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.

Trends in HIV-1 pretreatment drug resistance and HIV-1 variant dynamics among antiretroviral therapy-naive Ethiopians from 2003 to 2018: a pooled sequence analysis

“…The mutations observed are I85V (5.9%; 3/51), which was the most prevalent PI mutation, followed by M46I (3.9%; 2/51) and F53L (3.9%; 2/51). The I85V is a non-polymorphic mutation selected by Nelfinavir (NFV) and Atazanavir (ATV) [ 40 , 41 ] while the M46I and F53L are associated with reduced susceptibility to ATV and Lopinavir (LPV) [ 42 , 43 ]. M46I, a non-active site mutation in HIV-1 protease, has been clinically associated with saquinavir (SQV) resistance in HIV patients [ 44 ].…”

HIV Drug Resistance Mutations and Subtype Profiles among Pregnant Women of Ho Chi Minh City, South Vietnam

“…At the same time, in all these isolates, the L89M polymorphism was detected, which contributes to resistance to a number of protease inhibitor drugs [ 35 ]. An amino acid substitution at this position of L89T occurs in 8.4% of non-B subtype sequences but only in 0.4% of B subtype sequences [ 36 ]. The absence of a substitution at position 88 simultaneously with polymorphism 82, but the presence of a therapeutically significant substitution at position 89 may be associated with the features of CRF01_AE, which needs further research.…”

Incorporating temporal dynamics of mutations to enhance the prediction capability of antiretroviral therapy’s outcome for HIV-1

“…However, the latent viral population in the patient living with HIV (PLWH) accumulates a large number of resistance-associated mutations, which may not be observable in blood serum but rapidly reappear when it is advantageous, i.e. under the appropriate drug pressure ( Rhee et al 2022 , Wensing et al 2022 ). The many possible drug combinations complicate therapy selection, especially in advanced stages.…”