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Use of appropriate indicator for evaluate drug efficacy

Posted by montresor on 20 Jul 2012 at 09:43 GMT

By Bruno Levecke, Jozef Vercruysse, Chanthavisouk Chitsavang, Tuan Le Anh, Dirk Engels andAntonio Montresor.

With great interest we have read the study by Soukhathammavong and colleagues (1). They report the efficacy of benzimidazole drugs against soil-transmitted helminthes and concomitant infections with Opisthorchis viverrini.
However, we would like to express our concerns on some of the conclusions drawn. An unexpected low cure rate (CR) for both benzimidazole drugs against hookworm infections was observed. The authors explain this apparent poor efficacy by various factors, including differences in susceptibility between hookworm species, zoonotic Ancylostoma ceylanicum infections, day-to-day variation in egg excretion, relatively small sample size and anthelmintic resistance. In our opinion, however, the reason for this apparent poor drug efficacy is due to the use of CR that is an inappropriate indicator to evaluate drug efficacy. CR is indeed the most reported indicator, but it has recently been shown that it can be seriously thwarted by the sensitivity of the diagnostic method used and of the intensity of infection at baseline (2-3), as a result of this, with drug of identical efficacy, we observe less satisfactory CR when baseline intensity of egg excretion are high and/or a more sensitive diagnostic test is used (because the probability of detecting eggs after drug administration is relatively high) and more satisfactory CR when baseline levels of egg counts are low and/or a less sensitive diagnostic test is used (because the probability of detecting eggs after drug administration is low). This is confirmed for both drugs also in Table 2 of this article.
For this reason, WHO advocate (2) to interpret drug efficacy results on using egg reduction rate (ERR). For albendazole, the expected ERR evaluated in a study conducted in 7 countries is 90% (4). In the present study, a ERR of 86.7% was observed. Although this also indicates a poor efficacy, this needs to be carefully interpreted. First, this value should be interpret along its 95% confidence intervals. Secondly, in the present study, the group based formula using geometric mean is applied. However, it has been shown that this formula may thwart the true drug efficacy (5) and therefore arithmetic mean is the most appropriate (4).
To conclude, we feel that no poor anthelmintic efficacy can be claimed on the basis of CR, but the appropriate indicator should be used (i.e. ERR).
WHO is seriously concerned about unjustified claims of drug resistance made using inappropriate indicators. These claims create uncertainty among the managers of control programmes about the efficacy of the control measures to be implemented and undermine the scaling up of STH control activities.
As a consequence, a working group reporting to the WHO Strategic and Technical Advisory Group on Neglected Tropical Diseases (NTD) is developing a Standard Operating Procedure to evaluate anthelmintic drug efficacy. While we hope that this tool will be available before the end of the year, we take this opportunity to invite PLoS NTD and other scientific journals to carefully assess the grounds on which claims of drug failure are based, should similar papers be submitted for publication. 
1-Soukhathammavong PA, Sayasone S, Phongluxa K, Xayaseng V, Utzinger J, Vounatsou P, Hatz C, Akkhavong K, Keiser J, Odermatt P. Low Efficacy of Single-Dose Albendazole and Mebendazole against Hookworm and Effect on Concomitant Helminth Infection in Lao PDR. Plos NTD, 2012 6 e 1417

2- Montresor A. Cure rate is not a valid indicator for assessing drug efficacy and impact of preventive chemotherapy interventions against schistosomiasis and soil-transmitted helminthiasis. (2011) Transactions of the Royal Society of Tropical Medicine and Hygiene 2012, 105, 361-363.
3- Levecke B, Speybroeck N, Dobson RJ, Vercruysse J, Charlier J. Novel Insights in the Fecal Egg Count Reduction Test for Monitoring Drug Efficacy against Soil-Transmitted Helminths in Large-Scale Treatment Programs Plos NTD, 2011 5; e1427
4- Vercruysse J, Levecke B, Albonico M, Ame SM, Angebault C, Guillard B, Hoa NT, Kang G, Kattula D, Kotze A, McCartey J, Mekonnen Z, Montresor A, Ngassam RI, Tchuem Tchuenté LA, Thach DT, Zeynudin A, Behnke J. A multinational trial of the efficacy of Albendazole against soil-transmitted nematode infections in children. PLoS NTD 2011, 5 , e948

5-Dobson RJ, Sangster NC, Besier RB, Woodgate RG. Geometric means provide a biased efficacy result when conducting a faecal egg count reduction test (FECRT). Vet Parasitol. 2009;161:162-7.

No competing interests declared.