Antimalarial Chemoprophylaxis for Forest Goers in Southeast Asia: An Open-Label, Individually Randomised Controlled Trial

Summary Background Malaria in the eastern Greater Mekong subregion has declined to historic lows. Countries in the Greater Mekong subregion are accelerating malaria elimination in the context of increasing antimalarial drug resistance. Infections are now increasingly concentrated in remote, forested foci. No intervention has yet shown satisfactory efficacy against forest-acquired malaria. The aim of this study was to assess the efficacy of malaria chemoprophylaxis among forest goers in Cambodia. Methods We conducted an open-label, individually randomized controlled trial in Cambodia, which recruited participants aged 16–65 years staying overnight in forests. Participants were randomly allocated 1:1 to antimalarial chemoprophylaxis, a 3-day course of twice-daily artemether–lumefantrine followed by the same daily dosing once a week while travelling in the forest and for a further 4 weeks after leaving the forest (four tablets per dose; 20 mg of artemether and 120 mg of lumefantrine per tablet), or a multivitamin with no antimalarial activity. Allocations were done according to a computer-generated randomization schedule, and randomization was in permuted blocks of size ten and stratified by village. Investigators and participants were not masked to drug allocation, but laboratory investigations were done without knowledge of allocation. The primary outcome was a composite endpoint of either clinical malaria with any Plasmodium species within 1–28, 29–56, or 57–84 days, or subclinical infection detected by PCR on days 28, 56, or 84 using complete-case analysis of the intention-to-treat population. Adherence to study drug was assessed primarily by self-reporting during follow-up visits. Adverse events were assessed in the intention-to-treat population as a secondary endpoint from self-reporting at any time, plus a physical examination and symptom questionnaire at follow-up. This trial is registered at ClinicalTrials.gov (NCT04041973) and is complete. Findings Between March 11 and November 20, 2020, 1,480 individuals were enrolled, of whom 738 were randomly assigned to artemether–lumefantrine and 742 to the multivitamin. 713 participants in the artemether–lumefantrine group and 714 in the multivitamin group had a PCR result or confirmed clinical malaria by rapid diagnostic test during follow-up. During follow-up, 19 (3%, 95% CI 2–4) of 713 participants had parasitaemia or clinical malaria in the artemether– lumefantrine group and 123 (17%, 15–20) of 714 in the multivitamin group (absolute risk difference 15%, 95% CI 12–18; p \u3c 0·0001). During follow-up, there were 166 malaria episodes caused by Plasmodium vivax, 14 by Plasmodium falciparum, and five with other or mixed species infections. The numbers of participants with P. vivax were 18 (3%, 95% CI 2–4) in the artemether–lumefantrine group versus 112 (16%, 13–19) in the multivitamin group (absolute risk difference 13%, 95% CI 10–16; p \u3c 0.0001). The numbers of participants with P. falciparum were two (0.3%, 95% CI 0.03–1.01) in the artemether–lumefantrine group versus 12 (1·7%, 0.9–2.9) in the multivitamin group (absolute risk difference 1·4%, 95% CI 0.4–2·4; p = 0.013). Overall reported adherence to the full course of medication was 97% (95% CI 96–98; 1,797 completed courses out of 1,854 courses started) in the artemether–lumefantrine group and 98% (97–98; 1,842 completed courses in 1,885 courses started) in the multivitamin group. Overall prevalence of adverse events was 1.9% (355 events in 18,806 doses) in the artemether–lumefantrine group and 1.1% (207 events in 19,132 doses) in the multivitamin group (p \u3c 0.0001). Interpretation Antimalarial chemoprophylaxis with artemether–lumefantrine was acceptable and well tolerated and substantially reduced the risk of malaria. Malaria chemoprophylaxis among high-risk groups such as forest workers could be a valuable tool for accelerating elimination in the Greater Mekong subregion

High frequency of Fredrickson's phenotypes IV and IIb in Brazilians infected by human immunodeficiency virus

BACKGROUND: Human immunodeficiency virus (HIV) infection is very prevalent in Brazil. HIV therapy has been recently associated with coronary heart disease (CHD). Dyslipidemia is a major risk factor for CHD that is frequently described in HIV positive patients, but very few studies have been conducted in Brazilian patients evaluating their lipid profiles. METHODS: In the present work, we evaluated the frequency and severity of dyslipidemia in 257 Brazilian HIV positive patients. Two hundred and thirty-eight (93%) were submitted to antiretroviral therapy (224 treated with protease inhibitors plus nucleoside reverse transcriptase inhibitors, 14 treated only with the latter, 12 naive and 7 had no records of treatment). The average time on drug treatment with antiretroviral therapy was 20 months. None of the patients was under lipid lowering drugs. Cholesterol, triglyceride, phospholipid and free fatty acids were determined by enzymatic colorimetric methods. Lipoprotein profile was estimated by the Friedewald formula and Fredrickson's phenotyping was obtained by serum electrophoresis on agarose. Apolipoprotein B and AI and lipoprotein "a" were measured by nephelometry. RESULTS: The Fredrickson phenotypes were: type IIb (51%), IV (41%), IIa (7%). In addition one patient was type III and another type V. Thirty-three percent of all HIV+ patients presented serum cholesterol levels ≥ 200 mg/dL, 61% LDL-cholesterol ≥ 100 mg/dL, 65% HDL-cholesterol below 40 mg/dL, 46% triglycerides ≥ 150 mg/dL and 10% have all these parameters above the limits. Eighty-six percent of patients had cholesterol/HDL-cholesterol ratio ≥ 3.5, 22% increased lipoprotein "a", 79% increased free fatty acids and 9% increased phospholipids. The treatment with protease inhibitors plus nucleoside reverse transcriptase inhibitors increased the levels of cholesterol and triglycerides in these patients when compared with naïve patients. The HDL-cholesterol (p = 0.01) and apolipoprotein A1 (p = 0.02) levels were inversely correlated with the time of protease inhibitor therapy while total cholesterol levels had a trend to correlate with antiretroviral therapy (p = 0.09). CONCLUSION: The highly varied and prevalent types of dyslipidemia found in Brazilian HIV positive patients on antiretroviral therapies indicate the urgent need for their early diagnosis, the identification of the risk factors for CHD and, when needed, the prompt intervention on their lifestyle and/or with drug treatment

Rapid Dissemination of SIV Follows Multisite Entry after Rectal Inoculation

Receptive ano-rectal intercourse is a major cause of HIV infection in men having sex with men and in heterosexuals. Current knowledge of the mechanisms of entry and dissemination during HIV rectal transmission is scarce and does not allow the development of preventive strategies. We investigated the early steps of rectal infection in rhesus macaques inoculated with the pathogenic isolate SIVmac251 and necropsied four hours to nine days later. All macaques were positive for SIV. Control macaques inoculated with heat-inactivated virus were consistently negative for SIV. SIV DNA was detected in the rectum as early as four hours post infection by nested PCR for gag in many laser-microdissected samples of lymphoid aggregates and lamina propria but never in follicle-associated epithelium. Scarce SIV antigen positive cells were observed by immunohistofluorescence in the rectum, among intraepithelial and lamina propria cells as well as in clusters in lymphoid aggregates, four hours post infection and onwards. These cells were T cells and non-T cells that were not epithelial cells, CD68+ macrophages, DC-SIGN+ cells or fascin+ dendritic cells. DC-SIGN+ cells carried infectious virus. Detection of Env singly spliced mRNA in the mucosa by nested RT-PCR indicated ongoing viral replication. Strikingly, four hours post infection colic lymph nodes were also infected in all macaques as either SIV DNA or infectious virus was recovered. Rapid SIV entry and dissemination is consistent with trans-epithelial transport. Virions appear to cross the follicle-associated epithelium, and also the digestive epithelium. Viral replication could however be more efficient in lymphoid aggregates. The initial sequence of events differs from both vaginal and oral infections, which implies that prevention strategies for rectal transmission will have to be specific. Microbicides will need to protect both digestive and follicle-associated epithelia. Vaccines will need to induce immunity in lymph nodes as well as in the rectum