Abstract and Introduction
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/m2 was associated with increased CVF risk. These findings support the use of long-acting CAB+RPV in routine clinical practice.
Current antiretroviral therapy (ART) consists of a combination of two or more oral agents from at least two drug classes, such as an integrase strand transfer inhibitor (INSTI) as well as one or two nucleoside reverse transcriptase inhibitors (NRTIs).[1,2] Cabotegravir (CAB), an INSTI, and rilpivirine (RPV), a non-NRTI (NNRTI), have been developed as the first long-acting, injectable, two-drug ART regimen administered intramuscularly monthly or every 2 months for the maintenance of virologic suppression in people living with HIV-1.[3,4]
Long-acting CAB+RPV is indicated for the treatment of HIV-1 infection in virologically suppressed adults (HIV-1 RNA <50 copies/ml), per positive results from three Phase 3/3b studies. The Phase 3 FLAIR (NCT02938520) and ATLAS (NCT02951052) studies[3,4] demonstrated that long-acting CAB+RPV dosed every 4 weeks (Q4W) was noninferior to daily oral ART in maintaining virologic suppression in stably suppressed participants through 48 weeks; noninferiority was established within each study and in a pooled analysis. In addition, long-acting CAB+RPV dosed every 8 weeks (Q8W) demonstrated noninferior efficacy to Q4W dosing with a similar safety profile in the Phase 3b ATLAS-2M (NCT03299049) study. In the FLAIR, ATLAS and ATLAS-2M studies,[3,4,6] confirmed virologic failure (CVF; two consecutive plasma HIV-1 RNA measurements ≥200 copies/ml) was rare, occurring in 1% (n = 17/1636) of participants in the long-acting CAB+RPV arms combined. Similar CVF rates were observed among participants who continued daily oral therapy in FLAIR and ATLAS, with three out of 283 (1.1%) and four out of 308 (1.3%) participants meeting the CVF criterion, respectively.
Identifying the factors associated with virologic outcome is important to holistically understand any ART regimen and to assist healthcare professionals/prescribers regarding patient selection. Although few participants experienced CVF across the long-acting CAB+RPV arms of the Phase 3 studies, it is important to identify factors that may have predisposed this minority of participants to CVF. This information will help inform clinicians and patients, allowing them to assess the potential benefits and risks of this novel long-acting therapy. Early analyses in the individual studies sought to identify any participant, viral or pharmacokinetic factors that may warrant further investigation in relation to virologic outcome. One factor that appeared initially to be associated with CVF was the L74I integrase polymorphism;[3–5] however, its role in virologic outcome was unclear.
The small number of participants who experienced CVF in the three studies prevented the drawing of meaningful conclusions when the trials were analysed individually. Therefore, a post-hoc multivariable analysis was performed using pooled data from long-acting CAB+RPV participants in FLAIR, ATLAS and ATLAS-2M to explore potential drug (pharmacokinetic and dosing regimen), viral and participant factors predictive of Week 48 virologic failure.