Frequency and patterns of protease gene resistance mutations in HIV-infected patients treated with lopinavir/ritonavir as their first protease inhibitor

Selection of protease mutations on antiretroviral therapy (ART) including a ritonavir-boosted protease inhibitor (PI) has been reported infrequently. Scarce data exist from long-term cohorts on resistance incidence or mutational patterns emerging to different PIs. We studied UK patients receiving lopinavir/ritonavir as their first PI, either while naive to ART or having previously received non-PI-based ART. Virological failure was defined as viral load epsilon 400 copies/mL after previous suppression 400 copies/mL, or failure to achieve 400 copies/mL during the first 6 months. pol sequences whilst failing lopinavir or within 30 days after stopping were analysed. Major and minor mutations (IAS-USA 2008after exclusion of polymorphisms) were considered. Predicted susceptibility was determined using the Stanford HIVdb algorithm. Three thousand and fifty-six patients were followed for a median (IQR) of 14 (630) months, of whom 811 (27) experienced virological failure. Of these, resistance test results were available on 291 (36). One or more protease mutations were detected in 32 (11) patients; the most frequent were I54V (n12), M46I (n11), V82A (n7) and L76V (n3). No association with viral subtype was evident. Many patients retained virus predicted to be susceptible to lopinavir (14, 44), tipranavir (26, 81) and darunavir (27, 84). This study reflects the experience of patients in routine care. Selection of protease gene mutations by lopinavir/ritonavir occurred at a much higher rate than in clinical trials. The mutations observed showed only partial overlap with those previously identified by structural chemistry models, serial cell culture passage and genotypephenotype analyses. There remained a low degree of predicted cross-resistance to other widely used PIs.