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Viral Suppression in 60% for 96 Weeks
With Fostemsavir Salvage in BRIGHTE
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10th IAS Conference on HIV Science (IAS 2019), July 21-24, 2019, Mexico City
Mark Mascolini
Virologic response continued to improve from trial week 48 to week 96 in heavily pretreated people taking fostemsavir (an HIV attachment inhibitor) plus a background regimen [1]. CD4 count and CD4/CD8 ratio also continued to improve through 96 weeks.
Fostemsavir is a prodrug of temsavir, which inhibits HIV replication by binding directly to HIV-1 gp120 and thus blocking the virus from attaching to CD4 receptors on T cells. BRIGHTE recruited heavily pretreated people whose current regimen was failing and who had (1) 1 or more fully active licensed antiretrovirals in 1 or 2 classes available for a new regimen (the randomized cohort) or (2) no fully active licensed agents available (the nonrandomized cohort). Researchers randomized people in the first group to blinded fostemsavir (600 mg twice daily) or placebo plus the failing regimen for 8 days. At that point everyone took fostemsavir plus an optimized background regimen. Nonrandomized participants immediately received fostemsavir plus an optimized background regimen.
There were 272 people in the randomized cohort and 99 in the nonrandomized cohort. The randomized and nonrandomized groups had median ages of 48 and 50 years, median viral loads of 4.7 and 4.3 log10 copies/mL, and median CD4 counts of 99 and 41. Almost everyone in the nonrandomized group had exhausted every antiretroviral class. In the randomized group, 88% had exhausted nucleosides/nucleotides, 81% nonnucleosides, 74% protease inhibitors, 29% integrase inhibitors, 78% R5 receptor antagonists, and 85% fusion inhibitors. About half of the randomized group (52%) had 1 fully active antiretroviral available, 42% had 2 available, and 6% had none available. The most frequent agents in the randomized cohort's background regimen were dolutegravir, darunavir, tenofovir, etravirine, maraviroc, and enfuvirtide, but not of these agents were judged fully active in all participants.
At study week 48 in the randomized cohort, a snapshot intention-to-treat-exposed analysis determined that 54% had a viral load below 40 copies/mL [2]. That proportion stayed steady at week 72 and rose to 60% at week 96 (163 of 272 initial participants). Of the remaining participants, 30% had a viral load above 40 copies and 10% did not have virologic data available. In the nonrandomized cohort, 37 of 99 participants (37%) had a sub-40-copy viral load at week 96, the same proportion recorded at week 48. Five of 15 nonrandomized people who received the monoclonal antibody ibalizumab with fostemsavir had a week-96 viral load below 40 copies. In observed analyses, 79% in the randomized cohort and 59% in the nonrandomized cohort had a viral load under 40 copies at week 96. Respective proportions with a viral load below 400 copies were 88% and 68%.
In the randomized and nonrandomized groups, CD4 counts rose by averages of 205 and 119 cells through 96 weeks. Among 71 people with an initial sub-50 CD4 count, 56% had at least 200 CD4s at week 96. In the randomized cohort the CD4/CD8 ratio rose from 0.2 when the study began to 0.443 at week 96.
In the randomized and nonrandomized cohorts, 21% and 22% had a drug-related grade 2 to 4 adverse event, 34% and 48% had any serious adverse event, 5% and 12% had any adverse event leading to withdrawal from the study, and 4% and 17% died. The most frequent withdrawal-related adverse events were QT prolongation in 3, abdominal pain in 2, noncardiac chest pain in 2, and hepatic failure in 2.
References
1. Lataillade M, Lalezari J, Aberg J, et al. Week 96 safety and efficacy of the novel HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced participants infected with multi-drug resistant HIV-1 (BRIGHTE study). 10th IAS Conference on HIV Science (IAS 2019), July 21-24, 2019, Mexico City. Abstract MOAB0102.
2. Aberg J, Molina JM, Kozal M, et al. Week 48 safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced participants (BRIGHTE study). Glasgow HIV. October 28-31, 2018. http://www.natap.org/2018/GLASGOW/GLASGOW_28.htm
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