Loiasis scientific working group meeting, Yaounde, Cameroon: mission report, 7-9 February 2012

LOIASIS SCIENTIFIC WORKING GROUP MEETING Yaound6, Cameroon Mission Report, 7-9 February 2OL2 Dr. Mounkaila Noma, CEV/APOC The Meeting was opened by the State Minister in charge of epidemic and endemic disease the honorable A. Ayahatou. His delegation included the Directeur of disease control (DLM), the Onchocerciasis national Coordinator, and the focal point of Lymphatic filariasis control programme. The meeting was co-funded by Bill and Melinda Gate Foundation (represented by Dr. Julie Jacobson) and Mectizan Donation Program (Dr. Adrian Hopkins, Dr. Yao Sodahlon and Dr. Kisito Ogoussan). The meeting was held in the "Centre de recherche sur les filarioses et les autres maladies tropicales" led by Dr. Joseph Kamgno. Prof. Charles Mackenzie chaired the meeting. AGENDA ITEMS DISCUSSED ,.,....,..,.,,....2 Update on severe adverse events (SAEs)........ .....................2 Test and treat - Ongoing Research .....................2 Albendazole high dose trials - Ongoing Research ................3 Macrofilaricide (flubendazole) development- Ongoing Research .........3 AWOL project Update ......................3 Update on Loa loa mapping in support to Onchocerciasis elimination ...................4 Status of LF mapping and vector control activities in DRC overlap with Loa |oa............. ..........4 Status of LF mapping data in Congo; overlap with Loa loa............ ........4 Literature review on Loa loa ............ ..................4 Vector Control and Personal Protection Approaches for Chrysops spp........... ....... 5 Proposed study on neurological outcomes of the SAEs......... ...............5 Loiasis as a disease: update and lab diagnostic tests.......... ................... 5 Animal models: future research objectives (agenda) & strategic p1an........... .........6 Future proposed research agenda for Cameroon Filariasis & other Tropical Diseases Research Centre ...........6 Brainstorming on New research projects ..........7 stDE ACT|V|TIES......... .........7 Meeting with HKI and RT|..... ............7 Meeting with the Director of pharmacy and drugs ............... ................7 PARTICIPANTS TO LO]ASIS SCIENTIFIC WORK]NG GROUP MEETING.. ...,... 8 AGENDA ITEMS DISCUSSED Update on severe adverse events (SAEsl Presentation: Dr Yao Sodahlon, Mectizan Donation Programme Cameroon reported 9 cases following MDAwith ivermectin and Albendazole in zOlL.6 of these cases are neurologic among which one death was recorded. The nine cases were recorded in the province of Centre and occurred in people exposed to ivermectin treatment for the first time. 7 cases of SAEs were recorded in the province Orientale, Democratic Republic of Congo, in 2011. 5 cases were neurologic. No death was recorded. As of Februa ry 2OL2, a total of 16 cases of SAES were reported (9 from Cameroon and 7 from DRC). This figure will be update on receipt of the report of province de l'Equateur (DRC) where 13 cases occurred within no death. Between 1990 and ZOLL, a total of 1245 cases of SAEs were reported out of which 516 were neurologic (41.4%1. 97% of the reported cases of SAEs were recorded in Cameroon and Democratic Republic of Congo. Loa loa meeting Lusaka, June 2011 Presentation: Dr. Ki lchimori, WHO/HO/NTD The meeting was informed on the meeting Loa loa meeting held in June 2011 in Zambia Capital (Lusaka). Lusaka meeting was attended by 7 countries (Angola, Cameroon, CAR, Congo, DRC, Gabon, and Nigeria) where Loasis and LF are co-endemic, WHO, technical partners and funding agencies. The objectives of the meeting were (i) to discuss possible strategies for interruption of LF transmission in Loa Loa co-endemic areas (ii) to determine the steps necessary for development of national plans to implement recommended strategies. ln the vision of shrinking the MDA ffi?p, the meeting recommended the development of a strategic plan (which includes interruption LF transmission in Loa Loa-endemic countriesl by 2072 by WHO and its partners; completion of LF mapping in 20L2 and elimination of LF by 2020. Test and treat - Ongoing Research Presentation: Dr. Amy Klion, Laboratory of Parasitic Diseases, NIAID Research group: Michel Boussinesq, Joseph Kamgno, Amy Klion, Charles Mackenzie, Tom Nutman, Sebastien Pion, Wilma Stolk, SamuelWanji The research "Test and Treat" aims to develop a strategy for MDA in Loa-endemic areas. The research would like to face the following challenges: o Development of a rapid field-applicable diagnostic that can identify individuals with dangerous levels of Loa loa microfilaremia for exclusion from MDA o Large-scale implementation of such a strategy o Potential implications of systematically excluding a subset of individuals from MDA. Using one or more tests with 100% sensitivity and >80% specificity in identification of "at risk" individuals that are practical for large scale screening, the research group aims to: o Assess of the safety and practicality of identification and exclusion of "at-risk" individuals prior to MDA in areas endemic for LF or hypoendemic for Onchocerciasis o Conduct a pilot study in Loa-endemic area with hypoendemic onchocerciasis and population 20,000-30,000 r "test and treat" trials of the most promising tests in additional areas, including areas endemic for LF Loiasis Scientific Working Group Meeting, Mission report, Dr. M. Noma Evaluate through field studies and modeling, of the impact of applying a "test and treat" strategy on MDA and the prospect of elimination of LF and Onchocerciasis Make recommendations for MDA in Loa-endemic areas with LF and/or hypoendemic onchocerciasis to WHO and other key parties with the goal of successful implementation of the recommended strategy. During the three years of the study, the group will conduct an assessment of geographic overlap between Loa, LF and oncho at the community level using data obtained during screening to identify areas for field studies; assess the relationship between Wuchereria bancrofti and Loa loa microfilaremia at the individual level (night blood testing of a subset of subjects during field studies) and conduct an impact assessment of "test and treat" on MDA using mathematical modeling. Okola and Lolodorl Cameroon, where Onchocerciasis is hypo endemic (will be confirmed by a REAI), were identified as study sites. Albendazole high dose trials - Ongoing Research Presentation: Dr. Michel Boussinesq, IRD This research is part of Death of Onchocerciasis and Lymphatic filariasis (DOFL) project. The rational of this research is based on (i) the fact that individuals with a very high Loa loa microfilaremia (> 30,000 mfs/ml) can develop an encephalopathy after ivermectin (lVM)treatmen! (ii) IVM can be distributed to control onchocerciasis in loiasis areas because persons infected with O. volvulus get a direct benefit from lVM, in contrast, IVM has a little (if any) effect on the clinical manifestations of LF; (iii) it is thus unwise to distribute IVM (+ALB) to control LF in areas where loiasis is endemic and onchocerciasis non- or hypoendemic. The research hypotheses are (i) repeated treatments with Albendazole (ALB) alone lead to a progressive reduction in the Wuchererio boncrofti microfilaremia and to an interruption of W. boncrofti transmission (over a longer term than with IVM+ALB); (ii) ALB alone seems not to induce SAEs in individuals infected with Loa and thus can be distributed safely in loiasis-endemic areas. The criteria for selecting study sites are: the site is endemic for Loiasis, endemic for LF with prevalence of W. boncrofti. It is community study initiate in Congo republic in villages totalizing 800 people. The clinical trial will compare the effects of 3 regimens on W. bancrofti: (i) IVM + ALB 400mg annually x 2; (ii) ALB 400mg 6- monthly x 4 and (iii) ALB 800mg 5-monthly x 4. Macrofilaricide (flubendazole) development- Ongoing Research Presentation: Prof. Charles Mackenzie The potential use of Flubendazole as a field macrofilaricide based on the need of a macrofilaricde, it has poor/no microfilariacidal effect. it possibly affects selectively adult worms. lt is effective against a range of parasites in aquatic and veterinary areas. lt has been shown effective against Loa in jirds, Onchocerca in humans, cysticercosis in mice. AWOL project Update Presentation: Prof. Samuel Wanji This project was initiated in the framework of the search of new filaricides which could substitute lvermectin in areas of co-endemicity or could be used to treat Onchocerciasis without affecting L. loa. The Discovery of Wolbachia endobacteria in most of the pathogenic human filarial nematodes including O. volvulus and its absence in Loa loa was the basis for the use of Doxycycline 100 mg/day for 6 weeks. The study was based on one round of Doxycycline administration; the investigator pledged for higher 1 Rapid epidemiological assessment of Onchocerciasis Loiasis Scientific Working Group Meeting, Mission report, Dr. M. Noma a' number of rounds of treatment would likely have higher impact and which will enable to determine the required number of treatment. Update on Loa loa mapping in support to Onchocerciasis elimination Presentation: Dr. Mounkaila Noma, APOC The Loa loa mapping was initiated by APOC programme in 1999 in collaboration with Schoolof tropical medicine and public health of Liverpool following the occurrence of severe adverse events following ivermectin mass distribution in Centre province, Cameroon. The overlap between the spatial distribution of Loa loa and Onchocerciasis in APOC countries was determined using geographical information system (GlS) and remote sensing technologies. Three years later (2000), WHO/TDR develop the rapid assessment procedure for loa loa (RAPLOA) which was important in the development of MEC/TCC guideline for treatment of Onchocerciasis with Mectizan in areas co-endemic for Onchocerciasis and Loiasis. ln 2OO4, following the occurrence of severe adverse events in Bas Congo province, DRC, APOC decided to move from validation of the RAPLOA to its widely use to map loa loa in all the CDTI areas where Loa loa is suspected as indicated by the predictive map develop by Liverpool school of tropical medicine and public health. Expert analysis of eye worm prevalence data was used to identify based on a threshold of 40% areas of probable occurrence SAEs following ivermectin treatment. ln the context of co-implementation the programme decided in 2010 to map loa loa in all the suspected sub-Saharan African countries. ln overall 11 countries were mapped and 10 were found endemic for Loiasis with an estimated 14.4 million people live in high risk areas. The geographic distribution of Loa loa in Africa: results of large-scale implementation of the Rapid Assessment Procedure for Loiasis (RAPLOA)" has been published by Zoure &al in PLoS NTDs (PLoS Negl Trop Dis 5(6): e1210. doi:10.1371[ournal.pntd.0001210). This publication reveals that no further mapping of loa loa is needed. Status of LF mapping and vector control activities in DRC overlap with Loa loa Presentation: Dr L. Kelly Hope, Center of NTDs/Liverpool The meeting was informed about the completion of the mapping of LF in Katanga and Kasai provinces in DRC. The data will be shortly available. CNTD/Liverpool planned to carry study on vector movement in Bas Congo province in the framework of establishing Chrysops spp. control. lt willalso provide country- based technical support to DRC for LF control including capacity in GlS. Status of LF mapping data in Congo; overlap with Loa loa Presentation: Dr Michel Boussinesq The surveys conducted in 2010-2011 in 37 villages (3,835 persons sampled) of the south-western of confirmed the presence of W. boncrofti in the Republic of Congo, but these surveys did not confirm LF endemicity in many areas that had positive mapping results in 2008 (WHO/AFRO). The population at risk for LF in the country is likely to be much smaller that 2.7 million reported in the WHO PCT website. LF seems to be much focalized in the Republic of Congo; additional studies should be performed to explain this focality. A similar situation might exist in other countries of Central Africa where small foci of LF have been reported, including the DRC. Literature review on Loa loa Presentation: Prof. Ed Cupp Loiasis Scientific Working Group Meeting, Mission report, Dr. M. Noma The literature review was on integrated control of Loiasis in Onchocerco volvulus co-endemic areas: background information and potential approaches. To reach the objective 8 topics from 22 Peer- Reviewed References were reviewed. The topics are namely: Historical Background - Several Pathology Reports of Loa loa - associated Encephalopathy in the Peer- reviewed Literature o What Causes Drug-lnduced Pathology ln Loa loa Microfilariasis? o MicrofilarialSequestration . Killing of Microfilariae in Extra-Cranial Organs o Focalized Microfilarial Killing and Nitric Oxide o Nitric Oxide and Human Cerebral lschemia and lnfarcts o lf NO is Responsible for Loa-induced Cerebral Pathology, What Therapy Might Be Available? o Alternative Drug Treatments - Are There Other Choices? The Use modern microscopic, molecular and immuno - histochemicaltechniques to determine a refined etiology for the Loa/drug-induced pathology based on tissues from historical, documented cases (Belgium, AFIP). Collectively, details from both cases could serve as important points of reference for on-going pathology research using the baboon-Loa model. The Development of baseline information in the Loa - baboon model is proposed as follows: o Determine levels of nitric oxide (NO) in the circulatory system in animals with moderate and high microfilaremia following ivermectin treatment versus levels in treated, non-infected animals; o Determine the impact of using iNOS inhibitors on NO levels in infected, treated animals and the safety of these compounds at therapeutic doses emphasizing length of treatment, prophylactic versus general treatment, and broad versus specific neuronal and endothelial iNOS inhibitors; o Evaluate NO levels as a reliable clinical predictor/indicator for onset of CNS d isease/encepha lo pathy. Three candidate drugs were proposed as potential Loa loa microfilaracide in human: Levamisole, Furapyrimidone and haloxon. Vector Control and Personal Protection Approaches for Chrysops spp. were also discussed. Vector Control and Personal Protection Approaches for Chrysops spp. Presentation: Dr. lsabelle Morlais, IRD MIVEGEC, Yaound6 The study was carried out in a forest village of south Cameroon where two types of Chrysops were identified: Chrysops silaceo (10%) and Chrysops dimidiato (90%). The trap assays used are Sticky tyre, Loapi trap, Tse-tse trap (Gouteux) and Manitoba. Only females were caught; 70% nulliparus females and -3% presented L3 microfilaria in the head. The study concluded that: . Daily catching yields are low, 2flies/trap/day for the Loapi trap o The Manitoba trap had poor performances, maybe because of the smallcalabash size o CO2-baited traps(fire) significantly increase fly collections o Human landing catches are L0 -fold higher than trap catches o Dark colours are preferred Proposed study on neurological outcomes of the SAEs Presentation: Farrah Mateen, Johns Hopkins University An observational cohort study was proposed based on the hypothesis that adults who experience loa loa encephalopathy following lvermectin treatment for Onchocerciasis will have long-term neurological deficits, including psychomotor disability. Loiasis as a disease: update and lab diagnostic tests Presentation: Amy Klion Loiasis Scientific Working Group Meeting, Mission report, Dr. M. Noma The aim is to develop laboratory diagnostic test to: o ldentification of individual patient in order to treat definitively . ldentification of individuals within a community to exclude from MDA o ldentification of communities with prevalences above a pre-defined threshold o Exclusion of Loa loa in areas where LF, Ov, or Mansonella infection are endemic Expectations are based on: . Loa-specific serologic assays available in standard ELISA formats and in rapid, high throughput LIPS o Useful for screening large populations to '/ Exclude loiasis ,/ Estimate seroprevalence ,/ Screen for ongoing transmission o Quantitative molecular assays available o qPCR/qRTPCR o LAMP - Colorimetric, no fancy equipment needed o Microscopy still a possibility o lssue of periodicity o Confounding parasites (Mansonella perstans, others) o Other potentially quantitative techniques in development include agglutination assays, circulating antigen assays and a variety of simpler methods for visualization of mf in peripheral blood Animal models: future research objectives (agenda) & strategic plan Presentation: Prof. Charles Mackenzie & Prof. SamuelWanji The activities of Buea Primate Model of Loiasis were presented. The model verification was achieved and it has provided information on massive tissue eosinophilia/lymphadenopathy, thrombotic parasitic vaculopathy and secondary consequences (neuronal damage). As next step, the study will look at potential therapeutic/prophylactic approaches with aspirine and cortisone and will screening the potential of flubendazole and other drug candidates as Loa loa macrofilarcides. Future proposed research agenda for Cameroon Filariasis & other Tropical Diseases Research Centre Presentation: Dr. Joseph Kamgno The research agenda going on in Filariasis and other Tropical diseases Research Center was presented. o study was on going to examine the clinical impact (including ophthalmologic and cardiac) of Loiasis e lmpact of treatment on preclinical signs of LF will commence in April 2012 o The impact of long-term Onchocerciasis treatment has had on Loa loa in O. volvulus areas Protocol was submitted to APOC for consideration and will commence upon reception of funding. LF mapping in Cameroon was carried out (lCT test in 2010 and night blood in 2011) and maps are being prepared. Regarding the transmission of Wuchereria bancrofti in Loa endemic areas, there is a higher prevalence of LF and heavier load of bancrofti mf in Loa loa free area in Cameroon (Northern part of the country). ln contrast, the prevalence of LF and bancrofti mf are very low in Loa loa endemic areas (southern part of the country). A recent night blood collection campaign in Loa endemic areas for LF screening unexpectedly showed high prevalence and heavy loads of loa microfilaria (>10000 mf/ml) of blood, and only few cases of LF with weak microfilaria loads. 6Loiasis Scientific Working Group Meeting, Mission report, Dr. M. Noma From these results the following questions need to be addressed: o What are the vectors of LF in this region r What is the outcome of Loa microfilaria uptake when the vectors of W. boncrofti, Anopheles or Culex feed on their host? r ls the heavy presence of Loa mf within Anopheles or Culex negatively impact the life cycle of W. bancrofti?\ o ls there any interaction between Loa loa and W. bancroftiin the vertebrate host that may explain the low prevalence of LF and weak load of W, boncroftiin Loa endemic area? Brainstorming on New research projects Dr. Julie Jacobson was invited the meeting to brainstorm on new research projects which can be supported by Bill and Melinda Gate Foundation and the meeting was informed that the funds are available and given the process of disbursement, interested parties need to start soon submission of proposals. SIDE ACTIVITIES Meeting with HKI and RTI We were invited to attend a meeting at HKI office. The meeting (9 February 2012) was attended by the national Coordinator of Cameroon, the focal point of LF, the Country Director HKl, HKI project manager, two staff member of RTI (Dr. Eric Ottsen and Dr. Achille Kabor6) and Dr Mounkaila Noma (APOC). The meeting discussed the following: o the need for APOC to train projects and NOTF Secretariat accounts in financial management and reporting as requested by APOC. So far HKI which is supporting six projects (out of L5) is the one providing support to the national office and has to track the projects to get the financial returns. o RTI was funded country-wide mapping of LF and intends to funds HKI for undertaking treatment coverage in all HKI supported projects. APOC was invited to join in implementation of the treatment coverage evaluation. o ln 2012, evaluation epidemiological evaluations in 2Ot2 are planned in 5 projects in Cameroon (Adamaoua 2, Centre 2, Centre 3, South West 1 and South West 2). HKl, NGDO supporting Centre 2 and Centre 3, requested that the epidemiological evaluation in Centre 2 and Centre 3 be reported 20L3. Reasons given is that the epidemiological evaluations in the 2 projects may be the same than in Centre 1; the treatment cycle will be conducted between April and May as agreed with the communities and this will not give 11 months since the last treatment to conduct epidemiological evaluation. Meeting with the Director of pharmacy and drugs The Director of Mectizan Donation Programme (Dr. Adrian Hopkins), Deputy Directors of MDP (Dr. Kisito Ogoussan and Dr. Yao Sodalhon), the National Coordinator of Cameroon, the LF focal point of Cameroon and Dr. Mounkaila Noma met on 9th February 2012 the National Director of Pharmacy and drugs of Cameroon (Dr. Jean-Rollin Bertrand Ndo). The subject of the meeting was that the NOTF should pay tax for importation of Mectizan in Cameroon otherwise the drug will not be available to Oncho programme (in 2011, the NOTF paid more 160,000 FCFA). The Director Dr. Ndo clarified the issue that his department will release the drug but they are requesting to have from the pharmaceutical company a homologation document for Mectizan. He also inform the meeting a visa given from any drug (free donation or not) should be renewed every 5 years. The group pledge the release of the drug free donated to the Oncho Programme and I follow up will be conducted by the Director MDP to have a Loiasis Scientific Working Group Meeting, Mission report, Dr. M. Noma copy of Mectizan homologation in France from MSD/France. Dr. Ndo said the homologation document delivered in France will satisfy his request. PARTICIPANTS TO LOIASIS SCIENTIFIC WORKING GROUP MEETING t 2 3 4 5 6 7 8 9 10 11. t2 13 t4 15 16 t7 Prof. Charles Mackenzie Dr. Julie Jacobson Dr. Adrian Hopkins Dr. Joseph Kamgno Dr. Ogoussan Kisito Dr. Amy Klion Dr. Michel Boussinesq Dr. Mounkaila Noma Prof. Ed Cupp Dr. Kazyo lchimoru Dr. Achille Kabore Dr. Yao Sodalhon Dr. Marcelline Ntep Dr. Annette Kuesel Dr. Eric Ottensen Prof. SamuelWanji Dr Mateen Farrah Loiasis Scientific Working Group Meeting, Mission report, Dr. M. Noma