A HIV Vaccine Trial in Individuals Who Started Antiretrovirals During Primary or Chronic Infection (EHVA T02)

EHVA T02 (European HIV Vaccine Alliance Therapeutic Trial 02)/ANRS VRI07: A Phase II Randomised, Placebo-controlled Trial of Vedolizumab With or Without Therapeutic HIV MVA Vaccine in Individuals Who Started Antiretrovirals During Primary or Chronic Infection

EHVA T02 is an international, phase II, double-blind study to evaluate two experimental arms each compared to placebo control in HIV-1 positive participants to see if either has a clinically relevant impact on viral replication.

Screening will take place during the 6 weeks prior to randomisation. Eligible participants will be enrolled at week 0 and randomised to MVA HIV-B vaccine followed by vedolizumab, vedolizumab + placebo vaccine, or placebo vaccine + placebo infusions.

Participants will be randomised at each centre through web-based randomisation after entering the eligibility criteria. There will be two strata: one for those who started treatment during primary infection, and one for those who started treatment during chronic infection.

69 eligible individuals from collaborating European Countries will be enrolled, aiming for approximately half who started cART in primary infection and half who started in chronic infection. Participants continue from the screening visit (up to 6 weeks before enrolment) to the last visit, a maximum of 60 weeks (around 14 months), although follow-up will continue through to the time when virus is fully suppressed.

Treatment will be interrupted at week 18 and resumed when the viral load is confirmed to have rebounded to ≥100,000 copies/ml, or the CD4 falls to ≤350 cells/mm3, confirmed, or there is evidence of disease progression, or they have completed 24 weeks of treatment interruption.

Inclusion Criteria:

1. HIV-1-infected

2. Aged 18 - 65 years old on the day of screening

3. Weight >50kg

4. Willing and able to provide written informed consent

5. Nadir CD4 count > 300 cells/mm3

6. CD4 count at screening > 500 cells/mm3

7. Viral load <50 copies/ml at screening.

8. Started cART after 2009 and on cART for at least one year prior to screening

9. Willing to interrupt cART for up to 24 weeks and change cART regimen if required

10. If sexually active, willing to use a reliable method of reducing the risk of transmission to their sexual partners during treatment interruption (which could include PrEP for their sexual partners)

11. If heterosexually active and able to have children, willing to use a highly effective method of contraception with partner (combined oral contraceptive pill; injectable or implanted contraceptive; IUD/IUS; physiological or anatomical sterility (in self or partner) from 2 weeks before enrolment until 18 weeks after the last injection/infusion

12. If women of childbearing potential*, willing to undergo urine pregnancy tests prior to administration of an injection and an infusion

13. Willing to avoid all other vaccines within 4 weeks of scheduled study injections

14. Willing and able to comply with visit schedule and provide blood samples

15. Being covered by medical insurance or in National Healthcare System

    • A woman will be considered of childbearing potential following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.

Exclusion Criteria:

1. Pregnant or lactating

2. HIV-2 infection (either isolated or associated with HIV-1)

3. VL >200 copies/ml on 2 occasions in the 12 months prior to screening

4. Previous interruptions in cART

5. Previous virological failures defined by loss of virological suppression with the presence of resistant mutations

6. Haemoglobin (Hb <12g/dL for males, <11g/dL for females)

7. Concomitant or previous conditions that preclude injection of vaccines/infusion of monoclonal antibody and PML in the past

8. History of experimental vaccinations against HIV

9. Previous treatment with chemotherapy (except for chemotherapy injected into skin lesions for Kaposi's sarcoma)

10. Treatment with systemic corticoids or immuno-suppressive agents ongoing or in the 12 weeks prior to randomisation in the trial

11. Received natalizumab or rituximab ever in the past

12. Received a TNF blocker in the past 60 days

13. Administration of an inactivated vaccine within 30 days or a live vaccine within 60 days prior to randomisation

14. Presence of a skin condition or marking that precludes inspection of the injection/infusion site

15. History of cancer (except basal cellular skin carcinoma or Kaposi's sarcoma)

16. History of significant neurological disease or cardiovascular disease (angina, myocardial infarction, transient ischemic attack, stroke); participants with controlled blood pressure are eligible

17. History of clinical autoimmune disease

18. Ongoing diseases including uncontrolled active severe infection, cardiac, pulmonary (excluding mild asthma), thyroid, renal or neurological (peripheral or central) diseases

19. Active or latent tuberculosis (unless prophylaxis in past as per local practice) - (participant must be screened for tuberculosis before starting infusions, according to routine practice)

20. Presence of pathogenic bacteria or parasites in faeces at screening

21. Participating in another biomedical research study within 30 days of randomisation

22. Known hypersensitivity to any component of the vaccine formulation used in this trial including eggs or have severe or multiple allergies to drugs or pharmaceutical agents, or any hypersensitivity to the active substance or to any of the excipients of vedolizumab.

23. Liver disease including hepatitis B (surface antigen positive) or hepatitis C (antigen or PCR positive)

24. A clinically significant abnormality on ECG

25. Hypernatraemia or hyperchloraemia

26. History of severe local or general reaction to vaccination defined as

    1. local: extensive, indurated redness and swelling involving most of the arm, not resolving within 72 hours
    2. general: fever >= 39.5oC within 48 hours; anaphylaxis; bronchospasm; laryngeal oedema; collapse; convulsions or encephalopathy within 72 hours

27. Grade 2 or worse routine laboratory parameters. Hyperbilirubinaemia to be considered an exclusion criterion only when confirmed to be conjugated bilirubinaemia