Shock-and-Kill Trial Falls Short

Research Question

One of the most studied paradigms to cure HIV is the so-called shock-and-kill approach, in which dormant HIV is “shocked” by a latency-reversing agent (LRA) into making copies of itself and thus alerting the immune system to its presence, while boosting the ability of the immune system to kill infected cells. To date, each component of this approach has shown lackluster performance. To test whether they would work better in combination, a group of researchers led by amfAR grantees Dr. Michel Nussenzweig and Ole Søgaard tested the putative LRA romidepsin with the antibody 3BNC117.

Findings

The clinical trial, named ROADMAP, was conducted in Denmark, Germany and the U.S., and included 20 participants. Nine were treated with romidepsin alone, at weeks 0, 1, 2, 8, 9 and 10 of the treatment phase, while the other 11 were treated with romidepsin and 3BNC117 administered at weeks 0 and 8. At the conclusion of all treatments, and a resting phase during which the treatment drugs washed out, participants stopped antiretroviral therapy during a closely monitored analytic treatment interruption (ATI). The time it took until virus rebounded was used as the main measure of the effect of the treatment on the reservoir – a longer delay to rebound corresponds to a greater decrease in the reservoir. The delay to rebound in the romidepsin-alone group was 28 days, and was greater than the delay in the romidepsin plus 3BNC117 group, which was 18 days. However, neither group showed a clinically meaningful delay to rebound.

Impact

The authors concluded that “latency reversal with a single histone deacetylase inhibitor [i.e., romidepsin] and modulation of autologous HIV-1-specific immunity by a single broadly neutralizing antibody is not sufficient to achieve HIV-1 remission in people on long-term suppressive ART.”

amfAR’s Role

amfAR was the main funder of this trial.

Original Article

https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(21)00239-1/fulltext

Update

At the Conference on Retroviruses and Opportunistic Infections in February 2022, results from a similar study called eCLEAR were presented. Participants were treated with romidepsin and 3BNC117, but in contrast to the ROADMAP study, 7 of 20 participants did not rebound during 84 days of ATI, and one participant has maintained control of his HIV for more than 3.7 years. The difference appears to be due to the duration of prior infection and antiretroviral therapy (ART). Participants in ROADMAP had been diagnosed and treated several years prior to the study, whereas those in eCLEAR were newly diagnosed and started ART at the same time they received study drugs. These results suggest that antibodies like 3BNC117 may have a greater effect on the reservoir earlier during infection, before the virus has broadly diversified.

Dr. Johnston is an amfAR vice president and director of research.

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