No success for kick-and-kill strategy in HIV-infected persons

ROADMAP study showed that a kick-and-kill strategy with the HDAC inhibitor romidepsin and the bNAb 3BNC117 proved to be ineffective in 20 patients with chronic HIV infection under long-term ART.

HIV healing strategies for ongoing ART must be further optimized

A kick-and-kill strategy with the histone deacetylase (HDAC) inhibitor romidepsin and the broad neutralizing antibody (bNAb) 3BNC117 proved to be ineffective in 20 patients with chronic HIV infection under long-term antiretroviral therapy (ART). This was the result of the ROADMAP study presented by Ole Schmelz Søgaard, University of Aarhus, Denmark, at the virtual CROI in March 2020.

The “kick-and-kill” strategy is designed to awaken latent HIV reservoirs in the body from dormancy by a so-called "kick" so that the virus-producing cells can then be “killed”.

In order to "wake" cells from their latency, HDAC inhibitors such as vorinostat or panobinostat, which are already used in the treatment of tumors, were used. However, investigations with these two HDAC inhibitors have not been very successful so far, so that the HDAC inhibitor romidepsin was used in the ROADMAP study. In a pilot study, this inhibitor was used to measurably activate HI viruses from latency in 5 of 6 immunosuppressed patients. In November 2012, the EMA had not granted romidepsin with an approval for the treatment of peripheral T-cell lymphoma.

Romidepsin plus 3BNC117

In the ROADMAP study, the bNAb 3BNC117 was used as a killing strategy, which had also shown favorable results in pilot studies. 3BNC117 facilitated the elimination of cells that carried viral envelope (Env) protein on their surface. In untreated patients, it suppressed viremia and in patients who interrupted their ART, it delayed the time to viral rebound.

In the Phase Ib/IIa ROADMAP study, the administration of romidepsin alone compared to romidepsin + 3BNC117 was investigated in 20 HIV patients on ART. The combination group received 3BNC117 (30 mg/kg) 2 days prior to each cycle of romidepsin in which romidepsin (5 mg/m2) was administered at week 0, 1, and 2 (cycle 1) and at week 8, 9, and 10 (cycle 2). The control group received only 2 romidepsin cycles. In week 24 there was an analytical therapy interruption (ATI).

The primary endpoint was the time to viral rebound (≥ 200 copies/ml) during ATI. Secondary endpoints included tolerability, changes in HIV reservoir and effects on HIV-1 specific immunity.

Of the 20 patients included (3 women, 17 men, median age 44 years), 19  underwent all treatment cycles, 11 in the combination group and 8 in the monotherapy group.

Sobering results

However, the results were sobering, the “kick-and-kill” strategy had no effect. Despite the repeated administration of romidepsin, there was only a small increase in viral RNA and the viral reservoir was not reduced. The time until the viral load in ATI increased again was not changed and no HIV-specific immune response was induced. Romidepsin also had no negative influence on the pre-existing HIV-specific immune response.

This leads to the conclusion: "Reversal of latency with currently available LRA (latency reversal agents) and boosting of autologous HIV-specific immunity does not seem to be very effective in long-term suppressed HIV patients". Due to these negative results, HIV-healing strategies need to be further optimized with ongoing ART.

Source:
Schmelz Sogaard O, et al A randomized trial of the impact of 3BNC117 and Romidepsin on the HIV-1 reservoir. Virtual CROI 2020, Abstract 38. http://www.croiconference.org/sessions/randomized-trial-impact-3bnc117-and-romidepsin-hiv-1-reservoir

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