Combination of bNAb, romidepsin does not reduce HIV reservoir, delay viral rebound
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The combination of a latency-reversing agent, or LRA, and a potent broadly neutralizing antibody, or bNAb, designed to target the HIV-1 reservoir was determined to be safe for patients, but did not decrease the combined defective and intact HIV reservoir or delay viral rebound during analytical treatment interruption, according to findings from CROI 2020.
The study is the first reported trial using the combination of a latency-reversing agent and a potent bNAb designed to target the HIV-1 reservoir, according to the researchers.
“The study concept was based on the ‘shock and kill’ strategy and aimed to reduce the latent HIV reservoir in people on long-term antiretroviral therapy,” Ole Søgaard, MD, PhD, associate professor in the department of infectious diseases at Aarhus University Hospital in Denmark, told Healio. “Before this study was initiated, a pilot study had indicated that the [histone deacetylase] inhibitor romidepsin was a potent latency-reversing agent capable of demasking latently infected cells by turning on the transcription of proviral DNA in these cells. At the same time, a phase 1 study had demonstrated that the broadly neutralizing antibody 3BNC117 could reduce plasma virus in untreated individuals.”
Søgaard added that, in addition to reducing viremia, 3BNC117 also seemed to eliminate productively infected cells, which is something standard antiretroviral drugs cannot do. “Thus, we hypothesized that the administration of 3BNC117 prior to latency reversal with romidepsin could facilitate the elimination of latently infected cells and prolong time to viral rebound when the participants interrupted ART,” he said.
To test this, Søgaard and colleagues conducted a randomized phase Ib/IIa trial that included 20 adults with HIV-1 infection on long-term ART. Patients in group A were treated with 3BNC117 30 mg/kg 2 days before every romidepsin cycle; romidepsin 5 mg/m2 was given at weeks 0, 1 and 2 (cycle one) and weeks 8, 9 and 10 (cycle two). Patients in group B were treated with the cycles 1 and 2 of romidepsin, but did not receive 3BNC117. This was followed by an analytical treatment interruption, or ATI, at week 24, at which point the researchers expected bNAb levels to be low or undetectable.
The primary endpoint was time to viral rebound (200 copies/mL) during ATI. Secondary endpoints included safety, alterations in HIV-1 reservoir measures and the impact on HIV-1-specific immunity.
Overall, 19 of the 20 participants completed all of the treatment cycles (11 in group A and eight in group B). There were more men than women (17 vs. 3) and the median age of these patients was 44 years. The median number of CD4+ cells/mm3 was 645.
Two participants – one in each group – opted out of the ATI. Four participants in the romidepsin plus bNAb group (group A) had detectable viral blips (21-144 copies/mL) after romidepsin infusion, compared with three in group B. Additionally, unspliced HIV-1 RNA increased in most individuals after the second and third infusions in each romidepsin cycle. The researchers added that decrease in total HIV-1 DNA was 90 vs. 61 copies/106 CD4+ T cells for the romidepsin plus bNAb group (A) vs. the other group (B). The median time from interruption of ART to plasma HIV-1 RNA of 200 copies/mL or more during ATI was 2.5 weeks for group A vs. 4 weeks for group B.
“Although we did see evidence of latency reversal during romidepsin dosing, the magnitude of latency reversal as evidenced by changes in cell-associated HIV RNA and plasma HIV RNA were modest despite multiple administration of romidepsin,” Søgaard told Healio.
A total of 237 adverse events were recorded throughout the study, including 184 grade 1 events, 52 grade 2 events and 1 grade 3 event. Slightly more than a quarter of these events (27.4%; n = 64) were thought to “at least possibly” be related to the study drugs.
“The safety and tolerability of the interventions were relatively good and almost all of the possibly intervention-related side effect were mild to moderate,” Søgaard said.
The combination of “two potent interventions” was intended to activate and eliminate the latent HIV reservoir, he continued, but the researchers observed no strong positive impact of this intervention on either the size of the reservoir or the time to viral rebound during a subsequent treatment interruption.
“Thus, we conclude that latency reversal with currently available LRAs, despite the presence of potent antibodies against HIV, may not be very effective in reducing the latent reservoir among long-term suppressed patients,” Søgaard said. – by Caitlyn Stulpin
Reference
Søgaard O, et al. Abstract 38. Presented at: Conference on Retroviruses and Opportunistic Infections; March 8-11, 2020; Boston.
Disclosure: Søgaard reports no relevant financial disclosures.
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