Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials

Lancet. 2015 Jun 27;385(9987):2606-15. doi: 10.1016/S0140-6736(15)60616-X. Epub 2015 Apr 15.

Abstract

Background: Tenofovir disoproxil fumarate can cause renal and bone toxic effects related to high plasma tenofovir concentrations. Tenofovir alafenamide is a novel tenofovir prodrug with a 90% reduction in plasma tenofovir concentrations. Tenofovir alafenamide-containing regimens can have improved renal and bone safety compared with tenofovir disoproxil fumarate-containing regimens.

Methods: In these two controlled, double-blind phase 3 studies, we recruited treatment-naive HIV-infected patients with an estimated creatinine clearance of 50 mL per min or higher from 178 outpatient centres in 16 countries. Patients were randomly assigned (1:1) to receive once-daily oral tablets containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide (E/C/F/tenofovir alafenamide) or 300 mg tenofovir disoproxil fumarate (E/C/F/tenofovir disoproxil fumarate) with matching placebo. Randomisation was done by a computer-generated allocation sequence (block size 4) and was stratified by HIV-1 RNA, CD4 count, and region (USA or ex-USA). Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug were included in the primary intention-to-treat efficacy and safety analyses. The main outcomes were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by the the US Food and Drug Adminstration (FDA) snapshot algorithm (pre-specified non-inferiority margin of 12%) and pre-specified renal and bone endpoints at 48 weeks. These studies are registered with ClinicalTrials.gov, numbers NCT01780506 and NCT01797445.

Findings: We recruited patients from Jan 22, 2013, to Nov 4, 2013 (2175 screened and 1744 randomly assigned), and gave treatment to 1733 patients (866 given E/C/F/tenofovir alafenamide and 867 given E/C/F/tenofovir disoproxil fumarate). E/C/F/tenofovir alafenamide was non-inferior to E/C/F/tenofovir disoproxil fumarate, with 800 (92%) of 866 patients in the tenofovir alafenamide group and 784 (90%) of 867 patients in the tenofovir disoproxil fumarate group having plasma HIV-1 RNA less than 50 copies per mL (adjusted difference 2·0%, 95% CI -0·7 to 4·7). Patients given E/C/F/tenofovir alafenamide had significantly smaller mean serum creatinine increases than those given E/C/F/tenofovir disoproxil fumarate (0·08 vs 0·12 mg/dL; p<0·0001), significantly less proteinuria (median % change -3 vs 20; p<0·0001), and a significantly smaller decrease in bone mineral density at spine (mean % change -1·30 vs -2·86; p<0·0001) and hip (-0·66 vs -2·95; p<0·0001) at 48 weeks.

Interpretation: Through 48 weeks, more than 90% of patients given E/C/F/tenofovir alafenamide or E/C/F/tenofovir disoproxil fumarate had virological success. Renal and bone effects were significantly reduced in patients given E/C/F/tenofovir alafenamide. Although these studies do not have the power to assess clinical safety events such as renal failure and fractures, our data suggest that E/C/F/tenofovir alafenamide will have a favourable long-term renal and bone safety profile.

Funding: Gilead Sciences.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / administration & dosage
  • Adenine / adverse effects
  • Adenine / analogs & derivatives*
  • Adult
  • Anti-HIV Agents / adverse effects
  • Anti-HIV Agents / therapeutic use*
  • Arthralgia / chemically induced
  • Bone Density / drug effects
  • CD4 Lymphocyte Count
  • Carbamates / administration & dosage*
  • Carbamates / adverse effects
  • Cobicistat
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / adverse effects
  • Deoxycytidine / analogs & derivatives*
  • Double-Blind Method
  • Drug Combinations
  • Emtricitabine
  • Female
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • Headache / chemically induced
  • Humans
  • Kidney / drug effects
  • Male
  • Nausea
  • Organophosphonates / administration & dosage*
  • Organophosphonates / adverse effects
  • Quinolones / administration & dosage*
  • Quinolones / adverse effects
  • Respiration Disorders / chemically induced
  • Sleep Initiation and Maintenance Disorders / chemically induced
  • Tenofovir
  • Thiazoles / administration & dosage*
  • Thiazoles / adverse effects
  • Treatment Outcome
  • Viral Load / drug effects

Substances

  • Anti-HIV Agents
  • Carbamates
  • Drug Combinations
  • JTK 303
  • Organophosphonates
  • Quinolones
  • Thiazoles
  • Deoxycytidine
  • Tenofovir
  • GS-7340
  • Emtricitabine
  • Adenine
  • Cobicistat

Associated data

  • ClinicalTrials.gov/NCT01780506
  • ClinicalTrials.gov/NCT01797445