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Review
. 2025 Jun 1;39(7):781-787.
doi: 10.1097/QAD.0000000000004170. Epub 2025 Mar 17.

Noncanonical HIV drug resistance mutations: need to close existing gaps

Seth Inzaule  1 , Michael R Jordan  2 , Joseph Fokam  3 , Raph L Hamers  1   4 , Roger Paredes  5 , Trevor A Crowell  6 , Robert W Shafer  7 , Jonathan Schapiro  8 , Tobias F Rinke de Wit  1 , Manahttan Charurat  9 , Daniel R Kuritzkes  10 , Nicaise Ndembi  11   12
Affiliations
Review

Noncanonical HIV drug resistance mutations: need to close existing gaps

Seth Inzaule et al. AIDS. .

Abstract

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.

Keywords: noncanonical HIV drug resistance mutations.

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Conflict of interest statement

M.C. reports funding from NIH during the study period, and funding from CDC and NIH outside the study period. T.A.C. reports funding from NIH and US Department of Defense outside the study period. R.L.H. reports funding from Wellcome Trust outside of the submitted work. RP reports funding from MSD and ViiV Healthcare and personal fees from MSD, ViiV, Gilead Sciences, Pfizer, GlaxoSmithKline, Atea, Roche, ViiV Healthcare, and Shionogi outside the study period. J.S. reports personal fees from Gilead Sciences, AbbVie, Merck, GlaxoSmithKline, Pfizer, Moderna and Teva Pharmaceuticals outside of the submitted work.

D.R.K. reports funding from NIH during the conduct of the study and other funding from ViiV Health, GlaxoSmithKline, Gilead Sciences, Merck, Roche and Janssen outside the submitted work. J.F.R. reports other funding from, outside the submitted work. All other authors declare no competing interests. The views expressed in this Personal View are those of the authors and do not necessarily reflect those of the institutions for which they work.

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