Clinical Infectious Diseases Brief Report

World Health Organization (WHO) guidelines for HIV treatment currently recommend tenofovir disoproxil fumarate (TDF) with either lamivudine (3TC) or emtricitabine (FTC) plus dolutegravir (DTG) as preferred first-line antiretroviral therapy (ART). DTG replaced efavirenz (EFV) in 2019 in first-line regimens due to potency, barrier to resistance, cost, and safety benefits over EFV [1].

Tenofovir alafenamide (TAF), a prodrug of tenofovir, is the recommended alternative to TDF for patients with renal impairment or established osteoporosis but endorsed more broadly in higher income countries [1]. WHO does not currently advocate a wholesale programmatic switch from TDF to TAF, due to associations with increased weight gain, worsened lipid profile, equivalent renal and bone toxicity and virological potency when compared to unboosted TDF, as well as concerns regarding drug interactions, unknown pregnancy outcomes, and high cost [2] [3]. In contrast, some studies have observed the mitigating effect of TDF and EFV on weight gain. EFV has been associated with significant side effects including neuropsychiatric side effects and increases in lipids and serum glucose levels [4]. Weight loss is higher for people with cytochrome polymorphisms resulting in slower metabolism of the drug, this then conferring other neurological and metabolic toxicities [5, 6]. TDF has been associated with a higher risk of weight loss in a recent analysis of HIV-negative people taking pre-exposure prophylaxis therapy [5, 6].

ADVANCE was an investigator-led randomized controlled trial evaluating the efficacy and safety of two newer antiretroviral combinations; TAF/FTC+DTG and TDF/FTC+DTG, as compared with TDF/FTC/EFV [7]. The trial recruited from routine HIV testing sites, based in Johannesburg, South Africa. ADVANCE demonstrated virological non-inferiority at 48, 96 and 192 weeks, with significant weight gain in the two DTG-containing arms, which was especially marked in the TAF/FTC+DTG arm. After week 192, participants were switched to open-label TDF/3TC/DTG as per the national guidelines, and evaluated here after further informed consent processes, following at least 52 weeks of follow up in the state ART programme. The aim of the study, CHARACTERISE, was to evaluate the change in clinical and metabolic parameters after this move to the standard-of-care ART regimen.

The National Strategic Plan
Exploratory Study of Four Repurposed Anti-Infective Drug Regimens

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