HIV-1 integrase inhibitor resistance in viraemic-treated individuals and baseline capsid diversity relevant to future lenacapavir therapy

Abstract

Abstract Background Dolutegravir (DTG)-based antiretroviral therapy has been widely adopted across sub-Saharan Africa, yet resistance pathways in non-B HIV-1 subtypes remain poorly defined. As lenacapavir (LEN), a long-acting capsid inhibitor, is introduced for prevention and treatment, characterizing baseline capsid variation alongside emerging integrase resistance is increasingly important. Whether DTG resistance pathways coexist with known capsid resistance mutations in West African epidemics remains poorly described. Methods We performed deep sequencing of 87 HIV-1 samples from adults (n = 47) and paediatric participants (n = 40) failing DTG-based antiretroviral therapy in Nigeria. Resistance mutations were interpreted using Stanford HIVdb and IAS-USA criteria, with resistance estimates based on gene- or drug-panel-specific denominators. Low-frequency variants were assessed at 2%, 5%, 10% and 20% read-frequency thresholds. Capsid mutations associated with LEN resistance were characterized, structurally mapped and compared to global sequence data. HIV-1 subtype and recombinant forms were assigned using COMET HIV-1 v2.4. Results At consensus, predicted resistance to ≥1 integrase strand transfer inhibitor (INSTI) was detected in 13/50 integrase-genotypable participants (26.0%; 95% CI 15.9%–39.6%), including 5/50 with a major INSTI resistance mutation. Reduced predicted susceptibility specifically to DTG was present in 6/50 (12.0%; 95% CI 5.6%–23.8%). G118R was detected in 4/50 participants at consensus, while Q148H/K/R and N155H were absent. In exploratory deep-sequencing analysis, G118R was detected in 8/47 participants with sufficient codon-level coverage at the ≥20% read-frequency threshold. No known primary LEN resistance mutation was detected among 33 participants with complete coverage of all six primary resistance positions (0/33; 95% CI 0%–10.4%); T107A, a polymorphic capsid substitution of uncertain effect on LEN susceptibility, was detected in in 3/33 individuals where sequence could be evaluated. Conclusions These findings demonstrate DTG resistance in both adult and paediatric participants with virological failure with G118R emerging as a prominent resistance pathway. No known primary LEN resistance mutation was detected in the assessable capsid sequences, although phenotypic susceptibility and clinical outcomes were not evaluated. These findings support continued surveillance of integrase and capsid resistance as long-acting antiretroviral strategies expand.