Noncanonical HIV drug resistance mutations: need to close existing gaps

An increasing number of people with HIV (PWH) are failing treatment without HIV drug resistance in the drug target region. While sub-optimal adherence is likely the cause of treatment failure in many PWH, resistance emerging at noncanonical (HIV drug resistance mutations occurring outside the drug target site) drug target sites is also plausible. Noncanonical drug resistance mechanisms have been identified for integrase strand transfer inhibitors (INSTIs), protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) and NRTIs. Overall, they may act by restoring viral fitness caused by mutations in the drug target sites, enhance resistance when occurring with mutations at the drug target sites, independently cause resistance even in the absence of drug resistant mutations (DRMs) at the drug target site, and prime the emergence of resistant variants with DRMs at drug target sites. However, the clinical relevance of non-canonical HIV drug resistance mechanisms beyond in vitro and small in vivo studies is still needed and could include the assessment of such mechanisms in clinical trials and implementation studies. This information would be vital in guiding effective management of PWH with viral nonsuppression despite good adherence as well as informing public health surveillance strategies.