Comprehensive Analysis of HIV Reservoirs in Chronically Infected HIV-1 Treated Patients

NCT02628340 | Completed DMC

• 1 other identifier: CREPATS 002
• Study Type: observational
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

HIV infection can be efficiently controlled by antiretroviral therapy (ART), with in 2013 nearly 85 % of patients having a suppressed viremia, but HIV cannot, however, be eradicated with ART alone \[1\]. Overall, HIV has moved from a fatal to a chronic disease provided treatment is maintained life-long. Despite major improvement in antiretroviral drugs in terms of efficacy, tolerability and simplicity, life-long therapy is still associated with drug toxicity. Several drugs or drug classes, which have historically saved lives since 1996 and are currently widely used such as protease inhibitors and nucleosides analogues, are associated with long-term toxicities and increased incidence of comorbidities. Currently, worldwide there is an approximated 10 millions of HIV infected patients under cART. This number should increase in the next years, as most recent guidelines recommend earlier therapy given the benefits in terms of disease progression and prevention of transmission. Because of the increasing number of patients who will be under cART in the future, the cumulative ART toxicity, the difficulties to access ART in some areas of the world, the fatigue expressed by patients about ART and the cost issues, there is an urgent need to search for HIV CURE. To date, only two cases of sterilizing HIV cure were reported so far: the famous "Berlin Patient" after two homozygous Delta32-CCR5 bone-marrow grafts for an acute leukemia \[2\], and the Mississipi baby after very early initiation of cART 31 hours after delivery \[3\]. However those cases of sterilizing HIV cure remain exceptional and the alternative objective of a functional HIV cure appears to be more realistic, though still described in rare groups of patients like Elite controllers (EC) and post treatment controllers (PTC) patients. In addition new and complex therapeutic strategies are currently proposed to try purging the HIV reservoirs, but none of them proved so far able to reach this goal. Therefore the objective of finding a Cure to HIV \[4\] requires first to better understand the basic mechanisms of the persistence of HIV reservoirs in the population of chronically-infected fully-suppressed HIV+ patients in order to define future therapeutic strategies.

Conditions

HIV

Outcome Measures

Primary Outcomes (1)

• measure of HIV reservoirs in a selected HIV chronically infected ARV treated population assessed by HIV DNA distribution in PBMCs, total and sorted CD4 T cells subsets.

  Cell sorting experiments will allow the sorting of the different subsets of the CD4 reservoirs cells and their quantification for the study of the HIV reservoirs characteristics. We will sort resting CD4 T cells defined as CD3+CD4+CD69-CD25-HLA-DR- on a 5-laser flow cytometer in our L3 facility (UPMC Platform CyPS) in at least 4 subsets: * Naïve (TN: CD45RA+CCR7+CD27+), * Central-Memory (TCM: CD45RA-CCR7+CD27+), * Transitional-memory (TTM: CD45RA-CCR7-CD27+) * Effector-Memory (TEM CD45RA-CCR7-CD27-)

  one year

Secondary Outcomes (6)

• measure of host molecular signatures and transcriptional activity in each subset assessed by microfluidic qRT-PCR (Fluidigm)

  one year

• measure of in vitro inducibility of the HIV provirus in the different sorted CD4 subsets harboring the HIV réservoirs assessed by ultrasensitive real-time RT-PCR assay

  one year

• measure of defective viral population estimated by the proportion of stop codons in the integrated HIV-DNA assessed by ultra deep sequencing and

  one year

• measure of levels of unspliced HIV transcripts in total and different subsets of CD4 T cells.

  one year

• measure of serum inflammatory biomarkers assessed by ELISA assay

  one year

Interventions

Ex-vivo analysis OTHER

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

A total of 20 patients under cART with HIV-RNA pVL \< 50 cp/ml and HIV DNA \<200 copies/106 PBMCs will be recruited from a total of over 3,900 patients under follow-up in the Infectious Diseases Unit Pitié-Salpêtrière Hospital, in Paris.

You may qualify if:

• HIV-1 infected adult
• Age \> 18 years
• HIV-RNA plasma viral load (pVL) \< 50 copies/mL
• Under antiretroviral therapy (cART)
• CD4 \>400/mm3
• HIV DNA\<200 copies/106 PBMCs
• Ability to provide informed consent

You may not qualify if:

• cART initiated at the time of primary infection
• Chronic hepatitis B ( HBs +antigen)
• Chronic hepatitis C defined as positive HCV-RNA
• History of chemotherapy/radiotherapy or immunosuppressive therapy within the 5 years prior study entry.
• Any history of autoimmune disease

Sponsors & Collaborators

• Centre de Recherches et d'Etude sur la Pathologie Tropicale et le Sida: lead
• INSERM UMR S 1136: collaborator
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Groupe Hospitalier Pitié-Salpêtrière - Service des Maladies Infectieuses et Tropicales

Paris, 75013, France

Location

Study Officials

• Christine Katlama, MD

  Groupe Hospitalier Pitié-Salpêtrière

  STUDY DIRECTOR

• Ruxandra Calin, MD

  Groupe Hospitalier Pitié-Salpêtrière

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 4, 2015
• First Posted: December 11, 2015
• Study Start: June 1, 2014
• Primary Completion: June 1, 2016
• Study Completion: July 1, 2016
• Last Updated: August 2, 2016

Record last verified: 2016-08

Locations

FR (1)