Resistance mechanisms for INSTIs and NRTIs in bictegravir/FTC/TAF therapy

Abstract

Ten studies encompassing 19,608 participants demonstrated that bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) exhibits distinct resistance patterns depending on treatment history. Pre-existing NRTI resistance was common in treatment-experienced populations, ranging from 2.7% in treatment-naive individuals to 25% in real-world cohorts, with M184V/I mutations present in 10-16% of participants. Despite this, viral suppression rates remained 96-100% among individuals with archived NRTI resistance, indicating that these mutations do not compromise B/F/TAF efficacy. Pre-existing INSTI resistance was rare (0.6-4%), and treatment-emergent resistance to any B/F/TAF component was absent in randomized trials through 144 weeks but occurred in 3-4% of real-world treatment-experienced populations. The critical resistance mechanism identified was prior INSTI virologic failure, which increased viral rebound risk 2.68-fold, while major INSTI resistance mutations increased risk 4.21-fold.

Methods

We analyzed 10 sources from an initial pool of 200, using 8 screening criteria. Each paper was reviewed for 7 key aspects that mattered most to the research question.

Paper search

We performed a semantic search across over 138 million academic papers from the Elicit search engine, which includes all of Semantic Scholar and OpenAlex.

Screening

We screened in sources based on their abstracts that met criteria related to drug combinations, resistance outcomes, study populations, and methods of resistance detection.

Results

Characteristics of Included Studies

Ten studies evaluating resistance mechanisms in bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) therapy were included, encompassing 19,608 participants across clinical trials and real-world cohorts.

Pre-existing Resistance Mutations

Pre-existing NRTI resistance mutations were common across studies, while INSTI resistance mutations were rare.

• NRTI resistance prevalence ranged from 2.7% to 25%
• M184V/I mutations found in 10-16% of participants
• INSTI resistance prevalence ranged from 0.6-4%
• Specific INSTI mutations included Q148H, G140S, E92G.

Treatment-Emergent Resistance

Treatment-emergent resistance to B/F/TAF components was rare across all studies.

• Emergent resistance rates were reported at 0-4% in multiple studies.

Virologic Outcomes

High rates of viral suppression were maintained across studies, including among participants with pre-existing resistance mutations.

• Overall viral suppression rates ranged from 97-100% across clinical trials.
• Virologic failure rates were low, 5.3-6.8% reported.

Risk Factors for Virologic Failure

Prior INSTI virologic failure and major INSTI resistance mutations emerged as primary risk factors for viral rebound with B/F/TAF therapy.

• Significant risk factors included:
  • History of INSTI virological failure (aRH 2.68)
  • Major INSTI resistance mutations (aRH 4.21)

Resistance Mechanisms

Limited mechanistic data on resistance to B/F/TAF components were available. The Q148H+G140S combination in integrase showed high-level resistance to some INSTIs but maintained sensitivity to bictegravir, indicating bictegravir's structural properties allow it to maintain binding affinity even with resistance mutations.

Synthesis

The evidence demonstrates consistently low rates of treatment-emergent resistance to B/F/TAF, revealing important distinctions in resistance patterns between treatment-naive and treatment-experienced populations. For treatment-naive individuals, B/F/TAF displays a high barrier to resistance irrespective of archived NRTI mutations. Conversely, for treatment-experienced individuals with prior INSTI failure, alternative regimens may be preferable, given the observed increased risk of virologic failure.