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RIVER: Research In Viral Eradication of HIV Reservoirs

Sponsor
Imperial College London (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT02336074
Collaborator
Medical Research Council (Other), University of Oxford (Other), University of Cambridge (Other), Chelsea and Westminster NHS Foundation Trust (Other), Royal Free Hospital NHS Foundation Trust (Other), Brighton and Sussex University Hospitals NHS Trust (Other), Guy's and St Thomas' NHS Foundation Trust (Other), Central and North West London NHS Foundation Trust (Other)
60
Enrollment
6
Locations
2
Arms
83.6
Anticipated Duration (Months)
10
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief 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.

.

Condition or Disease Intervention/Treatment Phase
Phase 2

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
60 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Research In Viral Eradication of HIV Reservoirs
Actual Study Start Date :
Nov 27, 2015
Actual Primary Completion Date :
Nov 15, 2017
Anticipated Study Completion Date :
Nov 14, 2022

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Control

Combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed at week 0 for the duration of the study up to post-randomisation week 18 (42 weeks in total)

Drug: Combination Antiretroviral Therapy (cART)
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.

Drug: Raltegravir
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.
Other Names:
  • Isentress

    		•
    Experimental: Intervention

    Combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed at week 0 for the duration of the study up to post-randomisation week 18 (42 weeks in total) Plus ChAdV63.HIVconsv prime (post-randomisation week 00) and MVA.HIVconsv boost (post randomisation week 08 day 1) vaccines; followed by a 28-day course of vorinostat (10 doses in total).

    Drug: Combination Antiretroviral Therapy (cART)
    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.

    Drug: Raltegravir
    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.
    Other Names:
  • Isentress

    • Drug: Vorinostat
    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.

    Biological: ChAdV63.HIVconsv (ChAd)
    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.

    Biological: MVA.HIVconsv (MVA)
    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)

    Outcome Measures

    Primary Outcome Measures

    1. Total HIV DNA From CD4 T-cells [Averaged across post-randomisation week 16 and 18]

      The average of two measures taken at post-randomisation week 16 and 18

    Secondary Outcome Measures

    1. Clinical Adverse Events [From randomization to the final visit at week 18.]

      Clinical adverse events of any grade post-randomization.

    2. Quantitative Viral Outgrowth [At week 16]

      Number of Participants with undetectable quantitative viral outgrowth

    3. Percentage of CD4+ CD154+ IFNγ+ T Cells [12 weeks]

      Percentage of CD4+ CD154+ IFNγ+ T cells , assessed using an optimized and qualified flow cytometry panel.

    4. CD8+ T-cell Responses [12 weeks]

      Percentage of CD8+ CD107a+ IFNγ+ T cells , assessed using an optimized and qualified flow cytometry panel.

    5. Viral Inhibition [12 weeks]

      CD8+ T cell antiviral suppressive activity was expressed as percentage elimination and determined as follows: [(fraction of p24+ cells in CD4+ T cells cultured alone) - (fraction of p24 + in CD4+ T cells cultured with CD8+ cells)]/(fraction of p24+ cells in CD4+ T cells cultured alone) × 100. Viral inhibition Assay

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 60 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No

    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:

    4. 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)

    5. A positive p24 antigen result and a negative HIV antibody test

    6. Negative antibody test with either detectable HIV RNA or proviral DNA

    7. PHE RITA test algorithm (a) reported as "Incident" confirming the HIV-1 antibody avidity is consistent with recent infection (within the preceding 16 weeks).

    8. Weakly reactive or equivocal 4th generation HIV antibody antigen test

    9. Equivocal or reactive antibody test with <4 bands on western blot

    10. Adequate haemoglobin (Hb≥12g/dL for males, ≥11g/dL for females)

    11. Weight ≥50kg

    12. Willing to be treated with cART (preferably including raltegravir) and be randomised to continue cART alone or cART plus intervention (HIV vaccines plus HDACi)

    13. 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:

    23. Moderate to severe hepatic impairment as defined by Child-Pugh classification

    24. ALT >5xULN

    25. Platelets <150x109/L

    26. eGFR <60 (c)

    27. uPCR >30 mg/mmol

    28. 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

    29. Active alcohol or substance use that, in the Investigator's opinion, will prevent adequate adherence with study requirements

    30. Insufficient venous access that will allow scheduled blood draws as per protocol

    31. using current cut-offs for optical density as defined by PHE

    32. 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.

    33. eGFR is calculated by the local labs using CKD-EPI. Units ml/min/1.73m2.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Brighton and Sussex University Hospitals NHS Trust Brighton United Kingdom
    2 Central and North West London NHS Foundation Trust London United Kingdom
    3 Chelsea and Westminster NHS Foundation Trust London United Kingdom
    4 Guy's and St Thomas' NHS Foundation Trust London United Kingdom
    5 Imperial College Healthcare NHS Trust London United Kingdom
    6 Royal Free Hospital NHS Foundation Trust London United Kingdom

    Sponsors and Collaborators

    • Imperial College London
    • Medical Research Council
    • University of Oxford
    • University of Cambridge
    • Chelsea and Westminster NHS Foundation Trust
    • Royal Free Hospital NHS Foundation Trust
    • Brighton and Sussex University Hospitals NHS Trust
    • Guy's and St Thomas' NHS Foundation Trust
    • Central and North West London NHS Foundation Trust

    Investigators

    • Principal Investigator: Sarah Fidler, MD, Imperial College London

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Imperial College London
    ClinicalTrials.gov Identifier:
    NCT02336074
    Other Study ID Numbers:
    • CCT-NAPN-24772
    • 2014-001425-32
    First Posted:
    Jan 12, 2015
    Last Update Posted:
    Sep 20, 2021
    Last Verified:
    Aug 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Imperial College London
    HIV
    Vaccine
    Cure
    Early Intervention
    Infection
    Primary infection
    Reservoir
    Vorinostat
    HDAC
    Additional relevant MeSH terms:
    Raltegravir Potassium
    Anti-Retroviral Agents
    Vorinostat

    Study Results

    Participant Flow

    Recruitment Details Participants were recruited from 6 UK clinical sites. The recruitment period was from November 2015 until July 2017. Last patient last visit was completed in November 2017.
    Pre-assignment Detail Participants were recruited from two Strata: Recently diagnosed with primary HIV-1 infection - Eligible participants were enrolled at week 0 when combination ART (cART) began. Randomisation occurred at week 22 Previously diagnosed with primary HIV-1 infection - Randomisation occurred within 2 weeks of screening.
    Arm/Group Title Control Intervention
    Arm/Group Description Participants received combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed for the duration of the study Participants received combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed for the duration of the study Plus ChAdV63.HIVconsv prime (post-randomisation week 00) and MVA.HIVconsv boost (post randomisation week 08 day 1) vaccines; followed by a 28-day course of vorinostat (10 doses in total).
    Period Title: Overall Study
    STARTED 30 30
    COMPLETED 30 28
    NOT COMPLETED 0 2

    Baseline Characteristics

    Arm/Group Title Control (Arm A - ART Only) Intervention (Arm B - ART + Vaccines + Vorinostat) Total
    Arm/Group Description Combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed at week 0 for the duration of the study up to post-randomisation week 18 (42 weeks in total) Combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed at week 0 for the duration of the study up to post-randomisation week 18 (42 weeks in total) Plus ChAdV63.HIVconsv prime (post-randomisation week 00) and MVA.HIVconsv boost (post randomisation week 08 day 1) vaccines; followed by a 28-day course of vorinostat (10 doses in total). Total of all reporting groups
    Overall Participants 30 30 60
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    30
    100%
    30
    100%
    60
    100%
    >=65 years
    0
    0%
    0
    0%
    0
    0%
    Age (years) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [years]
    31
    35
    32
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    0
    0%
    0
    0%
    Male
    30
    100%
    30
    100%
    60
    100%
    Race/Ethnicity, Customized (Count of Participants)
    White
    16
    53.3%
    26
    86.7%
    42
    70%
    South Asian
    0
    0%
    1
    3.3%
    1
    1.7%
    South East Asian
    1
    3.3%
    0
    0%
    1
    1.7%
    Hispanic/Latino
    3
    10%
    2
    6.7%
    5
    8.3%
    Black Caribbean/American
    2
    6.7%
    0
    0%
    2
    3.3%
    Black African
    2
    6.7%
    0
    0%
    2
    3.3%
    Mixed ethnic group
    5
    16.7%
    1
    3.3%
    6
    10%
    Other
    1
    3.3%
    0
    0%
    1
    1.7%
    Mode of HIV Infection (Count of Participants)
    MSM
    26
    86.7%
    29
    96.7%
    55
    91.7%
    MSW
    1
    3.3%
    1
    3.3%
    2
    3.3%
    MSM + IDU
    2
    6.7%
    0
    0%
    2
    3.3%
    Unknown
    1
    3.3%
    0
    0%
    1
    1.7%
    CD4 at randomisation (cells/mm3) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [cells/mm3]
    694
    710
    708
    HIV RNA at randomisation (copies/ml) (Count of Participants)
    <50
    29
    96.7%
    30
    100%
    59
    98.3%
    50 - <200
    1
    3.3%
    0
    0%
    1
    1.7%
    Weeks since PHI diagnosis (Count of Participants)
    <= 1 week
    1
    3.3%
    0
    0%
    1
    1.7%
    >1 - 2 weeks
    3
    10%
    3
    10%
    6
    10%
    >2 - 3 weeks
    7
    23.3%
    7
    23.3%
    14
    23.3%
    >3 - 4 weeks
    15
    50%
    16
    53.3%
    31
    51.7%
    > 4 weeks
    4
    13.3%
    4
    13.3%
    8
    13.3%
    Weeks since PHI diagnosis (at randomisation) (weeks) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [weeks]
    28
    28
    28

    Outcome Measures

    1. Primary Outcome
    Title Total HIV DNA From CD4 T-cells
    Description The average of two measures taken at post-randomisation week 16 and 18
    Time Frame Averaged across post-randomisation week 16 and 18

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control (Arm A - ART Only) Intervention (Arm B - ART + Vaccines + Vorinostat)
    Arm/Group Description Combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed at week 0 for the duration of the study up to post-randomisation week 18 (42 weeks in total) Combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed at week 0 for the duration of the study up to post-randomisation week 18 (42 weeks in total) Plus ChAdV63.HIVconsv prime (post-randomisation week 00) and MVA.HIVconsv boost (post randomisation week 08 day 1) vaccines; followed by a 28-day course of vorinostat (10 doses in total).
    Measure Participants 30 30
    Mean (Standard Deviation) [HIV-DNA copies/mill CD4+ T cells (log10)]
    2.95
    (0.50)
    3.06
    (0.49)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Control (Arm A - ART Only), Intervention (Arm B - ART + Vaccines + Vorinostat)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.26
    Comments Treatment arms were compared in terms of absolute total HIV DNA levels (on a log10-scale) at post-randomization weeks 16 and 18 adjusted for the baseline (i.e. randomization) level and by stratum.
    Method Regression, Linear
    Comments
    2. Secondary Outcome
    Title Clinical Adverse Events
    Description Clinical adverse events of any grade post-randomization.
    Time Frame From randomization to the final visit at week 18.

    Outcome Measure Data

    Analysis Population Description
    All participants randomized
    Arm/Group Title Control (Arm A - ART Only) Intervention (Arm B - ART + Vaccines + Vorinostat)
    Arm/Group Description Combination Antiretroviral Therapy (cART): 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. Raltegravir: 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. ART plus vaccines plus vorinostat Combination Antiretroviral Therapy (cART): 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. Raltegravir: 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: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDA
    Measure Participants 30 30
    Not had any event
    8
    26.7%
    1
    3.3%
    Did have any event
    22
    73.3%
    29
    96.7%
    3. Secondary Outcome
    Title Quantitative Viral Outgrowth
    Description Number of Participants with undetectable quantitative viral outgrowth
    Time Frame At week 16

    Outcome Measure Data

    Analysis Population Description
    All participants randomized with valid assay results at week 16.
    Arm/Group Title Control (Arm A - ART Only) Intervention (Arm B - ART + Vaccines + Vorinostat)
    Arm/Group Description ART only Combination Antiretroviral Therapy (cART): 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. Raltegravir: 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. ART plus vaccines plus vorinostat Combination Antiretroviral Therapy (cART): 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. Raltegravir: 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: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDA
    Measure Participants 29 27
    Number [Participants with undetectable outgrowth]
    12
    40%
    6
    20%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Control (Arm A - ART Only), Intervention (Arm B - ART + Vaccines + Vorinostat)
    Comments Comparison of the proportion of patients with undetectable viral outgrowth using logistic regression. The analysis was adjusted for stratum and baseline viral outgrowth. Missing baseline values were imputed.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.145
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.41
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Percentage of CD4+ CD154+ IFNγ+ T Cells
    Description Percentage of CD4+ CD154+ IFNγ+ T cells , assessed using an optimized and qualified flow cytometry panel.
    Time Frame 12 weeks

    Outcome Measure Data

    Analysis Population Description
    All participants randomized with valid assay results
    Arm/Group Title Control (Arm A - ART Only) Intervention (Arm B - ART + Vaccines + Vorinostat)
    Arm/Group Description ART only Combination Antiretroviral Therapy (cART): 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. Raltegravir: 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. ART plus vaccines plus vorinostat Combination Antiretroviral Therapy (cART): 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. Raltegravir: 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: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDA
    Measure Participants 27 30
    Post randomisation week 9
    0.006
    0.097
    Post randomisation week 12
    0.006
    0.109
    5. Secondary Outcome
    Title CD8+ T-cell Responses
    Description Percentage of CD8+ CD107a+ IFNγ+ T cells , assessed using an optimized and qualified flow cytometry panel.
    Time Frame 12 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control (Arm A - ART Only) Intervention (Arm B - ART + Vaccines + Vorinostat)
    Arm/Group Description ART only Combination Antiretroviral Therapy (cART): 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. Raltegravir: 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. ART plus vaccines plus vorinostat Combination Antiretroviral Therapy (cART): 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. Raltegravir: 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: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDA
    Measure Participants 27 30
    Post randomisation week 9
    0.052
    0.194
    Post randomisation week 12
    0.062
    0.263
    6. Secondary Outcome
    Title Viral Inhibition
    Description CD8+ T cell antiviral suppressive activity was expressed as percentage elimination and determined as follows: [(fraction of p24+ cells in CD4+ T cells cultured alone) - (fraction of p24 + in CD4+ T cells cultured with CD8+ cells)]/(fraction of p24+ cells in CD4+ T cells cultured alone) × 100. Viral inhibition Assay
    Time Frame 12 weeks

    Outcome Measure Data

    Analysis Population Description
    All participants randomized with valid assay results
    Arm/Group Title Control (Arm A - ART Only) Intervention (Arm B - ART + Vaccines + Vorinostat)
    Arm/Group Description ART only Raltegravir: 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. ART plus vaccines plus vorinostat Combination Antiretroviral Therapy (cART): 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. Raltegravir: 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: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDA
    Measure Participants 27 30
    Mean (95% Confidence Interval) [Percentage elimination]
    -18.25
    1.50
    7. Post-Hoc Outcome
    Title Histone H4 Acetylation
    Description Histone H4 acetylation using a H4K5/8/12/16 immunoassay with thawed PBMC derived cell lysates added to an ELISA using anti-H4 monoclonal antibody
    Time Frame 12 weeks

    Outcome Measure Data

    Analysis Population Description
    Intervention arm only - histone H4 acetylation was only measured in participants in the intervention arm with the aim to compare values approximately 2 hours post vorinostat intake with values pre vorinostat intake. No data were collected from participants in the control arm.
    Arm/Group Title Intervention (Arm B - ART + Vaccines + Vorinostat)
    Arm/Group Description ART plus vaccines plus vorinostat Combination Antiretroviral Therapy (cART): 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. Raltegravir: 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: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDA
    Measure Participants 22
    Mean (95% Confidence Interval) [Fold increase pre to post vorinostat]
    3.19

    Adverse Events

    Time Frame 18 weeks
    Adverse Event Reporting Description
    Arm/Group Title Control Intervention
    Arm/Group Description ART only Combination ART (cART) preferably including raltegravir (control) ART plus vaccines plus vorinostat Combination ART (cART) preferably including raltegravir* plus ChAdV63.HIVconsv (ChAd) prime and MVA.HIVconsv (MVA) boost vaccines; followed by a 28-day course of vorinostat (10 doses in total).
    All Cause Mortality
    Control Intervention
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/30 (0%) 0/30 (0%)
    Serious Adverse Events
    Control Intervention
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/30 (0%) 1/30 (3.3%)
    Vascular disorders
    Vasovagal syncope 0/30 (0%) 0 1/30 (3.3%) 1
    Other (Not Including Serious) Adverse Events
    Control Intervention
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 6/30 (20%) 1/30 (3.3%)
    Hepatobiliary disorders
    Acute hepatitis A 1/30 (3.3%) 1 0/30 (0%) 0
    Infections and infestations
    Influenza 1/30 (3.3%) 1 0/30 (0%) 0
    Shingles 1/30 (3.3%) 1 0/30 (0%) 0
    Injury, poisoning and procedural complications
    Wrist injury 1/30 (3.3%) 1 0/30 (0%) 0
    Musculoskeletal and connective tissue disorders
    Back pain 1/30 (3.3%) 1 1/30 (3.3%) 1
    Skin and subcutaneous tissue disorders
    Proctitis herpes 1/30 (3.3%) 1 0/30 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The NHS Organisations shall not publish or otherwise disseminate conclusions of the Study, including all or any part of the Results of the Study without prior written consent of the Sponsor, such consent not to be unreasonably withheld or delayed.

    Results Point of Contact

    Name/Title Professor Sarah Fidler
    Organization Imperial College London
    Phone 004420331 ext 26790
    Email s.fidler@imperial.ac.uk
    Responsible Party:
    Imperial College London
    ClinicalTrials.gov Identifier:
    NCT02336074
    Other Study ID Numbers:
    • CCT-NAPN-24772
    • 2014-001425-32
    First Posted:
    Jan 12, 2015
    Last Update Posted:
    Sep 20, 2021
    Last Verified:
    Aug 1, 2021