Background
Persistence of latently infected cells is the main barrier to a cure for HIV. Latently infected cells are intrinsically resistant to apoptosis due to the overexpression of the pro-survival factor B cell lymphoma-2 (BCL-2). Inhibition of BCL-2 depleted HIV-infected cells ex vivo and delayed virus rebound in humanized mice. Venetoclax is a BCL-2 inhibitor, licensed for the treatment of haematological malignancies at a daily dose of 400 mg.
Methods
In this dose-escalation phase of a single-arm clinical trial, people with HIV (PWH) on ART and a CD4+ T cell count >500 cells/µL received oral venetoclax at 200 (n=4), 400 (n=3) or 600 (n=3) mg daily. Venetoclax was given for 14 days followed by 14 (200 and 400 mg) or 21 (600 mg) days off, followed by another 14 days of venetoclax. End of study was 3 weeks after last venetoclax cycle with the option of longer follow-up. The primary endpoint was safety with dose-limiting toxicities (DLTs) defined as all venetoclax-related adverse events (AEs) ≥grade 3, and reductions in CD4+ T cell count to <300 cells/µL (³grade 2) or a >50% reduction for >7 days. AEs were graded according to DAIDS v2.1, July 2017. Secondary endpoints included effects on leukocyte and lymphocyte populations, including memory subsets, and plasma levels of venetoclax.
Results
There were no grade 3 nor severe AEs, but 20 grade 1 and 3 grade 2 AEs, 21 grade 1 and 1 grade 2 AEs and 12 grade 1 AEs in the 200, 400 and 600 mg cohorts, respectively. The most reported AEs were gastrointestinal and fatigue. Venetoclax reduced the CD4+ T cell count in all three dose-groups, but with the greatest magnitude and duration in the 600 mg cohort, where participants had maximum declines of 43%, 49% and 51% (Figure 1). Venetoclax also reduced B cell frequencies, with similar decreases in the naïve and memory compartments. There were modest changes in CD4+ T cell memory subset composition and transient increases in T cell activation and proliferation markers during venetoclax. Median plasma venetoclax levels were consistently above 1,000 ng/mL in the 400 and 600 mg cohorts.
Conclusions
Despite causing reductions in the CD4+ T cell count, venetoclax was clinically well-tolerated at doses of 200 to 600 mg. Given the more sustained reduction in CD4+ T cell count at 600 mg, the 400 mg dose was identified as the optimal dose for the expansion cohort of the trial, which will investigate the impact of venetoclax on the HIV reservoir of PWH on suppressive ART.
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