Research in context
Evidence before this study
We searched PubMed and Scopus for articles published up to April 16, 2016, in any language, that reported clinical studies that aimed to reduce the size of the HIV reservoir through reversal of HIV latency with the search terms “HIV cure”, “HIV reactivation”, “HIV reservoir”, “HIV latency”, and “HIV eradication”, and we reviewed the results for relevance. Investigators of human studies of the histone deacetylase inhibitor vorinostat and antialcoholic abuse agent disulfiram have successfully shown increased HIV-1 expression measured as increased cellular HIV-1 RNA levels in latently infected cells. Investigators of two clinical trials of the potent histone deacetylase inhibitor panobinostat and romidepsin, in addition to showing an increase in cellular HIV-1 expression, showed increased levels of viral HIV-1 particles in plasma during histone deacetylase inhibitor dosing with standard clinical assays. Investigators of none of these studies found a significant effect of the interventions on the size of the latent HIV-1 reservoir, measured as total DNA, integrated DNA, or quantitative viral outgrowth.
Added value of this study
We report the first clinical trial of a combinatorial approach in which latency reversal is preceded by immunotherapy for improved targeting of the HIV-1 reservoir. In this phase 1B/2A trial, therapeutic HIV-1 immunisation with Vacc-4x and rhuGM-CSF combined with the histone deacetylase inhibitor romidepsin resulted in about a 40% reduction in the size of the HIV-1 reservoir from baseline to follow-up, a statistically significant reduction of not only the proviral HIV-1 reservoir on a cohort level, but also the replication-competent HIV-1 reservoir in a subset of individuals. Additionally, despite marked increases in histone acetylation and cell-associated unspliced HIV-1 RNA shortly after each romidepsin infusion, only four of 17 individuals pretreated by immunisation with Vacc-4x and rhuGM-CSF had quantifiable plasma HIV-1 RNA immediately after one of the romidepsin infusions, raising the possibility that priming of the immune system before latency reversal induced an immune pressure on virus-producing cells leading to their killing and therefore limited extracellular release of viral particles during romidepsin treatment. However, although these findings indicate that the size of the viral reservoir was diminished, the combined so-called shock and kill intervention did not seem to prolong median time to virus rebound during ART interruption.
Implications of all the available evidence
A combined approach to a shock and kill strategy for HIV cure is feasible, but optimisation of this strategy is needed to achieve a sizeable effect on the latent reservoir that will translate into clinically measurable benefits for people living with HIV-1.