Max Lataillade1, Jacob P Lalezari2, Michael Kozal3, Judith A Aberg4, Gilles Pialoux5, Pedro Cahn6, Melanie Thompson7, Jean-Michel Molina8, Santiago Moreno9, Beatriz Grinsztejn10, Ricardo S Diaz11, Antonella Castagna12, Princy N Kumar13, Gulam H Latiff14, Edwin De Jesus15, Marcia Wang16, Shiven Chabria17, Margaret Gartland18, Amy Pierce18, Peter Ackerman17, Cyril Llamoso17. 1. ViiV Healthcare, Branford, CT, USA. Electronic address: max.x.lataillade@viivhealthcare.com. 2. Quest Clinical Research, San Francisco, CA, USA. 3. Department of Internal Medicine, Infectious Diseases Section, Yale University School of Medicine, New Haven, CT, USA. 4. Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 5. Department of Infectious and Tropical Diseases, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France. 6. Fundación Huesped, Buenos Aires, Argentina. 7. AIDS Research Consortium of Atlanta, Atlanta, GA, USA. 8. Department of Infectious Diseases, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Paris, France. 9. Department of Infectious Diseases, Hospital Universitario Ramón y Cajal, Alcalá University, Madrid, Spain. 10. STD and AIDS Clinical Research Laboratory, Infectious Diseases, Instituto de Pesquisa Clínica Evandro Chagas FIOCRUZ, Rio De Janeiro, Brazil. 11. Infectious Diseases Division, Paulista School of Medicine, Federal University of São Paulo, São Paulo, Brazil. 12. Clinic of Infectious Diseases, Vita-Salute San Raffaele University, Milan, Italy. 13. Department of Medicine and Microbiology, Georgetown University Medical Center, Washington, DC, USA. 14. Maxwell Centre, Durban, South Africa. 15. Orlando Immunology Center, Orlando, FL, USA. 16. GlaxoSmithKline, Upper Providence Township, PA, USA. 17. ViiV Healthcare, Branford, CT, USA. 18. ViiV Healthcare, Research Triangle Park, NC, USA.
Abstract
BACKGROUND: Fostemsavir, a prodrug of the first-in-class attachment inhibitor, temsavir, is indicated for heavily treatment-experienced individuals with multidrug-resistant HIV-1. We previously reported superior efficacy of fostemsavir versus placebo in the randomised cohort of the BRIGHTE study after 8-day functional monotherapy (primary endpoint); here we report planned interim analyses through week 96. METHODS: BRIGHTE (NCT02362503) is an ongoing multicentre, two-cohort, phase 3 trial, done at 108 centres in 22 countries. We enrolled heavily treatment-experienced adults (≥18 years) failing antiretroviral therapy (HIV-1 RNA ≥400 copies per mL) into two cohorts: the randomised cohort, in which patients with one or two fully active antiretrovirals remaining received oral fostemsavir (600 mg twice a day) or placebo in combination with their failing regimen for 8 days, followed by fostemsavir plus optimised background therapy; or the non-randomised cohort, in which patients with no remaining antiretroviral options received oral fostemsavir (600 mg twice a day) plus optimised background therapy from day 1. Endpoints for the week 96 interim analyses included the proportions of participants with plasma HIV-1 RNA of less than 40 copies per mL, changes from baseline in CD4 cell counts, and the frequency of adverse events, adverse events leading to discontinuation, and deaths. The intention-to-treat exposed population and the safety population both included all participants who received at least one dose of study treatment. The response rates (proportion of participants with HIV-1 RNA <40 copies per mL) in the intention-to-treat exposed population were calculated via snapshot analysis at weeks 24, 48, and 96. FINDINGS: Between Feb 23, 2015, and Aug 11, 2016, 371 participants were enrolled and treated, of which 272 participants were in the randomised cohort and 99 in the non-randomised cohort. 320 (86%) of 371 reported a history of AIDS. In the randomised cohort, rates of virological suppression (HIV-1 RNA <40 copies per mL) increased from 53% (144 of 272) at week 24 to 60% (163 of 272) at week 96. Response rates in the non-randomised cohort were 37% (37 of 99) at week 24 and week 96. Mean increases in CD4 counts from baseline at week 96 were 205 cells per μL (SD 191) in the randomised cohort and 119 cells per μL (202) in the non-randomised cohort. Mean CD4/CD8 ratio increased from 0·20 at baseline to 0·44 at week 96 in the randomised cohort. Few adverse events led to discontinuation (26 [7%] of 371). 12 (4%) of 272 people in the randomised cohort and 17 (17%) of 99 in the non-randomised cohort died; the median baseline CD4 count for participants who died was 11 cells per μL. INTERPRETATION: In heavily treatment-experienced individuals with advanced HIV-1 disease and limited treatment options, fostemsavir-based antiretroviral regimens were generally well tolerated and showed a distinctive trend of increasing virological and immunological response rates through 96 weeks; these findings support fostemsavir as a treatment option for this vulnerable population. FUNDING: ViiV Healthcare.
BACKGROUND: Fostemsavir, a prodrug of the first-in-class attachment inhibitor, temsavir, is indicated for heavily treatment-experienced individuals with multidrug-resistant HIV-1. We previously reported superior efficacy of fostemsavir versus placebo in the randomised cohort of the BRIGHTE study after 8-day functional monotherapy (primary endpoint); here we report planned interim analyses through week 96. METHODS: BRIGHTE (NCT02362503) is an ongoing multicentre, two-cohort, phase 3 trial, done at 108 centres in 22 countries. We enrolled heavily treatment-experienced adults (≥18 years) failing antiretroviral therapy (HIV-1 RNA ≥400 copies per mL) into two cohorts: the randomised cohort, in which patients with one or two fully active antiretrovirals remaining received oral fostemsavir (600 mg twice a day) or placebo in combination with their failing regimen for 8 days, followed by fostemsavir plus optimised background therapy; or the non-randomised cohort, in which patients with no remaining antiretroviral options received oral fostemsavir (600 mg twice a day) plus optimised background therapy from day 1. Endpoints for the week 96 interim analyses included the proportions of participants with plasma HIV-1 RNA of less than 40 copies per mL, changes from baseline in CD4 cell counts, and the frequency of adverse events, adverse events leading to discontinuation, and deaths. The intention-to-treat exposed population and the safety population both included all participants who received at least one dose of study treatment. The response rates (proportion of participants with HIV-1 RNA <40 copies per mL) in the intention-to-treat exposed population were calculated via snapshot analysis at weeks 24, 48, and 96. FINDINGS: Between Feb 23, 2015, and Aug 11, 2016, 371 participants were enrolled and treated, of which 272 participants were in the randomised cohort and 99 in the non-randomised cohort. 320 (86%) of 371 reported a history of AIDS. In the randomised cohort, rates of virological suppression (HIV-1 RNA <40 copies per mL) increased from 53% (144 of 272) at week 24 to 60% (163 of 272) at week 96. Response rates in the non-randomised cohort were 37% (37 of 99) at week 24 and week 96. Mean increases in CD4 counts from baseline at week 96 were 205 cells per μL (SD 191) in the randomised cohort and 119 cells per μL (202) in the non-randomised cohort. Mean CD4/CD8 ratio increased from 0·20 at baseline to 0·44 at week 96 in the randomised cohort. Few adverse events led to discontinuation (26 [7%] of 371). 12 (4%) of 272 people in the randomised cohort and 17 (17%) of 99 in the non-randomised cohort died; the median baseline CD4 count for participants who died was 11 cells per μL. INTERPRETATION: In heavily treatment-experienced individuals with advanced HIV-1 disease and limited treatment options, fostemsavir-based antiretroviral regimens were generally well tolerated and showed a distinctive trend of increasing virological and immunological response rates through 96 weeks; these findings support fostemsavir as a treatment option for this vulnerable population. FUNDING: ViiV Healthcare.
Authors: 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 Journal: Antimicrob Agents Chemother Date: 2022-05-03 Impact factor: 5.938
Authors: Ronald Rose; Margaret Gartland; Zhufang Li; Nannan Zhou; Mark Cockett; Jagadish Beloor; Max Lataillade; Peter Ackerman; Mark Krystal Journal: AIDS Date: 2022-01-01 Impact factor: 4.177
Authors: Margaret Gartland; Eric Arnoult; Brian T Foley; Max Lataillade; Peter Ackerman; Cyril Llamoso; Mark Krystal Journal: J Antimicrob Chemother Date: 2021-10-11 Impact factor: 5.790