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

Amy G Cutrell, Jonathan M Schapiro, Carlo F Perno, Daniel R Kuritzkes, Romina Quercia, Parul Patel, Joseph W Polli, David Dorey, Yongwei Wang, Sterling Wu, Veerle Van Eygen, Herta Crauwels, Susan L Ford, Mark Baker, Christine L Talarico, Marty St Clair, Jerry Jeffrey, C Thomas White, Simon Vanveggel, Kati Vandermeulen, David A Margolis, Michael Aboud, William R Spreen, Jan van Lunzen, Amy G Cutrell, Jonathan M Schapiro, Carlo F Perno, Daniel R Kuritzkes, Romina Quercia, Parul Patel, Joseph W Polli, David Dorey, Yongwei Wang, Sterling Wu, Veerle Van Eygen, Herta Crauwels, Susan L Ford, Mark Baker, Christine L Talarico, Marty St Clair, Jerry Jeffrey, C Thomas White, Simon Vanveggel, Kati Vandermeulen, David A Margolis, Michael Aboud, William R Spreen, Jan van Lunzen

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/m2 was associated with increased CVF risk. These findings support the use of long-acting CAB+RPV in routine clinical practice.

Conflict of interest statement

A.C. is an employee of ViiV Healthcare and stockholder of GlaxoSmithKline.

J.S. reports personal fees and nonfinancial support from Gilead Sciences, Merck, ViiV Healthcare/GlaxoSmithKline, Teva, AbbVie, Virology Education and nonfinancial support from WHO outside the submitted work.

C.F.P. received grants and personal fees from Gilead Sciences, ViiV Healthcare and Merck Sharp and Dohme, and personal fees from Janssen and Theratechnologies outside the submitted work.

D.R.K. has received research support and consulting honoraria from ViiV Healthcare, Gilead Sciences and Merck, and consulting honoraria from GlaxoSmithKline outside the submitted work.

R.Q., P.P., J.W.P., D.D., Y.W., M.B., C.L.T., M.S.C, J.J., C.T.W., M.A., W.S. and J.V.L. are employees of ViiV Healthcare and stockholders of GlaxoSmithKline. D.M. was an employee of ViiV Healthcare during the conduct of this work and is a stockholder of GlaxoSmithKline. S.W. and S.L.F. are employees and stockholders of GlaxoSmithKline. H.C., S.V. and K.V. are employees and stockholders of Janssen, Pharmaceutical Companies of Johnson & Johnson. V.V.E. is an employee of Janssen, Pharmaceutical Companies of Johnson & Johnson.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.

Figures

Fig. 1
Fig. 1
Univariate analysis of CVF outcome by 10 prespecified factors.
Fig. 2
Fig. 2
Cabotegravir and rilpivirine trough concentrations at Week 8 (i.e. 4 weeks after first injections) and CVF through Week 48 (pooled Phase 3/3b) by regimen (a) and baseline BMI category (b).

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