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Background Islatravir (ISL) has shown sustained activity against multiple HIV-1 subtypes and high potency even in the presence of several NRTI resistance-associated mutations (RAMs). However, in vitro data indicate reduced susceptibility to ISL in viral strains harboring M184I/V alone or in combination with other mutations such as V90I, A114S, I142V, T165R or at least ≥1 thymidine analogue mutation (TAM). We therefore estimated the proportion of virologically suppressed people living with HIV with experience of combined antiretroviral therapy (Exp-PLWH) in the ARCA cohort who might be eligible for ISL, based on the prevalence of mutation patterns known to modify ISL susceptibility.Methods We performed a cross-sectional study including virologically suppressed Exp-PLWH in the ARCA cohort who were on stable ART, had active follow-up in 2024 and had ≥1 available genotypic resistance test (GRT). Mutations patterns associated with ISL-reduced susceptibility were evaluated. ISL activity was explored according to the following definitions: (1) absence of any ISL RAM; (2) absence of the combination M184V plus ≥1 TAM. As doravirine is currently being evaluated as a companion drug for ISL-based regimens, its genotypic susceptibility was also assessed through Stanford Algorithm version 10.1. Logistic regression models were built to identify predictors of ISL preserved activity according to the two resistance patterns.Results Overall, 1,809 virologically suppressed Exp-PLWH were included: 67.8% were males, with median age 58 years (IQR: 49-63), a median follow-up 20 years (IQR 12-31) and a median duration of viral suppression of 11 years (IQR 7-16) ( table 1).ISL RAMs were observed in 37.3% of PLWH (figure 1). Specifically, the M184I/V mutation was found as follows: alone in 21.7% of individuals; in combination with ≥1 TAM in 14.7%; with K65R in 1.1%; no subjects harbored the M184I/V with V90I, A114S or I142V+T165R. Compared with others, individuals with ISL RAMs were older, with a lower CD4+ cell count nadir, longer follow-up, and a more prolonged and extensive antiretroviral exposure (table 1).Multivariable analysis showed that antiretroviral initiation in more recent calendar years and a lower cumulative antiretroviral exposure were independently associated with the absence of any of the ISL resistance mutations (table 2).According to the historical genotypic susceptibility score, 82.8% of subjects had full susceptibility to doravirine.Conclusions In this of virologically suppressed Exp-PLWH receiving stable ART, the predicted activity of ISL was generally high, reflecting the absence of key ISL RAMs and the relatively low prevalence of NRTI mutations known to reduce ISL susceptibility. However, individuals with a long treatment history and extensive antiretroviral exposure may require careful resistance assessment prior to ISL initiation.Abstract OC13 Figure 1Frequency of mutation patterns associated to modified ISL susceptibilityAbstract OC13 Table 1–2