Research In Viral Eradication of HIV Reservoirs
Condition: HIV
Intervention: Combination Antiretroviral Therapy (cART); Raltegravir; Vorinostat; ChAdV63.HIVconsv (ChAd); MVA.HIVconsv (MVA)
Intervention description: 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)
Intervention MeSH terms: Raltegravir Potassium; Anti-Retroviral Agents; Vorinostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 60.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: HIV; Vaccine; Cure; Early Intervention; Infection; Primary infection; Reservoir; Vorinostat; HDAC

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.

      .
    

Eligibility criteria:

        Inclusion criteria

          1. Aged ≥18 to ≤60 years old

          2. Able to give informed written consent including consent to long-term follow-up

          3. Should be enrolled within a maximum of 4 weeks of a diagnosis of primary HIV-1
             infection confirmed by one of the following criteria:

               1. Positive HIV-1 serology within a maximum of 12 weeks of a documented negative
                  HIV-1 serology test result (can include point of care test (POCT) using blood for
                  both tests)

               2. A positive p24 antigen result and a negative HIV antibody test

               3. Negative antibody test with either detectable HIV RNA or proviral DNA

               4. PHE RITA test algorithm (a) reported as "Incident" confirming the HIV-1 antibody
                  avidity is consistent with recent infection (within the preceding 16 weeks).

               5. Weakly reactive or equivocal 4th generation HIV antibody antigen test

               6. Equivocal or reactive antibody test with <4 bands on western blot

          4. Adequate haemoglobin (Hb≥12g/dL for males, ≥11g/dL for females)

          5. Weight ≥50kg

          6. Willing to be treated with cART (preferably including raltegravir) and be randomised
             to continue cART alone or cART plus intervention (HIV vaccines plus HDACi)

          7. Willing and able to comply with visit schedule and provide blood sampling

        Exclusion criteria

          1. Women of child bearing potential (WCBP) (b)

          2. In women with intact ovaries and no uterus, any planned egg donation anytime in the
             future to a surrogate

          3. Intention to donate sperm or father a child within 6 months of the intervention

          4. Co-infection with hepatitis B (surface antigen positive or detectable HBV DNA levels
             in blood) or hepatitis C (HCV RNA positive or HVC antigen positive)

          5. Any current or past history of malignancy

          6. Concurrent opportunistic infection or other comorbidity or comorbidity likely to occur
             during the trial e.g.past history of ischaemic or other significant heart disease,
             malabsorption syndromes, autoimmune disease

          7. Any contraindication to receipt of BHIVA recommended combination antiretrovirals

          8. HIV-2 infection

          9. Known HTLV-1 co-infection

         10. Prior immunisation with any experimental HIV Immunogens (including any component of
             the vaccines used in the RIVER protocol; simian or human adenoviral vaccine; other
             experimental HIV vaccines)

         11. Current or planned systemic immunosuppressive therapy (inhaled corticosteroids are
             allowed)

         12. Any history of proven thromboembolism (pulmonary embolism or deep vein thrombosis)

         13. Any inherited or acquired bleeding diathesis including gastric or duodenal ulcers,
             varices

         14. Concurrent or planned use of any drugs contraindicated with vorinostat i.e.
             antiarrhythmics; any other drugs that prolong QTc; warfarin, aspirin, sodium valproate

         15. Prior intolerance of any of either the components of the vaccine or HDACi,

         16. Uncontrolled diabetes mellitus defined as an HBA1C>7%

         17. Any congenital or acquired prolongation of the QTc interval, with normal defined as
             ≤0.44s (≤440ms)

         18. Participation in any other clinical trial of an experimental agent or any
             non-interventional study where additional blood draws are required; participation in
             an observational study is permitted

         19. Allergy to egg

         20. History of anaphylaxis or severe adverse reaction to vaccines

         21. Planned receipt of vaccines within 2 weeks of the first trial vaccination administered
             at PR week 00 (including vaccines such as yellow fever; hepatitis B, influenza)

         22. Abnormal blood test results at screening including:

               1. Moderate to severe hepatic impairment as defined by Child-Pugh classification

               2. ALT >5xULN

               3. Platelets <150x109/L

               4. eGFR <60 (c)

               5. uPCR >30 mg/mmol

         23. Physical and laboratory test findings: Evidence of organ dysfunction or any clinically
             significant deviation from normal in physical examination and/or vital signs that the
             investigator believes is a preclusion from enrolment into the study

         24. Active alcohol or substance use that, in the Investigator's opinion, will prevent
             adequate adherence with study requirements

         25. Insufficient venous access that will allow scheduled blood draws as per protocol

               1. using current cut-offs for optical density as defined by PHE

               2. females aged <20 years of age, and weighing <65kg and <168cm in height will need
                  to have an estimation of blood volume (EBV) prior to enrolment, >3500mL before to
                  participate. This circumstance is unlikely to arise as most women between the
                  ages of 18 to 20 years would be of child-bearing potential (CBP) and excluded on
                  that basis.

               3. eGFR is calculated by the local labs using CKD-EPI. Units ml/min/1.73m2.