Spectrum of Atazanavir-Selected Protease Inhibitor-Resistance Mutations

Abstract

Ritonavir-boosted atazanavir is an option for second-line therapy in low- and middle-income countries (LMICs). We analyzed publicly available HIV-1 protease sequences from previously PI-naïve patients with virological failure (VF) following treatment with atazanavir. Overall, 1497 patient sequences were identified, including 740 reported in 27 published studies and 757 from datasets assembled for this analysis. A total of 63% of patients received boosted atazanavir. A total of 38% had non-subtype B viruses. A total of 264 (18%) sequences had a PI drug-resistance mutation (DRM) defined as having a Stanford HIV Drug Resistance Database mutation penalty score. Among sequences with a DRM, nine major DRMs had a prevalence >5%: I50L (34%), M46I (33%), V82A (22%), L90M (19%), I54V (16%), N88S (10%), M46L (8%), V32I (6%), and I84V (6%). Common accessory DRMs were L33F (21%), Q58E (16%), K20T (14%), G73S (12%), L10F (10%), F53L (10%), K43T (9%), and L24I (6%). A novel nonpolymorphic mutation, L89T occurred in 8.4% of non-subtype B, but in only 0.4% of subtype B sequences. The 264 sequences included 3 (1.1%) interpreted as causing high-level, 14 (5.3%) as causing intermediate, and 27 (10.2%) as causing low-level darunavir resistance. Atazanavir selects for nine major and eight accessory DRMs, and one novel nonpolymorphic mutation occurring primarily in non-B sequences. Atazanavir-selected mutations confer low-levels of darunavir cross resistance. Clinical studies, however, are required to determine the optimal boosted PI to use for second-line and potentially later line therapy in LMICs.

Keywords: HIV-1; antiviral therapy; atazanavir; drug resistance; mutation; protease; protease inhibitor.

Figure 1

Prevalence of PI-associated drug-resistance mutations (DRMs) in 264 sequences containing 1 or more DRMs from previously PI-naïve patients receiving a boosted or unboosted atazanavir-containing regimen. The distribution of DRMs is plotted separately according to the number of PI-associated DRMs in the sequence: (A) 1 DRM, (B) 2 to 3 DRMs, and (C) ≥4 DRMs. The DRMs shown are those occurring in ≥5% of the sequences, including 9 major DRMs indicated in red and 8 accessory DRMs indicated in yellow.

Figure 2

Bayesian network analysis of positively correlated mutation pairs with a hill-climbing search. The Bayesian network analysis yielded 11 mutation pairs, including 6 major DRMs (red), 3 accessory DRMs (yellow), and an additional nonpolymorphic treatment-selected mutation (light blue) with a significant Jaccard correlation coefficient (p < 0.01). The thickness of the arrows indicates the strength of the probabilistic relationship of the two mutations. The direction of the probabilistic causation is shown with an arrowhead. For the direction between V82A and I54V for which the probabilistic causation is not greater than the probabilistic causation of the opposite direction by 0.1, the arrowhead is not shown.