months of TB treatment are high, particularly in high HIV-prevalence settings, arguing for early treatment initiation (Corbett, 2003). On the other hand, considerations of drug interactions between rifampicin and several classes of ARVs, a high pill burden, toxicity and IRIS support the later initiation of ART. Table 3. Recommendations for starting antiretroviral therapy in adults and adolescents with documented HIV infection if CD4 testing is available Clinically advanced and severe/very advanced HIV disease WHO stage 4 WHO stage 3 Disease irrespective of CD4+ T-cell count Consider using CD4+ T-cell counts <350 cells/mm3 to assist decisionmakinga Treatment should be considered if CD4 cell counts ≤200 cells/mm3b Treatment should be considered in individuals with CD4 cell counts <350 cells/mm3, particularly if in the 200–250 cells/mm3 range a CD4 cell count advisable to assist with determining need for immediate therapy. For example, pulmonary TB may occur at any CD4 level and other conditions may be mimicked by non-HIV aetiologies (e.g. chronic diarrhoea, prolonged fever). The precise CD4 count above 200 cells/mm3 at which ART should be started has not been established.

Mildly symptomatic and asymptomatic disease WHO stage 2, 1

Table 4. Recommendations for starting antiretroviral therapy in adults and adolescents with documented HIV infection if CD4 testing is not available Clinically advanced and severe/very advanced HIV disease WHO stage 4 WHO stage 3 Irrespective of total lymphocyte count (TLC) Irrespective of (TLC)

Mildly symptomatic and asymptomatic disease WHO stage 2 a With TLC <1200 cells/mm3a

A TLC of ≤1200 cells/mm3 can be substituted for the CD4+ T-cell count when the latter is unavailable and there is moderate HIV disease (stage 2). It is not useful in asymptomatic patients. Thus, in the absence of CD4 testing, asymptomatic HIV-infected patients (WHO stage 1) should not be treated because there is currently no other reliable marker available in severely resourceconstrained settings.

Sub-module 9.2

Management of coinfections in HIV-positive injecting drug users

The optimum time at which to commence ART in a patient with TB/HIV coinfection is unknown. Initiation of ART is recommended for TB patients at very high risk for HIV disease progression and mortality. For patients with a CD4+ T-cell count <200 cells/mm3, ART is recommended as soon as the TB therapy is tolerated, usually between 2 weeks and 2 months (Table 5). For patients who develop TB with CD4+ T-cell counts in the 200–350 cells/mm3 range, ART should be started after the first two months of TB therapy, because the toxicity of TB treatment is greatest in the first two months of treatment. In patients with CD4+ T-cell counts >350 cells/mm3, ART should be deferred and the patient monitored closely. Where CD4 counts are not available, WHO recommends that ART be considered after the intensive phase of TB treatment. Clinical judgement may indicate earlier or later initiation. Table 5. ART recommendations for individuals with HIV-related TB if CD4 count is available CD4+ T-cell count <200 cells/mm3 Recommended regimen Start TB treatment. Start one of the regimens below as soon as TB treatment is tolerated (between 2 weeks and 2 months)a. EFV-containing regimen b 200–350 cells/mm3 Start TB treatment. Start one of the regimens below after initiation phase (if severely compromised start earlier). >350 cells/mm3 Not available Start TB treatment. Start TB treatment. Start one of the regimens below after initiation phase (if severely compromised start earlier). a b c d Timing of ART initiation should be up to clinical judgement based on other signs of immunodeficiency. First-line treatment regimen alternatives to EFV- or ABC (300 mg bid)-containing regimens. For other alternatives please see text below. Unless non-TB WHO stage 4 conditions are present. Otherwise, consider ART upon completion of TB treatment. If no other signs of immunodeficiency are present and patient is improving on TB treatment, ART should be started upon completion of TB treatment. Defer ARTc Consider ARTa,d Recommend ART Comments Recommend ART

First-line ART regimens in the setting of TB treatment for adults and adolescents An NNRTI plus two NRTIs is the recommended first-line ART regimen in resource-limited settings. Accumulating data from these settings support the use of first-line NNRTI-containing ARV regimens in patients receiving rifampicin for TB. EFV is the recommended NNRTI, but its use may be impaired by its limited availability in several nationally supported ART programmes and restrictions in pregnant women or women of childbearing age (Bristol-Myers Squibb Company, 2005). NVP is an alternative agent, but has a greater risk of hepatotoxicity, which can be life-threatening. This makes the drug less suitable for treating patients who use other hepatotoxic medications, such as rifampicin and for persons with high CD4+ T-cell count or for whom the CD4+ T-cell count is not known. Triple NRTIs (ABC + zidovudine [AZT] + 3TC or TDF + AZT + 3TC) are an additional option and can be used during pregnancy, in HIV-2 infection or in patients with higher CD4+ T-cell counts; data are limited to support this recommendation (Department of Health & Human Services, 2006).

Participant Manual

Management of coinfections in HIV-positive injecting drug users

efavirenz + 2 nrtIs EFV remains the NNRTI of choice. EFV blood levels are decreased in the presence of rifampicin. Until more data justify an EFV dose increase, WHO recommends the standard 600 mg dose of EFV, which can be administered as a once-daily tablet. Due to concerns related to teratogenicity, EFV should not be used in women of childbearing age (without adequate contraception) or those who are in the first trimester of pregnancy.

nevirapine +2 nrtIs NVP should only be used if EFV is not available. For all patients receiving NVP plus rifampicin, close clinical and laboratory monitoring of liver enzymes is advised due to the increased risk of hepatotoxicity. NVP levels are also decreased in the presence of rifampicin. However, given the high therapeutic index of NVP, and the recent studies from South Africa and Thailand showing good short-term outcome related to antiviral activity and few adverse events in patients receiving both drugs, expert opinion that states dose adjustment may not be required (Autar, 2004; Oliva, 2003; Ribera, 2001; Dean, 1999; Van Cutsem, 2005). This area requires further investigation, as there is a large interpatient variability in NVP levels and exposure among HIV-infected persons, independently of any rifampicin interaction (Cozzi-Lepri, 2002). NVP is not recommended for women with CD4+ T-cell counts >250 cells/mm3 and men with CD4+ T-cell counts >400 cells/ mm3 due to an increased risk of hepatotoxicity.

triple nrtI Triple NRTI therapy (ABC + AZT + 3TC or TDF + AZT + 3TC) is an alternative regimen for women likely to be or to become pregnant, in persons with higher CD4+ T-cell counts where the risk of NVP toxicity is increased and in special conditions such as HBV and HCV-induced hepatitis. Pregnant women can safely take ABC, 3TC and AZT. This regimen has no drug interactions with rifampicin. Concerns regarding this triple NRTI regimen are antiviral potency, limited data among patients with TB and monitoring for the hypersensitivity syndrome reaction (associated with ABC). TDF, 3TC and AZT have no or minimal interactions with rifampicin, but efficacy data are limited for patients with TB (Gulik, 2004).

Development of active TB in adults and adolescents receiving ART ART decreases the incidence of TB in treated cohorts by approximately 80%, but rates of TB among treated patients nevertheless remain persistently higher than among HIV-negative individuals (Williams, 2003). Although recent evidence shows that TB should be considered as an advanced/ late HIV OI, the development of an episode of TB still occurs across a wide range of CD4+ T-cell counts (Scano, 2005). In addition, subclinical or undiagnosed TB often presents within the first six months after initiation of ART (Seyler, 2005). For these reasons, it is difficult to determine if an episode of TB in a patient receiving ART indicates treatment failure and requires switching of the ART regimen. Until further data are available, WHO recommends that if an episode of TB occurs in a patient receiving ART, an ART regimen compatible with the TB treatment regimen should be continued during TB treatment. If a person is receiving a NVP-based regimen, EFV should be substituted for NVP and continued until two weeks after rifampicin is completed, then EFV should be substituted for NVP. If EFV is contraindicated or not available, the NVP-based regimen should be continued during TB treatment with careful monitoring of liver function and drug toxicity.

Sub-module 9.2

Management of coinfections in HIV-positive injecting drug users

ART second-line treatment options are limited for patients with TB with clear evidence of a failing ART regimen. The second-line treatment options are described elsewhere.

Immune reconstitution inflammatory syndrome IRIS, a worsening of clinical disease after initial improvement, may occur in up to a third of persons with TB who initiate ART (see Sub-module 6.5). The average time of onset is two months after ART initiation, but can occur as early as five days. TB-associated IRIS most commonly presents with fever and clinical deterioration of pre-existing lymphadenopathy or respiratory disease. Several reports suggest that IRIS is more common if ART is started early in the course of TB treatment and if the patient has a low CD4+ T-cell count. Most cases resolve without any intervention and ART can be safely continued. Serious reactions such as tracheal compression due to massive adenopathy may require a short course of steroids (1–2 mg/ kg of prednisolone) based on clinical judgement (Narita, 1998; Kumarasamy, 2004; Lawn, 2005).

References and recommended reading Agence Nationale de Recherche sur le SIDA (ANRS) 1260. See Nguyen Hong Duc et al. High prevalence of Pneumocystis carinii as a common cause of community-acquired pneumonia in patient with HIV-infection in Ho Chi Minh City, Viet Nam. www.unaids.org.vn/othersupport/ cmhcm/docs/PCPFeb2004-VF.pdf American Thoracic Society/Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Official Statement of the American Thoracic Society adopted by the ATS Board of Directors, July 1999. American Journal of Respiratory and Critical Care Medicine, 2000, 161:221S–247S. Autar RS et al. What is the clinical relevance of the drug interaction between nevirapine and rifampin? XV International AIDS Conference July 2004. Bangkok, 2004 (abstract B11784). Badri M, Wilson D, Wood R. Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet, 2002, 359:2059–2064. Bristol-Myers Squibb Company. Re: important change in SUSTIVA® (efavirenz) package insert — change from pregnancy category C to D. March 2005 (http://www.fda.gov/medwatch/safety/2005/ Sustiva_DHCPletter-061005.pdf ). Chariyalertsak S, Sirisanthana T, Saengwonloey O, Nelson KE. Clinical presentation and risk behaviors of patients with acquired immunodeficiency syndrome in Thailand, 1994–1998: regional variation and temporal trends. Clinical Infectious Diseases, 2001, 32:955–962. Epub 2001 Mar 7 Corbett EL et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Archives of Internal Medicine, 2003, 163:1009–1021. Cozzi-Lepri A et al. Virologic and immunologic response to regimens containing nevirapine or efavirenz in combination with 2 nucleoside analogues in the Italian cohort naïve antiretrovirals (ICoNA) study. Journal of Infectious Diseases, 2002, 185:1062–1069. Dean GL, Back DJ, De Ruiter A. Effect of tuberculosis therapy on nevirapine trough plasma concentrations. AIDS, 1999, 13: 2489–2490. Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Bethesda, MD, DHHS, 2006 (http://aidsinfo.nih.gov/contentfiles/ AdultandAdolescentGL.pdf ).

Participant Manual

Management of coinfections in HIV-positive injecting drug users

Girardi E et al. Changing clinical presentation and survival in HIV-associated tuberculosis after highly active antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes, 2001, 26:326–331. Gulik R M et al. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. New England Journal of Medicine, 2004, 350:1850–1861. Havlir DV, Barnes PF. Tuberculosis in patients with human immunodeficiency virus infection. New England Journal of Medicine, 1999, 340:367–373. Hira SK, Dore GJ, Sirisanthana T. Clinical spectrum of HIV/AIDS in the Asia–Pacific Region. AIDS, 1998, 12 (Suppl B):S145–S154. Kumarasamy N et al. Incidence of immune reconstitution syndrome in HIV/tuberculosis-coinfected patients after initiation of generic antiretroviral therapy in India. Journal of Acquired Immune Deficiency Syndromes, 2004, 37:1574–1576. Kumphitak A et al. Involvement of people living with HIV/AIDS in treatment preparedness in Thailand: case study. Geneva, WHO, 2004. Kwara A, Flaning T. Highly active antiretroviral therapy (HAART) in adults with tuberculosis: current status. International Journal of Tuberculosis and Lung Disease, 2005, 9:248–257. Lawn SD, Bekker L, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infectious Diseases, 2005, 5:361–373. Louie JK et al. Opportunistic infections in hospitalized HIV-infected adults in Ho Chi Minh City, Vietnam: a cross-sectional study. International Journal of STD and AIDS, 2004, 15:758–761. Ministry of Public Health Thailand. National guidelines for the clinical management of HIV infection in children and adults, 6th edition. Bangkok, MOPH Thailand, 2000. Ministry of Public Health, Thailand. Thai AIDS Newsletter. Bangkok, MOPH Thailand, 2003. Mwaungulu FB et al. Cotrimoxazole prophylaxis reduces mortality in human immunodeficiency virus-positive tuberculosis patients in Karonga District, Malawi. Bulletin of the World Health Organization, 2004, 82:354–363. Narain JP, Pontali E, Tripathy S. Epidemiology and control strategy. Symposium on HIV and TB. Indian Journal of TB, 2002, 49:3–9. Narita M et al. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. American Journal of Respiratory and Critical Care Medicine, 1998, 158:157–161. Oliva J et al. Co-administration of rifampin and nevirapine in HIV-infected patients with tuberculosis. AIDS, 2003, 17:637–642. Ribera E et al. Pharmacokinetic interaction between nevirapine and rifampin in HIV-infected patients with tuberculosis. Journal of Acquired Immune Deficiency Syndromes, 2001, 28:450–453. Santoro-Lopes G et al. Reduced risk of TB among Brazilian patients with advanced human immunodeficiency virus infection treated with highly active antiretroviral therapy. Clinical Infectious Diseases, 2002, 34:543–546. Scano F, Toskin I, Nunn P. Immunological status and prognosis of HIV-infected patients with active tuberculosis. 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment, 24–27 July 2005, Rio de Janeiro, Brazil.

Sub-module 9.2

Management of coinfections in HIV-positive injecting drug users

Seyler C, Toure S, Messou E. Risk factors for active tuberculosis after antiretroviral treatment initiation in Abidjan. American Journal of Respiratory and Critical Care Medicine, 2005, 172:123–127. Small PM, Fujiwara PI. Medical progress: management of tuberculosis in the United States. New England Journal of Medicine, 2001, 345:189–200. Tansuphasawadikul S et al. Clinical presentation of hospitalized adult patients with HIV infection and AIDS in Bangkok, Thailand. Journal of Acquired Immune Deficiency Syndromes, 1999, 21:326–332. USPHA/IDSA. Guidelines for preventing opportunistic infections among HIV-infected persons. USPHA/ IDSA, 2001 (http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5108a1.htm). Van Cutsem G et al. TB/HIV co-infected patients on rifampicin containing treatment have equivalent ART treatment outcomes, and concurrent use of nevirapine is not associated with increased hepatotoxicity. 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment, 24–27 July 2005, Rio de Janeiro, Brazil. Wagner KR, Bishai WR. Issues in the treatment of Mycobacterium tuberculosis in patients with human immunodeficiency virus infection. AIDS, 2001, 15 (Suppl 5):S203–S212. World Health Organization. Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents and adults: recommendations for a public health approach. Geneva, Switzerland, WHO, 2006. WHO. Planning and implementing HIV/AIDS care programmes: a step-by-step approach. New Delhi, WHO Regional office for South-East Asia, 2002a. WHO. Interim policy on TB/HIV collaborative activities. Geneva, WHO, 2004 (WHO/HTM/TB/2004.330, WHO/HTM/HIV/2004.1). WHO. The use of antiretroviral therapy: a simplified approach for resource constrained countries. New Delhi, WHO Regional office for South-East Asia, 2002b. WHO. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. Geneva, WHO, 2006. Wiktor S et al. Efficacy of trimethoprim–sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1-infected patients with tuberculosis in Abidjan, Cote d’Ivoire: a randomised controlled study. Lancet, 1999, 353:1469–1475. Wiktor SZ et al. Short-course oral zidovudine for prevention of mother-to-child transmission of HIV-1 in Abidjan, Côte d’Ivoire: a randomised trial. Lancet, 1999, 353:781–785. Williams B, Dye C. Antiretroviral drugs for tuberculosis control in the era of HIV/AIDS. Science, 2003, 301:1535–1537.

Participant Manual

Management of coinfections in HIV-positive injecting drug users

Exercise 9.2.1 Case studies Case 1 A 36-year-old male presents with a four-week history of fever, cough, fatigue, poor appetite and a weight loss of 6 kg. He just tested positive for HIV in the voluntary counselling and testing (VCT) centre today and was referred to the clinic for further evaluation. He does not have any previous illnesses and is not on any medications. He first injected drugs in 1999 and quit in 2003. He currently works as a motorcycle taxi driver and lives with his wife. Physical exam: Temp 390C, HR 110 beats/min, BP 110/90 mmHg, RR 18/min, weight 44 kg Head eye ear nose and throat (HEENT): oral thrush Neck: multiple lymph nodes on the right side 1–2 cm in size Lungs: scattered rales, no wheezing Heart, abdomen: normal Skin: no rashes

1) What WHO clinical stage is the patient in? 2) What further evaluation would you do at this time? 3) What is the most probable diagnosis? 4) What further diagnostic evaluation would you do? 5) What is the diagnosis? 6) What do you treat first: TB or HIV? 7) Does the patient meet the criteria for initiating ART? 8) When will you start ART? 9) What ART regimen would you start?

Sub-module 9.2

Management of coinfections in HIV-positive injecting drug users

Case 2 A 24-year-old male is referred from the TB clinic after testing positive for HIV. He is on the third week of treatment for pulmonary TB and is tolerating the treatment well. His fever has resolved and he gained 2 kg since starting treatment. His cough is better but he still coughs at night. His medical history is notable for chronic hepatitis B infection and one episode of herpes zoster two years ago. He smokes ½ pack of cigarettes a day. He does not drink alcohol. He still uses heroin twice a day, but has been trying to decrease the amount he uses each time. Physical exam: No significant abnormalities noted CBC: WBC 5600 cells/mm3 (25% lymphocytes), Hb 10 g/dl, platelets 155 000/µl CD4 225 cells/mm3 ALT 76 IU/ml, AST 65 IU/ml HCV positive, HBsAg positive

Laboratory exam:

1) Does the patient meet the criteria for initiating ART?

2) Does current injecting drug use disqualify the patient for ART?

3) When would you start ART in this patient?

4) Which ART regimen would you use?

Participant Manual

Management of coinfections in HIV-positive injecting drug users

Case 3 A 20-year-old male patient returns to the clinic for routine follow up. He was started on ART with d4T/3TC/NVP six weeks ago. Baseline CD4 count was 105 cells/mm3. At four weeks he was feeling well without any symptoms and results of routine blood testing (complete blood count [CBC], ALT, AST) were normal. Today he complains of fever, cough with white sputum, and a 1 kg weight loss over the past 10 days. He started injecting drugs when he was 14 years of age and was admitted to a rehabilitation centre four years ago. He was released from the centre six months ago and now lives with his family. He does not use drugs currently. Physical exam: Temp 38.0ºC, RR 16/min, HR 88 beats/min, BP 120/76 mmHg HEENT: no thrush Neck: no lymphadenopathy Lungs: rales and wheezing on the upper left side Heart: regular rhythm without murmurs Abdomen: normal Skin: no rashes Chest X-ray: left upper lobe infiltrate Sputum AFB: positive

1) What is the diagnosis?

2) Do these findings indicate failure of the ART regimen?

3) The patient is started on rifampicin, isoniazid, pyrazinamide and ethambutol (RHZE) for TB. Will you stop the ART?

4) Will you change the ART regimen?

Sub-module 9.2

Management of coinfections in HIV-positive injecting drug users

Case studies: answers and notes Case 1 1) What WHO clinical stage is the patient in? Clinical stage 3: weight loss >10% and oral thrush

2) What further evaluation would you do at this time? Routine laboratory tests, chest X-ray, sputum for acid-fast bacilli (AFB), CD4 count (if available) Results of laboratory testing: CBC: WBC 3600 (25% lymphocytes) Haematocrit 31%, Hb 9.2 g/dl, platelets 135 000/µl CD4: 95 cells/mm3 ALT 46 IU/ml, AST 50 IU/ml HCV positive, HBsAg negative AFB x 3: negative Chest X-ray: Right upper lobe infiltrates and interstitial infiltrate throughout

3) What is the most probable diagnosis? Although the sputum is AFB negative, the most likely diagnosis is TB. The interstitial infiltrate on CXR is commonly seen with miliary TB, in which tubercle bacilli spread through the blood and the sputum is usually negative for AFB. The differential diagnosis would also include PCP and bacterial pneumonia. Less common causes would be viral pneumonia, fungal pneumonia, and Mycobacterium avium complex (MAC).

4) What further diagnostic evaluation would you do? Rule out TB first: a repeat AFB would be reasonable. If AFB not found in the sputum, do a lymph node aspirate or biopsy. Sputum staining for bacteria, PCP and fungi should be done, if available. Cultures may also be helpful, although the results take longer. Result: Aspiration of a cervical lymph node is positive for AFB.

5) What is the diagnosis? TB lymphadenitis. TB is presumably causing the pulmonary disease as well.

6) What is the WHO clinical stage of the patient? Extrapulmonary TB indicates WHO clinical stage 4.

7) What do you treat first: the TB or the HIV? Start TB treatment first and consider ART when indicated.

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Management of coinfections in HIV-positive injecting drug users

8) Does the patient fulfil the criteria for ART? Yes, WHO stage 4 and CD4 count 95 cells/mm3.

9) When will you start ART? Between 2 and 8 weeks, as soon as the patient tolerates the TB treatment.

10) What ART would you start? Preferred regimen: 2 NRTI + EFV Other options: 2 NRTI + NVP, 3 NRTI

Case 2 1) Does the patient meet the criteria for initiating ART? Yes, clinical stage 3 (pulmonary TB) and CD4 count <350 cells/mm3

2) Does current injecting drug use disqualify the patient for ART? No, active drug use is not a reason to deny care or ART. However, the patient should be referred for counselling and drug treatment, where available. Drug use can be associated with decreased adherence: active IDUs should be carefully counselled and monitored for adherence.

3) When would you start ART in this patient? After 8 weeks, when the intensive phase of TB treatment is completed.

4) What ART regimen would you use? If the patient continues on rifampicin:  EFV-based regimens preferred  NVP or triple NRTI regimens can be given, but monitor closely for hepatic toxicity if NVP used If the patient continues on isoniazid and ethambutol:  EFV or NVP regimens can be given NOTE: The patient has high risk for hepatic toxicity due to chronic HBV, baseline elevated ALT, and use of TB drugs. Check ALT at 8 weeks before starting ART and follow closely.

Sub-module 9.2

Management of coinfections in HIV-positive injecting drug users

Case 3 1) What is the diagnosis? Active pulmonary TB.

2) Is this failure of the ART regimen? No, development of active pulmonary TB while on ART does not indicate treatment failure and is common in the first six months of treatment.

3) The patient is started on RHZE for TB. Will you stop the ART? NO! DO NOT STOP THE ART! You should continue ART while treating TB.

4) Will you change the ART regimen? Concerns about NVP use with rifampin. Preferred regimen is 2 NRTI + EFV, if available. Other options: 3 NRTI or continue 2 NRTI + NVP. If NVP continued: monitor closely for hepatic toxicity.

Participant Manual

Annex 1

presentation 9.1: HIV/HCV and HIV/HBV coinfections Session objectives Understand 

The epidemiology and background of HCV/HIV and HBV/HIV coinfection The influence of viral hepatitis on HIV progression The influence of HIV on progression of viral hepatitis Coinfection Treatment of HIV in viral hepatitis coinfection Treatment of viral hepatitis in HIV coinfection Future treatment of viral hepatitis in the presence of HIV infection

Viral hepatitis coinfection in HIV-infected IDUs

 

   

Epidemiology of HCV  

Hepatitis C coinfection 

Management of hepatitis C in HIVcoinfected IDUs



170 million people have hepatitis C worldwide Between 5% and 60% of HIV-positive individuals worldwide are HCV antibody positive (depending on the country) Over 90% of HIV-infected IDUs are also HCV-positive Transmitted by:   



Blood-to-blood contact Blood products (unscreened) such as transfusions Not commonly spread via sexual contact except (potentially) in setting of HIV/HCV coinfection in men who have sex with men (MSM) especially with sexually transmitted infections (STIs) Rarely mother-to-child except in setting of HIV/HCV coinfection [19% HIV/HCV versus 3.5% HCV]

Epidemiology Prevalence of HCV worldwide 

Background: HCV virus RNA flavivirus similar to dengue and Japanese encephalitis virus RNA viruses (such as HIV) are more prone to mutate than DNA viruses (such as HBV) and therefore often harder to treat Exists as many different variants during infection (quasispecies) 9 genotypes (subtypes), distribution varies   



Genotypes 1, 2, 3  Western countries and East Asia Genotype 4  Middle East and Central Africa Genotypes 5, 6  South Africa and South-East Asia

Source: Aceijas C, Rhodes T. International Journal on Drug Policy, 2007.

Management of coinfections in HIV-positive injecting drug users

Background: natural history HCV monoinfection Acute HCV infection 

Effect of HCV on HIV progression Limited long-term effect on HIV-associated mortality when CD4 count, age and HIV treatment taken into account 

Viral clearance (15%)

Chronic HCV infection Mild 30–40% Normal LFT Moderate – severe 60–70% Abnormal LFT

HCV/HIV coinfected individuals may do worse than others many as more likely to be IDUs



Increased LFT abnormalities following initiation of ARV (possibly immune, viral, toxicity) Liver-associated mortality increased in HIV/HCV coinfection Infection with multiple HCV genotypes may increase progression of HIV disease

 Chronic hepatitis Cirrhosis (20% @ 40 years)



End-stage liver diseas e

Hepatocellular cancer (HCC)

Coinfection: HIV and HCV Impact of HCV on HIV disease progression (EuroSIDA study: 33% HCV+, 1960/5957) 

Effect of HIV on HCV progression 

Univariate New AIDS 1.18 illness (1.03–1.35) Any death 1.79 (1.56–2.06) New AIDS/ 1.44 death (1.29–1.60) Liver disease- 10.02 related death (6.17–16.27)

Multivariate 0.78 (0.62–0.98) 1.80 (1.44–2.25) 1.06 (0.89–1.28) 12.31 (6.77–2.41)



Increased progression to cirrhosis [at 10 years HIV-uninfected 2.6% versus 14.9% HIV-infected] Increased liver failure, hepatocellular carcinoma (HCC) increased risk 6x to 11x in HIV coinfected Factors associated with progression of liver disease in HCV/HIV coinfection are: 

   

Heavy alcohol (ethanol) intake (>50 g/day) [some studies] Uncontrolled plasma HIV RNA Low CD4 count [some studies] Increased quasispecies variability Occult HBV infection (hepatitis B infection that is undetectable)



Source: Rockstroh JK et al; EuroSIDA Study Group. Journal of Infectious Diseases, 2005.

Effective ART improves outcome of HCV disease [especially if suppresses plasma HIV RNA]

Coinfection: HIV and HCV Impact of ART on liver disease mortality (EuroSIDA) 10 Incidence rate ratio (95% CI)

HCV/HIV coinfection: impact of ART 0.77

Percentage of patients with cirrhosis

<0.0001

0.0015

0.0039

0.0082

0.72

Other factors predictive Age at infection > 50g alcohol/day Low CD4 count

PI untreated 25 PI treated

Unadjusted 0.1 none <2 years 2–4 years >4 years none

Adjusted

0 <2 years 2–4 years > 4 years Duration of cART

Estimated HCV Infection duration (years) Source: Mocroft A et al; EuroSIDA Study Group. AIDS Research and Human Retroviruses, 2005. Source: Benhamou Y et al. Hepatology, 2001.

Participant Manual

Management of coinfections in HIV-positive injecting drug users

Mr NS – 1 

Mr NS, age 24 years, married man, presents after wife found to HIV-infected: prevention of motherto-child transmission (PMTCT) programme Well, past five years and occasional current IDU (heroin x 1/week), alcohol twice weekly Recent weight loss 8 kg Examination: weight 56 kg, no fever, no peripheral signs of chronic liver disease, liver edge palpable



 

Mr NS – 2      

Mr NS – 3     

HIV antibody test positive WCC 1000 cells/mm3 Hb 11 g/dl Platelets 43000/µl ALT 50 IU/ml What further investigations, advice, treatment should be considered?

WHO stage III HCVAb positive HBsAg negative; HBcAb positive Likely HCV infection, no evidence of HBV Management?

Mr NS – 4  

Mr NS – 5 

 

Cease alcohol Consider treatment for heroin addiction (e.g. methadone) Safe injection advice/education ART 

Advice about symptoms of hepatotoxicity  

Nausea and vomiting Dark urine and jaundice Feels well Gains 5 kg, non-tender liver Repeat Hb 11.4 g/dl; platelets 170 000 µl; WCC 2000 cells/mm3 ALT 160 IU/ml



At one-month follow up:   

AZT/3TC/EFV





Management/advice?

Annex 1

Management of coinfections in HIV-positive injecting drug users

Mr NS – 6 

Hepatitis C: dos and don’ts DO:  Vaccinate against hepatitis B    and A, if required Regular health check-ups Stop or reduce alcohol intake Protect from re-infection; having hepatitis C antibodies will not protect from reinfection Eat a balanced diet of fresh vegetables, fruits, beans, whole grains and lean meats; a healthy balance of protein in the diet Drink lots of fluids Exercise regularly Make a stress reduction plan

Continue and monitor 

Initial hepatotoxicity commonly transient

AVOID:  Drinking alcohol  Taking large amounts of  Acetaminophen and alcohol  acetaminophen (paracetamol) together can cause severe liver damage Breathing in pollutants, chemicals, cleaning products, fumes from paint, paint thinners, chemical solvents, spray adhesives, insect sprays and cleaners can be harmful to the liver Foods with high salt, sugar or fat content Fally foods High doses of vitamins A, D, E or K Taking iron supplements unless advised by the doctor



Future access to HCV treatment to be reconsidered



   

  

Treatment of HIV in HCV coinfection – 1 

Treatment of HIV in HCV coinfection – 2 Choice of ART regimen 



Abnormal LFT is common and often occur early and are asymptomatic so important to monitor symptoms and LFT Severe hepatotoxicity (symptoms +/or ALT >5 x upper limit of normal [ULN]) USUALLY requires stopping ART Monitoring during initiation and treatment  

Depends on individual, but avoid hepatotoxic drugs NNTRI-based regimens 



Caution with NVP Can cause hepatic steatosis (fatty liver) AVOID ddI and d4T with RBV Can cause liver injury (especially high-dose RTV)



HCV test and LFT prior to treatment Question about symptoms, regular (every 3 months) + LFT during treatment If NVP-containing ART, use with caution  Women have increased risk of reaction (rash without fever; fever and rash; fever, rash and hepatitis)



NTRI  



PI-based regimens 

Management of hepatotoxicity in HCV/HIV coinfected individuals 

Hepatitis C terminology in treatment response Acronym EVR Refers to Early virological response End-of-treatment response Sustained virological response Non-responder Meaning Usually a reduction in viral load 12 weeks into treatment, though this varies by level of reduction and timing Undetectable HCV RNA at the end of treatment Undetectable HCV RNA at 24 weeks after completion of treatment. Obtaining a sustained virological response is often referred to as a “cure” No significant reduction in HCV RNA levels (<2 log ) after a specified interval of treatment (usually 24 weeks), or no significant decrease in HCV RNA, but never becomes HCV RNA undetectable during treatment. Some non-responders may have improved liver histology after treatment 10

Overall rate 10% 

Risk factors > 5 x ULN enzymes: AST =/or ALT >1.25 ULN at ARV commencement Platelet count < 99 000/µl Other hepatotoxic medications Creatinine >1.5 ULN

ETR SVR



Mortality reduced in ART treated despite hepatotoxicity Educate patient about symptoms of hepatotoxicity: jaundice; darkening of urine; right upper quadrant pain; nausea, anorexia, pruritus or fatigue Mild initial abnormalities of LFT NOT indication to stop ART, rather to monitor

Participant Manual

Management of coinfections in HIV-positive injecting drug users

Treatment of HCV in HIV coinfection  

Treatment is expensive which limits accessibility Current preferred treatment regimen: 

HCV treatment - APRICOT study sustained virological response HCV treatment - APRICOT study Sustained virological Response 60% 50% % of Patients 40% 30% 20% 12% 10% 0% n = 285 n = 286 n = 289

Pegylated (PEG-IFN) interferon (SC weekly injection) + RBV 800 mg (PO daily) for 48 weeks [RBV weightbased in genotype 1] Sustained viral clearance in 27% interferon and 40% PEG/RBV overall, and up to 73% in genotype non-1 PEG/RBV Treat HIV first if CD4 <200 cells/mm3 Treat HCV first if CD4 >350 cells/mm3, significantly improved outcome if ART and plasma HIV RNA suppressed [consider concurrent ART]



Effectiveness (SVR) 

P < 0.0001 P < 0.0001

40% P = 0.0084



Which virus to treat first currently uncertain – guidelines say:  

20%

IFN alfa-2a + Rib

PEGINF alfa 2a + Placebo

PEGINF alfa 2a + Rib



New treatments on the horizon, HCV protease inhibitors

Source: Torriani FJ et al; APRICOT Study Group. New England Journal of Medicine, 2004.

Treatment of HCV in HIV coinfection – 1 

Treatment of HCV in HIV coinfection – 2 

Reinfection (infection with new virus)  

Limited data, probably uncommon Prevent with HCV transmission prevention interventions (needle–syringe programmes, etc.) Almost always happens in first six months after treatment 10% in genotype 1 2% in genotypes 2 and 3

Treatment is difficult but effective to clear/cure HCV especially in favourable genotypes. Side-effects: 



Relapse (return of original virus) 

 



IFN:  Depression (treat aggressively with selective serotonin reuptake inhibitors [SSRI])  Flu-like symptoms (treat with paracetamol)  Neutropenia (reduce dose if <0.75, <0.5 may require cessation of treatment) RBV  Haemolytic anaemia (may require dose reduction if symptomatic)  DO NOT use with ddI plus/minus d4T in liver failure

Treatment of HCV in HIV coinfection – 3 

Conclusion 

Substance use treatment 

Needs to be evidence-based (e.g. OST) Treatment of HCV is teratogenic (for both males and females) therefore two forms of contraception should be used (barrier and oral contraceptive pill) No pregnancy should occur before ~6 months of stopping RBV



Prevention of pregnancy 

    



 

HCV/HIV coinfection is very common in HIV-infected IDUs Test for HCV plus LFT prior to HIV treatment if possible Treat HIV in all as indicated (WHO 3 or 4) Avoid alcohol, treat substance use Advise use of sterile injecting equipment Use NVP in HIV treatment with care Asymptomatic change in LFT not an indication to cease ARVs Monitor LFT during HIV treatment If possible consider HCV treatment, currently PEG/ RBV, future HCV protease inhibitors

Annex 1

Management of coinfections in HIV-positive injecting drug users

Epidemiology  

Hepatitis B coinfection Management of hepatitis B in HIV coinfected IDUs



400 million infected worldwide, with 500 000 deaths each year as a result Endemic in Asia and Africa (10–15% chronically infected) Low prevalence in western Europe, North America and Australia Transmission    

Mother-to-child (5% chance) Close contact between infants, mother (perinatal) Unprotected sex Blood-to-blood (sharing injecting equipment, unscreened transfusions)



Chronic infection very common in infancy, very uncommon in adult acute infection Epidemiology of HBV/HIV less well understood, though IDUs in Asia are at high risk

Geographical distribution of chronic HBV infection

Hepatitis B prevalence Hepatitis B prevalence Overall U.S. prevalence: 0.3% Asian Americans: ~10–13% Laotians Vietnamese Korean Japanese

HBsAg prevalence >8% - High 2 - 7% - Intermediate <2% - Low

Filipino Chinese 0% 2% 2001.

10%

12%

14%

Source: World Health Organization. Hepatitis B. Geneva, WHO, Department of Communicable Diseases Surveillance and Response, 2002. http://www.who. int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf World Health Organization, 2002.

Son D. Asian American and Pacific Islander Journal of Health, 2001. Slide courtesy of Robert Gish, MD

Background: Hepatitis B virus    

Background: HBV markers Marker HBsAg HBsAb Full form Hepatitis B surface antigen Hepatitis B surface antibody Indicates Current infection with hepatitis B (a carrier) Immunoprotection against hepatitis from either vaccination or previous exposure Previous exposure to hepatitis B Marker of active replication/ active disease Marker of inactive disease, so called “e seroconversion” Presence indicates active replication and disease. Amount of DNA is “HBV viral load”

DNA hepadnavirus Infects liver cells (hepatocytes) Liver damage is from immune injury Eight hepatitis B genotypes: may relate to hepatocellular carcinoma (HCC) (including subtype Ba) or response to INF       

A is pandemic (USA, Africa, W. Europe) B and C are found in Asia D in Southern Europe, India and Africa E in West Africa F in the USA, Central and South America G in the USA and France H unclear

HBcAb Hepatitis B core antibody HBeAg Hepatitis B e antigen HBeAb Hepatitis B e antibody HBV Hepatitis B DNA DNA

Participant Manual

Management of coinfections in HIV-positive injecting drug users

Background: HBV markers Test combination HBsAg HBcAb HBsAb HBsAg HBcAb HBsAb HBsAg HBcAb HBsAb HBsAg HBcAb HBsAb Results + + + + Past history of HBV with current immunoprotection Immune due to hepatitis B vaccination Past history of HBV infection Interpretation Susceptible to hepatitis B

Hepatitis B disease progression Hepatitis B disease progression 5%-10% of chronic HBVinfected individuals 1 Liver Cancer (HCC)

Acute Infection

Chronic Infection

>30% of CHB individuals2 Cirrhosis

Liver Transplantation

Death

• > 90% of infected children progress to chronic disease • < 5% of infected immunocompetent adults progress to chronic disease

Liver Failure (Decompensation)

23% of patients decompensate within 5 years of developing cirrhosis 1

Fattovich G et al. Hepatology, 1995; Ikeda K et al. Cancer, 1998.

Adverse outcomes in chronic HBV: Adverse outcomes in chronic HBV: annual incidence annual incidence Chronic HBV Infection Chronic HBV Infection <1.0% 2-6% for HBeAg(+) hepatitis B 8-10% for HBeAg(-) hepatitis B

Effect of HBV on HIV progression 

Inactive Carrier State

Early studies suggested HBV may increase HIV progression BUT following ART now considered that HBV infection does not accelerate HIV progression Acute post-ART flare 10–15% with reported mortality; risk CD4 count <200 cells/mm3 Viral resistance is increased in HBV/HIV coinfected individuals, possible contributing factors:   

 <0.2%

Compensated Cirrhosis 3-5% Decompensated Cirrhosis

2-3%



7-8%

Hepatocellular Carcinoma 20-50%

20-50%

Death

Higher HBV viral load difficulty suppressing Monotherapy Interrupted treatment due to hepatotoxicity

Yim HJ, Lok AS. Hepatology, 2006; Fattovich G et al. Gastroenterology, 2004.

Effect of HBV on HIV progression 

Mr LM – 1  

HIV results in:     

32-year-old male IDU Injects heroin/methamphetamine, often mixing these with diazepam, less drug use recently Began injecting at 19 years, spent four years in prison Diagnosed HIV-positive seven years ago, during prison sentence Abnormal liver function test: ALT 60 IU/ml Now shingles, oral candidiasis Management?

Higher HBV viral load Reduced HBeAg seroconversion Increased liver fibrosis and cirrhosis No change in liver cancer rates Increased liver-related mortality



Effective ART can reduce progression, but care needs to be taken   





Resistance Immune flares: early Withdrawal hepatitis when cessation of 3TC and/or TDF Drug toxicity with NVP (early) and RTV

  

Annex 1

Management of coinfections in HIV-positive injecting drug users

Mr LM – 2 

Mr LM – 3 

Initial tests  

Possibilities:   

WCC 900 cells/mm3 CD4 count 40 cells/mm3, ALT 130 IU/ml, HBsAg positive, HCVAb negative



 

Commenced on d4T/3TC/NVP Two weeks later, developed nausea, fever, right upper quadrant tenderness Continues to inject occasionally Response? ALT = 957 IU/ml? Options? 

Probably immune reconstitution inflammatory syndrome (IRIS) from hepatitis B   

Immune restoration Hepatotoxicity (e.g. NVP) Superinfection with HCV

   

Management options:  

He has a low CD4 count  increased risk Known HBsAg positive Likely high viral load

 

Cease ART Cease ART except 3TC +/- other HBV active agent (e.g. TDF, entecavir) Ideally, commence 3TC before HIV treatment Monitor symptoms and recommence ART when normalized  d4T/3TC/EFV

Treatment of HIV in HBV coinfection 

Prevention of HBV in HIV infection 

Hepatotoxicity 

Prevention   

Does occur and causes are similar to HCV/HIV coinfection  Immune  Hepatotoxicity Use ARVs with activity against hepatitis B (3TC, TDF) possibly better if combined improved efficacy and resistance (no RCT data yet) Test for hepatitis B (at least HBsAg) and do LFT prior to ART commencement Monitor ALT regularly (every three months in the first year) during HIV treatment



Choice of ART regimen 



Monitoring during initiation and treatment 

Safe sex (barrier protection) Sterile injecting equipment Vaccination of all IDUs (if no existing immunoprotection)  0, 1 and 6 months or 0, 1, 2 and 12 months  Double dose (40 µg/ dose); repeat post-ART if no response  Need CD4 count>200 cells/mm3 for immune response – CONSIDER delay until immune recovery



Currently available treatment of HBV – 1 

Currently available treatment of HBV – 2 

3TC 300 mg/day 

Adefovir divipoxil 10 mg/day    

 

Cheapest, most prone to resistance (usually in 1–4 years), also used in HIV treatment Reduces viral load in 85% of people Few side-effects Low resistance, also used in HIV treatment Effective in 3TC-resistant hepatitis B Well tolerated, may cause renal dysfunction (rare) Cross-resistance with 3TC Reduces HBV viral load equivalent to 3TC Side-effects include rash, skin pigmentation



TDF 300 mg/day   

Entecavir 0.5 mg/day or 1 mg/day in 3TC resistance  

Reduction HBV DNA substantial but slow Not effective in HIV treatment at this dose Renal toxicity at increased doses Resistance develops slowly but not cross-resistant 3TC, reduced in combination with 3TC Low rates of resistance, no effect HIV Potent HBV suppression



PEG-IFN  



Emtricitabine (FTC) 200 mg/day   



Very expensive Most effective treatment (weekly SC injections for 48 weeks) Low resistance? But many side-effects especially in cirrhotics No advantage in combination with 3TC

Participant Manual

Management of coinfections in HIV-positive injecting drug users

Treatment of HBV in HIV coinfection 

In individuals requiring HIV treatment and HBV treatment: 

ARVs with hepatitis B activity should be included in the regimen.  If only one agent available use 3TC. 3TC can be used alone but resistance will develop.  If other single agents, use TDF [better resistance profile].  If two agents possible, then 3TC plus TDF.

In individuals requiring HBV treatment and not HIV treatment:  



In individuals requiring HIV treatment and not HBV treatment:  

Delay treatment Use pegylated interferon (PEG-IFN) or a non-ART agent to avoid resistance developing to the agent (e.g. adefovir [ADV], entecavir) Suspect if HBV viral load increases by 1 log10 copies/ ml or recurrent elevation of ALT after suppression Add TDF to regimen if only using 3TC. Can also add ADV or entecavir (if ART is not necessary)

Type of ART regimen should be determined by normal indications. If hepatitis B replication is under control (HBV DNA <4 log10 copies/ ml), ART does not have to contain agents with dual activity. These patients are at risk of hepatic decompensation (failure) when ART is initiated, particularly if CD4 count is low and HBV viral load is high. Therefore use combination (e.g. 3TC + TDF) initially to reduce HBV viral load before commencement of full ART if possible.



In individuals with 3TC resistance: 



In individuals with cirrhosis:  



Treatment of HBV in HIV coinfection: effectiveness 

HBV treatment: resistance   

HBV DNA level    

Most common with 3TC – 70% by four years Least common with TDF – rare single reports Dual therapy (ADV + 3TC) results in less risk of mutations–little data as yet Resistance mutations can be identified by analysis of HBV DNA, but this is expensive, recurrent HBV DNA , flare of ALT also occurs in some



HBeAg seroconversion  

This is called viral load and is the best way to monitor effectiveness of treatment. It is also the most expensive. 3TC reduces viral load by almost 3–5 log10 copies/ml after one year of treatment. ADV reduces viral load by 4 log10 copies/ml after one year of treatment. TDF reduces viral load by 5 log10 copies/ml regardless of resistance to 3TC. Development of HBeAb is a result of treatment which indicates control of replication. Only a minority of individuals on treatment will obtain HBeAg seroconversion: 3TC 25%; ADF 30%; PEG-INF 30%. Cheapest, but can be difficult to interpret Decreased viral load = decreased ALT Decreased ALT levels = better histology (on liver biopsy) during therapy ALT can rise during:  Control of viral replication (due to restoration of immune function)  Liver toxicity from drug therapy  Immune flares



ALT levels    

Development of resistance to 3TC Incidence of YMDD resistance increases with the duraction of therapy

Coinfection: HIV and HBV HBV polymerase resistance mutations M A1 T

V1 100%

LAM 80% Incidence of YMDD Mutants (%) 60% 42% 40% 20% 0% Year 1 Year 2 Year 3 Year 4 24% 53% 70%

ADV ETV LdT FTC

Source: Lai CL et al. Clinical Infectious Diseases, 2003.

Source: Locarnini S et al. Antiviral Therapy, 2004.

Annex 1

Management of coinfections in HIV-positive injecting drug users

Feasibility of HBV treatment in resource-limited settings 

Conclusion  

Can be difficult to treat HBV in HIV coinfection in resource-limited areas, therefore:    





Vaccinate for HBV Stabilize drug use (e.g. OST) Advise reduction or cessation of alcohol use Delay HBV treatment until commencement of ART unless cirrhotic and low CD4 count Use ARVs with HBV suppression activity in the treatment of HIV DO NOT withdraw 3TC without consideration of HBV disease (risk of flares)



HBV is very common in HIV-infected IDUs. All HIV-positive IDUs should be screened for HBV. HIV-positive IDUs should be vaccinated against HBV if not immune. Treatment for HBV should be withheld until indication to treat HIV. HIV treatment regimens in the context of HBV should include those ARVs that suppress HBV. ALT should be monitored during HIV/HBV treatment. Combined 3TC/TDF should be considered in HIV/HBV coinfection and in 3TC resistance.

Participant Manual

Annex 2

presentation 9.2: management of HIV/tB coinfection in Idus Session objectives 

Describe the epidemiology of HIV/TB coinfection in South-East Asia Use the WHO guidelines to prescribe co-trimoxazole (CTX) preventive treatment Describe care and treatment for HIV-infected IDUs with active TB Prescribe appropriate ARVs for HIV-infected IDUs with active TB



Management of HIV/TB coinfection in IDUs



Tuberculosis: pathogenesis 

TB transmission Transmitted by inhalation of infectious droplet nuclei from infected person Sputum smear positive (SS+) pulmonary TB cases account for most TB transmission in the community Most TB infections (90% in non-HIV infected people) remain latent PLWHA and IDUs have higher rates of progression to active TB or reactivation of latent infection



Source: Small PM, Fujiwara PI. New England Journal of Medicine, 2001

Incidence of active TB in persons with positive tuberculin skin test Risk factor Latent TB infection (>1 year) IDU HIV-negative Recent TB infection (<1 year) IDU HIV-positive HIV/AIDS TB cases/1000 person-years 1.6 10 12.9 76 35–162

TB/HIV coinfection 

TB is the most common opportunistic infection (OI) among HIV-infected patients in developing countries IDUs have a higher incidence of active TB infection, regardless of HIV status The manifestations of TB may be different in PLWHA WHO recommends screening: 





ALL TB patients for HIV (voluntary counselling and testing [VCT]) ALL HIV patients for TB infection

Source: American Thoracic Society/Centers for Disease Control and Prevention. American Journal of Respiratory and Critical Care Medicine, 2000.

Management of coinfections in HIV-positive injecting drug users

Prevalence of OIs among persons with AIDS, Thailand (2 series)         

OI distribution in 100 HIV/AIDS patients at Tropical Disease Hospital (HCMC, Viet Nam) – 2000        

Tuberculosis Cryptococcosis Wasting syndrome P. jiroveci pneumonia (PCP) Bacterial pneumonia Oesophageal candidiasis Penicillium marneffei infection Toxoplasmosis Cryptosporidiosis

Prevalence 29–37% 19–38% 8–28% 5–20% 4% 3–6% 3% 2–3% 1–2%

Oral thrush Tuberculosis Wasting syndrome Respiratory infections Cryptococcosis Penicilliosis PCP Septicaemia

53% 37% 34% 13% 9% 7% 5% 4%

Sources: Chariyalertsak S et al. Clinical Infectious Diseases, 2001; Tansuphasawadikul S et al. Journal of Acquired Immune Deficiency Syndromes, 1999.

Source: Louie JK et al. International Journal of STD and AIDS, 2004.

Causes of respiratory infections among 295 PLWHAs in Cambodia 

Pneumocystis jiroveci pneumonia (PCP) Common cause of respiratory infections in SE Asia Increased risk with CD4 count<200 cells/mm3 Prevention: CTX 960 mg once a day WHO criteria for CTX prophylaxis in adults:  

TB PCP Bacteria Mycosis Non-TB mycobacteria Strongyloides Cancer

39% 30% 16% 6% 5% 4.7% 0.3%

  

No CD4 testing: WHO clinical stages 2,3,4 CD4 testing available:  WHO clinical stages 3-4  CD4 count <200 cells/mm3 (for PCP and toxoplasmosis)

Source: Agence Nationale de Recherche sur le SIDA (ANRS) 1260, 2004.

2006 WHO guidelines for CTX prophylaxis in infants and children SITUATION INFANTS AND CHILDREN CONFIRMEDb TO BE LIVING WITH HIV <1 YEAR 1–4 YEARS ≥ 5 YEARS CTX prophylaxis is CTX prophylaxis WHO clinical Follow adult universally indicated, is indicated restages 2, 3 and recommendastarting at four to gardless of CD4 4 regarless of tions six weeks after birth percentage or CD4 percentand maintained until clinical status age OR cessation of risk of HIV Any WHO stage infection and CD4 <25% Universal option prophylaxis for all infants and children born to mothers confirmed or suspected of living with HIV. This strategy may be considered in settings with high prevalence of HIV high infant mortality due to infectious diseases and limited health infrastructure [C-IV]. HIV-EXPOSED INFANTS AND CHILDRENa

CTX prevents many infections in PLWHA: Infection Pneumonia Pathogen Pneumocystis jiroveci Strep. pneumoniae Haemophilus inﬂuenzae Salmonella Strep. pneumoniae Toxoplasma gondii Staph. and Strep. species Malaria

Bacteriaemias Encephalitis Skin infections Protozoa

a. Until six weeks after complete cessation of breastfeeding and infection can be excluded b. Confirmation by virological testing among children <18 months c. Once started, continue CTX until 5 years of age Source: WHO, 2006.

Participant Manual

Management of coinfections in HIV-positive injecting drug users

CTX preventive treatment (CPT) significantly decreases mortality and hospital admissions in HIV-associated active TB

PCP prophylaxis 

For patients allergic to CTX: 

Dapsone: adults 100 mg once a day Adults:  CD4 count >200–350 cells/mm3 after six months of ART  If no CD4 count available: on ART for one year with no new clinical stage 2, 3, or 4 events



30 25

When can CTX be stopped? 

CPT n=386 No CPT n=385

Per 100 person-years

20 15 10 5 0 With CPT Source: Wiktor SZ et al. Lancet, 1999.

Deaths Hospital admissions

No CPT

Treatment for TB  

Treatment of latent TB infection 

Latent TB infection Active TB infection  

Latent TB infection is diagnosed by tuberculin skin testing (TST) Rule out active TB infection before treating latent infection to avoid drug resistance Prophylaxis has been shown to decrease active TB infection for up to three years 

In patients on ART treatment In patients not yet on ARV



Refer to national TB programme guidelines Add pyridoxine 25–50 mg/day to INH to prevent neuropathy Be aware of interactions and cross-toxicities between ARV and TB drugs



Cautions: monitor for signs of hepatotoxicity 



Treatment of active TB infection 

ART and TB HIV-infected persons with active TB will often be offered ART because those with pulmonary TB meet criteria for WHO stage 3 and those with extrapulmonary TB for WHO stage 4 ART may be highly beneficial in these persons in reducing case-fatality rates in TB Patients already receiving ART may develop clinical TB TB treatment should be initiated promptly regardless of the HIV serostatus

General principles: 

Treatment of TB in PLWHA is the same as in nonHIV-infected patients Follow national guidelines for TB treatment Usual regimens for pulmonary and extrapulmonary TB:  

 



Two months intensive phase: RHSZ or RHZE Consolidation phase: four months RH or six months HE



Treatment for TB meningitis (9–12 months)

Annex 2

Management of coinfections in HIV-positive injecting drug users

Co-management of HIV and TB is challenging     

TB and ARV: general principles 

Drug interactions between rifampicin and several classes of ARVs High pill burden Adherence problems Drug toxicity Immune reconstitution inflammatory syndrome (IRIS)

Treat TB first! The patient should be tolerating TB therapy for at least two weeks before starting a new ART regimen. Do not stop the ART! – if the patient is already on ART before the diagnosis of TB 





Be aware of the interactions between TB therapy and ARV drugs Change the ART regimen if needed and available (i.e. change NVP to EFV)



Start ART! Consider starting ART as soon as possible following WHO and national guidelines.

When to start ART in adults and adolescents with active TB disease  

When to start ART in adults and adolescents with active TB disease: WHO 2006 CD4 count cells/mm3 <200 200–350 >350 not available ART recommendations Recommend ART Recommend ART Defer ART (1) Recommend ART (2) ART timing after TB treatment started 2–8 weeks After 8 weeks Re-evaluate at 8 weeks and after TB treatment completed 2–8 weeks

Optimal timing of initiation of ART is not known. Case-fatality rates in patients with TB during the first two months of TB treatment are high. Where CD4 counts are not available, WHO recommends that ART be considered in all patients after the intensive phase of TB treatment.



Notes: (1) Consider ART if other non-TB stage 3-4 conditions are present. (2) If clinically stable and responding to TB treatment, can defer ART until after TB treatment completed.

Source: WHO, 2006.

What ART to start? WHO 2006 recommendations Preferential two NRTIs/NNRTI approach

First-line ART regimens in the setting of TB treatment for adults and adolescents 

Preferred regimen: 2 NRTI + EFV 

Do not use in the first trimester of pregnancy  NVP levels with rifampicin Do not use in women with CD4 count >250 cells/ mm3 Monitor carefully for hepatotoxicity (ALT at 4, 8, 12 weeks) Safe for pregnant women, women with CD4 count >250 cells/mm3, hepatitis Concern about lower efficacy than NNRTIcontaining regimens



Alternate regimen: 2 NRTI + NVP  

AZT or d4T 3TC or FTC TDF or ABC Triple NRTI approach

EFV NVP 



Triple NRTI option: AZT + 3TC + (ABC or TDF) 



Source: WHO, 2006.

Participant Manual

Management of coinfections in HIV-positive injecting drug users

Active TB in adults and adolescents already on ART Issues: 

Active TB in adults and adolescents already on ART Does a new diagnosis of TB in a patient on ART represent treatment failure? 

Does a new diagnosis of TB in a patient on ART represent treatment failure? Do first-line regimens need to be changed? Do second-line regimens need to be changed?

 

TB in the first six months of ART is a common presentation of previously undiagnosed or subclinical TB. After six months, treatment failure can be assessed by CD4, viral load, or clinical criteria. Pulmonary TB alone after six months does not indicate treatment failure. Extrapulmonary or disseminated TB after six months may indicate treatment failure.



Active TB in adults and adolescents already on ART Do first-line regimens need to be changed? 

Active TB in adults and adolescents already on ART Do second-line regimens need to be changed? 

EFV-based or triple-NRTI regimens can be continued. Options for NVP-based regimens: 1. Switch to EFV-based or triple-NRTI regimen  Can switch back to NVP when rifampicin therapy

Unboosted PI cannot be taken with rifampicin due to decreased levels of the PI Options for second line:  



2 NRTI + LPV/RTV 2 NRTI + SQV/RTV

completed

2. Continue NVP-based regimen  Monitor closely for hepatotoxicity



RTV + rifampicin have  risk for hepatic toxicity: monitor clinical signs and ALT closely

Immune reconstitution inﬂammatory syndrome (IRIS) 

IRIS: treatment  

Parodoxical development of new signs and symptoms of OI, or worsening of symptoms of a previously treated OI after initiation of ART Usually occurs in the first 2–12 weeks of ART Occurs in up to 33% of TB patients who start ART Increased risk for IRIS if ART started soon after TB treatment or with low CD4 counts Symptoms of TB-IRIS include fever, lymphadenopathy, and worsening of respiratory disease



  



Rule out new or recurrent OI Continue ART unless symptoms are very severe or life-threatening IRIS will resolve in several weeks without specific treatment Treat symptoms as appropriate (e.g. NSAIDs or paracetamol for fever and pain) Severe symptoms can be treated with steroids 



Prednisone 0.5–1.0 mg/kg/day for 1–2 weeks then taper

Annex 2

Management of coinfections in HIV-positive injecting drug users

TB associated IRIS

TB IRIS 27-year-old male IDU in northern Viet Nam at month 5 of treatment for pulmonary TB. Presents after six weeks of ART with increased cough, fatigue and fever. Sputum AFB X 3 negative. Symptoms resolved after four weeks’ treatment with diclofenac. Source: D Colby

TB patient with worsening lymph node enlargement and drainage after starting ART

Source: D Colby

Conclusions 

Case study 1 A 36-year-old male presents with a four-week history of fever, cough, fatigue, poor appetite and a six kg weight loss. He just tested positive for HIV in the VCT today and was referred to the clinic for further evaluation. He does not have any previous illnesses and is not on any medications. He first injected drugs in 1999 and quit in 2003. He currently works as a motorcycle taxi driver and lives with his wife.

TB and HIV are often found together: screen all IDU patients for both Recommend CTX prophylaxsis to all HIV-positive TB patients Same TB treatment for HIV-infected and uninfected patients: follow national guidelines ART should be considered in all patients with TB/HIV coinfection Be aware of the interactions and overlapping toxicities of TB drugs and ART IRIS is common in TB patients after starting ART



Case study 1(cont.) Physical exam: Temp 39, HR 110, BP 110/90, RR 18, weight 44 kg HEENT: oral thrush Neck: multiple lymph nodes on the right side 1–2 cm Lungs: scattered rales, no wheezing Heart, abdomen: normal Skin: no rashes

Case study 1: right supraclavicular lymphadenopathy

Source: D Colby

Participant Manual

Management of coinfections in HIV-positive injecting drug users

Case study 1 (cont.) Questions: 1) What WHO clinical stage is the patient in? 2) What further evaluation is required?

Case study 1 (cont.) Results of laboratory testing: CBC: WBC 3600 (25% lymphocytes) Haematocrit 31%, Hb 9.2, platelet 135 000 CD4: 95 cells/mm3 ALT 46 IU/ml, AST 50 IU/ml HCV positive, HBsAg negative AFB x 3 negative

Case study 1: CXR Questions:

Case study 1 (cont.)

3) What is the most probable diagnosis? 4) What further diagnostic evaluation would you do?

Source: D Colby

Case study 1 (cont.) 

Case study 1: treatment 7) What do you treat first: the TB or the HIV? Start TB treatment first and consider ART when indicated Yes, WHO stage 4 and CD4 count 95 cells/mm3 Between 2 and 8 weeks, as soon as the patient is tolerating TB treatment Preferred regimen: 2 NRTI + EFV Other options: 2 NRTI + NVP, 3 NRTI

Result: aspiration of a cervical lymph node is positive for AFB 5) What is the diagnosis? 6) What is the WHO clinical stage of the patient?

8) Does the patient fulfil criteria for starting ART? 

9) When will you start ART? 

10) What ART would you start?  

Annex 2

Management of coinfections in HIV-positive injecting drug users

Case study 2 A 24-year-old male patient is referred from the TB clinic after testing positive for HIV. He is in the third week of treatment for pulmonary TB and is tolerating the treatment well. His fever has resolved and he has gained 2 kg since starting treatment. His cough is better but he still coughs at night. His medical history is notable for chronic HBV infection and one episode of herpes zoster two years ago. He smokes ½ pack of cigarettes a day. No alcohol. He still uses heroin twice a day, but has been trying to decrease the amount he uses each time.

Case study 2 (cont.) Physical examination: no significant abnormalities Laboratory examination: CBC: WBC 5600 (25% lymph), Hb 10, platelet 155 000 CD4 225 cells/mm3 ALT 76 IU/ml, AST 65 IU/ml HCV positive, HBsAg positive

Case study 2 (cont.) 1) Does the patient fulfil criteria for starting ART? 

Case study 2 (cont.) 3) When would you start ARV on this patient? 

Yes, clinical stage 3 (pulmonary TB) and CD4 count <350 cells/mm3

After 8 weeks, when the intensive phase of TB treatment is completed

2) Does current injecting drug use disqualify the patient for ART? 

4) What ARV regimen would you use? 



No, active drug use is not a reason to deny care or ART. However, the patient should be referred for counselling and drug treatment, where available. Drug use can be associated with decreased adherence: active IDUs should be carefully counselled and monitored for adherence.



If the patient continues on rifampicin:  EFV-based regimens preferred If the patient continues on HE:  EFV or NVP regimens can be given NOTE: The patient has high risk for hepatic toxicity due to chronic HBV and HCV infection, baseline elevated ALT, and use of TB drugs. Check ALT at eight weeks before starting ART and follow closely.

Case study 3 A 20-year-old male patient returns to the clinic for routine follow up. He started ART with d4T/3TC/NVP six weeks ago. Baseline CD4 count was 105 cells/ mm3. At four weeks he was feeling well without symptoms and results of routine blood testing (CBC, ALT, AST) were normal. Today he complains of fever, cough with white sputum, and a 1 kg weight loss over the past 10 days. He started injecting when he was 14 years old and was admitted to a rehabilitation centre four years ago. He was released from the centre six months ago and now lives with his family. He does not currently use drugs.

Case study 3 (cont.) Physical exam: Temp 38.0, RR 16, HR 88, BP 120/76 HEENT: no thrush Neck: no lymphadenopathy Lungs: rales and wheezing on the upper left side Heart: regular rhythm without murmurs Abdomen: normal Skin: no rashes

Participant Manual

Management of coinfections in HIV-positive injecting drug users

Case study 3 (cont.) Sputum AFB: positive 2+ 

Case study 3 (cont.) 1) What is the diagnosis? Active pulmonary TB

2) Is this failure of the ART regimen? 

No, development of active pulmonary TB while on ART does not indicate treatment failure and is common in the first six months of treatment

Source: D Colby

Case study 3 (cont.) 3) The patient is started on RHZE for TB. Will you stop the ART? 

NO! DO NOT STOP THE ART! You should continue ART while treating the TB.

4) Will you change the ART regimen?    

Concerns about NVP use with rifampicin Preferred regimen is 2 NRTI + EFV, if available Other options: 3 NRTI or continue 2 NRTI + NVP If NVP continued: monitor closely for hepatic toxicity

Annex 2

Treatment and Care for HIV-Positive Injecting Drug Users The “Treatment and Care for HIV-Positive Injecting Drug Users” training curriculum is designed for clinicians who provide treatment and care, including ART, for HIV-positive injecting drug users. The training curriculum consists of a trainer manual, 12 participant manuals, and a CD-ROM with PowerPoint presentations and reference articles. Topics covered in the curriculum include: Module 1: Drug use and HIV in Asia Module 2: Comprehensive services for injecting drug users Module 3: Initial patient assessment Module 4: Managing opioid dependence Module 5: Managing non-opioid drug dependence Module 6: Managing ART in injecting drug users Module 7: Adherence counselling for injecting drug users Module 8: Drug interactions Module 9: Management of coinfections in HIV-positive injecting drug users Module 10: Managing pain in HIV-infected injecting drug users Module 11: Psychiatric illness, psychosocial care and sexual health Module 12: Continuing medical education Trainer manual

The ASEAN Secretariat 70A, Jl. Sisingamangaraja Jakarta 12110 Indonesia Phone: +62 21 724 3372, 726 2991 E-mail: public@aseansec.org

World Health Organization Regional Office for South-East Asia Mahatma Gandhi Marg Indraprastha Estate, New Delhi - 110002 India Phone: +91 11 233 70804 E-mail: hiv@searo.who.int www.searo.who.int

Family Health International Asia/Pacific Regional Office 19th Floor, Tower 3, Sindhorn Building 130-132 Wireless Road, Lumpini, Phatumwan Bangkok 10330, Thailand Phone: +662 263 2300 E-mail: sunee@fhibkk.org www.fhi.org

ISBN 978 979 3496 63 4

978 979 3496 63 4

Informations clés

Organisation Organisation mondiale de la santé (OMS)

Type de document Publications

Date d'adoption 31 décembre 2007

Source Organisation mondiale de la santé