Comparing Immune Activation and Latent HIV Reservoir Size Between People Living With HIV on Tenofovir-containing Versus NRTI-free ART

NCT05584397 | Enrolling By Invitation

• 3 other identifiers: STUDY00011699R01AI134293KL2TR002317
• Study Type: observational
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

HIV-1-infection; HIV Disease Progression; Inflammation; HIV

Keywords

HIV reservoir; Interferon Stimulated Genes; Tenofovir; Interferon; Duodenum; Blood; Rectum; NRTI

Outcome Measures

Primary Outcomes (3)

• Type I/III Interferon pathway activation

  Quantification of the mRNA copy number of the following Interferon-Stimulated Genes (ISGs): ISG15 (ISG15 ubiquitin-like modifier), MX1 (MX dynamin-like GTPase 1) and IFI6 (interferon alpha inducible protein 6). Copy numbers will be determined by Crystal digital PCR (dPCR), using the levels of UBC (Ubiquitin C) mRNA copies as normalizers.

  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.

• Size of the latent intact proviral HIV reservoir in cell-associated HIV DNA (Ca-DNA)

  Determination of size (copy number) of the HIV proviral intact reservoir using a recently published assay the Hladik's lab conjointly with Jerome's lab developed (reference: Levy et al., 2021, Cell Reports Medicine 2, 100243). This outcome will be expressed as intact HIV copy numbers (found in cell-associated HIV DNA) per 10\^6 T cells. We will use a multiplexed digital PCR (dPCR) assay that simultaneously quantifies likely intact HIV-1 proviruses and T lymphocytes. We designed two triplex droplet digital PCR assays, each with 2 unique targets and 1 in common, and normalize the results to PCR-based T cell counts. Both HIV assays are specific, sensitive, and reproducible. Together, they estimate the number of proviruses containing all five primer-probe regions.

  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.

• Size of the latent defective proviral HIV reservoir in cell-associated HIV DNA (Ca-DNA)

  Determination of size (copy number) of the HIV proviral defective reservoir using a recently published assay the Hladik's lab conjointly with Jerome's lab developed (reference: Levy et al., 2021, Cell Reports Medicine 2, 100243). This outcome will be expressed as defective HIV copy numbers (found in cell-associated HIV DNA) per 10\^6 T cells.

  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 (1)

• Composition of gastrointestinal microbiota

  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 (2)

• Determination of proteins that are secreted in the rectum and duodenum

  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.

• Determination of the global transcriptome

  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.

Study Arms (2)

Tenofovir-containing ART

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.

Procedure: Venipuncture; Procedure: Targeted physical medical exam; Procedure: Urine pregnancy test; Procedure: Anoscopy; Procedure: Esophagogastroduodenoscopy (EGD)

NRTI-sparing ART

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

Procedure: Venipuncture; Procedure: Targeted physical medical exam; Procedure: Urine pregnancy test; Procedure: Anoscopy; Procedure: Esophagogastroduodenoscopy (EGD)

Interventions

Venipuncture PROCEDURE

Draw of peripheral blood (about 20 ml and 40 ml, during the screening and procedure visits, respectively).

Also known as: Peripheral blood draw by phlebotomy

NRTI-sparing ART; Tenofovir-containing ART

Targeted physical medical exam PROCEDURE

Study participants will be undergoing a physical exam where vitals will be recorded (e.g. temperature, blood pressure, heart rate). The registered nurse (RN) will also perform auscultation of heart and lungs. Study participants will be also asked to fill out a survey with questions related to his/her medical history, current use of medications, sexual history and substance abuse.

NRTI-sparing ART; Tenofovir-containing ART

Urine pregnancy test PROCEDURE

Women of childbearing potential will be asked to run an urine pregnancy test during the second (procedure) visit. Pregnant women will not be allowed to participate in the study.

NRTI-sparing ART; Tenofovir-containing ART

Anoscopy PROCEDURE

The anoscopy is an examination using a small, rigid, tubular instrument called anoscope (also called an anal speculum). This is inserted a few inches into the rectum in order to collect some small samples of mucosal tissue. We will collect 5 rectum biopsy samples and one cytobrush.

NRTI-sparing ART; Tenofovir-containing ART

Esophagogastroduodenoscopy (EGD) PROCEDURE

The EGD involves looking at the esophagus, stomach, and first and second portion of the duodenum. This procedure involves the use of an endoscope to remove small tissue samples. This procedure uses conscious sedation drugs given by a vein in the arm. The procedure takes about 1½-2 hours, including time for recovery. We will collect 5 duodenal biopsies and one cytobrush.

Also known as: Upper endoscopy

NRTI-sparing ART; Tenofovir-containing ART

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

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

You may not qualify if:

• Active malignancy including myelodysplastic syndrome, or myeloproliferative disease within 24 weeks prior to study entry
• Prior organ or bone marrow transplantation
• Diagnosed autoimmune disease
• Medical need for ongoing treatment with an immunosuppressive drug
• Diagnosis of AIDS (defined as any AIDS-defining opportunistic infection or cancer, or a history of blood CD4+ T cell count \< 200/μL)
• Active opportunistic infection
• Vomiting or diarrhea which prohibits consistent use of ART
• Pregnant or breastfeeding
• Excessive ingestion of ethanol determined by an AUDIT score of \>8
• Substance abuse
• History of medical non-compliance
• 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

Sponsors & Collaborators

• University of Washington: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• National Center for Advancing Translational Sciences (NCATS): collaborator

Study Sites (1)

University of Washington Positive Research and the Gastroenterology Clinic at Harborview Medical Center

Seattle, Washington, 98104, United States

Location

Related Publications (1)

• 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.

  PMID: 33015651 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Blood obtained from venipuncture during the first (screening) visit will be used to test for: 1) HIV plasma viral load; 2) peripheral blood CD4+ T cell count; 3) complete blood count (CBC); 4) prothrombin time (PT) and partial thromboplastin time (PTT); 5) and renal (kidney) function. Blood obtained from venipuncture during the second (procedure) visit will be used for RNA studies and PBMC and plasma isolation and storage. Biopsy samples (a total of 5 per site) will be isolated from the rectum and duodenum, by anoscopy and esophagogastroduodenoscopy (EGD), respectively. In both cases (anoscopy and EGD), samples will be preserved in RNAlater (for RNA and DNA analysis and potentially immunohistology) and some biopsies may be dry frozen (for potential proteomics study and determination of drug levels). Cytobrush samples will also be collected from both rectum and duodenum.

MeSH Terms

Conditions

Inflammation

Interventions

Phlebotomy; Proctoscopy; Endoscopy, Digestive System; Gastroscopy

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Blood Specimen Collection; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Therapeutics; Surgical Procedures, Operative; Investigative Techniques; Endoscopy, Gastrointestinal; Diagnostic Techniques, Digestive System; Endoscopy; Diagnostic Techniques, Surgical; Digestive System Surgical Procedures; Minimally Invasive Surgical Procedures

Study Officials

• German G Gornalusse, PhD, MSc

  University of Washington

  PRINCIPAL INVESTIGATOR

• Florian Hladik, MD, PhD

  University of Washington

  PRINCIPAL INVESTIGATOR

• Romel D Mackelprang, PhD, MSc

  University of Washington

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Acting Assistant Professor, School of Medicine, OBGYN

Study Record Dates

• First Submitted: October 5, 2022
• First Posted: October 18, 2022
• Study Start: September 1, 2022
• Primary Completion (Estimated): July 30, 2026
• Study Completion (Estimated): August 28, 2026
• Last Updated: April 29, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF, ANALYTIC CODE
• Time Frame: Data will be shared at the time of submission of the scientific paper(s).
• Access Criteria: The information from this study will be stored in a public unrestricted data bank that anyone can use. The National Institutes of Health (NIH) has developed data banks that collect genomic study data. The NIH will store the de-identified information in these data banks for other researchers to use in future studies on any topic. This will include de-identified information about the participants' HIV status, mRNA sequences or genomic allelic variants (e.g. single nucleotide polymorphisms and copy number variants). The researchers could be from government, academic, or commercial institutions. We have a Extramural Institutional Certification dated 01/07/2022, Genomic Program Administrator: Chris Marcus from the National Institute of Allergy and Infectious Diseases (NIAID), NIH, HHS.

Locations

US (1)