Clinical trial NCT04133012: 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
Official title: A Prospective Study Aiming to Determine the Cartography of Virological Reservoir Related to Antiretroviral Concentrations in Chronic HIV-1 Patients Treated with a First Line of Dolutegravir and Associated Nucleoside / Nucleotide Reverse Transcriptase Inhibitors (NRTIs).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV-1 Infection
Keywords: Viral cartography
Viral reservoir
Antiretroviral treatments diffusion
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: ViiV Healthcare
First posted: 2019-10-21
Enrollment: 20
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility criteria: Inclusion Criteria:

* Male HIV-1 infected subjects
* Age \> or = 18 years old
* Currently receiving as first line therapy 7 days a week for at least 18 months with dolutegravir (at 50 mg once a day) and two nucleoside/nucleotide reverse transcriptase inhibitors (abacavir/lamivudine or ,tenofovir/emtricitabine) or

  * Receiving first-line therapy 7 days a week for at least 18 months with dolutegravir (50 mg once daily) + abacavir/lamivudine followed by dual therapy with dolutegravir + lamivudine for at least 6 months; or
  * Receiving first-line therapy 7 days a week for at least 18 months with dolutegravir + tenofovir / emtricitabine followed by dual therapy with dolutegravir + lamivudine for at least 6 months.
* HIV RNA currently \<50 Cp/mL, , and \<50 Cp/mL 6 months after treatment initiation and \<50 Cp/mL confirmed at 12 months after treatment initiation
* Normal PT, APTT and platelet count values at screening
* Written and informed consent signed by the person and the investigator (no later than the day of pre-enrollment and prior to any examination carried out as part 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 or AME is not a social security scheme)

Exclusion Criteria:

* Single HIV-2 infection
* Dolutegravir antiretroviral monotherapy
* Contraindication to biopsy, taking anticoagulant and antiplatelet drugs
* Hemophilia
* Symptomatic sexually transmitted infection
* Being under guardianship or trusteeship mandate for future protection
* Participation in another research involving the human person, of category 1 or 2,
* Associated treatments (Carbamazepine, Oxcarbazepine, Phenytoin, Phenobarbital, Rifampicin, St. John's Wort)

Primary outcomes:
measure: Characterization of the diffusion of dolutegravir and associated backbone (abacavir/lamivudine or tenofovir/emtricitabine) in sperm
timeFrame: At Day 0, At time T0 (before taking treatments)
measure: Characterization of the diffusion of dolutegravir and associated backbone (abacavir/lamivudine or tenofovir/emtricitabine) in lymph nodes
timeFrame: At Day 0, between T1 (maximum 3 hours after tacking treatments) and T3 (8 hours after taking treatments)
measure: Characterization of the diffusion of dolutegravir and associated backbone (abacavir/lamivudine or tenofovir/emtricitabine) in fat tissues
timeFrame: At Day 0, between T1 (maximum 3 hours after tacking treatments) and T3 (8 hours after taking treatments)
measure: Characterization of the diffusion of dolutegravir and associated backbone (abacavir/lamivudine or tenofovir/emtricitabine) in rectal tissues
timeFrame: At Day 0, T1 (maximum 3 hours after taking treatment)
Secondary outcomes:
measure: Characterization of the level of the replication (RNA-HIV) and the level of infection (DNA-HIV) in the reservoirs
timeFrame: At Day 0
measure: Study of the spatial dynamics of viral quasi-species In the different reservoirs
timeFrame: At Day 0
measure: Study of the mutations of resistance in the integrase gene
timeFrame: At Day 0
measure: Description for each compartment of the relationship between exposure to therapeutic combinations and the level of infection / viral replication
timeFrame: At Day 0
Other outcomes:
Locations:
city: Clamart
country: France
facility: Antoine-Beclere Hospital
city: Le Kremlin-Bicêtre
country: France
facility: Bicetre Hospital
city: Paris
country: France
facility: Saint Antoine Hospital
city: Paris
country: France
facility: Bichat Hospital
city: Paris
country: France
facility: Hotel Dieu Hospital
city: Paris
country: France
facility: Necker Hospital
city: Paris
country: France
facility: Pitie Salpetriere Hospital
city: Tourcoing
country: France
facility: Tourcoing Hospital
Study officials:
affiliation: CHU Pointe-à-Pitre/Abymes
name: Antoine CHERET
role: PRINCIPAL_INVESTIGATOR
References: