iHIVARNA Clinical Trial in HIV Infected Individuals

iHIVARNA-01 is a novel therapeutic vaccine for the treatment of HIV-1-infected patients based on in vivo modification of DCs. It consists of HIVACAT-TriMix: mRNA encoding a mixture of APC activation molecules (CD40L, a constitutively active variant of TLR4 and CD70) and the HIV target antigens contained in HIVACAT to be administered through the intranodal route. iHIVARNA-01 aims to achieve the 'functional cure' of HIV infection, i.e. controlling viral replication in the absence of anti-retroviral therapy.

Objective: To evaluate the safety and immunogenicity of iHIVARNA-01 as a new therapeutic vaccine in HIV infected patients.

Study design and duration: Phase IIa, multicentre double-blind placebo controlled intervention study. Each patient will be followed for 30 weeks. The study duration will be 38 weeks from inclusion of the first patient.

Sites: Erasmus MC, Rotterdam The Netherlands (sponsor), Hospital Clínic de Barcelona and Institut de Recerca de la Sida - Caixa, Barcelona, Spain, Instituut voor Tropische Geneeskunde Antwerp, Belgium and Vrije Universiteit Brussel/UZ Brussel, Belgium

Study population: Chronically HIV-1- infected patients under stable cART with plasma viral load (pVL) ≤ 50 copies/ml and stable CD4+ T-cell counts ≥ 450/μl, aged 18 years or above.

Sample size: after recruitment and screening, 70 patients will be included and randomized to one of the study-arms.

Intervention: One group (n=40) receives the HIVACAT-TriMix (300 microgram TriMix + 900 microgram HIVACAT) vaccine intranodally on three occasions with a two-week interval. One control group (n=15) receives TriMix only (300 microgram TriMix) and one group (n=15) receives saline intranodally on three occasions with a two-week interval. Two weeks after the last vaccination cART treatment will be interrupted. If plasma virus is detectable, cART will be re-initiated twelve weeks after treatment interruption. cART can always be re-initiated for medical reasons, as judged by the clinical investigator.

Eligibility Criteria:
Inclusion Criteria:

1. ≥ 18 years of age;
2. Voluntarily signed informed consent;
3. Proven HIV-1 infection (with documented antibodies against HIV-1 and a detectable plasma HIV-1 RNA before initiation of therapy);
4. On stable treatment with cART regimen (antiretroviral therapy consisting of at least three registered antiretroviral agents) for at least 3 years;
5. Nadir CD4+ ≥ 350 cells/μl (up to 2 occasional determinations ≤ 350 cells/μl are allowed);
6. Current CD4+ cell count ≥ 450 cells/μl;
7. HIV-RNA below 50 copies/mL in the last 6 months prior to randomization, during at least two measurements (occasional so called 'blips' ≤ 500 copies/mL are permitted);
8. If sexually active, willing to use a reliable method of reducing the risk of transmission to their sexual partners during treatment interruption (including PrEP).

   1. For heterosexually active female, using an effective method of contraception with partner (combined oral contraceptive pill; injectable or implanted contraceptive; IUD/IUS; consistent record with condoms; physiological or anatomical sterility (in self or partner) from 14 days prior to the first vaccination until 4 months after the last vaccination.

For heterosexually active male, using an effective method of contraception with their partner from the first day of vaccination until 4 months after the last vaccination. -

Exclusion Criteria:

1. Treatment with non-cART regimen prior to cART regimen;
2. Previous failure to antiretroviral and/or mutations conferring genotypic resistance to antiretroviral therapy;
3. Non-subtype B HIV infection;
4. Active Hepatitis B virus and/or Hepatitis C virus co-infection;
5. History of a CDC class C event (see appendix A);
6. Pregnant female (screened with a positive pregnancy test), lactating or intending to become pregnant during the study;
7. Active malignancy ≤ 30 days (extended period on the clinical assessment of the investigator) prior to screening;
8. Active infection with fever (38°C or above) ≤ 10 days of screening and/or first vaccination;
9. Therapy with immunomodulatory agents (e.g. systemic corticosteroids), including cytokines (e.g. IL-2), immunoglobulins and/or cytostatic chemotherapy ≤ 90 days prior to screening. This does not include seasonal influenza, hepatitis B and/or other travel related vaccines;
10. Congenital, acquired or induced coagulation disorders, such as thrombocytopenia (thrombocytes \< 150x109/L) and/or current use of anti-coagulant medication (e.g. coumarins, inhibitors of Xa); Usage of NSAIDs (including acetylsalicylic acid) is allowed, however it is advised to interrupt therapy 10 days ahead of vaccination;
11. Usage of any investigational drug ≤ 90 days prior to study entry;
12. An employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, or is a family member of an employee or the investigator Any other condition, which, in the opinion of the investigator, may interfere with the evaluation of the study objectives