Safety and efficacy of dihydroartemisinin-piperaquine in falciparum malaria: a prospective multi-centre individual patient data analysis

Abstract

Background: The fixed dose antimalarial combination of dihydroartemisinin-piperaquine (DP) is a promising new artemisinin-based combination therapy (ACT). We present an individual patient data analysis of efficacy and tolerability in acute uncomplicated falciparum malaria, from seven published randomized clinical trials conducted in Africa and South East Asia using a predefined in-vivo protocol. Comparator drugs were mefloquine-artesunate (MAS3) in Thailand, Myanmar, Laos and Cambodia; artemether-lumefantrine in Uganda; and amodiaquine+sulfadoxine-pyrimethamine and artesunate+amodiaquine in Rwanda.

Methods and findings: In total 3,547 patients were enrolled: 1,814 patients (32% children under five years) received DP and 1,733 received a comparator antimalarial at 12 different sites and were followed for 28-63 days. There was no significant heterogeneity between trials. DP was well tolerated with 1.7% early vomiting. There were less adverse events with DP in children and adults compared to MAS3 except for diarrhea; ORs (95%CI) 2.74 (2.13 to 3.51) and 3.11 (2.31 to 4.18), respectively. DP treatment resulted in a rapid clearance of fever and parasitaemia. The PCR genotype corrected efficacy at Day 28 of DP assessed by survival analysis was 98.7% (95%CI 97.6-99.8). DP was superior to the comparator drugs in protecting against both P.falciparum recurrence and recrudescence (P = 0.001, weighted by site). There was no difference between DP and MAS3 in treating P. vivax co-infections and in suppressing the first relapse (median interval to P. vivax recurrence: 6 weeks). Children under 5 y were at higher risk of recurrence for both infections. The proportion of patients developing gametocytaemia (P = 0.002, weighted by site) and the subsequent gametocyte carriage rates were higher with DP (11/1000 person gametocyte week, PGW) than MAS3 (6/1000 PGW, P = 0.001, weighted by site).

Conclusions: DP proved a safe, well tolerated, and highly effective treatment of P.falciparum malaria in Asia and Africa, but the effect on gametocyte carriage was inferior to that of MAS3.

Figure 1. Note: DP; dihydroartemisinin-piperaquine, MAS3; mefloquine-artesunate, AQ+SP; amodiaquine+sulfadoxine-pyrimethamine, AL; artemether-lumefantrine, AS+AQ; artesunate+amodiaquine, Pf; P. falciparum, loss; loss to follow-up, ACR; adequate clinical response, ACT; artemisinin combination therapy.

Figure 2. Note: HR; hazard ratio, CI; confidence interval.

DP; dihydroartemisinin-piperaquine, MAS3; mefloquine-artesunate, AQ+SP; amodiaquine+sulfadoxine-pyrimethamine, AL; artemether-lumefantrine, AS+AQ; artesunate+amodiaquine. NC: not computable because of no recrudescent cases. *Overall number of failures does not add up because two comparators were used in Rwanda. Note: the forest plot represents the risk of parasite reappearance (PCR corrected; i.e. recrudescence, and not corrected i.e. recrudescence+new infection) of DP versus comparators in comparative studies. Groups size are equivalent except in Thailand where the DP group was twice as large (N = 686). Endpoints were assessed on Day 28 in Rwanda, Day 42 in Laos, Myanmar, and Uganda, and Day 63 in Cambodia, and Thailand. Overall results were stratified by site, and drugs. The size of the boxes is proportional to the number of patients included and thus to the overall effect. The diamond represents the overall hazard ratio and 95% CI.

Figure 3. Note: the forest plot represents the risk of clearing gametocytes comparing DP versus comparator drugs in randomised studies.

The endpoint was assessed at Day 14. Overall result was stratified by site. The size of boxes is proportional to the number of patients included and thus to the overall effect. The diamond represents the overall hazard ratio and 95% CI.

Figure 4. Note: DP; Dihydroartemisinin-piperaquine, MAS3; mefloquine-artesunate.

Figure 5. Note: the forest plot represents the risk of adverse event appearance after the start of dihydroartemisinin-piperaquine treatment in children (<15 y) and adults who did not present this symptom on admission versus comparators in comparative studies.

The size of boxes is proportional to the number of patients included. 95% confidence intervals (CI) are calculated for the odds ratio (OR).

Figure 6. P.vivax cumulative incidence density, dyhydroartemisinin-piperaquine treatment groups.

Patients receiving DP in Cambodia, Laos, Myanmar, and Thailand who had P. vivax parasitaemia detected during the follow-up.