Towards HIV Functional Cure (ULTRASTOP)

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

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:

1. Is it possible to discontinue the treatment in chronically-infected patients with a "normal" immune system and with an undetectable HIV-DNA reservoir?
2. 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

Study Overview

• Status: Completed
• Conditions: Chronic HIV-1 Infection
• Intervention / Treatment: Other: Antiretroviral treatment interruption

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Le Kremlin Bicêtre, France, 94275
    • University hospital of Bicêtre
  • Paris, France, 75013
    • Hospital Pitie-Salpetriere

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: STOP ART; 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; pilot study in chronically HIV-infected patients with an ultralow HIV reservoir undergoing treatment-interruption.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Objectif Recherche Vaccins SIDA
• Collaborators: Fondation Bettencourt-Schueller
• Investigators: Study Director: François LECARDONNEL, MSc, Objectif Recherche Vaccins SIDA; Principal Investigator: Christine KATLAMA, MD, Hospital Pitie-Salpetriere

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): July 1, 2015

Study Registration Dates

• First Submitted: May 31, 2013
• First Submitted That Met QC Criteria: June 10, 2013
• First Posted (Estimate): June 13, 2013

Study Record Updates

• Last Update Posted (Estimate): September 29, 2015
• Last Update Submitted That Met QC Criteria: September 28, 2015
• Last Verified: September 1, 2015

More Information

Terms related to this study

• Keywords: HIV-1; remission; chronic infection; cure
• Additional Relevant MeSH Terms: Infections; Anti-Infective Agents; Antiviral Agents; Anti-Retroviral Agents
• Other Study ID Numbers: ORVACS 012