Proguanil 100mg / Atovaquone 250mg tablets

BACKGROUND: Atovaquone/proguanil (AP) is a highly effective malaria chemoprophylaxis combination. According to current guidelines, AP is taken once daily during, and continued for seven days post exposure. A systematic review by Savelkoel et al. summarised data up to 2017 on abbreviated AP regimens, and concluded that discontinuing AP upon return may be effective, although the available data was insufficient to modify current recommendations. The same applies to other studies evaluating during-travel dose-sparing regimens. METHODS: A literature search in Pubmed and Embase was performed including search terms related to AP prophylaxis and pharmacokinetics to search for recent studies on abbreviated AP regimens published since 2017. RESULTS: Since the 2017 review, no new studies assessing discontinuing AP ad-hoc post-exposure prophylaxis have been published. Two new studies were identified assessing other abbreviated AP regimens; one investigated a twice-weekly AP regimen in 32 travellers, and one a three-day AP course in therapeutic dose (1000/400 mg) prior to exposure in 215 travellers. No malaria cases were detected in the study participants adhering to these regimens. CONCLUSIONS: Further research would be needed if the research question is considered of sufficient importance to facilitate evidence-based decision-making to modify current guidelines, as efficacy studies in travellers are fraught with confounders. We recommend human challenge trials to study abbreviated AP regimens pertaining to malaria chemoprophylaxis as they allow for rational, subject number, time- and cost-saving trial designs.

Abstract licence: CC BY

BACKGROUND: The 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). METHODS: This 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. FINDINGS: Recruitment 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. INTERPRETATION: Antimalarial 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. FUNDING: German Center for Infection Research.

Abstract licence: CC BY

ABSTRACT Atovaquone-proguanil (AP) is used as treatment for uncomplicated malaria, and as a chemoprophylactic agent against Plasmodium falciparum . Imported malaria remains one of the top causes of fever in Canadian returning travelers. Twelve sequential whole-blood samples before and after AP treatment failure were obtained from a patient diagnosed with P. falciparum malaria upon their return from Uganda and Sudan. Ultradeep sequencing was performed on the cytb, dhfr, and dhps markers of treatment resistance before and during the episode of recrudescence. Haplotyping profiles were generated using three different approaches: msp2-3D7 agarose and capillary electrophoresis, and cpmp using amplicon deep sequencing (ADS). A complexity of infection (COI) analysis was conducted. De novo cytb Y268C mutants strains were observed during an episode of recrudescence 17 days and 16 h after the initial malaria diagnosis and AP treatment initiation. No Y268C mutant reads were observed in any of the samples prior to the recrudescence. SNPs in the dhfr and dhps genes were observed upon initial presentation. The haplotyping profiles suggest multiple clones mutating under AP selection pressure (COI > 3). Significant differences in COI were observed by capillary electrophoresis and ADS compared to the agarose gel results. ADS using cpmp revealed the lowest haplotype variation across the longitudinal analysis. Our findings highlight the value of ultra-deep sequencing methods in the understanding of P. falciparum haplotype infection dynamics. Longitudinal samples should be analyzed in genotyping studies to increase the analytical sensitivity.

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BACKGROUND: The aim of this study was to evaluate the rates of parasitaemia clearance and the prevalence of treatment failure in patients with uncomplicated Plasmodium falciparum malaria treated with artemether-lumefantrine (AL), mefloquine (MQ), and atovaquone-proguanil (AP). METHOD: The retrospective descriptive study included adult patients with uncomplicated P. falciparum malaria treated at the University Hospital Bulovka in Prague from 2006 to 2019. Parasitaemia clearance was estimated using a linear regression model. RESULTS: The study included 72 patients with a median age of 33 years (IQR 27-45) and a male to female ratio of 3.2:1. Thirty-six patients (50.0%) were treated with AL, 27 (37.5%) with MQ and 9 (12.5%) with AP. The proportion of VFR and migrants was 22.2% with no significant differences among the three groups. The median time to the parasitaemia clearance was two days (IQR 2-3) in patients treated with AL versus four days in the MQ (IQR 3-4) and AP (IQR 3-4) groups, p < 0.001. The clearance rate constant was 3.3/hour (IQR 2.5-4.0) for AL, 1.6/hour (IQR 1.3-1.9) for MQ, and 1.9/hour (IQR 1.3-2.4) for AP, p < 0.001. Malaria recrudescence occurred in 5/36 (13.9%) patients treated with AL and in no patients treated with MQ or AP. CONCLUSIONS: The findings demonstrate the superior efficacy of AL compared to other oral antimalarials in early malaria treatment. However, we observed a higher rate of late treatment failure in patients treated with AL than previously reported. This issue warrants further investigation of possible dose adjustments, extended regimens, or alternative artemisinin-based combinations.

Abstract licence: CC BY-NC-ND

Avian malaria is a re-emerging threat to avian species worldwide. It is sustained by several protozoan species belonging to the genus Plasmodium, mainly Plasmodium relictum. The even wider diffusion of the disease, probably because of the increase in the areas covered by their mosquito vectors, may pose new risks for avian species lacking natural resistance (especially those from artic or sub-artic environments) or those hosted in structures like zoos and wildlife rescue centers. With that premise, this study describes the efficacy and safety of a therapeutic protocol to treat avian malaria in three snowy owls (Bubo scandiacus) hosted in a wildlife rescue center in Apulia, south of Italy, and affected by avian malaria by P. relictum. The protocol consisted of administering 10/4 mg/kg atovaquone/proguanil per os once a day for three consecutive days, repeating this seven days later. Seven days after the end of the treatment, P. relictum was not detected in the birds’ blood and no adverse effects were observed during the 60 days of monitoring after the end of the treatment. Therefore, a therapeutic regimen of 10/4 mg/kg/day may be considered safe and effective in a valuable and endangered species such as B. scandiacus.

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Abstract To develop a Plasmodium falciparum (Pf) vaccine that precludes replication inside the host for improved vaccine safety, we tested chemo-attenuation (CVac) of sporozoites (SPZ) with atovaquone–proguanil (AP). In mice, P. berghei sporozoites administered with AP invaded hepatocytes, arrested early, and induced robust protection, which correlated with parasite-specific effector-memory CD8+ T cell responses. In a clinical trial of PfSPZ-CVac (AP), in which three doses of 5.12 × 10 4 or 1.5 × 10 5 PfSPZ were administered by direct venous inoculation combined with oral single-dose AP (1000/400 mg), blood stage infections were fully prevented during immunisation. 2/8 and 2/10 of vaccinees, respectively, were protected when challenged with 3.2 × 10 3 PfSPZ 10 weeks later, inferior to PfSPZ-CVac (chloroquine/CQ) that allows in-host replication. Comparative analysis of responses to 228 Pf proteins revealed that protection with PfSPZ-CVac (CQ) was associated with antibodies to two liver-stage antigens (LISP2, LSA1) and a multi-stage antigen (PfMSP5), but not to the major surface protein PfCSP. The complete arrest of high numbers of Pf sporozoites by single-dose AP should allow a significant dose-frequency reduction of the current daily AP malaria chemoprophylaxis regimen.

Abstract licence: CC BY