Antiretroviral therapy alone versus antiretroviral therapy with a kick and kill approach, on measures of the HIV reservoir in participants with recent HIV infection (the RIVER trial): a phase 2, randomised trial

Abstract

kill' strategy, for future trials significant enhancement of both 'kick' and 'kill' agents will be required. Research in context panel Evidence before this study This randomised clinical trial was designed to test the concept of 'kick and kill' as a strategy to achieve a cure for HIV infection. Prior to this study, there was evidence from in vitro and single arm clinical studies that the histone deacetylase inhibitor (HDACi) class of drugs could induce viral transcription from latently infected cells, potentially creating a target for the immune system. In conjunction with this 'kick' to the latent HIV reservoir there was evidence that T cell immunitywhich determines HIV disease progression-could be enhanced through vaccination-induced responses, providing the 'kill'. Although the strategy of 'kick and kill' looked promising, there had been no powered RCTs to test it. Added value of the study RIVER tested 'kick and kill' using the HDACi vorinostat as the 'kick' combined with a vaccine strategy targeting conserved regions of the HIV genome. The vaccine aimed to produce T cells to kill latently-infected cells in which viral transcription had been induced by the HDACi. RIVER showed that the intervention was safe, with outstanding adherence to the complex trial protocol by the participants. However, even though there was evidence for both increased histone acetylation and potent vaccine-induced T-cell responses, the intervention did not confer any additional benefit on any measures of the HIV reservoir compared with antiretroviral therapy alone. Implications of all the available evidence. RIVER was the first RCT in treated recent HIV infection, and was not able to show any impact of 'kick and kill' on the primary outcome measure, or any marker of the HIV reservoir size. This is consistent with other studies which had tested HDACi alone. We did not, however, stop antiretroviral therapy in the RIVER trial participants, and future studies may include a treatment interruption as a further measure of impact. Whilst the RIVER trial suggests that this specific 'kick and kill' approach may not be an effective approach towards achieving HIV cure, the overall principle can not yet be dismissed, as more potent future interventions may have a greater impact.

HIVconsv Vaccines and Romidepsin in Early-Treated HIV-1-Infected Individuals: Safety, Immunogenicity and Effect on the Viral Reservoir (Study BCN02)

“…HIVconsv immunogen consists of a chimeric protein assembled from 14 highly conserved domains derived from HIV-1 genes Gag, Pol, Vif, and Env alternating, for each domain, the consensus sequence of the four major HIV-1 clades A, B, C, and D (12). Upon delivery to both HIV-1-negative and positive individuals by heterologous prime/boost regimens as DNA or in simian adenovirus of chimpanzee (ChAdV) and poxvirus MVA vectors, HIVconsv vaccines were safe and induced CD8 + T cells with broad inhibitory capacity of HIV-1 in vitro, but showed no effect on the viral reservoir (16)(17)(18)(19)(20)(21)(22)(23).…”

Specificity of CD8+ T-Cell Responses Following Vaccination with Conserved Regions of HIV-1 in Nairobi, Kenya

“…The GRIN immunogen was a fusion of full-length Gag, Reverse Transcriptase (RT), Integrase and Nef, and was delivered by replication-deficient human adenovirus serotype 35 (Ad35-GRIN or A) [ 66 , 67 ]. Ad35-GRIN substituted for the simian adenovirus serotype 63-vectored HIVconsv vaccine used in previous trials [ 50 , 56 , 57 , 58 , 59 ], to which we lost freedom to operate following GlaxoSmithKline acquisition of the ChAdV63 vaccine vector. GRIN had an extensive sequence match to HIVconsv as GRIN covered almost 80% of all HIVconsv ( Figure 1 ) [ 60 ].…”

“…In contrast, our working hypothesis postulates that focusing vaccine-elicited T cells on the functionally conserved regions of HIV-1, which are common to most global variants and are hard to mutate, will be effective in slowing and controlling HIV-1 infection [ 41 , 42 , 43 , 50 , 51 , 52 , 53 , 54 , 55 ]. These regions contain epitopes typically subdominant in natural HIV-1 infection, but are capable of inducting robust T-cell responses when delivered by a potent vaccination regimen [ 50 , 56 , 57 , 58 , 59 , 60 ]. Such vaccine-elicited responses thus represent a rich source of previously undescribed, potentially important epitopes [ 61 , 62 , 63 ].…”

Induction of selective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir

“…However, dependency on cell-mediated and humoral immune responses that are already compromised in HIV-infected individuals because of impaired CD4+ T cell help and exhausted immune compartments poses a considerable obstacle to these strategies. Indeed, early results from combinatorial clinical trials which combine LRAs and immune-enhancing clearance strategies demonstrated that although HIV-1-specific immune responses were induced, no decrease in the size of viral reservoir or viral control in the absence of cART were observed (8)(9)(10) , reviewed in 11 ).…”