Orphanet

Primaquine is the only available antimalarial drug that kills dormant liver stages of Plasmodium vivax and Plasmodium ovale malarias and therefore prevents their relapse (‘radical cure’). It is also the only generally available antimalarial that rapidly sterilises mature P. falciparum gametocytes. Radical cure requires extended courses of primaquine (usually 14 days; total dose 3.5–7 mg/kg), whereas transmissibility reduction in falciparum malaria requires a single dose (formerly 0.75 mg/kg, now a single low dose [SLD] of 0.25 mg/kg is recommended). The main adverse effect of primaquine is dose-dependent haemolysis in glucose 6-phosphate dehydrogenase (G6PD) deficiency, the most common human enzymopathy. X-linked mutations conferring varying degrees of G6PD deficiency are prevalent throughout malaria-endemic regions. Phenotypic screening tests usually detect <30% of normal G6PD activity, identifying nearly all male hemizygotes and female homozygotes and some heterozygotes. Unfortunately, G6PD deficiency screening is usually unavailable at point of care, and, as a consequence, radical cure is greatly underused. Both haemolytic risk (determined by the prevalence and severity of G6PD deficiency polymorphisms) and relapse rates vary, so there has been considerable uncertainty in both policies and practices related to G6PD deficiency testing and use of primaquine for radical cure. Review of available information on the prevalence and severity of G6PD variants together with countries’ policies for the use of primaquine and G6PD deficiency testing confirms a wide range of practices. There remains lack of consensus on the requirement for G6PD deficiency testing before prescribing primaquine radical cure regimens. Despite substantially lower haemolytic risks, implementation of SLD primaquine as a P. falciparum gametocytocide also varies. In Africa, a few countries have recently adopted SLD primaquine, yet many with areas of low seasonal transmission do not use primaquine as an antimalarial at all. Most countries that recommended the higher 0.75 mg/kg single primaquine dose for falciparum malaria (e.g., most countries in the Americas) have not changed their recommendation. Some vivax malaria–endemic countries where G6PD deficiency testing is generally unavailable have adopted the once-weekly radical cure regimen (0.75 mg/kg/week for 8 weeks), known to be safer in less severe G6PD deficiency variants. There is substantial room for improvement in radical cure policies and practices.

https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0006230&type=printable

Use of primaquine and glucose-6-phosphate dehydrogenase deficiency testing: Divergent policies and practices in malaria endemic countries.

Risk factors for COVID-19-related in-hospital mortality in a high HIV and tuberculosis prevalence setting in South Africa: a cohort study.

Understanding the historical, temporal changes of malaria risk following control efforts in Africa provides a unique insight into what has been and might be archived towards a long-term ambition of elimination on the continent Here, we use archived published and unpublished material combined with biological constraints on transmission accompanied by a narrative on malaria control to document the changing incidence of malaria in Africa since earliest reports pre-second World War One result is a more informed mapped definition of the changing margins of transmission in 1939, 1959, 1979, 1999 and 2009

The Changing Limits and Incidence of Malaria in Africa: 1939–2009

BackgroundMolnupiravir is an oral prodrug of β-D-N4-hydroxycytidine, active against SARS-CoV-2 in vitro and in animal models. We report data from the phase 2 component of MOVe-IN, a clinical trial evaluating molnupiravir in patients hospitalized with Covid-19.Methods We conducted a randomized, placebo-controlled, double-blind phase 2/3 trial in patients 18 years old and older requiring in-hospital treatment for laboratory-confirmed Covid-19 with symptom onset 10 or fewer days before randomization. Participants were randomly assigned to placebo or molnupiravir 200 mg, 400 mg, or 800 mg (1:1:1:1 ratio), twice daily for 5 days. Primary end points were safety and sustained recovery (participant alive and either not hospitalized or medically ready for discharge) through day 29.ResultsOf 304 randomly assigned participants, 218 received at least one dose of molnupiravir and 75 of placebo. At baseline, 74.0% had at least one risk factor for severe Covid-19. Adverse events were reported in 121 of 218 (55.5%) molnupiravir-treated and 46 of 75 (61.3%) placebo-treated participants, with no apparent dose effect on adverse event rates and no evidence of hematologic toxicity based on prespecified adverse events. Of 16 confirmed deaths, most were in participants with severe Covid-19 (75.0%), with underlying comorbidities (87.5%), older than 60 years of age (81.3%), and/or symptom duration longer than 5 days (75.0%) at randomization. Median time to sustained recovery was 9 days in all groups, with similar day 29 recovery rates ranging from 81.5% to 85.2%.ConclusionsIn this phase 2 trial of patients hospitalized with Covid-19, a 5-day course of molnupiravir up to 800 mg twice daily was not associated with dose-limiting side effects or adverse events, but did not demonstrate clinical benefit. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov NCT04575584.) 

Randomized Trial of Molnupiravir or Placebo in Patients Hospitalized with Covid-19

COVID-19 fatality rates in hospitalized patients: systematic review and meta-analysis.

Malaria has occurred in the Cabo Verde archipelago with epidemic characteristics since its colonization. Nowadays, it occurs in Santiago Island alone and though prophylaxis is not recommended by the World Health Organization, studies have highlight the prospect of malaria becoming a serious public health problem as a result of the presence of antimalarial drug resistance associated with mutations in the parasite populations and underscore the need for tighter surveillance. Despite the presumptive weak immune status of the population, severe symptoms of malaria are not observed and many people present a subclinical course of the disease. No data on the prevalence of sickle-cell trait and red cell glucose-6-phosphate dehydrogenase deficiency (two classical genetic factors associated with resistance to severe malaria) were available for the Cabo Verde archipelago and, therefore, we studied the low morbidity from malaria in relation to the particular genetic characteristics of the human host population. We also included the analysis of the pyruvate kinase deficiency associated gene, reported as putatively associated with resistance to the disease. Allelic frequencies of the polymorphisms examined are closer to European than to African populations and no malaria selection signatures were found. No association was found between the analyzed human factors and infection but one result is of high interest: a linkage disequilibrium test revealed an association of distant loci in the PKLR gene and adjacent regions, only in non-infected individuals. This could mean a more conserved gene region selected in association to protection against the infection and/or the disease.

Nilza Gonçalves

Papers

COVID-19 fatality rates in hospitalized patients: systematic review and meta-analysis.

Analysis of malaria associated genetic traits in Cabo Verde, a melting pot of European and sub Saharan settlers