Reactivation of viral transcription can sensitize viral reservoir cells to immune-mediated killing which may reduce long-term persistence of virally-infected CD4+ T cells in ART-treated individuals. The ACTIVATE study is an ongoing, prospective, randomized, dose-escalation clinical trial in which the histone deacetylase inhibitor (HDACi) panobinostat is administered as a latency-reversing agent in combination with pegylated IFN-α2a as an innate immune modulator.
ART-treated participants were randomized to receive three consecutive doses of 5mg (phase I) or 10mg (phase II) of panobinostat alone (Arm A, n=2 participants in stages I and II each), or in combination with one dose of pegylated IFN-α2a (Arm B, n=6 participants in stages I and II each). Before and at multiple timepoints after study drug administration, cell-associated HIV-1 RNA from the CD4+ T cells were quantified using ddPCR; moreover, innate and adaptive immune responses and acetylated H3 expression were analyzed by flow cytometry. HIV-1 DNA was evaluated using the IPDA.
Relative to baseline, the expression of acetylated histone H3 increased 1.5 times (p=0.025) on day 4 after 3 doses of panobinostat, an effect that was most visible in naïve, stem cell memory and central-memory CD4+ T cells. In parallel, a significant increase of HIV-1 gene expression relative to baseline levels was seen for TAR transcripts (p=0.0234) and long-LTR transcripts (p=0.0156) in stage II, but not in stage I. The frequency of activated CD38+ NK cells and NKp30+ NK cells increased significantly at day 4 and day 10 from participants receiving IFN-α2a in stages I and II, which was mostly seen in the cytokine producing (CD16– CD56+), cytotoxic (CD16+ CD56+) and immature (CD16+ CD56–) NK cell subsets. Moreover, the proportion of IL-2-producing HIV-1-specific CD4+ T cells increased during treatment with IFN-α2a, while IFN-g secreting CD4+ T cells were reduced. There were no changes in HIV-1 DNA levels among timepoints and between medication arms in both phases. No unexpected or severe clinical adverse events occurred so far.
First results indicate that the medication induces HIV-1 transcription and augments innate and adaptive immune cells. Phase III with 15mg panobinostat administered is ongoing.