Lipopeptide Immunisation With GTU-multiHIV Trial

Study Overview
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Brief Summary
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The combination of GTU-MultiHIV B DNA and LIPO-5 vaccines in a prime-boost strategy is expected to induce strong and diverse HIV-specific immune responses in HIV-infected patients. The investigators will carry out the clinical therapeutic immunization proof of concept trial in HIV infected patients. The investigators propose a multi-center double blind randomized versus placebo phase II clinical trial in patients who are chronic asymptomatic HIV-infected patients, with undetectable viral load while treated with a potent combination of antiviral drugs. Patients will continue antiviral therapy combined with either therapeutic vaccination or placebo vaccination. Patients will undergo the procedure which includes a prime with the GTU-MultiHIV B DNA vaccine or placebo administered by IM injections via Biojector (a needle-free injection system) followed by a boost of LIPO-5 vaccine or placebo also given IM. In total, 105 HIV-1 patients will be enrolled: 35 in the placebo arm and 70 in the vaccine arm. Patients will receive antiretroviral treatments and 3 administrations of DNA vaccine or its placebo at weeks 0, 4 and 12 (corresponding to prime vaccinations). They also receive 2 doses of LIPO-5 vaccines or its placebo at week 20 and 24 (corresponding to boost vaccinations). At week 36 antiretroviral treatments will be interrupted until week 48. Patients will be intensely monitored during the treatment interruption period. After start of cART treatment (at the latest in W48), a data collection from clinical car will be carried out. A blood sample with W74 will allow to study the persistence ot the immunizing responses, 1 year after the injection of the last vaccine/placebo. The primary efficacy endpoint is a plasma HIV-1 RNA level at week 48 (e.g. 12 weeks after stopping all antiviral treatment). The main hypothesis for conducting a phase II randomized trial is that immune responses in vaccinated patients may be associated with a better control of viral replication following c-ART interruption as compared to placebo-vaccinated patients.

Official Title
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Evaluation of a Therapeutic Immunization Strategy Associating a DNA Vaccine (GTU-MultiHIV B) Followed by a Lipopeptide Vaccine (LIPO-5) in the Control of Viral Replication Following Antiretroviral Treatment Interruption in HIV-1 Infected Patients With a CD4 Cell Count ≥ 600/mm3

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Biological: Placebos of GTU-multiHIV B and LIPO-5 vaccines
* Biological: GTU-multHIV B vaccine and LIPO-5 vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Documented HIV-1 infection (ELISA and Western blot) Age ≥ 18 years and < 60 years No history of CDC category C clinical events (1993), including cutaneous Kaposi's sarcoma CD4 Nadir ≥ 300/mm3 Under antiretroviral treatment CD4 ≥ 600/mm3 on all measurements within the previous 6 months* prior to W-3 screening visit (one single CD4 value between 550-600 cells/ mm3 is permitted) CD4 value ≥ 600/ mm3 at W-3 screening visit Plasma HIV1-RNA < 50 copies/mL on all measurements within the previous 6 months* (An occasional measurement of HIV-1 RNA (so-called  blip  between 50 and 200 copies/mL is permitted) HIV1-RNA < 50 copies/mL at W-3 screening visit * In the absence of measurement in the last 6 months, a measurement performed in the last 12 months is accepted Treatment with a combination of antiviral drugs (cART) for at least 18 months regardless of the combination, under condition that : in the W24 visit the non-nucleoside inhibitors are replaced by a protease inhibitor potentiated by ritonavir no failure or resistance to the protease inhibitor was previously reported With adequate method of contraception and negative pregnancy test (βHCG plasma) for women of childbearing potential Laboratory parameters at W-3: polynuclear neutrophils ≥ 1,000/mm3 haemoglobin ≥ 10 g/dl platelets ≥ 100,000/mm3 creatinine ≤ 1.5 x N AST, ALT, bilirubin ≤ 2.5 x N proteinuria ≤ 1 g/L (++) anti-nuclear antibodies ≤ 1/320 anticardiolipin antibodies ≤ 30 U no lupus anticoagulant Participant agreeing to be treated and followed for at least 74 weeks according to the protocol Participant agreeing to interrupt his/her cART treatment and, if applicable, to replace the non-nucleoside inhibitors by a protease inhibitor potentiated by ritonavir at W24 Participant agreeing to the use of condom, in particular during ART interruption period (between the visit S36 and the visite S48) Participant covered by HealthInsurance (article L1121-11 of Code de la Santé Publique) Written informed consent (at the latest the day of pre-inclusion and before all exams to be done in the context of the trial) (article L1122-1-1 of Code de la Santé Publique). Exclusion criteria Pregnancy or lactation, HIV-2 infection (isolated or associated with HIV-1), History of (experimental) vaccinations against HIV, Treatment with chemotherapy or interferon alpha (IFN-α-2b), sargramostim (GM-CSF), IL-2 or IL-7 ongoing or in the previous12 weeks before inclusion (W0), Treatment with corticoids or immunosuppressive agents ongoing or in the previous12 weeks before inclusion in the trial (W0), Administration of a live vaccine within 60 days prior to inclusion in the trial (W0) or any other inactivated vaccine within 14 days before W0 visit Planned administration, during the follow-up of participants, of a vaccine other than those recommended in France as part of the usual care of patients History of cancer (except basal cellular skin carcinoma), History of cardiovascular disease (angina, myocardial infarction, transient ischemic attack, stroke), History of renal failure related to HIV, History of thrombocytopenia related to HIV (<50,000/mm3), Ongoing cardiac, pulmonary, thyroid, renal or neurological (peripheral or central) diseases, Progressive infection, Co-infection with hepatitis B (HBsAg + or isolated anti-HBc antibodies +) or hepatitis C (anti-HCV antibody and PCR +), Known allergy to aminoglycosides, Person placed under juridical protection (article L1122-2 of Code de la Santé Publique) Person participating in another biomedical research with an exclusion period always ongoing at screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 59 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Vaccine placebos<br>Vaccine placebos corresponding to the dilutant of these vaccines | Biological: Placebos of GTU-multiHIV B and LIPO-5 vaccines<br>* Placebos corresponds respectively to 1X PBS pH = 7.2 and glucose 5%<br>|
| Experimental: Vaccine arm<br> | Biological: GTU-multHIV B vaccine and LIPO-5 vaccine<br>* Vaccines are respectively an HIV-DNA plasmid and a mixture of 5 HIV-lipopeptides.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma HIV-1 RNA level |  | week 48 (W48) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma HIV-RNA after stopping antiviral treatment |  | W40, W44, W48 and W74 | 
| Percentage of patients with plasma HIV-RNA below 10 000 copies/mL |  | W48 | 
| Ultrasensitive proviral DNA |  | W-3, W20, W32 and W44 | 
| CD4 T cell counts |  | W40, W44 and W48 or prior HAART resumption and W74 | 
| Percentages of patients who resumed HAART |  | between W36 and W48 | 
| Percentages of patients who reached CD4 cell counts < 350/mm3 confirmed two weeks apart |  | between W36 and W48 | 
| Strength of HIV-specific CD4/CD8 responses |  | W0, W16, W28, W48 or at the time of failure anw W74 | 
| Proportion of responders to at least one HIV peptide pool |  | W0, W16, W28, W48 or at the time of failure and W74 | 
| Breadth of CD4/CD8+ HIV-specific responses defined as the number of HIV pools recognized among the 18 pools |  | W0, W16, W28, W48 or at the time of failure and W74 | 
| Polyfunctionality of HIV specific T cell responses evaluated by the mean proportion of CD4/CD8+ T cells producing IL-2 and/or IFN-g following ex-vivo stimulation with HIV-1 peptide pools |  | W0, W16, W28, W48 and W74 | 
| Adverse Events > grade 2 |  | W0, W4, W12, W16, W20, W24, W28, W32, W36, W38, W40, W42, W44, W48 and W74 | 
| AIDS-defining events and serious non-AIDS events defined as cardiovascular diseases, kidney diseases, end stage liver diseases, non-AIDS defining malignancies except basal cellular skin cancer, and bacterial infections |  | W0, W4, W12, W16, W20, W24, W28, W32, W36, W38, W40, W42, W44, W48 and W74 | 
| Analysis of predictive factors for plasma HIV-RNA |  | W48 |