- Email: [email protected]
Efficacy of ivermectin against Onchocerca volvulus in Ghana – Authors' reply
Correspondence
WHO/TDR/OCP
colleagues base their conclusion on the microfilarial repopulation dynamics after treatment. In four villages, repopulation was faster than in five other villages, and OseiAtweneboana and colleagues took this as “evidence that ivermectin resistance is developing”. However, comparable repopulation dynamics have also been seen in situations where incomplete control led to renewed transmission and the introduction of young worms into an ageing worm population. The critical question is why these four villages had relatively high infection levels after 12–17 treatment rounds. One possible explanation is insufficient treatment coverage. Reports available to us are incomplete but suggest that treatment coverage has been highly variable, sometimes as low as 20–40%, and with no treatment reported for some years. Osei-Atweneboana and colleagues even report on a hyperendemic village that never received treatment. Such untreated villages, and the untreated members of villages with poor treatment coverage, will contribute to transmission and infections with new onchocercal worms, also in neighbouring villages and among those who received treatment. We believe that inadequate coverage provides a plausible explanation for the observations. We do not dismiss the possibility of resistance and the African Programme for Onchocerciasis Control will coordinate further investigations. Furthermore, WHO is working with partners towards the establishment of comprehensive systems for monitoring drug use and efficacy in large-scale anthelmintic treatment programmes. We declare that we have no conflict of interest.
*Jan H F Remme, Uche Amazigo, Dirk Engels, Andriamahefazafy Barryson, Laurent Yameogo [email protected] UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, World Health Organization, 20 Avenue Appia, 1211 Geneva, Switzerland (JHFR); African Programme for Onchocerciasis Control, World Health Organization, Ouagadougou, Burkina Faso (UA, LY); Preventive Chemotherapy and
1124
Transmission Control, World Health Organization, Geneva, Switzerland (DE); and Other Tropical Diseases, Regional Office for Africa, World Health Organization, Brazzaville, Congo (AB) 1
Osei-Atweneboana MY, Eng JK, Boakye DA, Gyapong JO, Prichard RK. Prevalence and intensity of Onchocerca volvulus infection and efficacy of ivermectin in endemic communities in Ghana: a two-phase epidemiological study. Lancet 2007; 369: 2021–29.
Authors’ reply Ed Cupp and colleagues suggest that an ivermectin resistance mechanism involving reduced suppression of reproduction by adult female Onchocerca volvulus would be unique. Although ivermectin resistance in trichostrongylids of livestock is manifested by the survival of the parasitic stages, including adult worms, the action of ivermectin against adult filariae is unique in that ivermectin mainly suppresses reproduction rather than killing adult filariae. Nevertheless, it is of interest that Caenorhabditis elegans unc-9 mutants share phenotypes of ivermectin resistance and an egg-laying defect.1 It has been suggested that low treatment coverage might explain the observed rapid skin repopulation with microfilariae, and Charles Mackenzie and Jan Remme and colleagues suggest treatment coverage of less than 50%. In fact, the average treatment coverage in the 5 years before the study, in the communities that showed poor parasitological responses, were: Jagbenbendo 71·5%, New Longoro and Kyingakrom 66·5% each, and Wiae 68·7%. These levels of coverage are in excess of the target of 65% set out by the African Programme for Onchocerciasis Control.2 Furthermore, the almost complete removal of skin microfilariae by 30 days after treatment confirms that treatment coverage was 100% for all patients in our study. A low treatment coverage cannot explain the rapid repopulation of skin microfilariae in these patients in the communities that showed poor parasitological response to ivermectin. Remme and colleagues point to the ivermectin-naive community
and suggest that incoming infections could cause newly maturing adult worms to rapidly repopulate the skin with microfilariae. Ivermectin-naive communities are rare in Ghana and the naive community found in this study was in the East Gonja district. This area is remote from Kyingakrom and New Longoro (Kintampo district), two of the communities in which skin repopulation with microfilariae was alarming. Cupp and colleagues also suggest that the rapid repopulation of the skin with microfilariae could be due to newly maturing adult parasites which had established in the 6–8 months when ivermectin might not fully suppress parasite reproduction. This explanation seems unlikely for several reasons. The infective larvae take at least 1 year to become reproductively active adults. At 30 days after treatment, virtually all microfilariae were removed from the skin. Yet by day 90 after treatment there were already significant differences between the communities that responded suboptimally and the ivermectin-naive community or the previously treated communities that responded as expected. This would leave only a 60-day window for newly maturing adult parasites to begin microfilaria production, while not being affected at the time of treatment. Furthermore, in the ivermectin-naive community where transmission could be expected to be highest, the percentage repopulation in comparison with pretreatment microfilaria levels (2·89%) was less (as were absolute microfilaria counts) than in the communities that showed the suboptimal responses (as high as 21·12% in Kyingakrom). Mackenzie also suggests that variability in microfilaria estimates in skin snips could explain the differences between the communities that responded poorly and those that responded as expected. Each community had between 12 and 68 study participants, with two skin snips taken at each sampling time. Individuals www.thelancet.com Vol 370 September 29, 2007
Correspondence
were followed up longitudinally, with the data being presented as geometric means for each community. Any sampling variability would be random and be accounted for in the statistical analyses. Comparisons were made with pretreatment microfilaria counts and analyses were done on individuals over time. Furthermore, in a subsequent unpublished study on these communities, adult worms, embryograms, and larval stages in the vector have been examined and the conclusions from these additional results are consistent with those reported. Our results cannot be explained by the alternative hypotheses suggested, which strengthens the concern that ivermectin resistance, manifested as an increase in the rate of microfilaria repopulation by adult worms, is developing. As suggested by many of the correspondents, this suggestion warrants increased monitoring for ivermectin resistance and an acceleration of efforts to develop better tools for such monitoring and for new means of onchocerciasis control. We declare that we have no conflict of interest.
Mike Osei-Atweneboana, Jeffrey Eng, Daniel Boakye, John Gyapong, *Roger Prichard [email protected] Institute of Parasitology, McGill University, 21111 Lakeshore Road, Sainte Anne-de-Bellevue, QC H9X 3V9, Canada (MO, JE, RP); Noguchi Memorial Institute for Medical Research, University of Ghana, Ghana (DB); and Health Research Unit, Ghana Health Services, Ghana (JG) 1
2
Barnes TM, Hekimi S, The Caenorhabditis elegans avermectin resistance and anesthetic response gene unc-9 encodes a member of a protein family implicated in electrical coupling of excitable cells. J Neurochem 1997; 69: 2251–60. Amazigo UV, Obono OM, Dadzie KY, et al. Monitoring community-directed treatment programmes for sustainability: lessons from the African Programme for Onchocerciasis Control (APOC). Ann Trop Med Parasitol 2002; 96 (suppl 1): S75–92.
The report by Mike Osei-Atweneboana and colleagues1 concerning possible ivermectin resistance in onchocerciasis is of concern. Although the microfilaricidal effects of ivermectin seemed www.thelancet.com Vol 370 September 29, 2007
undiminished, the study suggests that the poorly understood inhibition of embryogenesis in female macrofilariae was reduced in four of ten villages. Any suggestion of compromised effectiveness is of great concern for the Mectizan Donation Program, one of the most effective public-health mass treatment programmes of all time. The rates of repopulation of microfilariae were relatively small and occurred in an area where treatment coverage has not been particularly high. This is also an area where active transmission of Onchocerca volvulus continues. Nonetheless, this report is a warning against complacency and a call to redouble efforts in the search for a macrofilaricidal drug and for drugs that can affect embryogenesis through an alternative mechanism. Further it is an urgent message for increased scrutiny of populations after treatment. Some believe that elimination of onchocerciasis is possible in many foci through interruption of transmission through more aggressive treatment programmes with higher levels of population coverage.2–4 The findings from Ghana might encourage such efforts.
Coeliac disease and lymphocytic hypophysitis Ami Schattner and Taiba Zornitzki describe a man with anaemia, arthralgia, and gastrointestinal involvement (June 30, p 2214).1 Many ancillary tests were done, resulting in an eventual diagnosis of corticotropin deficiency possibly caused by lymphocytic hypophysitis. One test that was not done was for coeliac disease. This disease is very common and has protean manifestations2,3 matching most findings in Schattner and Zornitzki’s patient. Steroids are also used in its treatment,3 and the patient’s recovery might therefore be due to their effect on coeliac disease, which can occur with lymphocytic hypophysitis.4,5 Finally, as well as heeding Occam’s razor,1 “When you hear hoofbeats, don’t think zebras” should also be kept in mind. I declare that I have no conflict of interest.
Weekitt Kittisupamongkol [email protected] Surin Hospital, Surin 32000, Thailand
I am Chair of the Mectizan Expert Committee, which is a voluntary position without pay.
1
Gilbert Burnham
2
[email protected]
3
Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe Street, Baltimore, MD 21205, USA 1
2
3
4
Osei-Atweneboana MY, Eng JK, Boakye DA, Gyapong JO, Prichard RK. Prevalence and intensity of Onchocerca volvulus infection and efficacy of ivermectin in endemic communities in Ghana: a two-phase epidemiological study. Lancet 2007; 369: 2021–29. Cupp E, Cupp M. Short report: impact of ivermectin community-level treatments on elimination of adult Onchocerca volvulus when individuals receive multiple treatments per year. Am J Trop Med Hyg 2005; 73: 1159–61. Ndyomugheni R, Lakwo T, Habomugisha P, Male B. Progress towards the elimination of onchocerciasis as a public health problem in Uganda: opportunities, challenges and the way forward. Ann Trop Med Parasitol 2007; 101: 323–33. Winnen M, Plaisier AP, Alley ES, et al. Can ivermectin mass treatments eliminate onchocerciasis in Africa? Bull World Health Organ 2002; 80: 384–91.
4
5
Schattner A, Zornitzki T. When the wholebody scan shows no abnormality. Lancet 2007; 369: 2214. Green PH, Jabri B. Coeliac disease. Lancet 2003; 362: 383–91. Ciclitira PJ, King AL, Fraser JS. AGA technical review on celiac sprue. Gastroenterology 2001; 120: 1526–40. Collin P, Hakanen M, Salmi J, Mäki M, Kaukinen K. Autoimmune hypopituitarism in patients with coeliac disease: symptoms confusingly similar. Scand J Gastroenterol 2001; 36: 558–60. Greenfield JR, Samaras K. Evaluation of pituitary function in the fatigued patient: a review of 59 cases. Eur J Endocrinol 2006; 154: 147–57.
Authors’ reply We applaud the brilliant suggestion by Weekitt Kittisupamongkol that our patient’s isolated corticotropin deficiency could have been due to associated unrecognised coeliac disease. As many as 3·8% of blood donors in Israel have positive serology for coeliac disease, and when they undergo 1125
WHO/TDR/OCP
colleagues base their conclusion on the microfilarial repopulation dynamics after treatment. In four villages, repopulation was faster than in five other villages, and OseiAtweneboana and colleagues took this as “evidence that ivermectin resistance is developing”. However, comparable repopulation dynamics have also been seen in situations where incomplete control led to renewed transmission and the introduction of young worms into an ageing worm population. The critical question is why these four villages had relatively high infection levels after 12–17 treatment rounds. One possible explanation is insufficient treatment coverage. Reports available to us are incomplete but suggest that treatment coverage has been highly variable, sometimes as low as 20–40%, and with no treatment reported for some years. Osei-Atweneboana and colleagues even report on a hyperendemic village that never received treatment. Such untreated villages, and the untreated members of villages with poor treatment coverage, will contribute to transmission and infections with new onchocercal worms, also in neighbouring villages and among those who received treatment. We believe that inadequate coverage provides a plausible explanation for the observations. We do not dismiss the possibility of resistance and the African Programme for Onchocerciasis Control will coordinate further investigations. Furthermore, WHO is working with partners towards the establishment of comprehensive systems for monitoring drug use and efficacy in large-scale anthelmintic treatment programmes. We declare that we have no conflict of interest.
*Jan H F Remme, Uche Amazigo, Dirk Engels, Andriamahefazafy Barryson, Laurent Yameogo [email protected] UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, World Health Organization, 20 Avenue Appia, 1211 Geneva, Switzerland (JHFR); African Programme for Onchocerciasis Control, World Health Organization, Ouagadougou, Burkina Faso (UA, LY); Preventive Chemotherapy and
1124
Transmission Control, World Health Organization, Geneva, Switzerland (DE); and Other Tropical Diseases, Regional Office for Africa, World Health Organization, Brazzaville, Congo (AB) 1
Osei-Atweneboana MY, Eng JK, Boakye DA, Gyapong JO, Prichard RK. Prevalence and intensity of Onchocerca volvulus infection and efficacy of ivermectin in endemic communities in Ghana: a two-phase epidemiological study. Lancet 2007; 369: 2021–29.
Authors’ reply Ed Cupp and colleagues suggest that an ivermectin resistance mechanism involving reduced suppression of reproduction by adult female Onchocerca volvulus would be unique. Although ivermectin resistance in trichostrongylids of livestock is manifested by the survival of the parasitic stages, including adult worms, the action of ivermectin against adult filariae is unique in that ivermectin mainly suppresses reproduction rather than killing adult filariae. Nevertheless, it is of interest that Caenorhabditis elegans unc-9 mutants share phenotypes of ivermectin resistance and an egg-laying defect.1 It has been suggested that low treatment coverage might explain the observed rapid skin repopulation with microfilariae, and Charles Mackenzie and Jan Remme and colleagues suggest treatment coverage of less than 50%. In fact, the average treatment coverage in the 5 years before the study, in the communities that showed poor parasitological responses, were: Jagbenbendo 71·5%, New Longoro and Kyingakrom 66·5% each, and Wiae 68·7%. These levels of coverage are in excess of the target of 65% set out by the African Programme for Onchocerciasis Control.2 Furthermore, the almost complete removal of skin microfilariae by 30 days after treatment confirms that treatment coverage was 100% for all patients in our study. A low treatment coverage cannot explain the rapid repopulation of skin microfilariae in these patients in the communities that showed poor parasitological response to ivermectin. Remme and colleagues point to the ivermectin-naive community
and suggest that incoming infections could cause newly maturing adult worms to rapidly repopulate the skin with microfilariae. Ivermectin-naive communities are rare in Ghana and the naive community found in this study was in the East Gonja district. This area is remote from Kyingakrom and New Longoro (Kintampo district), two of the communities in which skin repopulation with microfilariae was alarming. Cupp and colleagues also suggest that the rapid repopulation of the skin with microfilariae could be due to newly maturing adult parasites which had established in the 6–8 months when ivermectin might not fully suppress parasite reproduction. This explanation seems unlikely for several reasons. The infective larvae take at least 1 year to become reproductively active adults. At 30 days after treatment, virtually all microfilariae were removed from the skin. Yet by day 90 after treatment there were already significant differences between the communities that responded suboptimally and the ivermectin-naive community or the previously treated communities that responded as expected. This would leave only a 60-day window for newly maturing adult parasites to begin microfilaria production, while not being affected at the time of treatment. Furthermore, in the ivermectin-naive community where transmission could be expected to be highest, the percentage repopulation in comparison with pretreatment microfilaria levels (2·89%) was less (as were absolute microfilaria counts) than in the communities that showed the suboptimal responses (as high as 21·12% in Kyingakrom). Mackenzie also suggests that variability in microfilaria estimates in skin snips could explain the differences between the communities that responded poorly and those that responded as expected. Each community had between 12 and 68 study participants, with two skin snips taken at each sampling time. Individuals www.thelancet.com Vol 370 September 29, 2007
Correspondence
were followed up longitudinally, with the data being presented as geometric means for each community. Any sampling variability would be random and be accounted for in the statistical analyses. Comparisons were made with pretreatment microfilaria counts and analyses were done on individuals over time. Furthermore, in a subsequent unpublished study on these communities, adult worms, embryograms, and larval stages in the vector have been examined and the conclusions from these additional results are consistent with those reported. Our results cannot be explained by the alternative hypotheses suggested, which strengthens the concern that ivermectin resistance, manifested as an increase in the rate of microfilaria repopulation by adult worms, is developing. As suggested by many of the correspondents, this suggestion warrants increased monitoring for ivermectin resistance and an acceleration of efforts to develop better tools for such monitoring and for new means of onchocerciasis control. We declare that we have no conflict of interest.
Mike Osei-Atweneboana, Jeffrey Eng, Daniel Boakye, John Gyapong, *Roger Prichard [email protected] Institute of Parasitology, McGill University, 21111 Lakeshore Road, Sainte Anne-de-Bellevue, QC H9X 3V9, Canada (MO, JE, RP); Noguchi Memorial Institute for Medical Research, University of Ghana, Ghana (DB); and Health Research Unit, Ghana Health Services, Ghana (JG) 1
2
Barnes TM, Hekimi S, The Caenorhabditis elegans avermectin resistance and anesthetic response gene unc-9 encodes a member of a protein family implicated in electrical coupling of excitable cells. J Neurochem 1997; 69: 2251–60. Amazigo UV, Obono OM, Dadzie KY, et al. Monitoring community-directed treatment programmes for sustainability: lessons from the African Programme for Onchocerciasis Control (APOC). Ann Trop Med Parasitol 2002; 96 (suppl 1): S75–92.
The report by Mike Osei-Atweneboana and colleagues1 concerning possible ivermectin resistance in onchocerciasis is of concern. Although the microfilaricidal effects of ivermectin seemed www.thelancet.com Vol 370 September 29, 2007
undiminished, the study suggests that the poorly understood inhibition of embryogenesis in female macrofilariae was reduced in four of ten villages. Any suggestion of compromised effectiveness is of great concern for the Mectizan Donation Program, one of the most effective public-health mass treatment programmes of all time. The rates of repopulation of microfilariae were relatively small and occurred in an area where treatment coverage has not been particularly high. This is also an area where active transmission of Onchocerca volvulus continues. Nonetheless, this report is a warning against complacency and a call to redouble efforts in the search for a macrofilaricidal drug and for drugs that can affect embryogenesis through an alternative mechanism. Further it is an urgent message for increased scrutiny of populations after treatment. Some believe that elimination of onchocerciasis is possible in many foci through interruption of transmission through more aggressive treatment programmes with higher levels of population coverage.2–4 The findings from Ghana might encourage such efforts.
Coeliac disease and lymphocytic hypophysitis Ami Schattner and Taiba Zornitzki describe a man with anaemia, arthralgia, and gastrointestinal involvement (June 30, p 2214).1 Many ancillary tests were done, resulting in an eventual diagnosis of corticotropin deficiency possibly caused by lymphocytic hypophysitis. One test that was not done was for coeliac disease. This disease is very common and has protean manifestations2,3 matching most findings in Schattner and Zornitzki’s patient. Steroids are also used in its treatment,3 and the patient’s recovery might therefore be due to their effect on coeliac disease, which can occur with lymphocytic hypophysitis.4,5 Finally, as well as heeding Occam’s razor,1 “When you hear hoofbeats, don’t think zebras” should also be kept in mind. I declare that I have no conflict of interest.
Weekitt Kittisupamongkol [email protected] Surin Hospital, Surin 32000, Thailand
I am Chair of the Mectizan Expert Committee, which is a voluntary position without pay.
1
Gilbert Burnham
2
[email protected]
3
Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe Street, Baltimore, MD 21205, USA 1
2
3
4
Osei-Atweneboana MY, Eng JK, Boakye DA, Gyapong JO, Prichard RK. Prevalence and intensity of Onchocerca volvulus infection and efficacy of ivermectin in endemic communities in Ghana: a two-phase epidemiological study. Lancet 2007; 369: 2021–29. Cupp E, Cupp M. Short report: impact of ivermectin community-level treatments on elimination of adult Onchocerca volvulus when individuals receive multiple treatments per year. Am J Trop Med Hyg 2005; 73: 1159–61. Ndyomugheni R, Lakwo T, Habomugisha P, Male B. Progress towards the elimination of onchocerciasis as a public health problem in Uganda: opportunities, challenges and the way forward. Ann Trop Med Parasitol 2007; 101: 323–33. Winnen M, Plaisier AP, Alley ES, et al. Can ivermectin mass treatments eliminate onchocerciasis in Africa? Bull World Health Organ 2002; 80: 384–91.
4
5
Schattner A, Zornitzki T. When the wholebody scan shows no abnormality. Lancet 2007; 369: 2214. Green PH, Jabri B. Coeliac disease. Lancet 2003; 362: 383–91. Ciclitira PJ, King AL, Fraser JS. AGA technical review on celiac sprue. Gastroenterology 2001; 120: 1526–40. Collin P, Hakanen M, Salmi J, Mäki M, Kaukinen K. Autoimmune hypopituitarism in patients with coeliac disease: symptoms confusingly similar. Scand J Gastroenterol 2001; 36: 558–60. Greenfield JR, Samaras K. Evaluation of pituitary function in the fatigued patient: a review of 59 cases. Eur J Endocrinol 2006; 154: 147–57.
Authors’ reply We applaud the brilliant suggestion by Weekitt Kittisupamongkol that our patient’s isolated corticotropin deficiency could have been due to associated unrecognised coeliac disease. As many as 3·8% of blood donors in Israel have positive serology for coeliac disease, and when they undergo 1125