title: Rare emergence of drug resistance in HIV-1 treatment-naïve patients after 48 weeks of treatment with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide.
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.
authors.affiliation: a Gilead Sciences Inc. , 333 Lakeside Drive, Foster City , CA , 94404 , USA.
authors.forename: Nicolas A
authors.initials: NA
authors.lastname: Margot
authors.affiliation: a Gilead Sciences Inc. , 333 Lakeside Drive, Foster City , CA , 94404 , USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Kitrinos
authors.affiliation: a Gilead Sciences Inc. , 333 Lakeside Drive, Foster City , CA , 94404 , USA.
authors.forename: Marshall
authors.initials: M
authors.lastname: Fordyce
authors.affiliation: a Gilead Sciences Inc. , 333 Lakeside Drive, Foster City , CA , 94404 , USA.
authors.forename: Scott
authors.initials: S
authors.lastname: McCallister
authors.affiliation: a Gilead Sciences Inc. , 333 Lakeside Drive, Foster City , CA , 94404 , USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.affiliation: a Gilead Sciences Inc. , 333 Lakeside Drive, Foster City , CA , 94404 , USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Callebaut
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000328:Adult; D000409:Alanine; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D018791:CD4 Lymphocyte Count; D000069547:Cobicistat / Q000008:administration & dosage*; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D000068679:Emtricitabine / Q000008:administration & dosage*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D015363:Quinolones / Q000008:administration & dosage*; D000068698:Tenofovir / Q000031:analogs & derivatives; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D015363:Quinolones; C509700:elvitegravir; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000068679:Emtricitabine; D000225:Adenine; D000069547:Cobicistat; D000409:Alanine
keywords: INSTI-R; M184V; Tenofovir; Tenofovir alafenamide; Tenofovir disoproxil fumarate