Report on the workshop development protocol to study the geographic, therapeutic coverage and compliance with ivermectin treatment in Ghana

a*! 1 (9/ WORLD HEALTH ORGANZATION AFRICAN PROGRAMME FOR ONCHOCERCIASIS CONTROL B.DPOB.T (DN THE WORKSHOP DEVELOPMENT PROTOCOL TO SruDY THE GEOGRAPHIq THERAPELMC COVERAGE AND COMPLIANCE WTFI IVERMECTIN TREATI\4ENT IN CHANA OUAGADOU@U, OCTOBER I3TH TO I6IH 2OO7 Re celvesi 1 6 0cT. ?rl;l I 7 0[], 2007 COU KD/APOC t2 INTRODUCTION The workshop on the protocol development for the assessment of geographic and therapeutic coverage as well as compliance to, and perceived benefits to annual long-term treatment with ivermectin was held in October 13- 16, 20OT in the meeting room of the Airican Programme for Onchocerciasis Control in Ouagadougou, Burkina Faso. The workshop drew participants from four African countries in the APOC partnership, namely Ghana, Cameroon, Nigeria. The project coordinator came from John Hopkins University, USA. Others at the workshop were APOC Management. The details are contained in the list of participants attached hereunder. DAY T 13 OCTOBER 2OO7 OPENING The Director of APOC, Dr Amazigo briefed the participants on the rationale of the workshop for the treatment coverage and compliance in Ghana. She said this study is motivated by information published recently in the Lancet journal on the possible emerging resistance in O. volvulus to ivermectin in Ghana. The management of APOC gives high consideration to that information she added. But since the policy in APOC is essentially decision based on science or evidence, it is necessary to carry out studies to clarify the situation to enable the programme to take evidence based decision. Other factors that could explain the observations in Ghana could be related to the geographic and therapeutic coverage as well as the compliance with the ivermectin treatment around the study areas. The Director expressed the hope that, at the end of the workshop the participants would have developed a study protocol aimed at realizing this important study as well as coming up with suggestions on the way forward. She concluded her remarks by wishing the participants good deliberations and a happy stay in Ouagadougou. A self-introduction of participants followed the remarks. During this activity, participants identified their links and experiences with Onchocerciasis control, either as researchers or field workers. The result is that the participants are a pool of scientists who have had a long experience with Onchocerciasis. Next was the adoption of the workshop agenda. Prof. Brieger, the chair of the meeting presented the provisional agenda, which the participants reviewed and adopted. The opening ceremony came to a close after this presentation from Prof. Brieger TECHNICAL SESSION Following the opening ceremony. Three presentations were made: One from prof Brieger on the Multi-Site Study on lvermectin Compliance which took place in Cameroon, Nigeria and Uganda. The second presentation was made by Dr. Nana Kwadwo Biritwum of the National onchocerciasis control programme in Ghana. The third presentation was done by Prof Bookye from the Naguchu Memoria! research institute IaJ Multi-Site Study on lvermectin Compliance r This study was coordinated by Professors Adenike Abiose and Bill Brieger with the following persons as principal investigators in their respective countries: Cameroon: Samuel Wanji Nigeria: Joseph Okeibunor Nigeria: Elizabeth Elhassan Uganda: Richard Ndyomugyenyi The study had two phases. ln the first phase, the feasibility of measuring compliance to ivermectin treatment was carried out and followed essentially three steps: ln stepl , 17 of 25 CDTI projects that started distributing ivermectin in 1998 were selected by APOC' ln step2, the adequacy of districts where distributions had occurred on a regular basis was checked and it was found that 121 districts (58.6%) undertook distribution in all the 7 years. ln step3, 852 villages were visited and community level records were found in all but three. Records showed that distribution occurred for a minimum of five consecutive times in 429 villages and ultimately, 7 projects were selected for the second phase of the study: South west 1, in Cameroon, ln Nigeria, Cross River, lmo, Kaduna and Taraba. ln Uganda, Phasel and Phase 2. The objectives of the main study were the following: 1. To determine the proportion of men, women, youth and chitdren above 5 years old have complied with ivermectin treatment annually since the inception of community directed treatment with ivermectin 2. To estimate the proportion of minority groups complied with ivermectin treatment every year since the inception of community directed treatment with ivermectin? To see if there are minority groups lf they have been treated annually and lf not, why not treated 3. To determine the factors influencing individual compliance to treatment including perceptions of social and health benefits 4. To determine for how long people are willing to take ivermectin and for what reasons are they willing to continue to take ivermectin for a long time 5. To get the community suggestions on improving compliance of individuals to annual and long-term ivermectin treatment Main findings: There was heterogeneity in the village coverage from one year to another, ranging from 67.1% in 1998 to 75.1o/o in 2005. All the study villages recorded coverage above 650/o'. The household survey revealed that in the villages where treatment occurred for 8 years, people complied on average 4.6 times (57.1o/o). Of those who have treatment opportunities; 58.8% received 5 or more treatments. Regarding the factors associated with compliance, it was observed a slight better compliance for male than for female (4.65 times versus 4.49 times). Adults also slightly complied better than youths (4.8 times versus 4.27 times). Christian seems to comply less than members of other religion groups. Married people complied better than those a4 who never married. The majority ethnic group complied better than the minority ethic groups. All these factors considered together explained only 7o/o of variation in the data set implying that there are other factors that explain the compliance or non compliance with ivermectin treatment. Still with factors influencing compliance, it was observed that individuals from high complier group perceived more benefits of taking ivermectin, while low compliers perceived more problems. Low compliers were more likely to experience symptoms of onchocerciasis such as skin rashes, blindness, swelling of the body, severe itching. People who are complying don't suffer from those symptoms again. Regarding the best medicine for onchocerciasis the low compliers use less western rnedicine but use more herbs and other drugs. 95% of high compliers said they were encouraged to take ivermectin against 88% for low complers; while 22o/o of low compliers were discouraged from taking ivermectin against only 7% for high compliers. The main recommendations from this study were the following: r Documentation of compliance should be institutionalized with annual summary columns in village registers and report forms r CDDs can then be trained to reach out to those who have taken ivermectin less than most people in the village r Health Workers and CDDs also need to be trained in counseling skills as traditional mass IEC/BCC materials may not be enough to overcome deep seated personal beliefs r Health education materials should be geared to specific low compliance groups and their perceptions and beliefs r lt should be ensured that the ivermectin stays in the village long enough (3 months) to reach low compliers (e.9. younger and more mobile people) r Programs must continue to provide adequate and timely supplies of drugs to enable villagers to comply annually Overview of lvermectin Distribution in Ghana by Dr. Nana Kwadwo Biritwum from the Ghana Onchocerciasis Gontrol Programme From his presentation, the following key points came out Endemicity of onchocerciasis and lymphatic filariasis in Ghana Onchocerciasis is endemic in 9 out of 10 regions in Ghana, about 3204 communities are in these endemic regions. 247 communities from 7 districts belong to the Special lntervention Zones in BA and Ash regions, the total at risk population is about 3.0M. lt was also learned that the Onchocerciasis activities started in Ghana in 1974 and focused on aerial larviciding, lvermectin distribution in Ghana started with the use of mobile teams in 1987, CDTI was introduced in 1998 and the SIZ was created in 2002 to serve as the focus of CDTI implementation after the devolution. 34 health districts are co-endemic for onchocerciasis and lymphatic filariasis, 32 health districts are endemic for only onchocerciasis and 27 are endemic for only lymphatic filariasis. ln total, a5 seven health districts are in the special intervention zones, with 1 being co-endemic for Lymphatic Filariasis and Onchocerciasis and 6 endemic for only onchocerciasis. lvermectin treatment and coverage lvermectin treatment started in LF/Oncho co-endemic areas in 2001. There was a gradual up- scaling plan to finally cover 61 districts(only!). lvermectin treatment has been consistent in these co-endemic areas. Change in management of oncho programme created a gap in data availability at the national level. However treatment data is available at the community level Tablel: Geographic coverage of ivermectin treatment in the different regions of Ghana since 1999. hic Region ncho o. mi ist omm (,eo ta, 1999 2000 2001 (LF) 2002 2003 2004 2005 2006 2007 Central 11 lo,, 92.1 95.2 100 20.1 0 100 100 100 100 "e.rongAhdfo I loro 81.8 85.1 83.7 66 100 100 0 62.5 TBA Upper West 4 L 0 0 100 100 100 100 100 100 100 Volta 6 L* 54 76.8 76.5 76.s 0 0 0 100 rBA Eastern 7 t,,, 49 66.3 100 0 0 0 83 67.7 TBA 12 l,u, 100 88.8 52.4 100 100 100 100 100 100 Ashanti I t,,, 0 40.8 64.9 100 0 0 16.7 100 TBA . .' .' ..fl;'i,. 'll'-l-r x,idi *l ffioiliiffi 7 1,, 0 98.2 100 92.7 100 10,0 100 100 100 3 h 100 100 100 100 100 100 100 100 100 Table2. Therapeutic coverage in different CDTI regions of Ghana since 1999 6utic Region 1999 2000 2001 2002 2003 2004 2005 2006 2007 Upper East 68.2 70.3 73 76 63.9 66.6 67 72.6 68.1 Upper West 73.6 64.4 76 74 67.4 73.1 74.5 79.7 72.7 Gentral 0 49.4 0 54.6 76.1 76.6 72.9 70.3 61.1 Northern 73.2 72.7 70 63 76 74.8 76.2 78.3 64.1 Brong Ahafo 60.3 56.9 45 46 74 70.9 0 61.5 0 Eastern 0 36.8 58.2 0 0 0 54 62.3 0 Ashanti 0 26.5 75 12.4 0 0 0 36.4 0 Western 0 53.7 68.4 64 75.6 73.3 81.4 76.9 67.8 Volta 0 55.9 53.1 60.1 0 0 69.5 0 Major Ghallenges for CDTI in Ghana The presenter also mentioned some difficulties the CDTI projects in Ghana have being facing: these include: -Delays in the submission of report -ln Co-endemic areas refusal to report on Onchocerciasis communities -Lack of financial support for non-SlZnon-LF supported onchocerciasis endemic communities -Apathy among regional and district staff in monitoring and supervising of community Onchocerciasis control activities -Lack of political commitment at the highest level -Diffuclties in Compiling of all available data Emerging resistance ol O. volvulus to ivermectin The third presentation was made by Daniel Boakye from Nagachu Memorial research institute in Ghana on the emerging resistance of O. volvulus to ivermectin. He started by giving the history of the use of ivermectin for the treatment of onchocerciasis, notably the combined effects of multiple treatment on the microfilariae and adult worms. a I neral t, i7 Regarding the question could there be resistance to ivermectin. He declared that the question was raised as far back as 1993, and by then WHO urged that methods be established to detect the development of such resistance, and to study the underlying mechanisms (WHO, 1995) ln reference to Ghana, lt is kmown that ln 1987 the OCP introduced large-scale distribution of ivermectin, beginning in the Pru and Lower Black Volta (LBV) river basins in Ghana. ln 1997 Field surveys in the LBV basin and in the Pru River basin, revealed individuals with persistent, significant microfilaridermia (PSM). Others subjects from the same communities, similar microfilarial loads in 1987, subsequently been exposed tothe same environmental factors and received an identical number of treatments to those found with PSM, were skin-snip-negative The second aspects of his presentation was on the epidemiological evidence of emerging resistance He started by defining the concept of "responders" and "sub-responders". lndividuals who still had at least 10 microfilariae/snip in 1997, after nine or more treatments with ivermectin, were labeled as 'sub-optimal responders' (SOR) in 1997. Subjects who were snip- negative in 1997 although known to have been positive in 1987 were considered'responders He went on to explain the possible reasons for sub-optimal responses which could be linked to the drug ivermectin, in term of stability, storage, transportation and distribution. lt could also be related to the subject, with failure to consume drug, adverse interactions with other drugs or herbs,, lnadequate drug exposure, Underlying disease (immunosuppression). The third explanation could come from the parasite with patent new infections or abnormal response (tolerance or resistance) Refering to the work of Awadzi et al (20Q4) he said that significant microfilaridermias that persist despite multiple treatments with ivermectin are mainly attributable to the non-response of the adult female worms and not to inadequate drug exposure or other factors. The possibility that some adult female worms have developed resistance to ivermectin cannot be excluded He also referred to the work of Osei-Atweneboana el al (2007), where they observed high microfilariae prevalence, reaching alarming levels in some communities; with some communities showing significant increases between year 2000 and 2005. The authors of the work concluded that lvermectin was still very effective against the microfilaria but that the early repopulation of mf by adult female worms in some communities indicates failure of lvermectin to suppress the release of intrauterine microfilariae by adult female worm and that these results indicate sub- optimal responses of O. volvulus populations to lvermectin in these communities. The authors also concluded that these information should be considered enough evidence to suggest that lvermectin resistance is emerging in some adult populations oI o.volvulus The third group of evidence came from Genetic studies from. Eng and Prichard (2005) They observed that P-glycoprotein (OvPGP-1) was in Hardy-Weinberg equilibrium in worms from untreated people, it was not in Hardy-Weinberg equilibrium in worms from treated people, indicating that selection on this gene was occuning. Using samples from Sierra Leone, Cote d'lvoire, Guinea, Ghana and Uganda these authors look at the frequency of p-tubulin alleles in O. volvulus obtained before any ivermectin was used in humans in Africa, and following its widespread use. ln H. contortus they also look at the frequency of E-tubulin alleles in a strain which has not seen any anthelmintic selection and in an ivermectin selected strain derived from the unselected strain. They found that ivermectin selects on p{ubulin in both of these nematode species. lvermectin selects for specific single nucleotide 8polymorphisms in the O. volvulus p-tubulin gene. These results constitute evidence that ivermectin selection changes the frequency of p{ubulin alleles in both the sheep parasite, H. contortus, and the human parasite, O. volvulus The third Genetic evidence came from the work of Bourguinat et al. (2007). These authors worked on genetic selection in the E-tubulin gene in O. volvulus following ivermectin treatment in Cameroon and observed the following: (ii) Relationship between F-tubulin genotype and female parasite fertility (ii)a significant selection for f-tubulin heterozygotes in female worms. (iii)Quarterly ivermectin treatment over three years reduced the frequency of the B-tubulin "aa" homozygotes from 68.6% to 25.60/o, while the "ab" heterozygotes increased from 20.9% to 69.2o/o in the female parasites. -The female worms homozygous at the Ptubulin locus were more fertile than the heterozygous female worms before treatment (67% versus 37%; p = 0.003) and twelve months after the last dose of ivermectin in the groups treated annually (60% versus 17o/oi p,0.001). The fourth genetic evidence presented came from the work of Ardelli and Prichards (2007) Genetic variation of an Onchocerca volvulus ABC transporter homologue (OvABC- 3) from several populations in Africa was examined to determine whether an association exists between alleles of this gene and lvermectin treatment. Allelic variation in a non-treated population from Ghana showed this locus to be highly polymorphic. One polymorph, polymorph C, was at a significantly higher frequency in worms from lvermectin{reated patients from some regions in Ghana compared with worms from untreated patients, as well as in worms from patients who exhibited a sub-optimal response to lvermectin compared with worms from patients showing a good response to lvermectin. This may be indicative of genetic selection by lvermectin in O. volvulus With all theses evidences for emerging resistance, the presenter suggested that there should be studies to confirm resistance or other hypothesis. And also there should be set up of a comprehensive system for monitoring drug use and efficacy in large-scale Current study and others underway were proposed: . Phases (i) coverage issues what is the effect of geographicar coverage . What is the effect of therapeutic and temporal coverage . What will be the impact of the results of compliance issues alone in providing evidence on the results of the publications (ii) Prevalence issues (iii)Entomological issues Protocol development Following the presentations, the participants agreed on the questions to be addressed by the study protocol as well as its structure It was accepted that the focus of the study should be on the 20 villages where the study on resistance were carried out. Communities in a radius of 20 km of each of the 20 primary communities should also be included in the study. The work will be carried out in two phases. During the first phase, the geographic and therapeutic coverage of those communities will be determined. Data will be collected from district and communities levels, with essentially great a t9 attention paid to treatment registers, treatment summary sheets since 1997. The compliance study will constitute the second phase of the study. (See the study protocol for more details) Day 2: October 142007 Participants were divided into three subgroups to draft different sections of the protocol(i) lntroduction, rationale and objectives(ii) Study site and study design(iii) Methodologyincludingresearchinstruments(iv) Budget(v) Time frame(vi) Procedure and instructions for data collection Day3: October 152007 Different subgroups presented their work in the plenary. Discussions were carried out and amendments done. All the sections were then merged to constitute the core of the first draft of the study protocol. The draft was distributed to participants for further improvement Day 4: October 162007: Works continue on the protocol, suggestions from different participants for the improvement of the protocol were considered. This led to the finalization of the study protocol which is the part of this report. Conclusions: The objective set for this workshop was achieved. The stud protocol has been developed. The first phase of the work on the coverage study will commence on the 27 October 2007 and the research team in the field will be led by Dr Samuel Wanji. The second phase of the work will take place after the first phase and will probably take place in January 2008. The workshop came to a close at about 5:30 pm on Tuesday 16 October 2007. The Coordinator, Professor Brieger thanked all that have contributed to the success of the workshop, especially the Director of APOC and his management team. The participants also expressed their delight and gratitude for being involved in this process. a10 a APPENDIX AFRICAN PROGRAMME FOR ONCHOCERCIASIS CONTROL (APOC) Ghana coverage and Compliance Study Protocol Development Workshop Agenda October 13-16, 2007, APOC, Ouagadougou, Burkina Faso Welcome, lntroductions, Purpose - Dr Amazigo Review of Multi-Site Compliance Study in APOC Countries -Prof Brieger Overview of Ivermectin Distribution in Ghana: Geographic and Temporal Coverage - Dr Biritwum Presentation on Resistance Issues, Implications for Compliance - Prof Boakye Discussion on Study Site Selection and Sampling Issues - Prof Boakye, Prof Brieger Review, Revision and Adaptation of Coverage and Compliance Study Instruments - Group Planning of Logistics and Budgeting - Group Issues of Quality Control - Dr. Okeibunor, Dr. Wanji First Draft of Protocol - Group Review of Protocol - Group Finalization of Protocol - Group a a a a a a a a a a lU) 0)q) aq) L E cg GI Fi H OI CJ o e oq) v) o I EI olql 6Jl EI cEl ,YI0t c'l EI ol -olGI ii d I I I I L o o cl >1 G) '= clt U) .; (€ -.1 >? 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