RIVER - Research In Viral Eradication of HIV Reservoirs

Recruitment & Eligibility

Status: Completed

Sex: All

Target Recruitment: 60

Inclusion Criteria

Current inclusion criteria as of 04/02/2016:
In total, 52 eligible individuals will be randomised across 6 UK collaborating centres according to the following criteria:
1. Aged 18 to 60 years old
2. Confirmed primary HIV-1 infection (PHI) by HIV antibody positive with a documented negative antibody test within the previous 3 months, antigen/antibody test positive or equivocal, or HIV-1 antibody positive with confirmed recent infection by PHE Recent Infection Testing Algorithm (RITA) avidity assay.
3. Willing to start immediate cART and be randomised to continue cART alone or cART plus intervention (HIV vaccines plus HDACi)
4. Hb 12 g/dL (Males), 11 g/dL (Females)
5. Weight = 50 kg
6. Written informed consent; agree to long-term follow-up (at least 5 years)
7. Willing and able to comply with visit schedule and provide blood sampling

Previous inclusion criteria:
In total, 52 eligible individuals will be randomised across 6 UK collaborating centres according to the following criteria:
1. Aged 18 to 60 years old
2. Confirmed primary HIV-1 infection (PHI) by HIV antibody positive with a documented negative antibody test within the previous 3 months, antigen/antibody test positive or equivocal, or HIV-1 antibody positive with confirmed recent infection by PHE Recent Infection Testing Algorithm (RITA) avidity assay.
3. Willing to start immediate ART and be randomised to continue ART alone or ART plus intervention (HIV vaccines plus HDACi) at week 24
4. Hb 12 g/dL (Males), 11 g/dL (Females)
5. Weight = 50 kg
6. Written informed consent; agree to long-term follow-up (at least 5 years)

Exclusion Criteria

Current exclusion criteria as of 04/02/2016:
1. Women of child bearing potential (WCBP)
2. Planning to undertake egg donation to a surrogate in a woman who has intact ovaries and no uterus
3. Intention to donate sperm or father a child within 6 months of the intervention
4. Co-infection with hepatitis B (SAg +ve or detectable HBV DNA levels in blood) or C (HCV RNA +ve)
5. Any current or past history of malignancy including anal intraepitheilal neoplasia (AIN) or cervical intraepithelial neopalasia (CIN)
6. Concurrent opportunistic infection or other comorbidity e.g. ischaemic or other significant heart disease, malabsorption syndromes, autoimmune disease
7. Any contraindication to receipt of BHIVA recommended combination antiretrovirals
8. Any contraindication to receipt of the strand-transfer integrase inhibitor (INSTI), raltegravir
9. HIV-2 infection
10. Known HTLV-1 coinfection
11. Prior immunisation with any experimental immunogens
12. Current or planned immunosuppressive therapy (inhaled corticosteroids are allowed)
13. Any history of thromboembolism
14. Any inherited or acquired bleeding diathesis including gastric or duodenal ulcers, varices
15. Any bleeding diathesis including gastric or duodenal ulcers, varices
16. Concurrent or planned use of any drugs contraindicated with vorinostat i.e. antiarrhythmics; any other drugs that prolong QTc; warfarin, aspirin, sodium valproate
17. Prior intolerance of any of the investigational medicinal products in the protocol
18. Uncontrolled diabetes mellitus defined as an HBA1C>7%
19. Any congenital or acquired prolongation of the QTc interval, with normal defined as 0.40s (=400 ms); bradycardia <55 bpm
20. 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
21. Allergy to egg
22. History of anaphylaxis or severe adverse reaction to vaccines
23. Planned receipt of vaccines (including vaccines such as yellow fever; hepatitis B, influenza)within 2 weeks of the first vaccination in the study
24. Moderate to severe hepatic impairment as defined by Child-Pugh classification
25. ALT >5xULN
26. Platelets <150x109/L
27. eGFR <90 ml/min
28. uPCR >30 mg/mmol
29. 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 enrollment into the study
30. Active alcohol or substance use that, in the Investigator?s opinion, will prevent adequate adherence with study requirements
31. Insufficient venous access that will allow scheduled blood draws as per protocol
PARTICIPANT INCLUSION CRITERIA FOR RANDOMISATION
Additional criteria assessed at approximately week 22 to proceed to randomisation :
1. Participant is willing to continue on combination antiretroviral therapy
2. HCV PCR negative
3. Plasma HIV RNA <50 copies/mL (or <200 copies/mL for the Taqman Roche assay)
4. Laboratory parameters:
4.1. Platelet count =150x109/L
4.2. eGFR =90 ml/min
4.3. Hb =12 g/dL(Males), =11 g/dL(Females)
4.4. ALT <5 x ULN
4.5 uPCR =30 mg/mmol
4.6. In diabetics, HbA1C <7%
5. QTc interval normal, with normal defined as 0.40 s (400 ms)
6. Physical examination: No evidence of organ dysfunction or any clinically significant deviation from normal in physical examination and/or vital signs that in that in the opinion of the investigator

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Current primary outcome measures as of 04/02/2016:<br>HIV total DNA from CD4 T cells average at post-randomisation week 16 and 18<br><br>Previous primary outcome measures:<br>HIV total DNA from CD4 T cells average at week 40 and 42

Secondary Outcome Measures

Name	Time	Method
1. Clinical and laboratory adverse events<br>2. Further assessment of the HIV reservoir e.g. HIV integrated DNA<br>3. HIV cell associated RNA; plasma HIV RNA measured with an ultra-low copy assay i.e. with a threshold of <1 copy/ml<br>4. Studies of immune function including measuring the latently infected resting memory T-cells and cytotoxic immune responses<br>5. Changes in inflammatory biomarkers

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