HIVRESACHRONNCT02628340
Comprehensive Analysis of HIV Reservoirs in Chronically Infected HIV-1 Treated Patients
An observational study of HIV, run by Centre de Recherches et d'Etude sur la Pathologie Tropicale et le Sida at 1 site in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- HIV
- What is being tested?
- Ex-vivo analysis
- How many people
- 20 participants
- Where
- 1 siteFrance
- Study dates
- Jun 2014to Jul 2016
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
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.
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
France1 site
Groupe Hospitalier Pitié-Salpêtrière - Service des Maladies Infectieuses et Tropicales
Paris, 75013
About this study
Official title: Comprehensive Analysis of HIV Reservoirs in Chronically Infected HIV-1 Treated Patients With a Low Total Cell-associated Blood HIV-DNA
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.
Read the detailed description
Extremely low levels of HIV reservoirs are achievable in some chronically-infected patients durably controlled with cART. Despite the multiplicity and heterogeneity of factors governing the persistence of HIV reservoirs, such low levels of HIV reservoirs seem necessary, though probably not sufficient, to reach the status of functional cure defined by virus control in the absence of treatment. The mechanisms associated with these low HIV reservoirs in chronic treated infection are unknown but might involve a low immune activation and inflammatory environment, and deleterious HIV mutations. Understanding those mechanisms will provide novel clues for future strategies aiming at obtaining an HIV Cure.
The main objective of RESACHRON Study is to define in chronically infected patients with suppressed viremia, cART and extremely low levels of HIV reservoirs, the viral and cellular mechanisms underlying the persistence, the size and the distribution of these HIV reservoirs among the various CD4 T cell-subpopulations via a comprehensive analysis using innovative highly miniaturized and complementary immunological and virological assays.
Our first hypothesis is that HIV reservoirs persist even in patients with low to undetectable HIV-DNA in the total PBMCs, and can be detected ex vivo or give rise to HIV production in some CD4 T cells subsets due to the mean 10-fold enrichment in peripheral blood TCM and TTM cells. The sorting of the various sorted CD4 TN, TCM, TTM, TEM and other key subsets will thus allow to test whether and in which subset:
- the virus genome is intact or contains deletions interfering with its replicative capacity,
- HIV production can be induced in vitro after distinct activation signals,
- HIV transcripts are detectable ex-vivo,
- Low immune activation and inflammatory environment is associated with these extremely low HIV reservoirs levels by testing a series of plasma pro-inflammatory molecules together with cell surface activation markers and intra-cellular transcriptional signatures .
- Conditions
- HIV
- Being tested
- Ex-vivo analysis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ex-vivo analysisOther
What is being measured
The primary outcome is the main question the study is designed to answer.
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-)
Measured: one year
Secondary outcomes (6)
measure of host molecular signatures and transcriptional activity in each subset assessed by microfluidic qRT-PCR (Fluidigm)
host molecular signatures and transcriptional activity performed by using microfluidic qRT-PCR (Fluidigm) quantifying the key host's genes among a panel of 90 host's molecular signatures including factors involved in restriction, repression or activation of HIV transcription
Measured: 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
The induction of replication-competent HIV forms measured in culture supernatants from each subset by using the ultrasensitive real-time RT-PCR assay
Measured: 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
ex vivo molecular characteristics phylogenetic analysis of the integrated HIV-DNA in the genome of sorted host CD4 subsets
Measured: one year
measure of levels of unspliced HIV transcripts in total and different subsets of CD4 T cells.
Levels of unspliced HIV transcripts performed by using microfluidic qRT-PCR (Fluidigm)
Measured: one year
measure of serum inflammatory biomarkers assessed by ELISA assay
Inflammatory biomarkers analyzed on plasma: hsCRP, IL6, sTNF I, IP-10, sCD14, sCD63 and D-dimers
Measured: one year
measure of immune activation in the different sorted CD4 T cell subsets assessed by flow cytometry on fresh blood
- The cell immune activation markers analyzed by flow cytometry on fresh blood. Activation markers will be analyzed on CD4 (HLA-DR) and CD8 (HLA-DR, CD38) subsets (ie N, TCM, TTM, TEM) and on monocytes subsets defined by the expression of CD14/CD16 (CD163/CD38). The expression of CD38 will be quantified by beads.
Measured: one year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Dec 2015 (estimated)
- Study startJun 2014
- Primary completionJun 2016
- Study completionJul 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HIVStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Time perspective
- Cross-sectional
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Centre de Recherches et d'Etude sur la Pathologie Tropicale et le Sida
- Sponsor type
- University, hospital or other
- Collaborators
- INSERM UMR S 1136, Bristol-Myers Squibb
- Responsible party
- Sponsor
- Investigators
- Christine Katlama, MD, Study director, Groupe Hospitalier Pitie-SalpetriereRuxandra Calin, MD, Principal investigator, Groupe Hospitalier Pitie-Salpetriere
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02628340
- Sponsor's protocol ID
- CREPATS 002
- Acronym
- RESACHRON
- Status last verified
- Aug 2016
- First submitted
- 4 Feb 2015
- Last updated
- 2 Aug 2016
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 2 Aug 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Comprehensive Analysis of HIV Reservoirs in Chronically Infected HIV-1 Treated Patients With a Low Total Cell-associated Blood HIV-DNA
- ClinicalTrials.gov ID
- NCT02628340
- Acronym / sponsor ID
- RESACHRON / CREPATS 002
- Conditions
- HIV
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Centre de Recherches et d'Etude sur la Pathologie Tropicale et le SidaUniversity, hospital or other
- Collaborators
- INSERM UMR S 1136, Bristol-Myers Squibb
- Study start
- Jun 2014
- Primary completion
- Jun 2016 (actual)
- Study completion
- Jul 2016 (actual)
- First posted
- 11 Dec 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Extremely low levels of HIV reservoirs are achievable in some chronically-infected patients durably controlled with cART. Despite the multiplicity and heterogeneity of factors governing the persistence of HIV reservoirs, such low levels of HIV reservoirs seem necessary, though probably not sufficient, to reach the status of functional cure defined by virus control in the absence of treatment. The mechanisms associated with these low HIV reservoirs in chronic treated infection are unknown but might involve a low immune activation and inflammatory environment, and deleterious HIV mutations. Understanding those mechanisms will provide novel clues for future strategies aiming at obtaining an HIV Cure.
The main objective of RESACHRON Study is to define in chronically infected patients with suppressed viremia, cART and extremely low levels of HIV reservoirs, the viral and cellular mechanisms underlying the persistence, the size and the distribution of these HIV reservoirs among the various CD4 T cell-subpopulations via a comprehensive analysis using innovative highly miniaturized and complementary immunological and virological assays.
Our first hypothesis is that HIV reservoirs persist even in patients with low to undetectable HIV-DNA in the total PBMCs, and can be detected ex vivo or give rise to HIV production in some CD4 T cells subsets due to the mean 10-fold enrichment in peripheral blood TCM and TTM cells. The sorting of the various sorted CD4 TN, TCM, TTM, TEM and other key subsets will thus allow to test whether and in which subset:
- the virus genome is intact or contains deletions interfering with its replicative capacity,
- HIV production can be induced in vitro after distinct activation signals,
- HIV transcripts are detectable ex-vivo,
- Low immune activation and inflammatory environment is associated with these extremely low HIV reservoirs levels by testing a series of plasma pro-inflammatory molecules together with cell surface activation markers and intra-cellular transcriptional signatures .
Study design
- Time perspective
- Cross-sectional
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- 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.
Key inclusion criteria (7 listed)
- HIV-1 infected adult
- Age > 18 years
- HIV-RNA plasma viral load (pVL) < 50 copies/mL
- Under antiretroviral therapy (cART)
- CD4 >400/mm3
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ex-vivo analysis | Other | – |
Primary outcome
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.
Time frame: one year
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-)
6 secondary outcomes
measure of host molecular signatures and transcriptional activity in each subset assessed by microfluidic qRT-PCR (Fluidigm)
Time frame: 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
Time frame: 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
Time frame: one year
measure of levels of unspliced HIV transcripts in total and different subsets of CD4 T cells.
Time frame: one year
measure of serum inflammatory biomarkers assessed by ELISA assay
Time frame: one year
measure of immune activation in the different sorted CD4 T cell subsets assessed by flow cytometry on fresh blood
Time frame: one year
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Aug 2016.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Christine Katlama, MD study director
Groupe Hospitalier Pitie-Salpetriere
Ruxandra Calin, MD principal investigator
Groupe Hospitalier Pitie-Salpetriere
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of HIV, run by Centre de Recherches et d'Etude sur la Pathologie Tropicale et le Sida at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Aug 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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. (time frame: one year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Aug 2016.