Proguanil 125mg/5ml oral solution

BackgroundIn many sub-Saharan African countries, it is recommended that children with sickle cell anaemia receive malaria chemoprevention with monthly sulfadoxine-pyrimethamine or daily proguanil as the standard of care. However, the efficacy of these interventions is compromised by high-grade antifolate resistance of Plasmodium falciparum and poor adherence. We aimed to compare the efficacy of weekly dihydroartemisinin-piperaquine and monthly sulfadoxine-pyrimethamine for the prevention of clinical malaria in children with sickle cell anaemia in areas with high-grade sulfadoxine-pyrimethamine resistance of P falciparum in Uganda and Malawi.MethodsWe did an individually randomised, parallel group, double-blind, placebo-controlled trial at two hospitals in Uganda and two hospitals in Malawi. Children (aged 6 months to 15 years) with sickle cell anaemia with a bodyweight of at least 5kg were randomly assigned (1:1) by computer-generated block randomisation, stratified by site and weight category, to receive either weekly dihydroartemisinin-piperaquine (approximately 2·5 mg per kg bodyweight dihydroartemisinin and 20 mg per kg bodyweight per day piperaquine) or monthly sulfadoxine-pyrimethamine (approximately 25 mg per kg bodyweight sulfadoxine and 1·25 mg per kg bodyweight). Placebos matching the alternative treatment were used in each treatment group to maintain masking of the different dosing schedules from the participants and caregivers, study staff, investigators, and data analysts. All children younger than 5 years received penicillin twice daily as standard of care. The primary endpoint was the incidence of clinical malaria, defined as a history of fever in the preceding 48 h or documented axillary temperature of 37·5°C or higher plus the detection of P falciparum parasites on microscopy (any parasite density). Secondary efficacy outcomes were any malaria parasitaemia (on either microscopy or malaria rapid diagnostic test), all-cause unscheduled clinic visits, all-cause and malaria-specific hospitalisation, sickle cell anaemia-related events (including vaso-occlusive crises, acute chest syndrome, stroke), need for blood transfusion, and death. All primary and secondary outcomes were assessed in the modified intention-to-treat population, which included all participants who were randomly assigned for whom endpoint data were available. Safety was assessed in in all children who received at least one dose of the study drug. Complete case analysis was conducted using negative-binomial regression. This study was registered with Clinicaltrials.gov, NCT04844099.FindingsBetween April 17, 2021, and May 30, 2022, 725 participants were randomly assigned; of whom 724 were included in the primary analysis (367 participants in the dihydroartemisinin-piperaquine group and 357 participants in the sulfadoxine-pyrimethamine group). The median follow-up time was 14·7 months (IQR 11·2-18·2). The incidence of clinical malaria was 8·8 cases per 100 person-years in the dihydroartemisinin-piperaquine group and 43.7 events per 100 person-years in the sulfadoxine-pyrimethamine group (incidence rate ratio [IRR] 0·20 [95% CI 0·14-0·30], pInterpretationMalaria chemoprophylaxis with weekly dihydroartemisinin-piperaquine in children with sickle cell anaemia is safe and considerably more efficacious than monthly sulfadoxine-pyrimethamine. However, monthly sulfadoxine-pyrimethamine was associated with fewer episodes of non-malaria-related illnesses, especially in children 5 years or older not receiving penicillin prophylaxis, which might reflect its antimicrobial effects. In areas with high P falciparum antifolate resistance, dihydroartemisinin-piperaquine should be considered as an alternative to sulfadoxine-pyrimethamine for malaria chemoprevention in children younger than 5 years with sickle cell anaemia receiving penicillin-V prophylaxis. However, there is need for further studies in children older than 5 years.FundingResearch Council of Norway and UK Medical Research Council.TranslationsFor the Chichewa, Acholi, Lusoga and Luganda translations of the abstract see Supplementary Materials section.

Abstract licence: CC BY-NC-ND

BackgroundThe emergence of Plasmodium falciparum strains with reduced susceptibility to the artemisinin component of artemisinin combination therapies poses a serious threat to the treatment and control of malaria in sub-Saharan Africa. Regimens consisting of combinations of three or more conventional antimalarials have been proposed as a new treatment paradigm to overcome the impending problem of drug-resistant malaria. It was the aim of the MultiMal study to assess the safety, tolerability, and efficacy of the two novel multidrug antimalarial combination therapies, artesunate-pyronaridine-atovaquone-proguanil (APAP) and artesunate-fosmidomycin-clindamycin (AFC), in comparison with standard artesunate-pyronaridine (AP).MethodsThis open-label, randomised, controlled, clinical, phase 2 trial was done in Lambaréné, Gabon, and Kumasi, Ghana. Patients with uncomplicated malaria who had fever or a history of fever in the preceding 24 h and a parasitaemia in the range of 1000-100 000 per μL of blood were enrolled. Random permuted blocks of variable block sizes stratified by country were computed to generate a treatment allocation sequence. Recruitment was done across three age groups: children aged 6 months to 10 years, adolescents aged 11-17 years, and adults aged 18-65 years. Weight-adjusted oral, once-daily therapy was administered for 3 consecutive days for AP and APAP regimens dosed according to the recommendations of the manufacturer and twice daily for AFC (dose: artesunate 2 mg/kg, fosmidomycin 30 mg/kg, and clindamycin 10 mg/kg). Participants were followed up over a 42-day period. The primary endpoints of the trial, related to pharmacokinetic analyses, are being reported elsewhere; this Article reports the secondary endpoints-safety, tolerability, and efficacy of the treatment regimens (defined as adequate clinical and parasitological response [ACPR]) at days 28 and 42 after treatment initiation. ACPRs were calculated in the intention-to-treat and PCR-corrected per-protocol populations at these timepoints, whereas safety and tolerability outcomes were assessed continuously over the 42-day follow-up period in the safety population. This trial is registered with pactr.samrc.ac.za, PACTR202008909968293 and is complete.FindingsRecruitment and follow-up took place between Jan 5 and Nov 5, 2021. Of 309 screened individuals, 100 patients with uncomplicated malaria were recruited into this clinical trial: 20 semi-immune patients aged 18-65 years, 40 adolescents aged between 11 and 17 years, and finally 40 patients aged 6 months to 10 years. PCR-corrected ACPR in the per-protocol set was 100% (95% CI 80-100) for AP, 100% (90-100) for APAP, and 97% (86-100) for AFC for day 28, and 87·5% (62-98) for AP, 85·3% (69-95) for APAP, and 94·4% (81-99) for AFC on day 42. Uncorrected ACPR in the intention-to-treat set was 85% (95% CI 62-97%) for AP, 87·5% (73-96) for APAP, and 82·5% (67-93) for AFC on day 28, and 70% (46-88) for AP, 75% (59-87) for APAP, and 75% (59-87) for AFC on day 42. There was no evidence for a differential efficacy across AP, APAP, and AFC. The proportion of patients with treatment-emergent adverse events (TEAEs) did not differ across study groups (p=0·37) and all treatment regimens were safe. Three (7%) of 46 TEAEs in the APAP group were severe compared with two (10%) of 20 in the AP control group and zero of 56 in the AFC group; all severe TEAEs were haematological alterations. The other TEAEs were mild or moderate. Moreover, there were two serious adverse events (SAEs) in the APAP group (peptic ulcer disease and chest contusion) and none in the other groups; these SAEs were rated as not related to the study medication.InterpretationAntimalarial regimens of APAP and AFC have unique characteristics to tackle the development and spread of drug-resistant P falciparum malaria. Given that APAP and AFC were safe, well tolerated, and highly efficacious in this clinical phase 2 study, they constitute promising multidrug combination regimens for further clinical development.FundingGerman Center for Infection Research.

Abstract licence: CC BY