Long-term efficacy and safety of fostemsavir among subgroups of heavily treatment-experienced adults with HIV-1

Supplemental Digital Content is available in the text 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.

[1]  M. Kozal,et al.  Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals: week 96 results of the phase 3 BRIGHTE study. , 2020, The lancet. HIV.

[2]  M. Kozal,et al.  Fostemsavir in Adults with Multidrug-Resistant HIV-1 Infection. , 2020, The New England journal of medicine.

[3]  Domenico Di Carlo,et al.  HIV MDR is still a relevant issue despite its dramatic drop over the years. , 2020, The Journal of antimicrobial chemotherapy.

[4]  Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV , 2020 .

[5]  Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV , 2020 .

[6]  P. Gorycki,et al.  2500. Fostemsavir Drug–Drug Interaction Profile, an Attachment Inhibitor and Oral Prodrug of Temsavir, for Heavily Treatment Experienced HIV-1-Infected Patients , 2019, Open Forum Infectious Diseases.

[7]  J. Leider,et al.  661. Ibalizumab Efficacy and Safety Through 48 Weeks of Treatment: Results of an Expanded Access Protocol (TMB-311) , 2019, Open Forum Infectious Diseases.

[8]  A. Mocroft,et al.  Aging and the evolution of comorbidities among HIV-positive individuals in a European cohort , 2018, AIDS.

[9]  Gary Richmond,et al.  Phase 3 Study of Ibalizumab for Multidrug‐Resistant HIV‐1 , 2018, The New England journal of medicine.

[10]  S. Weinheimer,et al.  Forty-eight-Week Safety and Efficacy On-Treatment Analysis of Ibalizumab in Patients with Multi-Drug Resistant HIV-1 , 2017, Open Forum Infectious Diseases.

[11]  Alon Herschhorn,et al.  Crystal structures of trimeric HIV Env with entry inhibitors BMS-378806 and BMS-626529 , 2017, Nature chemical biology.

[12]  Samit R. Joshi,et al.  Safety and Efficacy of the HIV-1 Attachment Inhibitor Prodrug Fostemsavir in Antiretroviral-Experienced Subjects: Week 48 Analysis of AI438011, a Phase IIb, Randomized Controlled Trial , 2017, Antiviral therapy.

[13]  D. Fierer,et al.  Enhanced FCGR2A and FCGR3A signaling by HIV viremic controller IgG. , 2017, JCI insight.

[14]  Samit R. Joshi,et al.  Safety and efficacy of the HIV-1 attachment inhibitor prodrug BMS-663068 in treatment-experienced individuals: 24 week results of AI438011, a phase 2b, randomised controlled trial. , 2015, The lancet. HIV.

[15]  M. Ramgopal,et al.  Dolutegravir versus Placebo in Subjects Harbouring HIV-1 with Integrase Inhibitor Resistance Associated Substitutions: 48-Week Results from VIKING-4, a Randomized Study , 2015, Antiviral therapy.

[16]  Peter D. Kwong,et al.  Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions , 2014, Science.

[17]  D. Langley,et al.  Genotypic correlates of susceptibility to HIV-1 attachment inhibitor BMS-626529, the active agent of the prodrug BMS-663068. , 2014, The Journal of antimicrobial chemotherapy.

[18]  R. Haubrich,et al.  Dolutegravir in Antiretroviral-Experienced Patients With Raltegravir- and/or Elvitegravir-Resistant HIV-1: 24-Week Results of the Phase III VIKING-3 Study , 2014, The Journal of infectious diseases.

[19]  M. Krystal,et al.  Activity of the HIV-1 Attachment Inhibitor BMS-626529, the Active Component of the Prodrug BMS-663068, against CD4-Independent Viruses and HIV-1 Envelopes Resistant to Other Entry Inhibitors , 2013, Antimicrobial Agents and Chemotherapy.

[20]  N. Meanwell,et al.  In Vitro Antiviral Characteristics of HIV-1 Attachment Inhibitor BMS-626529, the Active Component of the Prodrug BMS-663068 , 2012, Antimicrobial Agents and Chemotherapy.

[21]  Tommy F. Liu,et al.  The HIVdb System for HIV-1 Genotypic Resistance Interpretation , 2012, Intervirology.

[22]  D. Langley,et al.  In Vivo Patterns of Resistance to the HIV Attachment Inhibitor BMS-488043 , 2010, Antimicrobial Agents and Chemotherapy.

[23]  R. Haubrich,et al.  Efficacy and safety of etravirine at week 96 in treatment-experienced HIV type-1-infected patients in the DUET-1 and DUET-2 trials , 2010, Antiviral therapy.

[24]  F. Villarroya,et al.  Nadir CD4 T cell count as predictor and high CD4 T cell intrinsic apoptosis as final mechanism of poor CD4 T cell recovery in virologically suppressed HIV-infected patients: clinical implications. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[25]  B. Clotet,et al.  Long-term efficacy and safety of Raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[26]  R. Haubrich,et al.  Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials , 2009, AIDS.