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. Phenotypic data revealed that Q148H+G140S, which confers high-level resistance to first-generation INSTIs, maintained bictegravir sensitivity at <2.5-fold change, demonstrating bictegravir’s activity against some INSTI-resistant variants. B/F/TAF demonstrates an exceptionally high barrier to de novo resistance development in INSTI-naive populations but faces challenges in individuals with established INSTI resistance from prior treatment failures, while archived NRTI resistance does not predict virologic failure.

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. More on methods

Records from Elicit search

• n = 200

Papers screened using: Drug Combination, Resistance Outcomes, Study Population, Resistance Evidence, Study Design, Relevant Drug Focus, Beyond PK/PD Only, Resistance Analysis Included

• n = 200 papers screened out
• n = 190 papers included for extraction

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.

We ran this query: “Resistance mechanisms for INSTIs and NRTIs in bictegravir/FTC/TAF therapy” The search returned 200 total results from Elicit.

Screening

We screened in sources based on their abstracts that met specific criteria:

• Drug Combination: Patients treated with bictegravir/FTC/TAF combination therapy.
• Resistance Outcomes: Studies reporting resistance mechanisms for INSTIs and/or NRTIs.
• Study Population: HIV-positive patients of any age.
• Resistance Evidence: Laboratory or clinical evidence of drug resistance.
• Study Design: Randomized controlled trial, cohort study, etc.
• Relevant Drug Focus: Studies including bictegravir/FTC/TAF.
• Beyond PK/PD Only: Studies reporting resistance outcomes.
• Resistance Analysis Included: Studies including resistance analysis.

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 (Table 1).

Study Overview:

Pre-existing Resistance Mutations

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

Pre-existing Resistance Data:

Treatment-Emergent Resistance

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

Emergent Resistance Summary:

Virologic Outcomes

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

Virologic Outcomes: