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Highlights of the 35 and 36th meetings of the Mectizan Expert Committee/Albendazole Coordination The 35th meeting of the Mectizan Expert Committee/Albendazole Coordination was held in January 2006 in London, United Kingdom followed by the 36th meeting in late October in Atlanta, Georgia, USA. The following are highlights from the two meetings:

• Scenarios for long-term onchocerciasis control were discussed. The MEC recommended the formation of a task force to facilitate discussions on the future of long-term onchocerciasis control in Africa. The task force will collaborate closely with the WHO Special Programme for Research and Training in Tropical Diseases (TDR), APOC, and other interested parties.

• The MEC was impressed by the excellent progress made in the Americas towards the elimination of onchocerciasis in the Western hemisphere, however; concerns were expressed that some of the operational criteria for cessation of ongoing Mectizan treatment may be difficult to implement. The Committee therefore recommended that the existing criteria for the cessation of Mectizan treatment in the Americas be revised in consultation between OEPA, the Pan American Health Organization (PAHO), and WHO.

• TDR reported on a consultation held in 2005 to discuss safe strategies for adding albendazole to ivermectin in areas co-endemic, or potentially co-endemic, for onchocerciasis, LF, and loiasis. Based on the recommendations from the consultation, the MEC/AC developed a new policy “MEC/AC Recommendations for Mass Drug Administration of Ivermectin and Albendazole for LF Elimination in Loa loa Endemic Areas where Onchocerciasis is also Hyper- or Meso-Endemic,” which is available at http://www.mectizan.org/loarecs.asp.

• A report on the serious adverse experience (SAE) reporting workshop conducted in October 2006 in Kinshasa, Democratic Republic of the Congo (DRC) was given to the MEC. It was noted that preliminary data indicate that the “Mectizan Expert Committee/Technical Consultative Committee Recommendations for the treatment of onchocerciasis with Mectizan in loiasis endemic areas” have been well followed in DRC. Further data analysis and study on early indicators of SAEs, particularly sub-conjunctival hemorrhages, will be conducted.

• The MEC noted the progress made on SAE case management in Cameroon and DRC thanks to the availability of the L. loa technical advisors assigned to those countries. A L. loa advisor is being recruited in Angola, and it was recommended that another be appointed in South Sudan with joint APOC/MDP support. The session on lymphatic filariasis (LF) began with an update on the nine countries in Africa and Yemen currently implementing mass drug administration (MDA) with albendazole and Mectizan for LF elimination. In 2005, 42.6 million treatments were approved for MDA in these countries. Togo achieved 100% geographic coverage, and it is hoped that Burkina Faso and Ghana will achieve the same in 2006.

Highlights of the 34th Meeting of the Mectizan Expert Committee/Albendazole Coordination

  • The meeting began with the session on onchocerciasis during which an update was given on cases of serious adverse experiences (SAE) following treatment with Mectizan for onchocerciasis between 1989-2004. The overall incidence of reported neurologic SAE cases from endemic areas in Cameroon has declined from 8.5 per 100,000 treatments in the late 1980s/early 1990s to less than 1 per 100,000 in the last four years. The decline is primarily driven by more people being treated annually since the late 1990s when the African Program for Onchocerciasis Control’s (APOC) strategy of Community Directed Treatment with Ivermectin was implemented and due to more people being re-treated each year, which reduces the risk of post-treatment L. loa encephalopathy.
  • To address the distribution of Mectizan in areas where there is no mass treatment, a discussion was held on passive, or clinic-based treatment with Mectizan in Loa-endemic areas, and the MEC recommended that: National programs include all staff involved in clinic-based treatment of onchocerciasis in training opportunities provided in relation to the MEC/TCC guidelines for Mectizan treatment in L. loa endemic areas; The total area of loiasis endemicity be considered a “risk zone”, not only areas of mass treatment; and The MEC/TCC guidelines be routinely shipped with all Mectizan tablets provided for clinic-based treatment in countries suspected, or known, to be endemic for loiasis.
  • A discussion was held during MEC/AC 33 on the increase in SAEs that occurred in DRC between 2003-2004, and it was agreed that two technical advisors would be assigned to DRC for monitoring and surveillance, sensitization and training, and SAE reporting. In follow-up during MEC/AC 34, it was agreed that the posts will be co-funded by APOC and MDP, and that a similar arrangement will likely be made in Angola in the future.
  • The lymphatic filariasis (LF) session included an update on disease assessments, including mapping for LF in the WHO African Region. At the time of the MEC/AC 34, 18 of the 39 countries believed to be LF-endemic on the African continent had completed mapping of LF, and 7 were still in process. The total population at risk in the 18 completed countries is estimated at 139.6 million.
  • A report on the mission of the Global Alliance to Eliminate Lymphatic Filariasis Executive Group (GAELF EG) was given including progress made since the GAELF III meeting in March 2004. The GAELF EG had conducted a number of advocacy campaigns and visits to prospective donors for program implementation funding. Dr. Dadzie, GAELF EG chair, was optimistic that funds would be forthcoming from several promising major donor sources within the next 12 to 24 months.
  • Dr. Daniel Boakye of the Noguchi Memorial Institute for Medical Research in Ghana was invited to the MEC/AC 34 to present the preliminary results from a multi-center study to investigate transmission after MDA with Mectizan and albendazole in different Anopheles vector-Wuchereria bancrofti settings in Africa. An. gambiae s.s. was the most prevalent species in both sites. After three rounds of MDA, the annual transmission potential decreased at both sites. However, variations existed between the species; there was no apparent decrease in the An. gambiae population while An. funestus demonstrated a rapid decline even after the first MDA. Parasitological and clinical indices also decreased, but the rates of decline were much slower. The investigators’ preliminary conclusions are that interruption of LF transmission with MDA is dependent on the local vector-parasite combination and that it might not be possible to use MDA alone to interrupt transmission throughout Africa. It may be necessary to include mass distribution of insecticide-treated materials into the LF elimination strategy. More definitive conclusions will be available at the end of the study when 5 rounds of MDA will have been completed.
  • Dr. Edwin Michael, of the Imperial College Medical School in the United Kingdom, was invited to present on a mathematical model for LF elimination using MDA and vector control. A model that had been successfully tested by the Tanzanian PELF at the regional and district levels was presented to the MEC/AC. Dr. Michael reported that the model was met with great enthusiasm by district level program managers in Tanzania because of its use in demonstrating the impact of their work and how long they need to continue the elimination program. The MEC/AC will be updated as the model is refined and applied to program decision-making.
  • WHO presented on the future orientation of the Global Program to Eliminate Lymphatic Filariasis (GPELF). WHO is working on an integrated approach to the control of the tropical diseases in the same cluster as LF such as onchocerciasis, trachoma, schistosomiasis, and soil-transmitted helminthiasis. It is hoped that integration of interventions for these diseases will be presented to donors in the near future so that the approach can be launched widely. Dr. Corrie Brown of the University of Georgia was invited to present on her development of an animal model of L. loa infection to support research on the pathogenesis of encephalopathy following Mectizan treatment. The lesions seen in the brain, liver, lung, and kidney of treated animals are all consistent with an acute thromboembolic disorder subsequent to massive mortality of microfilariae within the circulatory system. However, the “apparent” full recovery in some individuals is not consistent with such a microvascular episode. Thus, it was concluded that other pathogenic mechanisms might also be involved.
  • Professor Tom Unnasch of the University of Alabama was invited to present a genetic analysis of L. loa conducted to determine if there is a distinct L. loa genotype associated with the development of SAEs after treatment with Mectizan. The data support the previous work by Professor Unnasch and colleagues presented at MEC/AC32 that suggested L. loa associated with SAEs is not a distinct population, although it is possible that some unknown virulence factor exists. A report was given on the health benefits of mass drug administration (MDA) for lymphatic filariasis (LF) with albendazole and Mectizan in Tanzania.
  • The MEC/AC was informed of a prospective study to investigate whether the MDA leads to an improvement of symptoms and signs of lymphoedema, acute dermatolymphangioadenitis, and hydrocoele. The MEC/AC 34 ended with plans to hold the next meeting in London, U.K. near the London School of Tropical Medicine and Hygiene. The meeting was held in January 2006.

News from the 33rd Meeting of the Mectizan Expert Committee/Albendazole Coordination Lymphatic Filariasis:

  • Recent developments for integration of LF elimination into other disease control initiatives, such as malaria control in Togo, were discussed at length. The donor community has expressed interest in integration within the framework of community-directed treatment. The MEC/AC endorsed the potential development of integration models and supports the development of a workshop proposed by the LF Executive Working Group on the integration of LF elimination with control programs for malaria, HIV/AIDS, and tuberculosis. Such integration could be particularly useful within the GAELF partnership.
  • The need for evidence of the interruption of transmission of LF in Africa was discussed during the LF session. The topic will be revisited at MEC/AC 34 with a presentation and background paper on the most recent data and field experiences from African countries. Onchocerciasis/Lymphatic Filariasis: During the joint onchocerciasis/LF session, a number of technical issues were updated including: genetic heterogeneity in L. loa parasites from Southern Cameroon, developments in animal models to study L. loa encephalopathy, safety studies on albendazole and ivermectin in LF/L. loa co-endemic areas, and multiple treatments of albendazole as pre-treatment for L. loa.
  • The WHO Special Programme for Disease Training and Research gave an update on filariasis research developments including the development of a suitable tool for early detection of the possible emergence of reduced efficacy of ivermectin against O. volvulus. Data were also presented that suggest positive effects of albendazole, and possibly Mectizan, on health status. It was recommended that a paper be prepared to aggregate data on the potential positive nutritional and other health benefits of mass distribution programs. This will also be discussed further at the MEC/AC 34.
  • The procedure for requesting Mectizan for use in clinical trials and other investigations was discussed during the joint session. Because Mectizan for these studies is not always correctly requested, Merck & Co., Inc. and MDP will work together to communicate the proper mechanism for such requests, which should be submitted to Merck along with a research protocol.

Onchocerciasis:

  • The session on onchocerciasis began with a discussion on Serious Adverse Experiences (SAEs) following Mectizan treatment and a report on the mission to the Bas Congo Province of the Democratic Republic of the Congo (DRC) to investigate the potential causes of the 2003 SAEs reported from that region. Following a recommendation made during MEC/AC 32, a joint African Program for Onchocerciasis Control (APOC)/MDP Expert Mission to Bas Congo took place in July 2004, and the conclusion was drawn that were no specific co-factors other than the hyperinfection with L. loa, identified to explain the high incidence rate of SAEs. The incidence rate of SAEs was, in fact, comparable to previous incidents in Cameroon. Other issues in the Bas Congo regions such as community sensitization, training of staff and general preparedness, are also being dealt with by the NOTF.
  • During a discussion on the treatment of onchocerciasis in hypo-endemic areas that are also endemic for L. loa, the Committee recommended that clinic-based treatment of onchocerciasis with Mectizan in these areas be included as a topic for further discussion at MEC34 because of the potential complexity of clinic-based treatment and because of the need to ensure that guidelines for treatment in Loa loa endemic areas are followed.
  • An update on Yemen was provided by the WHO liaison to MEC. It included a report of the ongoing development of an integrated program for onchocerciasis and leprosy control with LF elimination. The program in Yemen is in the process of securing additional financial resources for integrated activities, and it was suggested that WHO assume a coordinating role in bringing the partners in Yemen together for a fully integrated programme.

Highlights of the 32nd Meeting of the Mectizan Expert Committee/Albendazole Coordination Onchocerciasis:

New data presented from the recent RAPLOA validation exercises in DRC and Congo-Brazzaville indicate that RAPLOA methodology is valid for use outside of the original area in which it was developed (i.e. Nigeria and Cameroon)and can now be used to estimate the prevalence of L. loa in areas suspected to be endemic. In addition, progress has been made in mapping L. loa leading to a simplified version of the probability contour map (PCM) that illustrates "danger", "uncertain", and "safe" zones regarding the risk of developing L. loa encephalopathy following Mectizan treatment. TDR plans to use data from the RAPLOA validation studies in Congo-Brazzaville and DRC as well as data from recent RAPLOA surveys in Angola, to update the Environmental Risk Model for loiasis and to increase the accuracy of the map. The PCM will be particularly useful for operational planning of L. loa mapping and Mectizan treatment in Loa-endemic areas and will eventually be used as an annex to the MEC/TCC guidelines on Mectizan treatment in L. Loa endemic areas when they have been refined.

Based on the recommendations of MEC/AC 31, revisions to the MEC/TCC guidelines for mass treatment with Mectizan for onchocerciasis in areas co-endemic for onchocerciasis and loiasis were finalized. Revisions were also based on subsequent feedback from TCC 18, and reports on the validation of RAPLOA. In response to the higher than expected incidence of SAEs reported from the Bas Congo province of the Democratic Republic of the Congo, the Committee recommended that mass treatment with Mectizan for onchocerciasis in Bas Congo be halted temporarily and that investigations be conducted on the potential causes of these SAEs as soon as possible. Following the investigation, discussions will be held between the stakeholders on how to proceed with mass treatment, if possible, in Bas Congo. In addition, the Committee recommended that extensive RAPLOA surveys be conducted there in the next few months to better define the risk of SAEs potentially associated with L. loa in the region. The Committee welcomed the conclusions arising from the spatial analysis of encephalopathic SAE cases from Cameroon. The Committee recommended continuation of a case-control study on individuals to determine co-factors, other than L. loa, that may explain the clustering effect of encephalopathic SAEs in Central Province and other areas where clustering is observed. Consideration should be given to developing similar community and individual level studies of encephalopathic SAEs being reported from DRC.

Findings from studies on possible measures to prevent L. loa associated SAEs following treatment with Mectizan in L. loa endemic areas were presented during the meeting. Following the presentation of results from a study on the use of low dose Mectizan as a possible pre-treatment agent to reduce the intensity of L. loa infection, the MEC recommended further exploration of even lower doses of Mectizan for this purpose. The Committee endorsed a proposed study on the use of multiple doses of albendazole as a pre-treatment agent and recommended implementation of the study as soon as possible.

Finally, the Committee welcomed the comprehensive review of the literature for compounds, other than Mectizan, albendazole, and DEC, that may have efficacy against L. loa. Recognizing the potential leads that oxantel, praziquantel, and chloroquine may represent, the Committee endorsed the pursuit of small-scale studies to investigate these possibilities. Ongoing schistosomiasis control activities offer an opportunity to study the efficacy of praziquantel in reducing L. loa microfilaremia. The proposed safety studies on albendazole and Mectizan use in individuals infected with L. loa were also endorsed and recommended for immediate implementation to determine the feasibility of expanding LF treatment programs into L. loa endemic areas.

Lymphatic Filariasis:

It was noted that several African countries are preparing to initiate mass drug administration (MDA) in the absence of sufficient funding for effective drug delivery. In agreement with the recommendations of the 4th Meeting of the African Regional Programme Review Group, the Committee recommended that MDA should not be initiated in a country unless there are reasonable assurances that funds for the first 2 years are forthcoming. There is also concern over countries planning to upscale existing MDA with limited or insufficient financial support. It was recommended that MDP, in collaboration with other interested parties, facilitate the identification of funding sources to ensure maintenance of the previous years' achievements with MDA, and, if possible, enable the planned expansion. Once there is reasonable assurance that sufficient funds are available, MDP, on behalf of the MEC/AC, may approve the requested number of tablets of Mectizan and albendazole.

The Committee requested detailed prevalence information on the potential L. loa endemic areas that the program may be expanding into this year so as to ensure that these areas are excluded from the MDA since mass treatment of LF with Mectizan and albendazole in L. loa endemic areas remains prohibited until the safety studies of the co-administration of these two drugs in such areas have been conducted. If prevalence data are not available, the program is recommended to conduct RAPLOA surveys according to the TDR protocol. The Committee welcomed the preliminary findings from the cost analysis of the MDA program in Burkina Faso and urged that these findings, and those from the studies in Ghana and Tanzania, be finalized and published in peer-reviewed journals as soon as possible.

The Committee was informed of plans to develop regional LF support centers in support of the Global Alliance to Eliminate Lymphatic Filariasis. The Committee recommends the pursuit of this matter, which could allow for more effective program implementation and support to national capacity building. In particular, the Committee endorsed the ongoing development of the first of such centers in West Africa at the Noguchi Memorial Institute for Medical Research in Accra, Ghana.

Highlights of the 31st Meeting of the Mectizan Expert Committee/Albendazole Coordination Lymphatic Filariasis:

The programmes to eliminate lymphatic filariasis (PELFs)are facing serious financial constraints jeopardizing their ability to upscale their programs rapidly enough to achieve the elimination goal in a reasonable timeframe. It was recommended that mechanisms for mobilizing resources for LF elimination specifically in Africa must be urgently investigated. Resources are also needed to purchase immunochromatographic (ICT) cards to allow mapping to proceed. Consideration should also be given to the development of an alternative tool for the epidemiologic assessment of LF.

Integration and sustainability of disease control programs was discussed, and conclusions were made that integration is key to sustainability with the caveat that integration strategies must be tempered against the need for rapid upscaling and high coverage critical to the success of the PELFs. Current integration activities at the community and district levels were recognized as successful, and the opportunity for expanded integration both at the national and international levels was recognized.

A research plan was formulated to address safety concerns of the co-administration of albendazole and Mectizan in loiasis endemic areas. The research will be led by TDR in collaboration with all interested parties.

Onchocerciasis:

TDR reported that the rapid assessment technique for community prevalence of L. loa (RAPLOA) is now valid for use in Cameroon and Nigeria. Validation in other countries will be completed by February 2004. It is hoped that the technique will then be available for widespread use to identify areas at high risk for associated Serious Adverse Events, which involve disturbances of the Central Nervous System (CNS) following Mectizan treatment. It was also reported that work on the search for macrofilaricidal drugs for onchocerciasis and LF is ongoing.

The need for revisions to the existing MEC/Technical Consultative Committee guidelines for treatment with Mectizan in L. loa endemic areas was discussed based on information provided by an informal working group that had reviewed the guidelines at Merck headquarters the day before the MEC/AC meeting. After further review and discussion of the guidelines and the report by the informal working group, the MEC endorsed the conclusions and recommendations of the working group, which stated that the guidelines should be revised to: 1) Emphasize the need to use the most up-to-date L. loa endemicity map, based on remote sensing and prevalence data, in decision-making for mass treatment with Mectizan. 2) Discontinue community-by-community rapid epidemiological assessment (REA) used to exclude communities hypo-endemic for onchocerciasis in loiasis-endemic areas from mass treatment with Mectizan because the benefit of treatment was deemed insufficient to outweigh the risk of post-treatment L. loa associated CNS disturbances. Instead, decisions about mass treatment strategies should be based upon the risk of high L. loa endemicity as determined by the L. loa endemicity map mentioned above. 3) Include guidelines on clinical management of encephalopathy as an appendix.

The decision-making process surrounding when to stop Mectizan mass treatment for onchocerciasis control in Africa was discussed, and it was concluded that operational epidemiologic, parasitologic, and entomologic parameters for defining the achievement and maintenance of the elimination of onchocerciasis as a public health problem (in the presence of possible ongoing low-level transmission of the parasite) are still unknown and need urgent investigation. The MEC recognized the importance of this work and agreed to assist TDR in finding the necessary funding for this vital research in collaboration with other parties.

Highlights of the 30th Meeting of the Mectizan Expert Committee/Albendazole Coordination

Clinic-based Mectizan distribution in previously untreated hypo-endemic areas It is estimated that there are 45 million people living in areas that are hypo-endemic for onchocerciasis (prevalence of onchocerciasis nodules <20% or positive skin snip <40%). Overall, approximately 10% of these people are estimated to have the disease. Clinic-based treatment in these communities would reduce the burden of disease, particularly skin disease, and would probably contribute to decreasing transmission in these communities and neighboring communities that may be hyper- or meso-endemic for onchocerciasis. However, the issues of ensuring drug safety and security as well as integration of these clinic-based treatments into the national onchocerciasis programs were seen as challenges that had to be addressed before such a scheme could be considered.

In addition, it was recommended that the extent and distribution of the number of people requiring treatment who live in hypo-endemic areas be more clearly defined. Multiple treatments per year with Mectizan Recently published data by Jaques Gardon and colleagues in the Lancet  on the potential benefits of quarterly treatments of Mectizan were presented and discussed. The operational experiences of biannual treatment in the Onchocerciasis Elimination Program for the Americas and certain parts of the Onchocerciasis Control Programme in West Africa were also discussed. Even though multiple treatments per year might be beneficial for onchocercal skin disease and may possibly shorten the total duration required for mass treatment, the Committee could not, at this stage, recommend widespread adoption of this strategy because of the operational challenges of implementing and sustaining such a scheme, particularly in Africa. Further research on feasibility of multiple treatments was encouraged.

Other News

Member Changes

The Mectizan Donation Program would like to thank Dr. Mamoun Homeida for his participation on the Mectizan Expert Committee from 1999-2002. Dr. Homeida made significant contributions to the Committee, which were very much appreciated by the Mectizan Donation Program.

We will welcome Professor Ekanem Braide to the Committee at the upcoming meeting in March 2003. Professor Braide also serves as chair of the Technical Consultative Committee for WHO’s African Program for Onchocerciasis Control (APOC). She received her PhD in parasitology from Cornell University in New York. Professor Braide is currently a faculty member at the University of Calabar, in Nigeria. She has worked on a number of committees and task forces addressing the problems of onchocerciasis and dracunculiasis in Nigeria and participated in several training and monitoring projects for community-directed treatment with ivermectin. Most recently, Prof. Braide was a co-investigator for the RAPLOA surveys conducted in eastern Nigeria in collaboration with WHO’s Tropical Disease Research program. She has published more than 35 scientific papers, on human and animal onchocerciasis. We look forward to her participation on the Mectizan Expert Committee.

Recommendation from the 29th Meeting of the MEC

Should People with Epilepsy and Growth Retardation Syndromes be Excluded from Mass Treatment Programs using Mectizan?

In recent years there have been questions raised by field personnel about whether epilepsy and/or growth retardation constitute ‘chronic illnesses’ such that affected persons should be excluded from Mectizan treatment in mass treatment programs. Anecdotal evidence from the field has suggested an association between onchocerciasis and epilepsy and/or growth retardation syndromes as well as a change in seizure activity in epileptics after Mectizan treatment. A comprehensive review of the published literature was therefore undertaken for the Mectizan Expert Committee (MEC) to address these questions.

Conclusions: 1. No conclusive evidence of cause and effect was found between onchocerciasis and epilepsy and/or growth retardation syndromes such as Nakalanga syndrome. 2. No serious adverse event following Mectizan treatment has ever been reported during the past 15 years of the Mectizan Donation Program that was associated with epilepsy. Yet it is estimated that about 1 to 2 million epileptics would have been treated with Mectizan during the same time period. For persons with growth retardation syndromes, a similar estimate of numbers treated cannot be determined. 3. There is insufficient data exist to determine whether Mectizan has a positive or negative effect on seizures.

Thus, the MEC recommends the following strategies for Mectizan administration in onchocerciasis mass treatment programs: 1. Epileptics, unless actively seizing or post-ictal, should not be considered ‘chronically ill’ and thus, should not be excluded unless they have other contraindications to treatment. 2. People with Nakalanga syndrome or other growth retardation syndromes associated with wasting, anorexia, weakness or other chronic debilitating condition, with or without epilepsy, should be excluded from mass treatment on the basis of their ‘chronic illness’. However, they should be eligible for clinic-based treatment once the diagnosis of onchocerciasis is confirmed, and the benefit of treatment is deemed to outweigh any potential risks.