Rare emergence of drug resistance in HIV-1 treatment-naïve patients after 48 weeks of treatment with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide

HIV Clin Trials. 2016 Mar;17(2):78-87. doi: 10.1080/15284336.2016.1142731.

Abstract

Tenofovir alafenamide (TAF), a novel prodrug of the NtRTI tenofovir (TFV), delivers TFV-diphosphate (TFV-DP) to target cells more efficiently than the current prodrug, tenofovir disoproxil fumarate (TDF), with a 90% reduction in TFV plasma exposure. TAF, within the fixed dose combination of elvitegravir /cobicistat / emtricitabine (FTC)/TAF (E/C/F/TAF), has been evaluated in one Phase 2 and two Phase 3 randomized, double-blinded studies in HIV-infected treatment-naive patients, comparing E/C/F/TAF to E/C/F/TDF. In these studies, the TAF-containing group demonstrated non-inferior efficacy to the TDF-containing comparator group with 91.9% of E/C/F/TAF patients having <50 copies/mL of HIV-1 RNA at week 48. An integrated resistance analysis across these three studies was conducted, including HIV-1 genotypic analysis at screening, and genotypic/phenotypic analysis for patients with HIV-1 RNA>400 copies/mL at virologic failure. Pre-existing primary resistance-associated mutations (RAMs) were observed at screening among the 1903 randomized and treated patients: 7.5% had NRTI-RAMs, 18.2% had NNRTI-RAMs, and 3.4% had primary PI-RAMs. Pre-treatment RAMs did not influence treatment response at Week 48. In the E/C/F/TAF group, resistance development was rare; seven patients (0.7%, 7/978) developed NRTI-RAMs, five of whom (0.5%, 5/978) also developed primary INSTI-RAMs. In the E/C/F/TDF group, resistance development was also rare; seven patients (0.8%, 7/925) developed NRTI-RAMs, four of whom (0.4%, 4/925) also developed primary INSTI-RAMs. An additional analysis by deep sequencing in virologic failures revealed minimal differences compared to population sequencing. Overall, resistance development was rare in E/C/F/TAF-treated patients, and the pattern of emergent mutations was similar to E/C/F/TDF.

Trial registration: ClinicalTrials.gov NCT01780506 NCT01797445.

Keywords: INSTI-R; M184V; Tenofovir; Tenofovir alafenamide; Tenofovir disoproxil fumarate.

Publication types

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

MeSH terms

  • Adenine / administration & dosage
  • Adenine / analogs & derivatives*
  • Adult
  • Anti-HIV Agents / administration & dosage*
  • CD4 Lymphocyte Count
  • Cobicistat / administration & dosage*
  • Drug Resistance, Viral*
  • Drug Therapy, Combination
  • Emtricitabine / administration & dosage*
  • Female
  • HIV Infections / drug therapy*
  • HIV Infections / immunology
  • HIV Infections / virology
  • HIV-1 / drug effects
  • HIV-1 / physiology
  • Humans
  • Male
  • Middle Aged
  • Quinolones / administration & dosage*
  • Young Adult

Substances

  • Anti-HIV Agents
  • JTK 303
  • Quinolones
  • GS-7340
  • Emtricitabine
  • Adenine
  • Cobicistat

Associated data

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