Long-Term Efficacy and Safety of Fostemsavir Among Subgroups of Heavily Treatment-Experienced Adults With HIV-1

Peter Ackerman; Melanie Thompson; Jean-Michel Molina; Judith Aberg; Isabel Cassetti; Michael Kozal; Antonella Castagna; Marcelo Martins; Moti Ramgopal; Eduardo Sprinz; Sandra Treviño-Pérez; Adrian Streinu-Cercel; Gulam H. Latiff; Gilles Pialoux; Princy N. Kumar; Marcia Wang; Shiven Chabria; Amy Pierce; Cyril Llamoso; Max Lataillade

Disclosures

AIDS. 2021;35(7):1061-1072. 

In This Article

Abstract and Introduction

Abstract

Objectives: The aim of this study was to understand how demographic and treatment-related factors impact responses to fostemsavir-based regimens.

Design: BRIGHTE is an ongoing phase 3 study evaluating twice-daily fostemsavir 600 mg and optimized background therapy (OBT) in heavily treatment-experienced individuals failing antiretroviral therapy with limited treatment options (Randomized Cohort 1–2 and Nonrandomized Cohort 0 fully active antiretroviral classes).

Methods: Virologic response rates (HIV-1 RNA <40 copies/ml, Snapshot analysis) and CD4+ T-cell count increases in the Randomized Cohort were analysed by prespecified baseline characteristics (age, race, sex, region, HIV-1 RNA, CD4+ T-cell count) and viral susceptibility to OBT. Safety results were analysed by baseline characteristics for combined cohorts (post hoc).

Results: In the Randomized Cohort, virologic response rates increased between Weeks 24 and 96 across most subgroups. Virologic response rates over time were most clearly associated with overall susceptibility scores for new OBT agents (OSS-new). CD4+ T-cell count increases were comparable across subgroups. Participants with baseline CD4+ T-cell counts less than 20 cells/μl had a mean increase of 240 cells/μl. In the safety population, more participants with baseline CD4+ T-cell counts less than 20 vs. at least 200 cells/μl had grade 3/4 adverse events [53/107 (50%) vs. 24/96 (25%)], serious adverse events [58/107 (54%) vs. 25/96 (26%)] and deaths [16/107 (15%) vs. 2/96 (2%)]. There were no safety differences by other subgroups.

Conclusion: Week 96 results for BRIGHTE demonstrate comparable rates of virologic and immunologic response (Randomized Cohort) and safety (combined cohorts) across subgroups. OSS-new is an important consideration when constructing optimized antiretroviral regimens for heavily treatment-experienced individuals with limited remaining treatment options.

Introduction

There is a continued need for development of new classes of antiretroviral drugs with novel mechanisms of action that are well tolerated and lack cross-resistance to currently available therapies. This need is particularly urgent for heavily treatment-experienced individuals with multidrug-resistant HIV-1 who are unable to form a suppressive antiretroviral regimen from remaining currently available agents.[1–4] For individuals with multidrug-resistant HIV-1 experiencing virologic failure, current international guidelines recommend a new treatment regimen with at least 2, preferably 3, fully active antiretroviral agents based on resistance mutations (current and historical) and treatment history.[1,3] Use of experimental agents or those with novel mechanisms of action is advised where other options are limited.[1,3] Management of multidrug-resistant HIV-1 in heavily treatment-experienced adults may be complicated by a range of factors, including advanced HIV disease with low CD4+ T-cell count (≤200 cells/μl), multiple comorbid medical conditions requiring concomitant medications, difficult social circumstances and a lack of adherence (periodic or persistent) to complex regimens.[1,3,5,6]

Fostemsavir (Rukobia, ViiV Healthcare, Research Triangle Park, North Carolina, USA), a prodrug of the first-in-class attachment inhibitor temsavir, was recently approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of multidrug-resistant HIV-1 infection in heavily treatment-experienced adults with limited antiretroviral treatment options.[7–11] Temsavir has a novel mechanism of action, binding to HIV-1 gp120 and preventing viral attachment to and entry into host CD4+ T cells and other immune cells.[12] Fostemsavir has no cross-resistance to currently available antiretrovirals, including other entry inhibitors, and can be used regardless of tropism.[13–15] Fostemsavir has few drug–drug interactions and can be administered with most drugs prescribed for the management of HIV-1 and associated comorbidities without the need for dose adjustment.[16]

BRIGHTE (ClinicalTrials.gov, NCT02362503) is an ongoing phase 3 study investigating the efficacy and safety of fostemsavir and optimized background therapy (OBT) in heavily treatment-experienced individuals who were failing their current antiretroviral regimen (confirmed HIV-1 RNA ≥400 copies/ml) with limited remaining antiretroviral treatment options.[7,17] The study has two cohorts, a Randomized Cohort including participants with at least one but no more than two fully active antiretroviral agents that could be paired with fostemsavir upon entry into the trial and a Nonrandomized Cohort of heavily treatment-experienced participants with zero remaining fully active and approved antiretroviral options at study start who were allowed the use of other investigational antiretrovirals in their OBT through co-enrolment in other clinical trials. The Nonrandomized Cohort was essentially a compassionate-use group intended to make investigational therapy available to the most vulnerable individuals in the HTE population.

In the Randomized Cohort, treatment with fostemsavir plus OBT resulted in a virologic response (HIV-1 RNA <40 copies/ml by Snapshot analysis) in 144 out of 272 (53%) participants at Week 24 and 163 out of 272 (60%) at Week 96, and a continuous increase in CD4+ T-cell count through Week 96 (mean +205 cells/μl at Week 96).[7,17] Across both cohorts, fostemsavir and OBT was well tolerated with few adverse events leading to discontinuation and no new safety signals observed relative to earlier fostemsavir clinical trials.[7,17]

Heavily treatment-experienced individuals with HIV-1 represent a diverse population and it is important to understand how different demographic and treatment-related factors may affect responses to fostemsavir treatment. We previously reported subgroup analyses of efficacy data from the Randomized Cohort of the BRIGHTE study showing no effect of age, sex, race or geographic region on short-term virologic response to fostemsavir functional monotherapy (8 days of blinded fostemsavir and failing antiretroviral regimen) or durability of response (through Week 48) to fostemsavir and OBT.[7] Here, we present prespecified and post hoc subgroup analyses of virologic and immunologic responses through Week 96 for the Randomized Cohort and post hoc subgroup analyses of cumulative safety endpoints for the combined cohorts.

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