Characterization of HIV-1 Resistance to Tenofovir AlafenamideIn Vitro

Abstract

Tenofovir alafenamide (TAF) is an investigational prodrug of the HIV-1 nucleotide reverse transcriptase (RT) inhibitor (NtRTI) tenofovir (TFV), with improved potency and drug delivery properties over the current prodrug, tenofovir disoproxil fumarate (TDF). TAF is currently in phase 3 clinical studies for the treatment of HIV-1 infection, in combination with other antiretroviral agents. Phase 1 and 2 studies have shown that TAF was associated with increased peripheral blood mononuclear cell (PBMC) drug loading and increased suppression of HIV-1 replication compared to treatment with TDF. In this study, selection of in vitro resistance to both TAF and the parent compound, TFV, led to the emergence of HIV-1 with the K65R amino acid substitution in RT with 6.5-fold-reduced susceptibility to TAF. Although TAF is more potent than TFV in vitro, the antiviral susceptibilities to TAF and TFV of a large panel of nucleoside/nucleotide RT inhibitor (NRTI)-resistant mutants were highly correlated (R 2 ‫؍‬ 0.97), indicating that the two compounds have virtually the same resistance profile when assessed as fold change from the wild type. TAF showed full antiviral activity in PBMCs against primary HIV-1 isolates with protease inhibitor, nonnucleoside RT inhibitor (NNRTI), or integrase strand transfer inhibitor resistance but reduced activity against isolates with extensive NRTI resistance amino acid substitutions. However, the increased cell loading of TFV with TAF versus TDF observed in vivo suggests that TAF may retain activity against TDF-resistant mutant viruses.

HIV-1 with HBV-associated Q151M substitution in RT becomes highly susceptible to entecavir: structural insights into HBV-RT inhibition by entecavir

“…We confirmed that HIV-1 Q151M also caused moderate-level resistance to AZT (~5-fold); the combination of Q151M and F116Y decreased AZT sensitivity further, as expected (IC 50 : 0.2 μM) (Table 2 ). Notably, mutations including Q151M and some accessory mutations are also reportedly cause intermediate-level resistance to 3TC and TDF 25 ; however, such resistance was not caused by any variants tested in this study (Table 2 ). Critically, EFdA activity against HIV-1 Q151M and HIV-1 Q151M/Y115F/F116Y increased (IC 50 : 30 pM for both variants) when compared to that against HIV-1 WT (IC 50 : 0.4 nM).…”

In Vitro Virology Profile of Tenofovir Alafenamide, a Novel Oral Prodrug of Tenofovir with Improved Antiviral Activity Compared to That of Tenofovir Disoproxil Fumarate

“…Finally, the increase in TFV-DP levels may also lead to an improved resistance profile for TAF over TDF. In vitro, the resistance profile of TAF is similar to that of TDF/TFV (see our accompanying paper [27]). However, as previously demonstrated, the intracellular TFV-DP levels achieved with TAF were 5 times higher than those with TDF.…”

Collaborative update of a rule-based expert system for HIV-1 genotypic resistance test interpretation

“…The panel agreed that TDF and TAF should receive similar mutation penalty scores but stipulated that this decision should be re-evaluated if the greater intracellular levels of tenofovir produced by TAF could be shown to be clinically significant in the presence of reduced in vitro tenofovir susceptibility [ 32 , 33 ]. In response to the panel’s recommendation to indicate which of the two DRV/r and DTG dosing schedules should be used, the HIVDB output was modified to include comments indicating that the higher dosing schedule should be used in the presence of low-level, intermediate, or high-level resistance to these ARVs [ 12 , 14 , 34 ].…”