Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis

Abstract

Objective: Efficacy and safety of long-acting cabotegravir (CAB) and rilpivirine (RPV) dosed intramuscularly every 4 or 8 weeks has been demonstrated in three Phase 3 trials. Here, factors associated with virologic failure at Week 48 were evaluated post hoc . Design and methods: Data from 1039 adults naive to long-acting CAB+RPV were pooled in a multivariable analysis to examine the influence of baseline viral and participant factors, dosing regimen and drug concentrations on confirmed virologic failure (CVF) occurrence using a logistic regression model. In a separate model, baseline factors statistically associated with CVF were further evaluated to understand CVF risk when present alone or in combination. Results: Overall, 1.25% ( n = 13/1039) of participants experienced CVF. Proviral RPV resistance-associated mutations (RAMs), HIV-1 subtype A6/A1, higher BMI (associated with Week 8 CAB trough concentration) and lower Week 8 RPV trough concentrations were significantly associated ( P < 0.05) with increased odds of CVF (all except RPV trough are knowable at baseline). Few participants (0.4%) with zero or one baseline factor had CVF. Only a combination of at least two baseline factors (observed in 3.4%; n = 35/1039) was associated with increased CVF risk (25.7%, n = 9/35). Conclusion: CVF is an infrequent multifactorial event, with a rate of approximately 1% in the long-acting CAB+RPV arms across Phase 3 studies (FLAIR, ATLAS and ATLAS-2M) through Week 48. Presence of at least two of proviral RPV RAMs, HIV-1 subtype A6/A1 and/or BMI at least 30 kg/m 2 was associated with increased CVF risk. These findings support the use of long-acting CAB+RPV in routine clinical practice.

A new paradigm for antiretroviral delivery: long-acting cabotegravir and rilpivirine for the treatment and prevention of HIV

“…Across all three phase 3 and 3b studies, CVF was rare, occurring in only 1% ( n = 17/1636) of participants in the long-acting CAB and RPV arms of each study [ 22 ▪▪ ]. To better identify the factors associated with virologic outcomes in participants receiving long-acting therapy, investigators performed a post-hoc analysis of data from 13 of 1039 participants who developed CVF while on long-acting therapy [ 22 ▪▪ ].…”

“…Across all three phase 3 and 3b studies, CVF was rare, occurring in only 1% ( n = 17/1636) of participants in the long-acting CAB and RPV arms of each study [ 22 ▪▪ ]. To better identify the factors associated with virologic outcomes in participants receiving long-acting therapy, investigators performed a post-hoc analysis of data from 13 of 1039 participants who developed CVF while on long-acting therapy [ 22 ▪▪ ]. Factors associated with CVF included proviral RPV resistance-associated mutations, HIV-1 subtype A6/A1, BMI at least 30 kg/m 2 (associated with week 8 CAB trough concentration), and lower week 8 RPV trough concentrations.…”

Molecular epidemiology and HIV-1 variant evolution in Poland between 2015 and 2019

“…Together with evidence of novel A6/B URFs, this suggest considerable heterogeneity of HIV-1 in the polish population. Our results might support drug therapy interventions because infections with the A6 variant may bear resistance to cabotegravir, the long-acting antiviral soon to be implemented in the clinical practice 12 .…”

“…In Poland, up to date, a small percentage of immigrants (< 5%) have been observed among the HIV-1 diagnosed individuals, however, the observed data suggest introduction and spread of novel variants in the country 23 . Molecular surveillance over A6 variants is of importance due to possible emergence of resistance and virological failure after therapy containing the HIV-1 integrase strand transfer inhibitor cabotegravir 12 , 24 . In addition to A6 samples, ten samples of the A1 and one of the A3 variant were identified.…”

Highlights from the virtual conference on retroviruses and opportunistic infections (CROI) 2021: SARS-CoV-2 pathogenesis, new data about antiretroviral treatments, HIV-associated comorbidities, pediatrics and pregnancy

“…We must consider that this was in the context of 100% adherence as therapy was directly observed. Although several factors have been associated with a higher risk of CVF, 18 including the presence of ≥2 of proviral RPV resistance mutations, HIV-1 subtype A6/A1, and/or BMI ≥30 kg/m2, it is hard to reliably predict who is more likely to fail IM CAB/RPV. We will need to counsel patients about a small risk of virological failure with resistance, even in the context of optimal adherence.…”