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

HIV-1 Infection Clinical Trial

— DOLUVOIR  

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).

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04133012
• Other study ID #: ANRS EP64 DOLUVOIR
• Status: Completed
• Phase: N/A
• Start date: February 10, 2020
• Est. completion date: June 9, 2023

Study information

• Verified date: August 2023
• Source: ANRS, Emerging Infectious Diseases
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: June 9, 2023
• Est. primary completion date: June 9, 2023
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• HIV-1 Infection

Intervention

Other:
• Samplings
blood samples rectal biopsies nodes biopsies cutaneous fat tissues biopsies semen sample

Locations

Country	Name	City	State
France	Antoine-Beclere Hospital	Clamart
France	Bicetre Hospital	Le Kremlin-Bicêtre
France	Bichat Hospital	Paris
France	Hotel Dieu Hospital	Paris
France	Necker Hospital	Paris
France	Pitie Salpetriere Hospital	Paris
France	Saint Antoine Hospital	Paris
France	Tourcoing Hospital	Tourcoing

Sponsors (2)

Lead Sponsor	Collaborator
ANRS, Emerging Infectious Diseases	ViiV Healthcare

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Characterization of the diffusion of dolutegravir and associated backbone (abacavir/lamivudine or tenofovir/emtricitabine) in sperm	Dosage of the different antiretroviral drugs molecules in sperm	At Day 0, At time T0 (before taking treatments)
Primary	Characterization of the diffusion of dolutegravir and associated backbone (abacavir/lamivudine or tenofovir/emtricitabine) in lymph nodes	Dosage of the different antiretroviral drugs molecules in lymph nodes	At Day 0, between T1 (maximum 3 hours after tacking treatments) and T3 (8 hours after taking treatments)
Primary	Characterization of the diffusion of dolutegravir and associated backbone (abacavir/lamivudine or tenofovir/emtricitabine) in fat tissues	Dosage of the different antiretroviral drugs molecules in fat tissues	At Day 0, between T1 (maximum 3 hours after tacking treatments) and T3 (8 hours after taking treatments)
Primary	Characterization of the diffusion of dolutegravir and associated backbone (abacavir/lamivudine or tenofovir/emtricitabine) in rectal tissues	Dosage of the different antiretroviral drugs molecules in rectal tissues	At Day 0, T1 (maximum 3 hours after taking treatment)
Secondary	Characterization of the level of the replication (RNA-HIV) and the level of infection (DNA-HIV) in the reservoirs	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	At Day 0
Secondary	Study of the spatial dynamics of viral quasi-species In the different reservoirs	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	At Day 0
Secondary	Study of the mutations of resistance in the integrase gene	Description of resistance mutations in Integrase gene which could be linked to suboptimal concentrations of dolutegravir	At Day 0
Secondary	Description for each compartment of the relationship between exposure to therapeutic combinations and the level of infection / viral replication	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	At Day 0

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