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Cartography of Virologic Reservoir Related to Antiretroviral Concentrations in HIV-1 Chronic Patients Treated by a First Line Treatment Containing Dolutegravir and Associated Nucleoside / Nucleotide Reverse Transcriptase Inhibitors Backbone (DOLUVOIR)

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ClinicalTrials.gov Identifier: NCT04133012
Recruitment Status : Not yet recruiting
First Posted : October 21, 2019
Last Update Posted : October 21, 2019
Sponsor:
Collaborator:
ViiV Healthcare
Information provided by (Responsible Party):
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)

Brief Summary:
The main objective of the study is to characterize the diffusion of dolutegravir and associated backbone (abacavir/lamivudine or tenofovir/emtricitabine) in HIV-1 chronic patients in the main putative reservoirs, namely inguinal lymph nodes, rectal, fat tissues and sperm.

Condition or disease Intervention/treatment Phase
HIV-1 Infection Other: Samplings Not Applicable

Detailed Description:

The major obstacle to a functional cure of HIV infection is the persistence of the latent HIV reservoir.

Several arguments suggest the persistence of a residual viral replication in different compartments, despite an effective antiretroviral treatment. This residual viral replication partially comes from pharmacological sanctuaries where the drugs do not largely penetrate. In such sanctuaries a recent report published in Nature has shown that the virus can replicate with less antiviral pressure contributing to continuously replenish the reservoirs. Nevertheless, this study concerned a limited number of patients and only blood and lymph-node samples were collected for viral analysis. Moreover, the drug distribution was estimated based on mathematical hypotheses without drug measure concentration.

The International AIDS Society recommend for most patients an optimal initial regimen containing 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (InSTI)2. The new integrase inhibitor dolutegravir is more and more widely used in combination with nucleoside/nucleotide reverse transcriptase. Indeed, this drug shows a good tolerance and demonstrates a particularly fast inhibition of the viral replication. Moreover, dolutegravir is active against HIV strains that are resistant to the first generation of integrase inhibitors, raltegravir and elvitegravir. However the penetration of dolutegravir in deep compartments has not been fully characterized: the studies comprised a small number of patients and were not able to estimate the distribution in several compartments at the same time for each patient. Moreover the levels of residual viral replication in those compartments during treatment are unknown, making it difficult to evaluate the capacity of this drug and associated backbone to efficiently act against viral reservoirs maintenance.

The aim of the study is to measure simultaneously dolutegravir and nucleoside/nucleotide reverse transcriptase inhibitors in different compartments to obtain cartography of dolutegravir and associated backbone distribution and the spatial dynamics of virus in each patient.

The decision to study dolutegravir and the two associated backbones (abacavir / lamivudine or tenofovir /emtricitabine) was decided as:

  • The International AIDS Society recommend for most patients an optimal initial regimen containing 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (InSTI)2.
  • Dolutegravir viral power is established for high levels of viral load 90 and this drug is widely used.
  • This study is very complementary of studies ANRS SIVART and ANRS 169 OPTIPRIM 2.
  • Dolutegravir is combined with abacavir + lamivudine in a single-tablet and is largely prescribed.
  • Raltegravir and elvitegravir will not be analysed because the number of recruited patients should be more important to obtain sufficient data and the feasibility would not be sure.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 34 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: A Prospective Study to Determine the Cartography of Virologic Reservoir Related to Antiretroviral Concentrations in HIV-1 Chronic Patients Treated by a First Line Treatment Containing Dolutegravir and Associated Nucleoside / Nucleotide Reverse Transcriptase Inhibitors Backbone
Estimated Study Start Date : November 1, 2019
Estimated Primary Completion Date : November 1, 2020
Estimated Study Completion Date : November 1, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Single Arm
Single arm composed by 34 HIV-1 infected male subjects
Other: Samplings
  • blood samples
  • rectal biopsies
  • nodes biopsies
  • cutaneous fat tissues biopsies
  • semen sample




Primary Outcome Measures :
  1. Characterization of the diffusion of dolutegravir and associated backbone (abacavir/lamivudine or tenofovir/emtricitabine) in sperm [ Time Frame: At Day 0, At time T0 (before taking treatments) ]
    Dosage of the different antiretroviral drugs molecules in sperm

  2. Characterization of the diffusion of dolutegravir and associated backbone (abacavir/lamivudine or tenofovir/emtricitabine) in lymph nodes [ Time Frame: At Day 0, between T1 (maximum 3 hours after tacking treatments) and T3 (8 hours after taking treatments) ]
    Dosage of the different antiretroviral drugs molecules in lymph nodes

  3. Characterization of the diffusion of dolutegravir and associated backbone (abacavir/lamivudine or tenofovir/emtricitabine) in fat tissues [ Time Frame: At Day 0, between T1 (maximum 3 hours after tacking treatments) and T3 (8 hours after taking treatments) ]
    Dosage of the different antiretroviral drugs molecules in fat tissues

  4. Characterization of the diffusion of dolutegravir and associated backbone (abacavir/lamivudine or tenofovir/emtricitabine) in rectal tissues [ Time Frame: At Day 0, T1 (maximum 3 hours after taking treatment) ]
    Dosage of the different antiretroviral drugs molecules in rectal tissues


Secondary Outcome Measures :
  1. Characterization of the level of the replication (RNA-HIV) and the level of infection (DNA-HIV) in the reservoirs [ Time Frame: At Day 0 ]
    Analyze and comparison of the level of viral transcription by measuring the cell-associated HIV- RNA in the different tissues and fluids: lymphoid, rectal, genital secretion, blood and fat biopsies as well as cerebrospinal fluid. Analyze and comparison of the reservoir level by measuring the cell-associated total HIV- DNA in the different tissues and fluids

  2. Study of the spatial dynamics of viral quasi-species In the different reservoirs [ Time Frame: At Day 0 ]
    Analyze of the spatial dynamics of HIV-DNA and HIV-RNA from Lymphoid, rectal, genital secretion, blood, fat cells by phylogenetic analyses after sequencing Env HIV-DNA and HIV-RNA

  3. Study of the mutations of resistance in the integrase gene [ Time Frame: At Day 0 ]
    Description of resistance mutations in Integrase gene which could be linked to suboptimal concentrations of dolutegravir

  4. Description for each compartment of the relationship between exposure to therapeutic combinations and the level of infection / viral replication [ Time Frame: At Day 0 ]
    Characterization of the relationship between the concentration of dolutegravir and backbone drugs with the level of wild type viral replication in the different compartments. Analyze of the impact of backbone drugs associated to dolutegravir on viral level production. Correlation between the level of resistant virus replication and the exposure to dolutegravir and the backbone drugs. Evaluation by simulation the effect of different dosing regimen of dolutegravir (including higher doses) on the level of viral replication and on resistance



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male HIV-1 infected subjects
  • Age >or = 18 years old
  • Currently receiving as first line a stable antiretroviral therapy (ARV) regimen containing dolutegravir (at 50 mg once a day) and two nucleoside/nucleotide reverse transcriptase inhibitors (abacavir/lamivudine or tenofovir/emtricitabine) from minimum 18 months
  • HIV RNA <50 cp/mL, undetectable 6 months after treatment initiation and confirmed at 12 months after treatment initiation
  • Normal laboratory value of Prothrombin Time and Activated Partial Thromboplastin Time and platelets numbers at screening
  • Ability to understand and sign a written informed consent form
  • Written and informed consent signed by the person and the investigator (no later than the day of pre-inclusion and prior to any examination realized in the frame of the study) (article L1122-1-1 of the Public Health Code)
  • Person affiliated or beneficiary of a social security scheme (article L1121-11 of the Public Health Code) (State Medical Aid (AME) is not a social security scheme)

Exclusion Criteria:

  • Isolated HIV-2 infection
  • Dolutegravir antiretroviral monotherapy
  • Biopsies contraindications, taking anticoagulant and antiplatelet drugs are not allowed
  • Haemophilia
  • Symptomatic sexually transmitted infection
  • Being under guardianship or trusteeship mandate for future protection
  • Participate to another research involving human person, categories 1 or 2,
  • Associated treatments: Carbamazepine, Oxcarbazepine, Phenytoin, Phenobarbital, Rifampicin, St. John's Wort.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04133012


Contacts
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Contact: Laura NAILLER +33 1 53 94 80 64 laura.nailler@anrs.fr
Contact: Katia BOURDIC + 33 1 45 21 63 16 katia.bourdic@aph.fr

Locations
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France
Antoine-Beclere Hospital
Clamart, France
Principal Investigator: Sophie ABGRALL         
Bicetre Hospital
Le Kremlin-Bicêtre, France
Principal Investigator: Antoine CHERET         
Hotel Dieu Hospital
Paris, France
Principal Investigator: Dominique SALMON-CERON         
Necker Hospital
Paris, France
Principal Investigator: Claudine DUVIVIER         
Pitie Salpetriere Hospital
Paris, France
Principal Investigator: Valérie MARTINEZ         
Sponsors and Collaborators
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
ViiV Healthcare
Investigators
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Principal Investigator: Antoine CHERET Bicetre Hospital

Additional Information:
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Responsible Party: French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
ClinicalTrials.gov Identifier: NCT04133012    
Other Study ID Numbers: ANRS EP64 DOLUVOIR
First Posted: October 21, 2019    Key Record Dates
Last Update Posted: October 21, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS):
Viral cartography
Viral reservoir
Antiretroviral treatments diffusion
Additional relevant MeSH terms:
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Anti-Retroviral Agents
Dolutegravir
Reverse Transcriptase Inhibitors
Antiviral Agents
Anti-Infective Agents
HIV Integrase Inhibitors
Integrase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Nucleic Acid Synthesis Inhibitors