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Good Later Responses in Some People
Whose Ibalizumab "Failed" After 7 Days
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HIV Drug Therapy, Glasgow 2018, October 28-31, 2018, Glasgow
Mark Mascolini
Three of 7 phase 3 trial participants who failed to attain at least a 0.5-log (about 3-fold) drop in viral load with ibalizumab monotherapy for multidrug-resistant HIV later reach a viral load below 50 copies with ibalizumab plus an optimized regimen of additional antiretrovirals [1]. Other people had virologic response signals that did not meet trial definitions of success. Ibalizumab researchers suggested that virologic responses may take longer in people with multidrug-resistant virus.
The FDA licensed ibalizumab (Trogarzo) for heavily pretreated adults with multidrug-resistant HIV and taking a current failing regimen [2]. The long-acting monoclonal antibody, which blocks HIV entry into CD4 cells, requires a 2000-mg intravenous loading dose followed by 800 mg every 2 weeks. European drug regulators are considering licensing ibalizumab.
TMB-301 was a phase 3 single-arm 24-week study of ibalizumab in heavily pretreated people with multidrug-resistant HIV [3]. The 40 participants took their current failing regimen or no antiretrovirals for a 7-day control period. They got their ibalizumab loading dose on day 7 and continued their failing antiretrovirals for 7 days. The primary endpoint was at least a 0.5-log drop in viral load 7 days after the loading dose. At that point participants added an optimized background regimen and received the 800-mg maintenance dose every 2 weeks. At week 25 viral load dropped an average 1.7 log (50-fold) from the baseline measure, 55% of participants had at least a 1-log (10-fold) drop, 43% had a viral load below 50 copies, and 50% had a load below 200 copies [3].
As planned, the 40 trial participants had heavy antiretroviral experience. They had HIV infection for a median of 23 years (range 2 to 30), median CD4 count lay at 73, and median viral load measured 35,350 copies. Seventeen people (43%) needed fostemsavir, an investigational HIV entry inhibitor, to construct an optimized background regimen. Thirty-three people (82.5%) met the target of at least a 0.5-log viral load drop after 7 days of ibalizumab monotherapy. The new analysis focused on the 7 people who did not.
These 7 people had a median baseline viral load of 21,700 copies (lower than the overall group median of 35,350) and a median CD4 count of 63. Despite failing to meet the 0.5-log reduction cutoff, 3 of the 7 reached a viral load below 50 copies after adding an optimized background regimen. Another person had a 1.1-log viral load drop by week 25. Another 2 people attained viral load dips 2.1 log and 1.6 log below their baseline measure. Their viral loads then rebounded but remained below their baseline load through the end of the study. The seventh person had a 0.5-log viral load drop at day 21 but then withdrew from the trial. Together, these 7 people averaged a 1.3-log viral load drop through the end of the study, compared with a 0.1-log viral load decline 7 days after taking the ibalizumab loading dose.
Given the eventual virologic responses in some participants who failed to meet the 7-day 0.5-log target, the ibalizumab researchers proposed that "virologic responses with multidrug-resistant HIV-1 may take longer to achieve."
References
1. DeJesus E, Emu B, Weinheimer, Cohen Z, Cash B, Lewis S. Outcomes of patients not achieving primary endpoint from an ibalizumab phase III trial. HIV Drug Therapy, Glasgow 2018, October 28-31, 2018, Glasgow. Abstract P064.
2. US Department of Health and Human Services. AIDSinfo. Ibalizumab. https://aidsinfo.nih.gov/drugs/511/ibalizumab/205/professional
3. Lewis S, Fessel J, Emu B, et al. Long-acting ibalizumab in patients with multi-drug resistant HIV-1: a 24-week study. Conference on Retroviruses and Opportunistic Infections (CROI). February 13-16, 2017, Seattle. http://www.natap.org/2017/CROI/croi_20.htm
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