Towards HIV Functional Cure - Full Text View

Purpose

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

Condition	Intervention
Chronic HIV-1 Infection	Other: Antiretroviral treatment interruption


Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label
Official Title:	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

Resource links provided by NLM:

MedlinePlus related topics: HIV/AIDS

U.S. FDA Resources

Further study details as provided by Objectif Recherche Vaccins SIDA:

Primary Outcome Measures:

Proportion of patients in success [ Time Frame: Week 24 ] [ Designated as safety issue: Yes ]
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)

Secondary Outcome Measures:

Changes from baseline in CD4 and CD8 lymphocytes counts [ Time Frame: Up to Week 48 ] [ Designated as safety issue: No ]
Changes from baseline in immune activation and inflammation markers [ Time Frame: Up to Week 48 ] [ Designated as safety issue: No ]
Changes from baseline in anti-HIV specific T cells response [ Time Frame: Up to Week 48 ] [ Designated as safety issue: No ]
Quantitative and qualitative changes from baseline in the HIV-1 reservoir as measured on sorted CD4 lymphocytes subsets [ Time Frame: Up to Week 48 ] [ Designated as safety issue: No ]
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.
Proportion of patients in virologic success (HIV-1-RNA plasma viral load < 400 copies/mL) [ Time Frame: Up to Week 48 ] [ Designated as safety issue: No ]
Changes from baseline in the HIV-1 reservoir as measured by HIV-1 DNA copies per million PBMCs [ Time Frame: Up to Week 48 ] [ Designated as safety issue: No ]
Changes from baseline in the proportion of defective HIV-1 DNA [ Time Frame: Up to Week 48 ] [ Designated as safety issue: No ]
Evaluation of the stop codons in the HIV-1 DNA sequence
Changes from baseline in the plasma concentrations of antiretroviral molecules [ Time Frame: Up to Week 48 ] [ Designated as safety issue: No ]
Changes from baseline in the patient quality of life and in the disease-related symptoms [ Time Frame: Up to Week 48 ] [ Designated as safety issue: No ]


Enrollment:	15
Study Start Date:	September 2013
Study Completion Date:	July 2015
Primary Completion Date:	December 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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.

Arms

Assigned Interventions

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.

Eligibility


Ages Eligible for Study:	18 Years to 70 Years (Adult, Senior)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01876862

Locations


France
University Hospital of Bicêtre
Le Kremlin Bicêtre, France, 94275
Hospital Pitié-Salpêtrière
Paris, France, 75013

Sponsors and Collaborators

Objectif Recherche Vaccins SIDA

Fondation Bettencourt-Schueller

Investigators


Study Director:	François LECARDONNEL, MSc	Objectif Recherche Vaccins SIDA
Principal Investigator:	Christine KATLAMA, MD	Hospital Pitié-Salpêtrière

More Information


Responsible Party:	Objectif Recherche Vaccins SIDA
ClinicalTrials.gov Identifier:	NCT01876862 History of Changes
Other Study ID Numbers:	ORVACS 012
Study First Received:	May 31, 2013
Last Updated:	September 28, 2015
Health Authority:	France: National Agency for Drugs Safety (ANSM)

Keywords provided by Objectif Recherche Vaccins SIDA:


HIV-1 chronic infection cure remission

ClinicalTrials.gov processed this record on September 30, 2016

Towards HIV Functional Cure (ULTRASTOP)