Research In Viral Eradication of HIV Reservoirs

• Status: Active, not recruiting
• Trial end date: 2022-11-14
• Target enrollment: 0
• Participant gender: All

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.

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• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Imperial College London
• Collaborators: Brighton and Sussex University Hospitals NHS Trust; Central and North West London NHS Foundation Trust; Chelsea and Westminster NHS Foundation Trust; Guy's and St Thomas' NHS Foundation Trust; Medical Research Council; Royal Free Hospital NHS Foundation Trust; University of Cambridge; University of Oxford
• Treatments: Anti-Retroviral Agents; Raltegravir Potassium; Vaccines; Vorinostat

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.