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Practical Guide for in vivo Antimalarial Drug-Efficacy Studies in the Americas
(RAVREDA-AMI, revised version, October 2003*)
Resistance of Plasmodium falciparum to antimalarial drugs is one of the most serious challenges facing national malaria control programs in the Americas. At present, P. falciparum is resistant to both chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) throughout the Amazon Basin and to CQ alone on the Pacific Coast of South America.
Additionally, in recent years several investigators have reported cases of P. vivax therapeutic failure to CQ. In response to the public-health threat of drug resistance, several ministries of health in the region have begun studies to map the distribution and intensity of P. falciparum and P. vivax resistance to antimalarial drugs within their borders. Peru and Bolivia have finished their baseline studies and have already changed their first-line treatments for uncomplicated P. falciparum infections. These countries are also establishing surveillance systems for drug resistance at sentinel sites throughout the country.
Although a variety of methods have been used by ministries of health to evaluate antimalarial drug resistance, in vivo drug-efficacy studies are generally considered the method of choice because their results correlate best with the clinical response of patient to these drugs. The World Health Organization (WHO) has published guidelines for in vivo drug-efficacy studies, originally intended for use in settings with intense transmission, such as Africa, but more recently with modifications appropriate for areas of low to moderate transmission, such us the Americas. In South America, most of the changes in national malaria treatment policies that have been made during the last 3–4 years have been based on the results of these in vivo studies.
While in vivo drug efficacy studies do not require sophisticated technology, they are not simple to conduct correctly. They require a well-trained and experienced clinical and laboratory team that closely follows the study protocol. Because of the low levels of malaria transmission in the Americas, it may be a challenge to meet the required sample sizes, particularly for P. falciparum infections. Also, in regions such as the Amazon Basin, where the population is widely dispersed and highly mobile, it may be extremely difficult to limit the number of patients lost to follow-up to no more than 10–15% of enrolled patients, as recommended by the WHO.
Even though most in vivo studies carried out in the Americas during the last 3–4 years have made use of standardized study protocols based on the WHO guidelines, those recommendations do not describe in detail how to carry out a study or how to avoid the pitfalls that can be encountered when working in the field. The purpose of the recommendations in this guide, which is based on recent experiences with antimalarial drug efficacy studies in South America, was to complement to the WHO guidelines and standardized protocols. It is hoped that this guide, together with the generic protocols, will contribute to the successful implementation of in vivo studies and a surveillance system for antimalarial drug resistance in the Americas.
* Date of original version: January 2003.