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HIVPhase 2RIVERNCT02336074

Research In Viral Eradication of HIV Reservoirs

A Phase 2 study testing Combination Antiretroviral Therapy (cART), Raltegravir and Vorinostat in people with HIV, run by Imperial College London at 6 sites in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 60 years
Conditions the study is for
HIV
What is being tested?
Combination Antiretroviral Therapy (cART), Raltegravir and Vorinostat
Could I receive a placebo?
No, everyone receives an active treatment
How many people
60 participants
Where
6 sitesUnited Kingdom
Study dates
27 Nov 2015to 31 Mar 2023
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 60 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • Aged ≥18 to ≤60 years old
  • Able to give informed written consent including consent to long-term follow-up
  • Should be enrolled within a maximum of 4 weeks of a diagnosis of primary HIV-1 infection confirmed by one of the following criteria:
  • 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)
  • A positive p24 antigen result and a negative HIV antibody test
  • Negative antibody test with either detectable HIV RNA or proviral DNA
Show all 13Show fewer
  • PHE RITA test algorithm (a) reported as "Incident" confirming the HIV-1 antibody avidity is consistent with recent infection (within the preceding 16 weeks).
  • Weakly reactive or equivocal 4th generation HIV antibody antigen test
  • Equivocal or reactive antibody test with <4 bands on western blot
  • Adequate haemoglobin (Hb≥12g/dL for males, ≥11g/dL for females)
  • Weight ≥50kg
  • Willing to be treated with cART (preferably including raltegravir) and be randomised to continue cART alone or cART plus intervention (HIV vaccines plus HDACi)
  • Willing and able to comply with visit schedule and provide blood sampling

Who cannot join

  • Women of child bearing potential (WCBP) (b)
  • In women with intact ovaries and no uterus, any planned egg donation anytime in the future to a surrogate
  • Intention to donate sperm or father a child within 6 months of the intervention
  • 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)
  • Any current or past history of malignancy
  • 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
Show all 33Show fewer
  • Any contraindication to receipt of BHIVA recommended combination antiretrovirals
  • HIV-2 infection
  • Known HTLV-1 co-infection
  • 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)
  • Current or planned systemic immunosuppressive therapy (inhaled corticosteroids are allowed)
  • Any history of proven thromboembolism (pulmonary embolism or deep vein thrombosis)
  • Any inherited or acquired bleeding diathesis including gastric or duodenal ulcers, varices
  • Concurrent or planned use of any drugs contraindicated with vorinostat i.e. antiarrhythmics; any other drugs that prolong QTc; warfarin, aspirin, sodium valproate
  • Prior intolerance of any of either the components of the vaccine or HDACi,
  • Uncontrolled diabetes mellitus defined as an HBA1C>7%
  • Any congenital or acquired prolongation of the QTc interval, with normal defined as ≤0.44s (≤440ms)
  • 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
  • Allergy to egg
  • History of anaphylaxis or severe adverse reaction to vaccines
  • 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)
  • Abnormal blood test results at screening including:
  • Moderate to severe hepatic impairment as defined by Child-Pugh classification
  • ALT >5xULN
  • Platelets <150x109/L
  • eGFR <60 (c)
  • uPCR >30 mg/mmol
  • 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
  • Active alcohol or substance use that, in the Investigator's opinion, will prevent adequate adherence with study requirements
  • Insufficient venous access that will allow scheduled blood draws as per protocol
  • using current cut-offs for optical density as defined by PHE
  • 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.
  • eGFR is calculated by the local labs using CKD-EPI. Units ml/min/1.73m2.

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

United Kingdom6 sites

  • Brighton and Sussex University Hospitals NHS Trust

    Brighton

  • Central and North West London NHS Foundation Trust

    London

  • Chelsea and Westminster NHS Foundation Trust

    London

  • Guy's and St Thomas' NHS Foundation Trust

    London

  • Imperial College Healthcare NHS Trust

    London

  • Royal Free Hospital NHS Foundation Trust

    London

Other trials in United Kingdom

About this study

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.

.

Read the 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.

Conditions
HIV
Being tested
Combination Antiretroviral Therapy (cART), Raltegravir, Vorinostat, ChAdV63.HIVconsv (ChAd), MVA.HIVconsv (MVA)
Keywords
HIV, Vaccine, Cure, Early Intervention, Infection, Primary infection, Reservoir, Vorinostat, HDAC
Medical subject headings
Infections

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Combination Antiretroviral Therapy (cART)Drug

    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.

  • RaltegravirDrug

    Also called Isentress

    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.

  • VorinostatDrug

    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.

  • ChAdV63.HIVconsv (ChAd)Biological

    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.

  • MVA.HIVconsv (MVA)Biological

    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 groups in NCT02336074
Study groupRoleWhat they receive
ControlActive comparatorCombination 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)
Receives: Drug: Combination Antiretroviral Therapy (cART); Drug: Raltegravir
InterventionExperimentalCombination 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).
Receives: Drug: Combination Antiretroviral Therapy (cART); Drug: Raltegravir; Drug: Vorinostat; Biological: ChAdV63.HIVconsv (ChAd); Biological: MVA.HIVconsv (MVA)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Total HIV DNA From CD4 T-cells

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

    Measured: Averaged across post-randomisation week 16 and 18

Secondary outcomes (5)

  1. Clinical Adverse Events

    Clinical adverse events of any grade post-randomization.

    Measured: From randomization to the final visit at week 18.

  2. Quantitative Viral Outgrowth

    Number of Participants with undetectable quantitative viral outgrowth

    Measured: At week 16

  3. Percentage of CD4+ CD154+ IFNγ+ T Cells

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

    Measured: 12 weeks

  4. CD8+ T-cell Responses

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

    Measured: 12 weeks

  5. Viral Inhibition

    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

    Measured: 12 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Jan 2015 (estimated)
  2. Study start27 Nov 2015
  3. Primary completion15 Nov 2017
  4. Study completion31 Mar 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
60 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02336074
Sponsor's protocol ID
CCT-NAPN-24772
Other IDs
2014-001425-32, 2014
Acronym
RIVER
Status last verified
Oct 2023
First submitted
23 Oct 2014
Last updated
23 Oct 2023
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • International AIDS Society Scientific Working Group on HIV Cure; Deeks SG, Autran B, Berkhout B, Benkirane M, Cairns S, Chomont N, Chun TW, Churchill M, Di Mascio M, Katlama C, Lafeuillade A, Landay A, Lederman M, Lewin SR, Maldarelli F, Margolis D, Markowitz M, Martinez-Picado J, Mullins JI, Mellors J, Moreno S, O'Doherty U, Palmer S, Penicaud MC, Peterlin M, Poli G, Routy JP, Rouzioux C, Silvestri G, Stevenson M, Telenti A, Van Lint C, Verdin E, Woolfrey A, Zaia J, Barre-Sinoussi F. Towards an HIV cure: a global scientific strategy. Nat Rev Immunol. 2012 Jul 20;12(8):607-14. doi: 10.1038/nri3262.

    PubMed 22814509

  • Rasmussen TA, Schmeltz Sogaard O, Brinkmann C, Wightman F, Lewin SR, Melchjorsen J, Dinarello C, Ostergaard L, Tolstrup M. Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation. Hum Vaccin Immunother. 2013 May;9(5):993-1001. doi: 10.4161/hv.23800. Epub 2013 Jan 31.

    PubMed 23370291

  • Richman DD. Introduction: challenges to finding a cure for HIV infection. Curr Opin HIV AIDS. 2011 Jan;6(1):1-3. doi: 10.1097/COH.0b013e328340ffa6.

    PubMed 21242886

  • Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006 Sep;5(9):769-84. doi: 10.1038/nrd2133.

    PubMed 16955068

  • Archin NM, Cheema M, Parker D, Wiegand A, Bosch RJ, Coffin JM, Eron J, Cohen M, Margolis DM. Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection. PLoS One. 2010 Feb 23;5(2):e9390. doi: 10.1371/journal.pone.0009390.

    PubMed 20186346

  • Contreras X, Schweneker M, Chen CS, McCune JM, Deeks SG, Martin J, Peterlin BM. Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells. J Biol Chem. 2009 Mar 13;284(11):6782-9. doi: 10.1074/jbc.M807898200. Epub 2009 Jan 9.

    PubMed 19136668

  • Archin NM, Espeseth A, Parker D, Cheema M, Hazuda D, Margolis DM. Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid. AIDS Res Hum Retroviruses. 2009 Feb;25(2):207-12. doi: 10.1089/aid.2008.0191.

    PubMed 19239360

  • Archin NM, Vaidya NK, Kuruc JD, Liberty AL, Wiegand A, Kearney MF, Cohen MS, Coffin JM, Bosch RJ, Gay CL, Eron JJ, Margolis DM, Perelson AS. Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9523-8. doi: 10.1073/pnas.1120248109. Epub 2012 May 29.

    PubMed 22645358

  • Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, Parker DC, Anderson EM, Kearney MF, Strain MC, Richman DD, Hudgens MG, Bosch RJ, Coffin JM, Eron JJ, Hazuda DJ, Margolis DM. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012 Jul 25;487(7408):482-5. doi: 10.1038/nature11286.

    PubMed 22837004

  • Shan L, Deng K, Shroff NS, Durand CM, Rabi SA, Yang HC, Zhang H, Margolick JB, Blankson JN, Siliciano RF. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity. 2012 Mar 23;36(3):491-501. doi: 10.1016/j.immuni.2012.01.014. Epub 2012 Mar 8.

    PubMed 22406268

  • Letourneau S, Im EJ, Mashishi T, Brereton C, Bridgeman A, Yang H, Dorrell L, Dong T, Korber B, McMichael AJ, Hanke T. Design and pre-clinical evaluation of a universal HIV-1 vaccine. PLoS One. 2007 Oct 3;2(10):e984. doi: 10.1371/journal.pone.0000984.

    PubMed 17912361

  • Rollier CS, Reyes-Sandoval A, Cottingham MG, Ewer K, Hill AV. Viral vectors as vaccine platforms: deployment in sight. Curr Opin Immunol. 2011 Jun;23(3):377-82. doi: 10.1016/j.coi.2011.03.006. Epub 2011 Apr 20.

    PubMed 21514130

  • Kostense S, Koudstaal W, Sprangers M, Weverling GJ, Penders G, Helmus N, Vogels R, Bakker M, Berkhout B, Havenga M, Goudsmit J. Adenovirus types 5 and 35 seroprevalence in AIDS risk groups supports type 35 as a vaccine vector. AIDS. 2004 May 21;18(8):1213-6. doi: 10.1097/00002030-200405210-00019.

    PubMed 15166541

  • Tatsis N, Blejer A, Lasaro MO, Hensley SE, Cun A, Tesema L, Li Y, Gao GP, Xiang ZQ, Zhou D, Wilson JM, Ertl HC. A CD46-binding chimpanzee adenovirus vector as a vaccine carrier. Mol Ther. 2007 Mar;15(3):608-17. doi: 10.1038/sj.mt.6300078. Epub 2007 Jan 16.

    PubMed 17228314

  • Colloca S, Barnes E, Folgori A, Ammendola V, Capone S, Cirillo A, Siani L, Naddeo M, Grazioli F, Esposito ML, Ambrosio M, Sparacino A, Bartiromo M, Meola A, Smith K, Kurioka A, O'Hara GA, Ewer KJ, Anagnostou N, Bliss C, Hill AV, Traboni C, Klenerman P, Cortese R, Nicosia A. Vaccine vectors derived from a large collection of simian adenoviruses induce potent cellular immunity across multiple species. Sci Transl Med. 2012 Jan 4;4(115):115ra2. doi: 10.1126/scitranslmed.3002925.

    PubMed 22218691

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Combination Antiretroviral Therapy (cART), Raltegravir and Vorinostat in people with HIV, run by Imperial College London at 6 sites in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 25 Sep 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Total HIV DNA From CD4 T-cells (time frame: Averaged across post-randomisation week 16 and 18). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02336074, which also lists 42 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Oct 2023.

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