Background In Phase II/III randomized controlled clinical trials for the treatment of acute uncomplicated malaria, pyronaridine–artesunate demonstrated high efficacy and a safety profile consistent with that of comparators, except that asymptomatic, mainly mild-to-moderate transient increases in liver aminotransferases were reported for some patients. Hepatic safety, tolerability, and effectiveness have not been previously assessed under real-world conditions in Africa. Methods and findings This single-arm, open-label, cohort event monitoring study was conducted at 6 health centers in Cameroon, Democratic Republic of Congo, Gabon, Ivory Coast, and Republic of Congo between June 2017 and April 2019. The trial protocol as closely as possible resembled real-world clinical practice for the treatment of malaria at the centers. Eligible patients were adults or children of either sex, weighing at least 5 kg, with acute uncomplicated malaria who did not have contraindications for pyronaridine–artesunate treatment as per the summary of product characteristics. Patients received fixed-dose pyronaridine–artesunate once daily for 3 days, dosed by body weight, without regard to food intake. A tablet formulation was used in adults and adolescents and a pediatric granule formulation in children and infants under 20 kg body weight. The primary outcome was the hepatic event incidence, defined as the appearance of the clinical signs and symptoms of hepatotoxicity confirmed by a >2× rise in alanine aminotransferase/aspartate aminotransferase (ALT/AST) versus baseline in patients with baseline ALT/AST >2× the upper limit of normal (ULN). As a secondary outcome, this was assessed in patients with ALT/AST >2× ULN prior to treatment versus a matched cohort of patients with normal baseline ALT/AST. The safety population comprised 7,154 patients, of mean age 13.9 years (standard deviation (SD) 14.6), around half of whom were male (3,569 [49.9%]). Patients experienced 8,560 malaria episodes; 158 occurred in patients with baseline ALT/AST elevations >2×ULN. No protocol-defined hepatic events occurred following pyronaridine–artesunate treatment of malaria patients with or without baseline hepatic dysfunction. Thus, no cohort comparison could be undertaken. Also, as postbaseline clinical chemistry was only performed where clinically indicated, postbaseline ALT/AST levels were not systematically assessed for all patients. Adverse events of any cause occurred in 20.8% (1,490/7,154) of patients, most frequently pyrexia (5.1% [366/7,154]) and vomiting (4.2% [303/7,154]). Adjusting for Plasmodium falciparum reinfection, clinical effectiveness at day 28 was 98.6% ([7,369/7,746] 95% confidence interval (CI) 98.3 to 98.9) in the per-protocol population. There was no indication that comorbidities or malnutrition adversely affected outcomes. The key study limitation was that postbaseline clinical biochemistry was only evaluated when clinically indicated. Conclusions Pyronaridine–artesunate had good tolerability and effectiveness in a representative African population under conditions similar to everyday clinical practice. These findings support pyronaridine–artesunate as an operationally useful addition to the management of acute uncomplicated malaria. Trial registration ClinicalTrials.gov NCT03201770.

The <i>in vitro</i> antiprotozoal and cytotoxic activity of the aqueous extract, the 80% methanol extract, and its different soluble fractions and subfractions from <i>Brucea sumatrana</i> seeds were assessed against two Trypanosoma (<i>T. cruzi</i> and <i>T. brucei brucei</i>), <i>Leishmania infantum</i> and chloroquine and pyrimethanine-resistant K1strain of <i>P. falciparum</i> and against MRC-5 cell-lines respectively. Results indicated that the 80% methanol extract showed a cytotoxic effect against MRC-5 cell lines with CC₅₀ value of 0.54 µg/ml. It however exhibited pronounced and non selective activity against <i>T. cruzi</i> (IC₅₀ = 1.52 µg/ml, SI = 0.03) and <i><i>L. infantum</i></i> (IC₅₀ = 2.41 µg/ml, SI = 0.22). It however displayed pronounced and selective effect against T. brucei brucei (IC₅₀ < 0.25, SI > 2.16) and chloroquine and pyrimethamine-resistant K1 strain of <i>P. falciparum</i> (IC₅₀ < 0.25 µg/ml, SI > 2.16). All soluble fractions and subfractions from the partition of the 80% methanol extract were found to exhibit an antiprotozoal activity with IC₅₀ values ranging from <0.25 to 30 µg/ml. The most active was the alkaline aqueous soluble fraction exhibiting pronounced antiprotozoal activity against <i>T .cruzi</i>, <i>T. b. brucei</i>, <i>L. infantum</i> and chloroquine and pyrimethamine-resistant K1 strain of <i>P. falciparum</i> with IC₅₀ values of 0.33, <0.25, 0.25, <0.25 µg/ml respectively resulting in high selective index values of 61.36, > 81, 81 and >81 respectively. The chloroform soluble fraction rich in alkaloid was cytotoxic against MRC-5 cell lines (CC₅₀ = 27.09 µg/ml) and showed good activity against T. b. brucei (IC₅₀ = 8.36 and SI = 3.24) and moderate activity against <i>T. cruzi</i>, <i>L. infantum</i> and chloroquine-pyrimethane-resistant K1 strain of <i>P. falciparum</i> (20 < IC₅₀ < 30 µg/ml). Although the aqueous extract (decoction) and the total alkaloids extract showed a cytotoxic effect against MRC-5 cell lines (CC₅₀ = 1.55 and 0.43 µg/ml respectively), they however displayed pronounced antiprotozoal activity against <i>T. cruzi</i>, T. b. brucei and chloroquine and pyrimethamine-resistant K1 strain of <i>P. falciparum</i> with IC₅₀ values ranging from < 0.25 to 0.6 µg/ml with only a selective action against chloroquine and pyrimethamine-resistant K1 strain of <i>P. falciparum</i> (SI = >6.2 and >1.72 respectively). These extracts however showed good and low activity respectively against <i>L. infantum</i> (IC...

IntroductionArtemisinin-based combination therapy is currently the best option for the treatment of uncomplicated malaria. Quinine is recommended as a rescue treatment. Safety information during repeated treatment with the same drug is scarce. We report safety data from the Quinact randomized clinical trial (RCT) that was designed to assess efficacy and safety of artesunate-amodiaquine (ASAQ), artemether-lumefantrine (AL) and quinine+clindamycin (QnC).MethodologyMales and females aged 12 to 59 months with uncomplicated malaria were treated with ASAQ and followed up during 42 days (preRCT). Clinical failures were randomized to one of the 3 treatments and followed up for 28 days (RCT). Subsequent failures were repeatedly treated with ASAQ several times as needed (postRCT1, postRCT2 and so on) until a 28-days follow up period without parasitaemia.ResultsEight hundred and sixty-five, 242 and 64 patients were recruited respectively in preRCT, RCT and postRCTs. In preRCT, 433 (50.0%) patients experienced at least one drug-related adverse event (AE). The most reported AEs were anorexia (22.9%), asthenia (19.4%), and abnormal behavior (14.6%). Twenty-nine AEs (3.5%) were reported to be severe. In RCT, at least one drug-related AE was reported in 54.7%, 21.5% and 40.0% of patient randomized respectively to ASAQ, AL and QnC (p<0.001). During postRCT1 (n = 64), postRCT 2 (n = 17) and postRCT3 (n = 7), respectively 32.8%, 35.3% and 71.4% of patients experienced at least one drug-related AE. Three serious adverse events occurred but not judged related to study medication.ConclusionThe proportion of AEs did not increase over the treatment courses with ASAQ. However, continuous monitoring is important.

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objective To characterise the factors associated with HIV treatment failure (HIVTF) from reported pharmacovigilance data in Africa.materials and methods This is an observational pharmacovigilance analysis of the safety data of HIVTF available in the WHO International Pharmacovigilance database 'VigiBase â '. We used the Standardised MedDRA Queries (SMQ) to identify all the terms corresponding to HIVTF. To identify all relevant molecules and classes of antiretroviral therapy, we used the anatomic, therapeutic, and chemical classification. We presented results as a percentage or an adjusted Reporting Odds Ratio (aROR) with a 95% confidence interval (95% CI).results HIVTF was more reported in Africa compared with the rest of the world with 19.1% (18.1%-20.1%) corresponding to 1206 of all 6304 HIVTF reports. Among all the 37 WHO country members in Africa, South Africa was the main source of origin for these HIVTF reports with 86.8% (84.9%-88.7%). Compared to adults, children and adolescents were the most population groups affected by HIVTF, aROR = 2.7, (95% CI) 1.7-4.2 and aROR = 7.9, (95% CI) 4.5-13.9, respectively. conclusion South Africa was the leading country of the reporting of HIVTF in Africa. The proportion of HIVTF was higher in both HIV-infected children and adolescents than in adults. There is a need for the improvement of medical care for children and adolescents with HIV infection in Africa.keywords anti-HIV agents, treatment failure, drug resistance, Africa Sustainable Development Goals (SDGs): Good health and well-being, universal health coverage; end epidemics

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