Multicentric assessment of the efficacy and tolerability of dihydroartemisinin-piperaquine compared to artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in sub-Saharan Africa

Abstract

BackgroundThe choice of appropriate artemisinin-based combination therapy depends on several factors (cost, efficacy, safety, reinfection rate and simplicity of administration). To assess whether the combination dihydroartemisinin-piperaquine (DP) could be an alternative to artemether-lumefantrine (AL), the efficacy and the tolerability of the two products for the treatment of uncomplicated falciparum malaria in sub-Saharan Africa have been compared.MethodsA multicentric open randomized controlled clinical trial of three-day treatment of DP against AL for the treatment of two parallel groups of patients aged two years and above and suffering from uncomplicated falciparum malaria was carried out in Cameroon, Côte d'Ivoire and Senegal. Within each group, patients were randomly assigned supervised treatment. DP was given once a day for three days and AL twice a day for three days. Follow-up visits were performed on day 1 to 4 and on day 7, 14, 21, 28 to evaluate clinical and parasitological results. The primary endpoint was the recovery rate by day 28.ResultsOf 384 patients enrolled, 197 were assigned DP and 187 AL. The recovery rates adjusted by genotyping, 99.5% in the DP group and 98.9% in the AL group, were not statistically different (p = 0.538). No Early Therapeutic Failure (ETF) was observed. At day 28, two patients in the DP group and five in AL group had recurrent parasitaemia with Plasmodium falciparum. In the DP group, after PCR genotyping, one of the two recurrences was classified as a new infection and the other as recrudescence. In AL group, two recurrences were classified after correction by PCR as recrudescence. All cases of recrudescence were classified as Late Parasitological Failure (LPF). In each group, a rapid recovery from fever and parasitaemia was noticed. More than 90% of patients did no longer present fever or parasitaemia 48 hours after treatment. Both drugs were well tolerated. Indeed, no serious adverse events were reported during the follow-up period. Most of the adverse events which developed were moderate and did not result in the treatment being stopped in either treatment group.ConclusionsDihydroartemisinin-piperaquine was as effective and well-tolerated as artemether-lumefantrine in the treatment of uncomplicated falciparum malaria. In addition, dihydroartemisinin-piperaquine, a single daily dose, could be an advantage over artemether-lumefantrine in Africa because of better treatment observance.

The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data

“…We present the largest pooled analysis of DP efficacy yet described, to our knowledge, including more than two-thirds of all data from the published literature. Overall the efficacy of DP was excellent, exceeding 98% at day 28 and 97% at day 42, consistent with published results from Africa [12],[17],[18],[21],[25],[26],[29],[31],[35]–[37], Asia [13],[19],[20],[23],[24],[27],[28],[30],[32]–[34], and South America [22]. However our study reveals an important sub-group of patients who are at particular risk of treatment failure.…”

In Vitro Sensitivities of Plasmodium falciparum Isolates from the China-Myanmar Border to Piperaquine and Association with Polymorphisms in Candidate Genes

“…However, it is noteworthy that the difference between the PPQ responses in CQsensitive and -resistant strains which led to the suggestion of cross-resistance between CQ and PPQ resistance was insignificant and only at 3-to 4-fold (Table 2). Moreover, the overall good clinical efficacy of DHA-PPQ in treating falciparum malaria in areas of high prevalence of CQ-resistant parasites argues against a shared resistance mechanism between CQ and PPQ (15,47,48). Besides, most in vitro studies of laboratory strains and field parasite isolates failed to detect marked reductions in PPQ sensitivity in comparison with 3D7 or other laboratory strains (25,27,29,30).…”

Antimalarial chemotherapy: Orally curative artemisinin-derived trioxane dimer esters

“…14–15 Several short-lived, artemisinin-derived 1,2,4-trioxanes have been prepared and some, especially artemether ( 2 ) and artesunate ( 3 ), are currently used combined with long-lived, nitrogen-containing antimalarials. 16–22 Such a rtemisinin c ombination t herapy (ACT) is recommended as standard chemotherapeutic protocol by the World Health Organization (WHO). 23 Typically, multidose regimens of ACT daily for several days are needed to achieve a complete cure of malaria-infected people.…”

“…23 Typically, multidose regimens of ACT daily for several days are needed to achieve a complete cure of malaria-infected people. 16–20 A major problem arises, however, when infected individuals stop taking the ACT prematurely, thereby leading often to parasite recrudescence. Therefore, a major goal of modern antimalarial chemotherapy is to develop new endoperoxides capable of single oral dose ACT cures.…”