Drug Resistance Mutation Profiles in Patients with Virologic Failure

Abstract

Virologic failure on antiretroviral therapy is, in most cases, accompanied by a recognizable pattern of HIV-1 drug resistance mutations whose composition depends on which drug class failed and how long failure went undetected. This article synthesizes the literature on these mutation profiles across the four major antiretroviral classes in current use. Nucleoside reverse transcriptase inhibitor resistance follows two largely mutually exclusive pathways, thymidine analogue mutations and the K65R/M184V pathway, whose specific combination determines residual backbone activity. Non-nucleoside reverse transcriptase inhibitor resistance arises from single, low-genetic-barrier mutations such as K103N and Y181C that rapidly foreclose the class. Protease inhibitor resistance, particularly to boosted darunavir, instead requires the combinatorial accumulation of individually modest mutations, conferring a high genetic barrier. Integrase strand transfer inhibitor resistance, most consequential now that dolutegravir anchors first-line therapy worldwide, is generally rare in treatment-naive patients with an intact nucleoside backbone but emerges disproportionately when that backbone is already compromised, a pattern increasingly documented in programmatic cohorts in sub-Saharan Africa. We also examine how next-generation sequencing is revealing clinically relevant minority-variant resistance below the detection threshold of conventional genotyping, and where programmatic surveillance, detection technology, and treatment-switching protocols remain unresolved.