AIMS Genetic factors, notably CYP2B6 516G→T [rs3745274] and 983T→C[rs28399499], explain much of the interindividual variability in efavirenz pharmacokinetics, but data from Africa are limited. We characterized relationships between genetic polymorphisms and plasma efavirenz concentrations in HIV-infected Black South African adults and children. METHODSSteady-state mid-dosing interval efavirenz concentrations were measured. We genotyped 241 polymorphisms in genes potentially relevant to efavirenz metabolism and transport, including ABCB1, CYP2A6, CYP2B6, CYP3A4, CYP3A5, NR1I2 and NR1I3. ). Among individual CYP2B6 polymorphisms, 516G→T best predicted efavirenz concentrations (β = 0.22, 95% CI 0.13, 0.30, P = 1.27 × 10 RESULTS Among À6). There was also associations with 983T→C (β = 0.27, 95% CI 0.10, 0.44, P = 0.002) and 15582C→T (β = 0.11, 95% CI 0.01, 0.22, P = 0.04). Associations were consistent in adults and children. No other polymorphisms were independently associated with efavirenz concentrations. CONCLUSIONSComposite CYP2B6 genotype based on CYP2B6 516G→T, 983T→C, and 15582C→T best described efavirenz exposure in HIV-infected Black South African adults and children. WHAT IS ALREADY KNOWN ABOUT THE SUBJECT• The polymorphisms CYP2B6 516G→T (rs3745274) and 983T→C (rs28399499) are strongly associated with plasma efavirenz concentrations, but do not entirely explain interindividual variability.• A recent genome-wide association study implicated CYP2B6 15582C→T (rs4803419) as an independent predictor of efavirenz trough concentrations.• Reported pharmacokinetic associations beyond CYP2B6 are inconsistent. WHAT THIS STUDY ADDS• We provide evidence to show that CYP2B6 15582C→T is associated with plasma efavirenz concentrations in Black South Africans, in addition to CYP2B6 516G→T and 983T→C.• We show that genetic associations are consistent in adults and children.• We found no additional associations with plasma efavirenz concentrations beyond these CYP2B6 polymorphisms.

Background Dolutegravir is associated with more weight gain than efavirenz. Loss-of-function polymorphisms in CYP2B6 result in higher efavirenz concentrations, which we hypothesized would impair weight gain among people living with human immunodeficiency virus (HIV; PLWH) starting efavirenz-based antiretroviral therapy (ART). Methods We studied ART-naive participants from the ADVANCE study randomized to the efavirenz /emtricitabine/tenofovir disoproxil fumarate (TDF) and dolutegravir/emtricitabine/TDF arms. We compared changes in weight and regional fat on DXA from baseline to week 48 between CYP2B6 metabolizer genotypes in the efavirenz arm, and with the dolutegravir arm. Results There were 342 participants in the dolutegravir arm and 168 in the efavirenz arm who consented to genotyping. Baseline characteristics were similar. Weight gain was greater in women than men. In the efavirenz arm CYP2B6 metaboliser genotype was associated with weight gain (P = .009), with extensive metabolizers gaining the most weight, and with changes in regional fat in women, but not in men. Weight gain was similar in CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm (P = .836). The following variables were independently associated with weight gain in all participants: baseline CD4 count, baseline human immunodeficiency virus type 1 (HIV-1) RNA, and CYP2B6 metaboliser genotype. Conclusions CYP2B6 metaboliser genotype was associated with weight gain in PLWH starting efavirenz-based ART. Weight gain was similar between CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm, suggesting that impaired weight gain among CYP2B6 slow or intermediate metabolizers could explain the increased weight gain on dolutegravir compared with efavirenz observed in ADVANCE and other studies.

Objectives An efavirenz-based antiretroviral therapy (ART) regimen is preferred for children more than 3 years of age with tuberculosis. However, rifampin, a key component of antituberculosis therapy, induces CYP2B6. An increased dose of efavirenz is recommended in adults weighing more than 50 kg who require rifampin, but there is scant information in children being treated for tuberculosis. Design Plasma efavirenz concentrations were compared in 40 children during concomitant treatment for tuberculosis and HIV-1, after stopping rifampicin, and in a control group of children without tuberculosis. Associations with antituberculosis treatment, metabolizer genotype (based on CYP2B6 516G→T, 983T→C, and 15582C→T), weight, and time after dose were evaluated. Results Compared to children with extensive metabolizer genotypes, efavirenz concentrations were increased 1.42-fold (95% confidence interval, CI 0.94–2.15) and 2.85-fold (95% CI 1.80–4.52) in children with intermediate and slow metabolizer genotypes, respectively. Concomitant antituberculosis treatment increased efavirenz concentrations 1.49-fold (95% CI 1.10–2.01) in children with slow metabolizer genotypes, but did not affect efavirenz concentrations in extensive or intermediatemetabolizer genotypes. After adjustment for dose/kg, each kilogram of weight was associated with a 2.8% (95% CI 0.9–4.7) decrease in efavirenz concentrations. Despite higher milligram per kilogram doses, a higher proportion of children in the lowest weight band (10–13.9 kg) had efavirenz concentrations less than 1.0 mg/l than larger children. Conclusion Antituberculosis treatment was not associated with reduced efavirenz concentrations in children, which does not support increased efavirenz doses. Children with slow metabolizer genotype have increased efavirenz concentrations during antituberculosis treatment, likely due to isoniazid inhibiting enzymes involved in accessory metabolic pathways for efavirenz.

MMV390048 is a novel antimalarial compound that inhibits Plasmodium phosphatidylinositol-4-kinase. The safety, tolerability, pharmacokinetic profile, and antimalarial activity of MMV390048 were determined in healthy volunteers in three separate studies. A first-in-human, double-blind, randomized, placebo-controlled, single-ascending-dose study was performed. Additionally, a volunteer infection study investigated the antimalarial activity of MMV390048 using the Plasmodium falciparum induced blood-stage malaria (IBSM) model. Due to the high pharmacokinetic variability with the powder-in-bottle formulation used in both of these studies, a third study was undertaken to select a tablet formulation of MMV390048 to take forward into future studies. MMV390048 was generally well tolerated when administered as a single oral dose up to 120 mg, with rapid absorption and a long elimination half-life. Twelve adverse events were considered to be potentially related to MMV390048 in the first-in-human study but with no obvious correlation between these and MMV390048 dose or exposure. Although antimalarial activity was evident in the IBSM study, rapid recrudescence occurred in most subjects after treatment with 20 mg MMV390048, a dose expected to be subtherapeutic. Reformulation of MMV390048 into two tablet formulations (tartaric acid and Syloid) resulted in significantly reduced intersubject pharmacokinetic variability. Overall, the results of this study suggest that MMV390048 is well tolerated in humans, and the pharmacokinetic properties of the compound indicate that it has the potential to be used for antimalarial prophylaxis or inclusion in a single-dose cure. MMV390048 is currently being tested in a phase 2a study in Ethiopian adults with acute, uncomplicated falciparum or vivax malaria monoinfection. (The three clinical trials described here were each registered with ClinicalTrials.gov as follows: first-in-human study, registration no. NCT02230579; IBSM study, registration no. NCT02281344; and formulation optimization study, registration no. NCT02554799.)

Background Unwanted weight gain affects some people living with HIV who are prescribed integrase strand transfer inhibitors (INSTI). Mechanisms and risk factors are incompletely understood. Methods We utilized two cohorts to study pharmacogenetics of weight gain following switch from efavirenz- to INSTI-based regimens. In an observational cohort, we studied weight gain at 48 weeks following switch from efavirenz- to INSTI-based regimens among patients who had been virologically suppressed for at least 2 years at a clinic in the United States. Associations were characterized with CYP2B6 and UGT1A1 genotypes that affect efavirenz and INSTI metabolism, respectively. In a clinical trials cohort, we studied weight gain at 48 weeks among treatment-naïve participants who were randomized to receive efavirenz-containing regimens in AIDS Clinical Trials Group studies A5095, A5142 and A5202 and did not receive INSTIs. Results In the observational cohort (N=61), CYP2B6 slow metabolizers had greater weight gain after switch (p=0.01). This was seen following switch to elvitegravir or raltegravir, but not dolutegravir. UGT1A1 genotype was not associated with weight gain. In the clinical trials cohort (N=462), CYP2B6 slow metabolizers had lesser weight gain at week 48 among participants receiving efavirenz with tenofovir disoproxil fumarate (p=0.001) but not those receiving efavirenz with abacavir (p=0.65). Findings were consistent when stratified by race/ethnicity and by sex. Conclusions Among patients who switched from efavirenz- to INSTI-based therapy, CYP2B6 genotype was associated with weight gain, possibly reflecting withdrawal of the inhibitory effect of higher efavirenz concentrations on weight gain. The difference by concomitant nucleoside analogue is unexplained.

Background-Tenofovir-diphosphate (TFV-DP) in dried blood spots (DBS) is an objective longterm adherence measure but data are limited on its ability to predict virologic suppression (VS) in people on antiretroviral (ARV) treatment. There are also no data comparing DBS TFV-DP with plasma ARV concentrations as predictors of VS.Methods-Women who were on a first-line regimen of tenofovir, emtricitabine, and efavirenz (EFV) were enrolled in a cross-sectional study. Plasma EFV and tenofovir (TFV), DBS TFV-DP assays, and 30-day self-reported adherence were evaluated as predictors of VS (<50 copies/mL) with area under the curve (AUC) of receiver operating characteristics (ROC) and logistic regression.Results-We enrolled 137 women; mean age 33 years; median 4 years on ART; 88 (64%) had VS. In ROC analyses: DBS TFV-DP (0.926 [95%CI 0.876-0.976]) had a higher AUC than plasma TFV (0.864 [0.797-0.932]; p=0.006), while plasma EFV (0.903 [0.839-0.967]) was not significantly different from DBS TFV-DP (p=0.138) or plasma TFV (p=0.140

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