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Research In Viral Eradication of HIV Reservoirs (RIVER)

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ClinicalTrials.gov Identifier: NCT02336074
Recruitment Status : Active, not recruiting
First Posted : January 12, 2015
Results First Posted : September 25, 2019
Last Update Posted : March 17, 2020
Sponsor:
Collaborators:
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
Information provided by (Responsible Party):
Imperial College London

Tracking Information
First Submitted Date  ICMJE October 23, 2014
First Posted Date  ICMJE January 12, 2015
Results First Submitted Date  ICMJE June 24, 2019
Results First Posted Date  ICMJE September 25, 2019
Last Update Posted Date March 17, 2020
Actual Study Start Date  ICMJE November 27, 2015
Actual Primary Completion Date November 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 27, 2016)		 Total HIV DNA From CD4 T-cells [ Time Frame: Averaged across post-randomisation week 16 and 18 ]
The average of two measures taken at post-randomisation week 16 and 18
Original Primary Outcome Measures  ICMJE
 (submitted: January 7, 2015)		 Total HIV DNA From CD4 T-cells [ Time Frame: Averaged across week 40 and 42 ]
The average of two measures taken at week 40 and 42
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 22, 2019)
  • Clinical Adverse Events [ Time Frame: From randomization to the final visit at week 18. ]
    Clinical adverse events of any grade post-randomization.
  • Quantitative Viral Outgrowth [ Time Frame: At week 16 ]
    Number of Participants with undetectable quantitative viral outgrowth
  • Percentage of CD4+ CD154+ IFNγ+ T Cells [ Time Frame: 12 weeks ]
    Percentage of CD4+ CD154+ IFNγ+ T cells , assessed using an optimized and qualified flow cytometry panel.
  • CD8+ T-cell Responses [ Time Frame: 12 weeks ]
    Percentage of CD8+ CD107a+ IFNγ+ T cells , assessed using an optimized and qualified flow cytometry panel.
  • Viral Inhibition [ Time Frame: 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
Original Secondary Outcome Measures  ICMJE
 (submitted: January 7, 2015)
  • Clinical and laboratory adverse events [ Time Frame: 42 weeks ]
  • Further assessment of the HIV reservoir [ Time Frame: 42 weeks ]
    Further assessment of the HIV reservoir e.g. HIV integrated DNA; HIV cell associated RNA; plasma HIV RNA measured with an ultra-low copy assay i.e. with a threshold of <1 copy/ml and viral outgrowth assays.
  • Studies of immune function [ Time Frame: 42 weeks ]
    Studies of immune function including measuring the latently-infected resting memory T-cells and cytotoxic immune responses
  • Changes in plasma IL-6 (an inflammatory biomarker) [ Time Frame: 42 weeks ]
    Effectiveness of the treatment will be assessed by monitoring the levels of IL-6, an inflammatory biomarker
  • Changes in plasma hCRP (an inflammatory biomarker) [ Time Frame: 42 Weeks ]
    Effectiveness of the treatment will be assessed by monitoring the levels of hCRP, an inflammatory biomarker
  • Changes in plasma TNF-alpha (an inflammatory biomarker) [ Time Frame: 42 Weeks ]
    Effectiveness of the treatment will be assessed by monitoring the levels of TNF-alpha, an inflammatory biomarker
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Research In Viral Eradication of HIV Reservoirs
Official Title  ICMJE Research In Viral Eradication of HIV Reservoirs
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.

.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE HIV
Intervention  ICMJE
  • 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 Name: 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)
Study Arms  ICMJE
  • 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)
    Interventions:
    • Drug: Combination Antiretroviral Therapy (cART)
    • Drug: Raltegravir
  • 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).
    Interventions:
    • Drug: Combination Antiretroviral Therapy (cART)
    • Drug: Raltegravir
    • Drug: Vorinostat
    • Biological: ChAdV63.HIVconsv (ChAd)
    • Biological: MVA.HIVconsv (MVA)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 28, 2018)		 60
Original Estimated Enrollment  ICMJE
 (submitted: January 7, 2015)		 52
Estimated Study Completion Date  ICMJE November 2022
Actual Primary Completion Date November 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02336074
Other Study ID Numbers  ICMJE CCT-NAPN-24772
2014-001425-32 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Imperial College London
Study Sponsor  ICMJE Imperial College London
Collaborators  ICMJE
  • 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  ICMJE
Principal Investigator: Sarah Fidler, MD Imperial College London
PRS Account Imperial College London
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP