Immune priming prior to reversal of latency may facilitate killing of infected CD4+ T cells and could be a component of an HIV cure. To clinically assess this concept, we evaluated whether therapeutic HIV immunization followed by latency reversal would impact measures of viral transcription, plasma viremia, and reservoir size in HIV patients on suppressive antiretroviral therapy (ART).
This single-arm phase Ib/IIa trial enrolled 20 HIV-infected adults who received 6 intradermal immunizations with Vacc-4x adjuvanted with GM-CSF prior to receiving intravenous romidepsin 5 mg/m2 once weekly for 3 weeks while maintaining ART. This “shock & kill” approach was followed by a monitored antiretroviral pause (MAP). Co-primary endpoints were changes from baseline in total HIV DNA in CD4+ T cells (by ddPCR) and infectious units per million ([IUPM] by quantitative viral outgrowth assay [qVOA]) as markers of the reservoir size. HIV transcription was quantitated by cell-associated unspliced HIV RNA in CD4+ T cells. Plasma HIV RNA was analyzed by the Cobas Taqman assay. Safety was evaluated at each study visit.
Seventeen of 20 enrolled participants (3 females, 17 males, median age 48.5 years, median CD4 670 cells/mm3) completed all Vacc-4x/GM-CSF immunizations and romidepsin infusions. Reductions in the latent reservoir were observed with both assays. Total HIV DNA was reduced by 40% (95% CI: 11–59, p=0.012). qVOA was evaluable at baseline and at least one follow-up time point in 6/17 participants. The 6 evaluable participants had a median reduction in IUPM of 40% (p=0.019). As previously observed, HIV transcription increased rapidly within the first hours after each romidepsin administration. Eight participants had at least one quantifiable plasma HIV RNA (range: 21–619 c/ml) during the romidepsin infusion period. Median time from interrupting ART to plasma HIV RNA>50 copies/ml during the MAP was 14 days. Three SAEs were observed, none related to study therapy. A total of 141 AEs in 20 participants were recorded, 133 grade 1, five grade 2 and three grade 3. None of the grade 3 AEs were related to study medications.
This is the first reported dual intervention designed to target the HIV reservoir. We used Vacc-4x/GM-CSF therapeutic HIV immunization prior to romidepsin treatment and found a significant reduction in the latent HIV reservoir. These results may serve as a benchmark for further optimization of this strategy.