Clinical trial NCT02972931: LoViReT (Low Viral Reservoir Treated Patients)
Official title: Impact of Antiretroviral Treatment and Predictors in Subjects With Extremely Low HIV-1 Reservoir: Optimization of New Cure Strategies
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Hiv
Keywords: HIV infection
low HIV reservoir
functional cure
Lead sponsor: IrsiCaixa
Sponsor class: OTHER
First posted: 2016-11-25
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: HIV-infected subjects with extremely low or undetectable HIV-1 DNA levels in peripheral blood despite having initiated cART during chronic HIV-1 infection

Brief summary: The main purpose of this study is to unravel the mechanisms by which the "Low Viral Reservoir Treated" patients (LoViReT) maintain extremely low HIV-1 DNA levels despite having initiated cART during chronic HIV-1 infection. This group may have specific and different clinical, virological and immunogenetical characteristics, compared to patients with regular reservoir size, which might be useful to design new and more effective treatment approaches.

Detailed description: Combination antiretroviral therapy (cART) is highly successful suppressing HIV-1 replication and clinical progression in infected patients. However, it does not hamper the establishment of viral reservoirs, generating latently infected cells that provoke a quick rebound of HIV viremia after treatment interruption. Different strategies to tackle HIV-1 reservoirs have been suggested during last years with limited success. Actually, the few cases of described HIV-1 functional cure are found in elite and post-treatment controllers. Thus, some patients with regular HIV progression can control replication spontaneously, most of them after receiving cART during primary HIV-1 infection. Indeed, the "Mississippi baby", who was treated 36h after birth, had sustained undetectable viremia for 27 months after treatment interruption. Recently, it has also been proven in successfully treated patients that low proviral reservoir is related to better HIV-1 control after treatment discontinuation. Thus, the identification of patients with lower latent reservoir in chronic infection will allow unveiling potential mechanisms to achieve a functional cure after cART withdrawal.

Our center in Badalona allocates a biological sample collection containing 72,000 specimens from HIV-1-infected subjects. Samples from 319 patients under suppressive cART for more than 3 years have been screened using the high sensitive BioRad droplet digital Polymerase Chain Reaction platform (ddPCR). Among the screened patients, a cohort of 20 "Low Viral Reservoir Treated" patients (LoViReT) with extremely low or undetectable HIV-1 DNA levels in peripheral blood despite having initiated cART during chronic HIV-1 infection have been established, which is expected to be increased up to 40 patients. Discovering the factors that reduce HIV reservoir and make LoViReT patients maintain extremely low levels of proviral HIV-1 DNA will open new treatment strategies based on maintaining the reservoir to the lowest levels beside the regular clinical marker of viral load. In addition, a further second step of controlled cART interruption can be designed to evaluate the real impact of harboring extremely low levels of latent reservoir for further functional HIV cure.

To unravel the mechanisms by which the LoViReT cohort maintain extremely low HIV-1 DNA levels despite having initiated cART during chronic HIV-1 infection, this cohort will be studied from different points of view. All the results will be compared to a control group of 40 individuals with standard levels of total HIV DNA (reservoir). Three mayor aims will be addressed to then extrapolate our results to larger chronic HIV-1-infected populations:

* To investigate the role of cART on the suppression of the HIV reservoir in the LoViReT patients, compared to controls. To address this objective, a longitudinal analysis of proviral HIV DNA for each patient will be performed, including time points previous to cART. In total, 200 samples will be analyzed and dynamic models will be built for the two different levels of reservoir establishment. General immune phenotype of cellular populations, including also activation markers, will be also assessed in all time points.
* To investigate the integrity of HIV sequences in the LoViReT patients and its relationship with pathogenesis, in comparison to controls. Genotypic HIV tropism and the full viral genome will be analyzed through sequencing from DNA of patients' Peripheral Blood Mononuclear Cells (PBMC). Fresh blood samples will be taken from the 40 LoViReT and 40 control patients in the study. In addition, for those exerting virus production, viral isolates will be used to analyze viral replication capacity and cell pathogenesis.
* To investigate the role of immune-genetic factors that along with cART contribute to reduce the HIV reservoirs in the LoViReT patients. Functional T-cell response will be measured isolating CD8 T cells and measuring the inhibition capacity for HIV replication in each patient. Specific HIV-related CD8 T-cell interferon production will be also evaluated under epitope stimulus. Other progression associated genetic factors as Human Leukocyte Antigen (HLA) type, and chemokine receptor 5 (CCR5) and 2 (CCR2), and SIGLEC-1 Single Nucleotide Polymorphisms (SNPs) will be also explored.

Eligibility criteria: Inclusion Criteria:

* ≥ 18 years of age
* Voluntarily signed informed consent
* Proven HIV-1 infection
* On stable cART regimen (antiretroviral therapy consisting of at least 3 registered antiretroviral agents) for at least 3 years
* HIV-RNA \<50 copies/mL during the last 3 years prior to the study
* Proviral HIV-DNA \<50 copies/million PBMCs by using the ultrasensitive BioRad residual ddPCR quantification platform

Exclusion Criteria:

* cART discontinuation between previous screening and Visit #1.
* HIV-RNA above 50 copies/mL between previous screening to Visit #1

Primary outcomes:
measure: Longitudinal Analysis of Total HIV DNA and Immune-phenotype by Digital Droplet Polymerase Chain Reaction (PCR) and Flow Cytometry, Respectively, Comparing This Outcome Before and After cART (Evaluation of cART Effect on This Parameters)
timeFrame: The time frame for the outcome measure is an average of 5 years. Including a baseline, 18 months, and 5 years post cART initiation.
measure: Replication Competent Reservoir in Patients With Low (LoViReT) Normal (Controls) Levels of Total HIV DNA
timeFrame: The time frame for the outcome measure is on patients on cART for at least 5 years.
measure: Evaluation and Comparison of CD8 T-cell Responses by Inhibition Assays, Between Patients With Low (LoViReT) and Normal (Controls) Levels of Total HIV DNA
timeFrame: The time frame for the outcome measure is on samples before initiation of cART and after 5 years on cART
measure: Analysis and Comparison of Progression-associated Genetic Factors, Between Patients With Low (LoViReT) and Normal (Controls) Levels of Total HIV DNA
timeFrame: The time frame for the outcome measure is on patients on cART for at least 5 years.
measure: Measurement of Genotypic Tropism in Patients With Low (LoViReT) and Normal (Controls) Levels of Total HIV DNA
timeFrame: The time frame for the outcome measure is on patients on cART for at least 5 years.
Secondary outcomes:
Other outcomes:
Locations:
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Barcelona
Study officials:
affiliation: IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol
name: Javier Martinez-Picado, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Galvez C, Urrea V, Dalmau J, Jimenez M, Clotet B, Monceaux V, Huot N, Leal L, Gonzalez-Soler V, Gonzalez-Cao M, Muller-Trutwin M, Saez-Cirion A, Garcia F, Blanco J, Martinez-Picado J, Salgado M. Extremely low viral reservoir in treated chronically HIV-1-infected individuals. EBioMedicine. 2020 Jul;57:102830. doi: 10.1016/j.ebiom.2020.102830. Epub 2020 Jun 21.
citation: Galvez C, Urrea V, Garcia-Guerrero MDC, Bernal S, Benet S, Mothe B, Bailon L, Dalmau J, Martinez A, Nieto A, Leal L, Garcia F, Clotet B, Martinez-Picado J, Salgado M. Altered T-cell subset distribution in the viral reservoir in HIV-1-infected individuals with extremely low proviral DNA (LoViReTs). J Intern Med. 2022 Aug;292(2):308-320. doi: 10.1111/joim.13484. Epub 2022 Mar 28.