Major protease inhibitor drug resistance mutations among patients with virological failure on second-line antiretroviral therapy in Zimbabwe: a retrospective cross-sectional study

Abstract

BACKGROUND: Virological failure (VF) on protease inhibitor (PI)-based second-line antiretroviral therapy (ART) remains an important driver of HIV drug resistance (HIVDR) in sub-Saharan Africa. Despite widespread adoption of dolutegravir (DTG)-based first-line ART, many people living with HIV (PLWH) remain on PI-based second-line regimens. Data on major PI drug resistance mutations (DRMs) in Zimbabwe remain limited. METHODS: We conducted a retrospective cross-sectional study of archived plasma specimens from PLWH with VF (viral load (VL) ≥ 1,000 copies/mL) receiving PI-based second-line ART in Zimbabwe between January 2021 and June 2025. HIV-1 protease and reverse transcriptase regions were Sanger-sequenced, and resistance was interpreted using the Stanford HIV Drug Resistance Database. Factors associated with major PI DRMs were evaluated using multivariable logistic regression. RESULTS: Among 297 participants, 153 (51.5%, 95% confidence interval [CI] 45.8-57.2%) harboured major PI DRMs. The most frequent mutations were M46I (22.6%), V82A (19.2%), and I54V (17.2%). NRTI- and NNRTI-associated DRMs were present in 70.4% and 79.5% of participants, respectively, while 47.8% exhibited triple-class resistance. Predicted susceptibility to darunavir/ritonavir remained high (78.8%), despite resistance to atazanavir/ritonavir (45.5%) and lopinavir/ritonavir (50.8%). In multivariable analysis, increasing age (adjusted odds ratio [aOR] 1.04, P < 0.001), higher VL (aOR 1.55, P = 0.011) and male sex (aOR 1.59, P = 0.044) were independently associated with major PI DRMs. CONCLUSIONS: Major PI DRMs and multiclass HIVDR were common among PLWH with VF on PI-based second-line ART. Routine VL monitoring and early resistance testing are needed to detect and guide second-line ART failure in Zimbabwe.