Towards HIV Functional Cure

Study Overview
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Brief Summary
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During the ERAMUNE-01 and -02 studies, the HIV-DNA quantification in the PBMCs (Peripheral Blood Mononuclear Cells) showed showed that some patients had a very low or undetectable reservoir. Recent studies showed that a low reservoir is associated to a spontaneous virologic control in three specific categories of patients: Elite Controllers: these rare patients are able to spontaneously maintain an HIV-RNA viral load below 50 copies/mL and elevated CD4 counts without any treatment. These patients belong to the B27/B57 haplotypes associated to a reduced risk of HIV contamination but these haplotypes are very rare in the global population (0,3 %) Visconti patients: early-treated patients, during the primo-infection stage. After 3 to 5 years of treatment, these patients are able to maintain an undetectable HIV-RNA viral load. Salto patients: these patients are treated a bit later compared to the Visconti cohort, when their CD4 count was above 350 cells/mm3 and their HIV-RNA viral load below 50 000 copies/mL. The follow-up of these patients showed the same capacity of control of the HIV infection for at least 2 years following treatment interruption. Taking into account these 3 categories of patients which common characteristics is a low reservoir, our objective is to answer the 2 following questions: Is it possible to discontinue the treatment in chronically-infected patients with a normal immune system and with an undetectable HIV-DNA reservoir? Is a low viral reservoir predictive of a treatment-free remission of the HIV infection in chronically-infected patients? The main objective of the proof-of-concept ERAMUNE-03 trial is to evaluate the proportion of patients in success (i.e. able to maintain a virologic and an immunologic control of the infection) after treatment discontinuation, failure is defined as: An HIV-RNA viral load > 400 copies/mL on 2 consecutive tests starting from Week 4 Or CD4 count < 400 cells/mm3 on 2 consecutive measures starting from Week 4 Or the onset of an AIDS-related event

Official Title
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A Pilot Study Evaluating the Maintenance of Viral Suppression After 24 Weeks of Therapeutic Interruption in Chronically HIV-1 Infected Patients With a Low Circulating HIV-DNA Reservoir

Conditions
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Chronic HIV-1 Infection

Intervention / Treatment
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* Other: Antiretroviral treatment interruption


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infected patient CD4 count > 500 cells/mm3 CD4/CD8 ratio > 0.9 CD4 nadir > 300 cells/mm3 HIV-1-RNA plasma viral load < 50 copies/mL under antiretroviral treatment for at least 2 years HIV-1-RNA plasma viral load < 20 copies/mL at baseline HIV-DNA reservoir < 100 copies/million PBMCs Signed fully informed consent form Ability to attend the complete schedule of assessments and patient visits Patient eligible for national social insurance Exclusion Criteria: Medical history of AIDS-staging event Antiretroviral treatment initiated during primo-infection in absence of anti-HIV antibodies (negative ELISA and Western Blot tests) Change in the antiretroviral treatment combination within the 3 months prior inclusion HIV-2 co-infection History of thrombocytopenia (< 100 000 cells/mm3) Acute neurologic event during primo-infection Chronic and active hepatitis B as defined as positive HBs antigen or positive isolated anti-HBc antibodies Chronic and active hepatitis C as defined as positive anti-HCV antibodies and positive HCV-RNA PCR History of cancer within the 5 years prior inclusion except basocellular cutaneous cancers Comorbidity associated to lifespan < 12 months according investigator's opinion History of auto-immune disease (lupus erythematous, Hashimoto's thyroiditis, ...) Hemoglobin < 7 g/dL, Creatinine clearance < 60 mL/min using the MDRD formula Patients refusal to use a condom for any sexual relationship during the course of the study Refusal from women of childbearing potential to use at least one additional barrier method other than condoms Ongoing pregnancy as documented by a positive blood test performed at screening or later Lactating woman Psychologic unstability or patient state-of-mind incompatible with the participation in the study as evaluated by psychologist at screening Drug or alcohol addiction or abuse Concomitant participation to another trial involving any investigational treatment or device

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: STOP ART<br>Antiretroviral treatment interruption in 3 successive groups of 5 patients. Zero-risk strategy If after 8 weeks of treatment interruption, at least 1 patient from group 1 does not present any of the failure criteria, patients from group 2 will be included and their treatment interrupted. If after 8 weeks of treatment interruption, at least 2 patients from groups 1 and 2 do not present any failure criteria, patients from group 3 will be included and their treatment interrupted. | Other: Antiretroviral treatment interruption<br>* pilot study in chronically HIV-infected patients with an ultralow HIV reservoir undergoing treatment-interruption.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients in success | Success is defined as the maintenance of the controlled viral infection after 24 weeks of therapeutic interruption. Failure is defined as: An HIV-1-RNA plasma viral load > 400 copies/mL starting from Week 4 as confirmed by two consecutive measures within 2 to 4 weeks Or a CD4 count < 400 cells/mm3 starting from Week 4 as confirmed by two consecutive measure within 2 to 4 weeks Or the onset of an AIDS-grading clinical event (grade B or C in the CDC classification, version 1993) | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes from baseline in CD4 and CD8 lymphocytes counts |  | Up to Week 48 | 
| Changes from baseline in immune activation and inflammation markers |  | Up to Week 48 | 
| Changes from baseline in anti-HIV specific T cells response |  | Up to Week 48 | 
| Quantitative and qualitative changes from baseline in the HIV-1 reservoir as measured on sorted CD4 lymphocytes subsets | CD4 subpopulations will be live-sorted and purified. In each subset defined by surface markers, HIV-1 DNA will be quantified and transcriptional potential of HIV will be evaluated. | Up to Week 48 | 
| Proportion of patients in virologic success (HIV-1-RNA plasma viral load < 400 copies/mL) |  | Up to Week 48 | 
| Changes from baseline in the HIV-1 reservoir as measured by HIV-1 DNA copies per million PBMCs |  | Up to Week 48 | 
| Changes from baseline in the proportion of defective HIV-1 DNA | Evaluation of the stop codons in the HIV-1 DNA sequence | Up to Week 48 | 
| Changes from baseline in the plasma concentrations of antiretroviral molecules |  | Up to Week 48 | 
| Changes from baseline in the patient quality of life and in the disease-related symptoms |  | Up to Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-1, chronic infection, cure, remission