Efficacy and safety of tenofovir disoproxil fumarate versus low-dose stavudine over 96 weeks: a multi-country randomised, non-inferiority trial.

BACKGROUND: Reducing doses of antiretroviral drugs, including stavudine (d4T), may lower toxicity, while preserving efficacy. There are substantial concerns about renal and bone toxicities of tenofovir disoproxil fumarate (TDF).

SETTING: HIV-1-infected treatment-naive adults in India, South Africa and Uganda METHODS: A phase-4, 96-week, randomized, double-blind, non-inferiority trial compared d4T 20mg BD and TDF, taken in combination with lamivudine (3TC) and efavirenz (EFV). The primary endpoint was the proportion of participants with HIV-1 RNA <50 copies/ml at 48 weeks. Adverse events assessments included measures of bone density and body fat. The trial is registered on Clinicaltrials·gov (NCT02670772).

RESULTS: Between 2012 and 2014, 536 participants were recruited per arm. At week-96, trial completion rates were 75.7% with d4T/3TC/EFV (n=406) and 82.1% with TDF/3TC/EFV (n=440, p=0.011). Non-completion was largely due to virological failure (6.2% [33] with d4T/3TC/EFV versus 5.4% [29] with TDF/3TC/EFV; p=0.60). For the primary endpoint, d4T/3TC/EFV was non-inferior to TDF/3TC/EFV (79.3%, 425/536 versus 80.8% 433/536; difference=-1.49%, 95%CI=-6.3,3.3; p<0.001). Drug-related adverse event discontinuations were higher with d4T (6.7%, 36), than TDF (1.1%, 6; p<0.001). Lipodystrophy was more common with d4T (5.6%, 30) than TDF (0.2%, 1; p<0.001). Creatinine clearance increased in both arms, by 18.1 mL/min in the d4T arm and 14.2 mL/min with TDF (p=0.03). Hip bone density measures, however, showed greater loss with TDF.

CONCLUSIONS: Low-dose d4T combined with 3TC/EFV demonstrated non-inferior virological efficacy compared to TDF/3TC/EFV, but mitochondrial toxicity remained high. Little renal toxicity occurred in either arm. Implications of bone mineral density changes with TDF warrant investigation.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.