Research In Viral Eradication of HIV Reservoirs
Condition: HIV
Study type: Interventional
Phase: Phase 2

Summary: 
      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.

      .
    

Detailed description: 
      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.
    

Intervention name(s): Combination Antiretroviral Therapy (cART); Raltegravir; Vorinostat; ChAdV63.HIVconsv (ChAd); MVA.HIVconsv (MVA)
Intervention type(s): Drug; Drug; Drug; Biological; Biological
Intervention description(s): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study.; All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.; Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDAC3 (Class I) and HDAC6 (Class II).
Vorinostat is supplied as capsules containing 100mg vorinostat and the following inactive ingredients: microcrystalline cellulose, sodium croscarmellose and magnesium stearate.; Dosage: 5x1010vp .This dose is obtained by injecting 0.37ml of the vaccine at 1.35x1011vp/ml without dilution. This prime vaccination is administered intramuscularly (IM) into the deltoid muscle of the non-dominant arm at post-randomisation week 00.; Dosage: 2x108pfu Administration: This dose is obtained by injecting 0.23 ml of the vaccine IM at 8.6x108pfu/ml without dilution. This boost vaccination is administered intramuscularly (IM) into the deltoid muscle of the non-dominant arm at post-randomisation week 08 Day 1 (2 prior to start of vorinostat)
Other intervention name(s): Isentress
Intervention MeSH terms: Raltegravir Potassium; Anti-Retroviral Agents; Vorinostat
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: HIV; Vaccine; Cure; Early Intervention; Infection; Primary infection; Reservoir; Vorinostat; HDAC