Abstract and Introduction
Objective: We investigated the prevalence of preexisting M184V/I and associated risk factors among clinical trial participants with suppressed HIV and evaluated the impact of M184V/I on virologic response after switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF).
Design: Participant data were pooled from six clinical trials investigating the safety and efficacy of switching to B/F/TAF in virologically suppressed people with HIV.
Methods: Preexisting drug resistance was assessed by historical genotypes and/or baseline proviral DNA genotyping. Virologic outcomes were determined by last available on-treatment HIV-1 RNA. Stepwise selection identified potential risk factors for M184V/I in a multivariate logistic regression model.
Results: Altogether, 2034 participants switched treatment regimens to B/F/TAF and had follow-up HIV-1 RNA data, and 1825 of these participants had baseline genotypic data available. Preexisting M184V/I was identified in 182 (10%), mostly by baseline proviral DNA genotype (n = 167). Most substitutions were M184V (n = 161) or M184V/I mixtures (n = 10). Other resistance substitutions were often detected in addition to M184V/I (n = 147). At last on-treatment visit, 98% (179/182) with preexisting M184V/I and 99% (2012/2034) of all B/F/TAF-treated participants had HIV-1 RNA less than 50 copies/ml, with no treatment-emergent resistance to B/F/TAF. Among adult participants, factors associated with preexisting M184V/I included other resistance, black race, Hispanic/Latinx ethnicity, lower baseline CD4+ cell count, advanced HIV disease, longer duration of antiretroviral therapy, and greater number of prior third agents.
Conclusion: M184V/I was detected in 10% of virologically suppressed clinical trial participants at study baseline. Switching to B/F/TAF demonstrated durable efficacy in maintaining viral suppression, including in those with preexisting M184V/I.
For people with HIV (PWH) receiving antiretroviral treatment (ART) that includes nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (3TC) or emtricitabine (FTC), the M184V and M184I substitutions in reverse transcriptase occur rapidly with incomplete suppressive therapy. M184V/I confers high-level resistance to 3TC and FTC, decreases susceptibility to abacavir (ABC) and didanosine, and increases susceptibility to tenofovir and zidovudine. In PWH who experienced virologic failure on 3TC, M184I typically emerges first, because of a more common nucleotide substitution, only to be replaced by M184V, which results in virus with higher replicative fitness.[3–6] Consequently, in clinical practice, M184V is more often detected after virologic failure on 3TC-containing or FTC-containing regimens than M184I, and has been observed in up to 71% of PWH who fail their first line therapy.[7–9] However, in cases of rilpivirine-based therapy failure, emergent M184I is more common, highlighting the clinical relevance of both M184V and M184I substitutions.
As 3TC and FTC have been part of most recommended regimens for decades, the prevalence of M184V/I among PWH is high. Nonetheless, M184V/I is often underestimated in clinical practice. In the absence of drug pressure, M184V/I variants are replaced by wild-type virus in the circulating quasispecies and are no longer able to be detected by routine plasma HIV genotyping.[11,12] The replacement of M184V/I with wild-type also occurs in the context of transmission: M184V/I is detected in ~4% of acute HIV infections,[7,13–21] but only ~1% of newly diagnosed PWH by Sanger sequencing-based genotyping.[22,23] Despite this decline in circulating virus, drug-resistant variants are archived in the latent viral reservoir and can reemerge under therapeutic selective pressure.[24,25] Given the nature of HIV integration into CD4+ T cells, mutations are likely present for life.
The single tablet regimen bictegravir/FTC/tenofovir alafenamide (B/F/TAF) is a guideline-recommended initial therapy for HIV.[26–28] It is also approved as a replacement regimen when switching therapies in virologically suppressed PWH who have no known substitutions associated with resistance to its individual components. Given the high prevalence of M184V/I and widespread use of B/F/TAF in clinical practice, whether suppressed PWH with this substitution can be switched to B/F/TAF is of interest. We summarize here the results of a comprehensive review of PWH enrolled in clinical trials of switching therapy to B/F/TAF, with a focus on those with M184V/I.
AIDS. 2022;36(11):1511-1520. © 2022 Lippincott Williams & Wilkins
Lippincott Williams & Wilkins