ypic susceptibility to bictegravir was reduced 1.3-, 2.2-, and 2.9-fold for M50I, R263K, and M50I+R263K, respectively. In a second selection, amino acid substitutions T66I and S153F emerged and phenotypic susceptibility to bictegravir was shifted 0.4-, 1.9-, and 0.5-fold for T66I, S153F, and T66I+S153F, respectively.
HIV-1 isolates with reduced susceptibility to emtricitabine have been selected in cell culture and had M184V/I mutations in HIV-1 RT.
HIV-1 isolates with reduced susceptibility to tenofovir alafenamide have been selected in cell culture and had the K65R mutation in HIV-1 RT; in addition, a K70E mutation in HIV-1 RT has been transiently observed. HIV-1 isolates with the K65R mutation have low level reduced susceptibility to abacavir, emtricitabine, tenofovir, and lamivudine. In vitro drug resistance selection studies with tenofovir alafenamide have shown no development of high-level resistance after extended culture.
In treatment-naïve (Studies GS-US-380-1489 and GS-US-380-1490) and virologically-suppressed patients (Studies GS-US-380-1844 and GS-US-380-1878), no patient receiving Biktarvy had HIV-1 with treatment emergent genotypic or phenotypic resistance to bictegravir, emtricitabine, or tenofovir alafenamide in the resistance analysis population (n=13 with HIV-1 RNA ≥ 200 copies/mL at the time of confirmed virologic failure, Week 48, or early study drug discontinuation). At the time of study entry, six treatment-naïve patients and one virologically-suppressed patient receiving Biktarvy had pre-existing INSTI resistance-associated mutations (6 subjects with T97A and one treatment-naïve subject with Q148H + G140S); all had HIV-1 RNA < 50 copies/mL at Week 48.
Cross-resistance
The susceptibility of bictegravir was tested against 64 INSTI-resistant clinical isolates (20 with single substitutions and 44 with 2 or more substitutions). Of these, all single and double mutant isolates lacking Q148H/K/R and 10 of 24 isolates with Q148H/K/R with additional INSTI resistance associated substitutions had ≤ 2.5-fold reduced susceptibility to bictegravir; > 2.5-fold reduced susceptibility to bictegravir was found for 14 of the 24 isolates that contained G140A/C/S and Q148H/R/K substitutions in integrase. Of those, 9 of the 14 isolates had additional mutations at L74M, T97A, or E138A/K. In addition, site-directed mutants with G118R and T97A+G118R had 3.4- and 2.8-fold reduced susceptibility to bictegravir, respectively. The relevance of these in vitro cross-resistance data remains to be established in clinical practice.
Bictegravir demonstrated equivalent antiviral activity against 5 NNRTI-resistant, 3 NRTI-resistant, and 4 PI-resistant HIV-1 mutant clones compared with the wild-type strain.
Emtricitabine-resistant viruses with the M184V/I substitution were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine.
The K65R and K70E mutations result in reduced susceptibility to abacavir, didanosine, lamivudine, emtricitabine, and tenofovir, but retain sensitivity to zidovudine. Multinucleoside resistant HIV-1 with a T69S double insertion mutation or with a Q151M mutation complex including K65R showed reduced susceptibility to tenofovir alafenamide.
Clinical data
The efficacy and safety of Biktarvy in HIV-1 infected, treatment-naïve adults are based on 48-week data from two randomized, double-blind, a |
