Clinical trial NCT05584397: Comparing Immune Activation and Latent HIV Reservoir Size Between People Living With HIV on Tenofovir-containing Versus NRTI-free ART
Official title: Comparing Immune Activation and Latent HIV Reservoir Size Between People Living With HIV (PWH) on Tenofovir-containing Versus NRTI-sparing ART
Study type: OBSERVATIONAL
Overall status: ENROLLING_BY_INVITATION
Conditions: HIV-1-infection
HIV Disease Progression
Inflammation
HIV
Keywords: HIV reservoir
Interferon Stimulated Genes
Tenofovir
Interferon
Duodenum
Blood
Rectum
NRTI
Lead sponsor: University of Washington
Sponsor class: OTHER
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: National Center for Advancing Translational Sciences (NCATS)
First posted: 2022-10-18
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: People living with HIV (PWH) on stable use of antiretroviral therapy (ART). They will be between 18 and 65 years of age. Children less than 18 years of age are excluded. Women of childbearing potential should not be pregnant to participate.

Brief summary: The goal of the project is to determine the difference in immune activation and HIV reservoir size between People living with HIV (PWH) on tenofovir-containing antiretroviral therapy (ART) versus PWH on nucleoside reverse transcriptase inhibitor (NRTI)-sparing ART. Tenofovir (TFV), a phosphonated nucleoside reverse transcriptase inhibitor (NRTI), is being used for oral pre-exposure prophylaxis (PrEP).

The investigators will test this hypothesis: tenofovir, and perhaps NRTIs in general, stimulate a type I/III interferon also in PWH who take these drugs. Because chronic interferon stimulation may promote the survival and proliferation of cells with integrated provirus, the investigators also hypothesize that these drugs antagonize decay of the HIV latent reservoir in PWH on ART. Consequently, the researchers hypothesize that PWH who have switched from NRTI-containing ART to NRTI-sparing ART exhibit lower type I/III interferon pathway activation and lower latent HIV reservoir size.

The investigators also hypothesize that independently of treatment, the extent of type I/III interferon activation correlates with latent HIV reservoir size.

Thus, the proposed study seeks to answer these two questions. Can the gastrointestinal epithelium be impacted by ART, and contribute to chronic immune activation and expansion of the HIV-1 reservoir? If so, what therapeutic approaches can the investigators implement to reduce the HIV-1 proviral load? The data will reveal pathways that can be targeted therapeutically to treat chronic immune activation in PWH. The findings of this study will immediately translate to optimize the standard of care in PWH.

Detailed description: The study will be open-label, cross-sectional, two-cohort study (20 participants per cohort will be recruited).

Cohort 1: Tenofovir-containing ART (tenofovir disoproxil fumarate \[TDF\] OR tenofovir alafenamide \[TAF\] PLUS any other ART drugs) prescribed for daily use by participants' primary care providers.

Cohort 2: NRTI-sparing ART (specifically: rilpivirine PLUS dolutegravir OR rilpivirine PLUS cabotegravir) prescribed for daily use by participants' primary care providers.

The investigators plan to test type I/III IFN (interferon) pathway activation using Crystal digital PCR (Crystal-dPCR) to quantify mRNA copy numbers of ISG15 (ISG15 ubiquitin-like modifier), MX1 (MX dynamin like GTPase 1) and IFI6 (interferon alpha inducible protein 6). RNA will be isolated from the rectal and duodenal biopsies stored in RNALater using the RNeasy Fibrous Tissue Mini Kit (Qiagen) and from the PBMC using the RNeasy Plus Mini Kit (Qiagen). Crystal-dPCR will be performed on a 6-color Naica Crystal digital PCR instrument (Stilla Technologies).

The latent HIV reservoir will be measured in DNA derived from peripheral blood mononuclear cells (PBMCs) using a novel intact/defective proviral HIV DNA Crystal-dPCR assay developed jointly by the Hladik and Jerome groups in Seattle.

Eligibility criteria: Inclusion Criteria:

1. Confirmed HIV infection, by two different positive antibody tests and/or detectable plasma HIV RNA on two different dates
2. ≥18 and ≤65 years of age
3. Stable use of ART medication for ≥ 1 year
4. No switch of ART regimen within the past 180 days
5. CD4 \> 350/mm3 within the past 180 days
6. HIV RNA \<40 copies / mL on ≥ 2 occasions during continuous ART of ≥ 1 years, with no blip of \>1000 HIV RNA copies / mL
7. Karnofsky score ≥80
8. Willingness and ability to provide informed consent for study participation
9. Willingness to undergo all required study procedures

Exclusion Criteria:

1. Active malignancy including myelodysplastic syndrome, or myeloproliferative disease within 24 weeks prior to study entry
2. Prior organ or bone marrow transplantation
3. Diagnosed autoimmune disease
4. Medical need for ongoing treatment with an immunosuppressive drug
5. Diagnosis of AIDS (defined as any AIDS-defining opportunistic infection or cancer, or a history of blood CD4+ T cell count \< 200/μL)
6. Active opportunistic infection
7. Vomiting or diarrhea which prohibits consistent use of ART
8. Pregnant or breastfeeding
9. Excessive ingestion of ethanol determined by an AUDIT score of \>8
10. Substance abuse
11. History of medical non-compliance
12. The following laboratory values (\< 30 days before enrollment):

    * Hemoglobin \< 8.5 mg/dL
    * Platelet count \< 100,000/μL
    * Coagulation (PT/PTT) tests above the normal reference
    * Creatinine clearance \< 60 mL/min
13. Using disallowed medications:

    * Systemic corticosteroids
    * Other immunosuppressive medications (e.g., cyclosporine, sirolimus, tacrolimus, pimecrolimus, tofacitinib)
14. BMI \> 40
15. Pulmonary dysfunction.
16. Use of narcotics.

Primary outcomes:
measure: Type I/III Interferon pathway activation
timeFrame: Biopsy samples to assess interferon pathway activation will be collected during surgery. The assessment of this outcome (the determination of mRNA copy number) will be done around within one year of completing sample collection.
measure: Size of the latent intact proviral HIV reservoir in cell-associated HIV DNA (Ca-DNA)
timeFrame: Blood samples to assess the latent HIV reservoir will be collected during surgery. The assessment of this outcome (the determination of HIV copy number) will be done around within one year of completing sample collection.
measure: Size of the latent defective proviral HIV reservoir in cell-associated HIV DNA (Ca-DNA)
timeFrame: Blood samples to assess the latent HIV reservoir will be collected during surgery. The assessment of this outcome (the determination of HIV copy number) will be done around within one year of completing sample collection.
Secondary outcomes:
measure: Composition of gastrointestinal microbiota
timeFrame: Cytobrush samples to assess gut microbiota will be collected during surgery. The assessment of this outcome (the determination of 16s repertoire) will be done around within one year of completing sample collection.
Other outcomes:
measure: Determination of proteins that are secreted in the rectum and duodenum
timeFrame: Cytobrush samples to assess secreted proteins will be collected during surgery. The assessment of this outcome (the determination of the proteome) will be done around within one year of completing sample collection.
measure: Determination of the global transcriptome
timeFrame: Blood and biopsy samples will be collected during surgery. The assessment of this outcome (the characterization of the transcriptome will be done around within one year of completing sample collection.
Locations:
city: Seattle
country: United States
facility: University of Washington Positive Research and the Gastroenterology Clinic at Harborview Medical Center
state: Washington
Study officials:
affiliation: University of Washington
name: German G Gornalusse, PhD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Washington
name: Florian Hladik, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Washington
name: Romel D Mackelprang, PhD, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hughes SM, Levy CN, Calienes FL, Stekler JD, Pandey U, Vojtech L, Berard AR, Birse K, Noel-Romas L, Richardson B, Golden JB, Cartwright M, Collier AC, Stevens CE, Curlin ME, Holtz TH, Mugo N, Irungu E, Katabira E, Muwonge T, Lama JR, Baeten JM, Burgener A, Lingappa JR, McElrath MJ, Mackelprang R, McGowan I, Cranston RD, Cameron MJ, Hladik F. Treatment with Commonly Used Antiretroviral Drugs Induces a Type I/III Interferon Signature in the Gut in the Absence of HIV Infection. Cell Rep Med. 2020 Sep 22;1(6):100096. doi: 10.1016/j.xcrm.2020.100096.