Low efficacy of chloroquine: time to switchover to artemisinin-based combination therapy for falciparum malaria in India.

Drug resistance in Plasmodium falciparum poses a major threat to malaria control globally; including India. Chloroquine is still the most widely used drug in the country because of its safety and cost effectiveness. Although chloroquine resistance was first reported in 1973 in North Eastern India, the extent of the problem was realized only after the more intensive 28-day drug efficacy studies were used to monitor drug resistance. In the present study, efficacy of chloroquine in treatment of uncomplicated falciparum malaria was investigated using standard World Health Organization (WHO) procedures in three distinct epidemiological settings. The prevalence of molecular markers of drug resistance, Pfcrt K76T, Pfmdr1 N86Y, was also studied. A total of 374 children and adults with uncomplicated P. falciparum malaria were enrolled at six sites in four states, treated with chloroquine and follow-up was done for 28 days. The cumulative incidence of success of chloroquine at Day 28 by the Kaplan Meier analysis in the state of Orissa (District Sundargarh, CHC Bisra and Kuarmunda) was 57 (95% CI 43-68) and 54 (95% CI 40-66); in the state of Jharkhand (District Ranchi, PHC Angara and District Simdega, PHC Jaldega) it was 72 (95% CI 59-81) and 65 (95% CI 50-76); in the state of Goa (District North-Goa, Panaji Town), it was 20 (95% CI 10-2) and in the state of Rajasthan (District Udaipur, PHC Rishabdev), it was 96 (95% CI 85-99). Treatment failure was related to Pfcrt mutations but not Pfmdr mutations. Early treatment failure was observed only in 15.8% out of total failures, probably due to the semi-immune nature of the population. This type of response may give false perception about efficacy of the failing drug to patients, clinicians and National Authorities. In a large country like India it is not feasible to conduct in vivo studies in all districts and lack of direct correlation between molecular markers, in vitro studies and treatment outcome makes it difficult to predict the areas requiring change of policy. In this scenario, it is a challenge for National Programmes to make evidence-based revisions in the drug policy. However, considering the global, especially Southeast Asian, scenario and interpretation of available in vivo data, trends of mutations, availability of effective drugs and support of international donors, India should consider changing the first line treatment, at least for all diagnosed P. falciparum cases.