Week 96 Genotypic and Phenotypic Results of the Fostemsavir Phase 3 BRIGHTE Study in Heavily Treatment-Experienced Adults Living with Multidrug-Resistant HIV-1

Margaret Gartland, Pedro Cahn, Edwin DeJesus, Ricardo Sobhie Diaz, Robert Grossberg, Michael Kozal, Princy Kumar, Jean-Michel Molina, Fernando Mendo Urbina, Marcia Wang, Fangfang Du, Shiven Chabria, Andrew Clark, Louise Garside, Mark Krystal, Frank Mannino, Amy Pierce, Peter Ackerman, Max Lataillade, Margaret Gartland, Pedro Cahn, Edwin DeJesus, Ricardo Sobhie Diaz, Robert Grossberg, Michael Kozal, Princy Kumar, Jean-Michel Molina, Fernando Mendo Urbina, Marcia Wang, Fangfang Du, Shiven Chabria, Andrew Clark, Louise Garside, Mark Krystal, Frank Mannino, Amy Pierce, Peter Ackerman, Max Lataillade

Abstract

In the phase 3 BRIGHTE study in heavily treatment-experienced adults with multidrug-resistant HIV-1, fostemsavir plus optimized background therapy (OBT) resulted in sustained rates of virologic suppression through 96 weeks. HIV-1 RNA <40 copies/mL was achieved in 163/272 (60%) Randomized Cohort (RC) participants (with 1 or 2 remaining approved fully active antiretrovirals) and 37/99 (37%) Non-randomized Cohort (NRC) participants (with 0 fully active antiretrovirals). Here we report genotypic and phenotypic analyses of HIV-1 samples from 63/272 (23%) RC participants and 49/99 (49%) NRC participants who met protocol-defined virologic failure (PDVF) criteria through Week 96. The incidence of PDVF was as expected in this difficult-to-treat patient population and, among RC participants, was comparable regardless of the presence of predefined gp120 amino acid substitutions that potentially influence phenotypic susceptibility to temsavir (S375H/I/M/N/T, M426L, M434I, M475I) or baseline temsavir 50% inhibitory concentration fold change (IC50 FC). The incidence of PDVF was lower among participants with higher overall susceptibility score to newly used antiretrovirals (OSS-new), indicating that OSS-new may be a preferred predictor of virologic outcome in heavily treatment-experienced individuals. Predefined gp120 substitutions, most commonly M426L or S375N, were emergent on treatment in 24/50 (48%) RC and 33/44 (75%) NRC participants with PDVF, with related increases in temsavir IC50 FC. In BRIGHTE, PDVF was not consistently associated with treatment-emergent genotypic or phenotypic changes in susceptibility to temsavir or to antiretrovirals in the initial OBT. Further research will be needed to identify which factors are most likely to contribute to virologic failure in this heavily treatment-experienced population (ClinicalTrials.gov, NCT02362503).

Keywords: HIV-1; antiretroviral agents; attachment inhibitor; fostemsavir; heavily treatment experienced; multiple antiretroviral drug resistance; optimized background therapy.

Conflict of interest statement

The authors declare a conflict of interest. M.G., S.C., A.C., M.K., A.P., P.A., and M.L. are employees of ViiV Healthcare and may own stock in GlaxoSmithKline (GSK). P.C. has served on advisory boards for GSK, ViiV Healthcare, and Merck; served as an investigator for Abbott, Gilead, ViiV Healthcare, GSK, Merck, and Richmond; and has received honoraria for his speaking or chairing engagements from Abbott, GSK, Gilead, Merck, and ViiV Healthcare. E.D. has received grants from GSK and Gilead, which were paid to his institution. M.K. served as the principal investigator for clinical trials and laboratory research at Yale University, which received grant funding from ViiV Healthcare and Gilead. P.K. has received grants and/or personal fees for advisory board participation from GSK, Merck, and Theratechnologies and holds stock in GSK, Pfizer, Johnson and Johnson, Merck, and Gilead. J.-M.M. has received honoraria from Gilead, Merck, ViiV Healthcare, and Janssen for participation in advisory boards. L.G. and F.M. are employees of and may own stock in GSK. R.S.D., R.G., and F.M.U. have nothing to disclose.

Figures

FIG 1
FIG 1
Changes in the distribution of overall susceptibility scores for the initial optimized background therapy from baseline to PDVF among Randomized Cohort participants with PDVF through Week 96 (N = 63). #FAA, number of fully active antiretrovirals; OSS, overall susceptibility score; PDVF, protocol-defined virologic failure. aFull activity was based on susceptibility according to current or historical resistance measures and availability (tolerance, eligibility, and in the case of enfuvirtide only, willingness to take the antiretroviral agent). bSusceptibility scores were based on Monogram susceptibility assays. For OSS-new, only antiretroviral agents not previously used by the participant were scored. If resistance testing results were unavailable for individual components of the initial OBT, this impacted the number of participants included in each population (#FAA, OSS, and OSS-new) differently, depending on whether the agent with missing data was a fully active agent, a new agent, or neither. cPDVF susceptibility data are selected from first of confirmed PDVF date, suspected PDVF (sentinel) date, or first date within 6 months after sentinel date. Percentages reported are based on the sample size of each baseline value.
FIG 2
FIG 2
Changes in the distribution of overall susceptibility ratings for common components of the initial optimized background therapy from baseline to PDVF among Randomized Cohort participants with PDVF through Week 96 (N = 63). Participants with missing data at baseline or PDVF are not shown. Percentages reported are based on the sample size of each baseline value. FAA, fully active antiretroviral; DRV, darunavir; DTG, dolutegravir; ETR, etravirine; MVC, maraviroc; OSR, overall susceptibility rating; PDVF, protocol-defined virologic failure; RAL, raltegravir. aAll 6 had previous integrase inhibitor treatment experience, 6/6 with RAL, 2/6 with DTG. bAll 7 had previous integrase inhibitor treatment experience, 1/7 with DTG, 2/7 with RAL, 4/7 with DTG + RAL. cAll 6 had previous integrase inhibitor treatment experience, 6/6 with RAL. dAll 23 had previous DRV treatment experience.

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