Two large randomised trials of pre-exposure prophylaxis (PrEP) showed that long-acting cabotegravir administered intramuscularly every 8 weeks was superior to daily oral tenofovir disoproxil fumarate plus emtricitabine in preventing HIV infection in diverse populations. 1 Landovitz RJ Donnell D Clement ME et al. Cabotegravir for HIV prevention in cisgender men and transgender women. N Engl J Med. 2021; 385: 595-608 Crossref PubMed Scopus (355) Google Scholar , 2 Delany-Moretlwe S Hughes JP Bock P et al. Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial. Lancet. 2022; 399: 1779-1789 Summary Full Text Full Text PDF PubMed Scopus (185) Google Scholar This was not a complete surprise because earlier placebo-controlled trials had observed a low proportion of participants with drug concentrations compatible with daily tenofovir disoproxil fumarate plus emtricitabine, particularly in cisgender women in sub-Saharan Africa, 3 Van Damme L Corneli A Ahmed K et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012; 367: 411-422 Crossref PubMed Scopus (1292) Google Scholar , 4 Marrazzo JM Ramjee G Richardson BA et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2015; 372: 509-518 Crossref PubMed Scopus (1001) Google Scholar and cisgender men who have sex with men and transgender women in Latin America. 5 Grant RM Lama JR Anderson PL et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010; 363: 2587-2599 Crossref PubMed Scopus (4007) Google Scholar , 6 Amico KR Marcus JL McMahan V et al. Study product adherence measurement in the iPrEx placebo-controlled trial: concordance with drug detection. J Acquir Immune Defic Syndr. 2014; 66: 530-537 Crossref PubMed Scopus (69) Google Scholar In The Lancet HIV, Mark Marzinke and colleagues 7 Marzinke MA Hanscom B Wang Z et al. Efficacy, safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir for HIV pre-exposure prophylaxis in transgender women: a secondary analysis of the HPTN 083 trial. Lancet HIV. 2023; (published online Sept 29.)https://doi.org/10.1016/S2352-3018(23)00200-X Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar report a secondary analysis from the HIV Preventions Trials Network (HPTN) 083 trial of injectable cabotegravir, focused on the 570 participants enrolled under the umbrella of transgender women. Although the sample size was too small to achieve statistical significance, the magnitude and direction of effect were in line with the results from the overall trial population. Gender identity was only captured at enrolment and the authors recommend that this be assessed longitudinally in future trials as they observed fluidity in this demographic variable, with self-identified men who have sex with men reporting gender affirming hormonal therapy at enrolment and during follow-up. There were no differences in cabotegravir concentrations between transgender women reporting using gender affirming hormone therapy and those who did not, which is reassuring. However, additional pharmacological studies capturing the details of dosing are needed to fully assess drug–drug interactions. Efficacy, safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir for HIV pre-exposure prophylaxis in transgender women: a secondary analysis of the HPTN 083 trialHIV prevention strategies for transgender women cannot be addressed separately from social and structural vulnerabilities. Transgender women were well represented in HPTN 083 and should continue to be prioritised in HIV prevention studies. Our results suggest that injectable cabotegravir is a safe and effective pre-exposure prophylaxis option for transgender women. Full-Text PDF

Objectives: The antiretroviral efavirenz decreases serum levonorgestrel (LNG) concentrations among LNG implant users. Our primary objective was to compare LNG concentrations between LNG implant users who were or were not taking efavirenz, for up to 33 months after implant initiation. Our secondary objective was to evaluate the pregnancy rate among LNG implant users on efavirenz.

The goal of this study was to explore the relationships between tenofovir (TFV) and emtricitabine (FTC) disposition and markers of biologic aging, such as the frailty phenotype and p16 INK4a gene expression. Chronologic age is often explored in population pharmacokinetic (PK) analyses, and can be uninformative in capturing the impact of aging on physiology, particularly in human immunodeficiency virus (HIV)‐infected patients. Ninety‐one HIV‐infected participants provided samples to quantify plasma concentrations of TFV/FTC, as well as peripheral blood mononuclear cell (PBMC) samples for intracellular metabolite concentrations; 12 participants provided 11 samples, and 79 participants provided 4 samples, over a dosing interval. Nonlinear mixed effects modeling of TFV/FTC and their metabolites suggests a relationship between TFV/FTC metabolite clearance (CL) from PBMCs and the expression of p16 INK4a , a marker of cellular senescence. This novel approach to quantifying the influence of aging on PKs provides rationale for further work investigating the relationships between senescence and nucleoside phosphorylation and transport.

Unbound drug is the pharmacodynamically relevant concentration. This study aimed to determine if chronologic age or markers of biologic aging, such as the frailty phenotype and p16 INK4a gene expression, altered unbound pharmacokinetics (PKs) of efavirenz (EFV) and atazanavir/ritonavir (ATV/RTV). Sixty human immunodeficiency virus (HIV)‐infected participants receiving EFV and 31 receiving ATV/RTV provided 1 to 11 samples to quantify total and unbound plasma concentrations. Population PK models with total and unbound concentrations simultaneously described are developed for each drug. The unbound fractions for EFV, ATV, and RTV are 0.65%, 5.67%, and 0.63%, respectively. Covariate analysis suggests RTV unbound PK is sensitive to body size; unbound fraction of RTV is 34% lower with body mass index (BMI) above 30 kg/m 2 . No alterations in drug clearance or unbound fraction with age, frailty, or p16 INK4a expression were observed. Assessing functional and physiologic aging markers to inform potential PK changes is necessary to determine if drug/dosing changes are warranted in the aging population.