Systematic review of renal and bone safety of the antiretroviral regimen efavirenz, emtricitabine, and tenofovir disoproxil fumarate in patients with HIV infection

Abstract

Background: Tenofovir disoproxil fumarate (TDF) is a component of many combinations of antiretroviral treatment (ART) regimens. Although potent and generally well tolerated, TDF may cause renal and bone toxicity. The magnitude of off-target side effects is proposed to be related to tenofovir plasma concentrations, which are affected by food and drug–drug interactions with concomitant antiretrovirals. Objective: To perform a systematic literature review and qualitatively report on renal and bone safety outcomes associated with efavirenz (EFV), emtricitabine (FTC), and TDF (EFV+FTC+TDF) ART. Methods: Embase and PubMed databases were searched for randomized clinical trials and observational cohort studies reporting on HIV treatment with EFV+FTC+TDF. Relevant articles were hand-searched for renal (Grade 3–4 serum creatinine/estimated glomerular filtration rate elevations, renal adverse events [AEs], discontinuation due to renal AEs, and urinary biomarkers) and bone outcomes (bone mineral density [BMD] reductions, bone turnover markers, and fracture), and results compiled qualitatively. Results: Of 337 retrieved articles, 29 reporting renal and 11 reporting bone outcomes met the review criteria. EFV+FTC+TDF was associated with a low frequency of renal AEs and treatment discontinuations due to renal AEs. Renal AEs were more frequent when TDF was taken with protease inhibitor (PI)- or cobicistat-containing ART. EFV+FTC+TDF was associated with reduced BMD and increased bone turnover markers, but BMD reductions were less than with PI-containing ART. No treatment-related bone fractures were identified. Conclusions: EFV+FTC+TDF appeared to have a more favorable renal safety profile than TDF administered with a PI or cobicistat. BMD decreased with EFV+FTC+TDF, but no treatment-related fractures were identified.