Comparing Immune Activation and Latent HIV Reservoir Size Between People Living With HIV on Tenofovir-containing Versus NRTI-free ART
NCT ID: NCT05584397
Last Updated: 2024-12-05
Study Results
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Basic Information
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ENROLLING_BY_INVITATION
40 participants
OBSERVATIONAL
2022-09-01
2025-12-28
Brief Summary
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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
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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.
Conditions
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Keywords
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Study Design
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CASE_CONTROL
CROSS_SECTIONAL
Study Groups
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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.
Venipuncture
Draw of peripheral blood (about 20 ml and 40 ml, during the screening and procedure visits, respectively).
Targeted physical medical exam
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.
Urine pregnancy test
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.
Anoscopy
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.
Esophagogastroduodenoscopy (EGD)
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.
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.
Venipuncture
Draw of peripheral blood (about 20 ml and 40 ml, during the screening and procedure visits, respectively).
Targeted physical medical exam
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.
Urine pregnancy test
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.
Anoscopy
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.
Esophagogastroduodenoscopy (EGD)
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.
Interventions
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Venipuncture
Draw of peripheral blood (about 20 ml and 40 ml, during the screening and procedure visits, respectively).
Targeted physical medical exam
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.
Urine pregnancy test
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.
Anoscopy
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.
Esophagogastroduodenoscopy (EGD)
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.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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
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.
18 Years
65 Years
ALL
No
Sponsors
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National Institute of Allergy and Infectious Diseases (NIAID)
NIH
National Center for Advancing Translational Sciences (NCATS)
NIH
University of Washington
OTHER
Responsible Party
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German Gornalusse
Acting Assistant Professor, School of Medicine, OBGYN
Principal Investigators
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German G Gornalusse, PhD, MSc
Role: PRINCIPAL_INVESTIGATOR
University of Washington
Florian Hladik, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
University of Washington
Romel D Mackelprang, PhD, MSc
Role: PRINCIPAL_INVESTIGATOR
University of Washington
Locations
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University of Washington Positive Research and the Gastroenterology Clinic at Harborview Medical Center
Seattle, Washington, United States
Countries
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References
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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.
Provided Documents
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Document Type: Study Protocol
Document Type: Informed Consent Form
Other Identifiers
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