Research In Viral Eradication of HIV Reservoirs

Overview

This study will be a two-arm prospective 1:1 randomised controlled trial comparing: Arm A: cART preferably including raltegravir (combination ART cART - control) Arm B: cART preferably including raltegravir (cART) plus ChAdV63.HIVconsv (ChAd) prime and MVA.HIVconsv (MVA) boost vaccines; followed by a 28-day course of vorinostat (10 doses in total). We hypothesise that this intervention in primary HIV infection will confer a significant reduction in the latent HIV reservoir when compared with cART alone. .

The study design is a two-arm, open label randomised study. Eligible participants are recruited from two participant cohorts (Cohort I - Recently diagnosed or Cohort II - Previously diagnosed with HIV). All participants receive combination ART (cART) for the duration of the intervention phase of the study (Cohort I: 42 weeks, Cohort II: 18 weeks). In patients meeting the criteria for randomisation (eligibility assessed at week 22/screening), participants will either continue cART or receive an intervention consisting of two anti-HIV vaccines separated by 8 weeks followed by 10 doses of the HDACi, vorinostat, in addition to cART. We hypothesise that the prime-boost vaccination will result in the generation of vaccine induced HIV specific CTLs that will recognise HDACi-activated cells of the HIV reservoir and destroy them. The net effect will be a greater reduction in the HIV reservoir defined as HIV total DNA in CD4+ T-cells in the cART+vaccine+HDACi compared to the cART alone. Our strategy is entirely different from previous therapeutic vaccination approaches which have been largely unsuccessful. Immunological priming to conserved HIV proteins will drive CD8+ T-lymphocyte recognition of latently-infected cells rendered immunogenic by HDACi. We anticipate that the viral antigens expressed by latently-infected cells will be unable to adapt to, or escape from, the immune response as they will be expressed directly from chromosomal DNA, avoiding the steps of the viral life-cycle that facilitate immune-driven adaptation. We have chosen a prime-boost immunisation strategy with recombinant replication-defective chimpanzee adenovirus and modified vaccinia Ankara vectors, bearing conserved HIV antigens; these products have been shown to induce high titres of HIV-specific CD8+ T-cells. In addition, these vaccines will drive immune responses against conserved regions of the virus that may be well preserved in individuals with PHI. Primary HIV Infection (PHI) is a unique period when HIV proviral reservoir is smaller than in chronic disease, is likely to be more homogeneous than in later stage disease and hence is more susceptible to immunological elimination. This provides an opportunity to use a vaccine to re-direct HIV-specific immune responses towards genetically fragile regions in the viral proteome. Immunisation in PHI should result in potent immune responses because ART initiated in PHI preserves CD4 function and early ART-mediated viral suppression limits viral diversification, reducing the chance of immune escape. The other key reason for conducting this trial in patients treated in PHI is that, in some patients, an early sustained course of ART started very early in infection may induce a state of viral remission in which therapy can be stopped without any rebound viraemia. This has been most notably reported in the VISCONTI cohort in which 'post-treatment control' was identified in 15.6% of selected individuals. Data from our group and others has shown that whilst there is a rapid decline in measures of total HIV DNA following ART initiation up to 6 months after seroconversion this then plateaus out to approximately 2 years after diagnosis of acute infection. Hence randomisation of individuals starting immediate ART in acute infection have comparable levels of HIV reservoirs to those who have started treatment within a similar timeframe, but have remained on suppressive therapy for up to 2 years after initiation. Furthermore, since the primary endpoint of the RIVER study design compares total HIV DNA between the two arms from randomisation to post-randomisation weeks 16 \& 18 Cohorts I and II will be comparable. We hypothesise that the combination of HDACi with immunisation in cART-suppressed PHI will significantly impact the HIV reservoir. 1. Patients in Cohort I - Recently diagnosed will receive combination antiretroviral therapy designed to reduce the plasma viral load as quickly as possible, hence the rationale for the preferred inclusion of raltegravir, an integrase inhibitor. Both cohorts will have been treated in PHI, which may restrict the size of the reservoir compared with people initiating ART in later stages of HIV infection. Cohort II - Previously diagnosed participants are screened the same as Cohort I and are maintained on ART throughout the study. The ART regimen is preferably a combination that includes raltegravir, as hypothetically, if vorinostat induced viral transcription an integrase inhibitor may protect uninfected cells. However, there is no evidence to support this hypothesis and the key inclusion criteria must be the continuation of a virally suppressive ART regimen throughout the study. 2. The prime-boost vaccination is designed to enhance the killing capacity of the cytotoxic T cells. This must be given before the HDACi in order to prime and boost a maximal HIV-specific T-cell response to recognise activated viral antigen expression on reservoir cells. 3. The HDACi is designed to cause viral transcription from latently infected cells; activate the reservoir, and in the presence of the enhanced killing capacity of the CD8+ T cells, results in killing of the cells previously harbouring latent virus, leading to further reductions in the reservoir. This exact combined approach in treated PHI has never previously been used, we hypothesise there will be a 50% reduction in the proviral DNA (the 'reservoir'), in this 'proof-of-concept' study, in those randomised to the vaccine-HDACi intervention compared to those receiving antiretroviral therapy alone.

Conditions

Interventions

Eligibility

Locations (6)

Outcomes