"Kick and Kill" Therapy Plus ART Evaluated in New Study

At the heart of HIV research is the problem of the reservoir of HIV cells that typically stays dormant during antiretroviral therapy (ART) but can reactivate should ART be interrupted. Investigators have been working on ways to drain that reservoir in the hopes of finding a permanent cure. One therapy that has shown promise is the so-called kick and kill method, in which latent HIV is activated and then attacked with a vaccine designed to induce a virus-destroying response.

A recent trial, published in The Lancet, compared the kick and kill approach plus ART with ART alone. The Research In Viral Eradication of HIV Reservoirs (RIVER) study, conducted by investigators at Imperial College London, Oxford University and other institutions, enrolled 60 adult men who were diagnosed with HIV within the past 6 months and began ART 1 month or less after diagnosis. Subjects were randomly divided into 2 arms, 1 receiving just ART and 1 receiving ART plus vorinostat—a drug providing the kick—and 2 vaccines aimed at eradicating HIV. Subjects had blood drawn at baseline and then at weeks 8, 12, 16, and 18, at 6 different trial sites across Britain, and were overwhelmingly adherent to their medication regimens.

The kick and kill plus ART recipients and the ART-only recipients all saw their HIV levels decrease by week 18. The estimated total mean HIV level by weeks 16 and 18 was 3.02 log₁₀ copies per 10⁶ CD4+ T cells in the men who were given ART only, and 3. 06 log₁₀ copies per 10⁶ CD4+ T cells in those who had ART along with the kick and kill medications, or a difference of about 9%.

Although evidence pointed to the kick and kill method yielding a potent anti-vaccine response, that response was not better than the response provoked by ART alone. “[T]here was no difference in any measures of the HIV reservoir between the ART-only and the ART+V+V [vaccine] treatment groups,” the researchers wrote in their report. “We were able to show evidence for an effect of both the kick (increased histone acetylation following vorinostat) and kill (enhanced functional T cell responses induced by vaccination) but found no change in measures of the HIV reservoir, which raises challenging questions.”

The authors noted that it’s possible a longer study period or different timing of the kick and kill medications would have yielded a different result, and considered that the HIV reservoirs in people who are newly diagnosed could react differently than those with chronic HIV, none of whom participated in the RIVER trial. They also acknowledged, with a caveat, that because of the lack of agreement on the best methods for measuring the latent HIV reservoir, stopping ART might be the only way to gain a true picture of the size of the reservoir: “Although, as of January 2020, there is a growing consensus that analytical treatment interruption can be done safely, there is some progress to unifying protocols to do this,” they wrote.

Despite the fact that the trial results did not yield the hoped-for outcome, the team emphasized that its work “helps to set the standard for how future trials might be done because of the new insights gained with regard to trial design, the inclusion of community representation, the need for better interventions, the necessity for clarity regarding the most relevant measures of the reservoir, and probably the use of an analytical treatment interruption approach.”