Imaging and Biopsy of HIV-Infected Individuals Undergoing Analytic Treatment Interruption

• ClinicalTrials.gov Identifier: NCT05419024
• Recruitment Status: Recruiting
• First Posted: June 15, 2022
• Last Update Posted: May 10, 2024
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information

• First Submitted Date: June 11, 2022
• First Posted Date: June 15, 2022
• Last Update Posted Date: May 10, 2024
• Actual Study Start Date: January 9, 2023
• Estimated Primary Completion Date: August 1, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 14, 2022)

Proportion of participants who have a 3 fold increase in HIV RNA levels in tissue sites identified by imaging as having increased SUV on FDG-PET as defined below [ Time Frame: Up to day 90 ]

To evaluate if changes in glucose metabolism (as measured by FDG PET SUV) correlate with changes in levels of HIV RNA in lymphoid tissue before and after ATI.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 12, 2022)

• 1.Levels of HIV DNA and integration site analysis to assess clonal distribution at different biopsy sites, semen, vaginal swabs, and PBMCs. [ Time Frame: Up to Month 6 ]
  1.Characterize HIV populations (sequences) in sampled tissues, PBMCs, and plasma prior to and following ATI, and after treatment resumption.
• 2.Correlation between regional and overall change in PET SUV with HIV DNA and RNA sequencing characteristics pre-ATI to post ATI [ Time Frame: Up to Month 6 ]
  2.Assess relationship between changes in PET SUV and genetic characteristics (eg, diversity, phylogenetics, and clonality) of HIV populations
• 3.Cytokine and T-cell profiles during suppression and after ATI criteria for treatment resumption are met. [ Time Frame: Up to Month 6 ]
  3.Assess relationship between changes in soluble and cellular immune parameters and imaging findings during viral rebound
• 4.HIV RNA and DNA sequence analyses for genetic studies and potential for replication competence. [ Time Frame: Up to Month 6 ]
  4.Estimate replication competence of HIV variants from different anatomic compartments (sample tissues, PBMCs, plasma, semen, vaginal secretions, and CSF)
• 5.Correlation of HIV RNA levels and cytokine and T-cell profiles [ Time Frame: Up to Month 6 ]
  5.Compare kinetics of viral rebound after ATI with changes in immune activation markers.

Original Secondary Outcome Measures (submitted: June 14, 2022)

• 3.Cytokine and T-cell profiles during suppression and after ATI criteria for treatment resumption are met. [ Time Frame: Up to Month 6 ]
  3.Assess relationship between changes in soluble and cellular immune parameters and imaging findings during viral rebound
• 2.Correlation between regional and overall change in PET SUV (see section 9.3) with HIV DNA and RNA sequencing characteristics pre-ATI to post ATI [ Time Frame: Up to Month 6 ]
  2.Assess relationship between changes in PET SUV and genetic characteristics (eg, diversity, phylogenetics, and clonality) of HIV populations
• 1.Levels of HIV DNA and integration site analysis to assess clonal distribution at different biopsy sites, semen, vaginal swabs, and PBMCs. [ Time Frame: Up to Month 6 ]
  1.Characterize HIV populations (sequences) in sampled tissues, PBMCs, and plasma prior to and following ATI, and after treatment resumption.
• 4.HIV RNA and DNA sequence analyses for genetic studies and potential for replication competence. [ Time Frame: Up to Month 6 ]
  4.Estimate replication competence of HIV variants from different anatomic compartments (sample tissues, PBMCs, plasma, semen, vaginal secretions, and CSF)
• 5.Correlation of HIV RNA levels and cytokine and T-cell profiles [ Time Frame: Up to Month 6 ]
  5.Compare kinetics of viral rebound after ATI with changes in immune activation markers.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Imaging and Biopsy of HIV-Infected Individuals Undergoing Analytic Treatment Interruption
• Official Title: Imaging and Biopsy of People With HIV-1 Undergoing Analytic Treatment Interruption

Brief Summary

Background:

Human immunodeficiency virus (HIV) infects CD4 T cells. There is no cure for HIV. People with HIV need to take daily medications called antiretroviral therapy (ART) to control their infection. ART stops HIV from infecting cells, but HIV does not go away. Some infected cells remain. If ART is stopped, then HIV levels will rise and infect more cells.

Objective:

To find where HIV-infected cells are located in the body, even when ART is keeping levels low.

Eligibility:

Adults aged 18 years or older who are undergoing ART for HIV infection.

Design:

Participants will be screened with a physical exam, including blood tests. They will be assigned to 1 of 2 groups:

One group will stay on ART. They will have 2 study visits: the first 45 days after screening, and the second 12 to 16 weeks later. They will have a PET/CT scan at each visit. A substance called a tracer will be injected into their arm. They will lie still on a table that moves through a doughnut-shaped machine. This process takes up to 2 hours.

The other group will stop ART for no more than 90 days. This group will have 3 PET/CT scans over 8 months. Once they stop ART, they will visit the clinic weekly for blood tests. After restarting ART, they will continue to visit the clinic weekly until their HIV level is safe.

All participants will have small samples of tissue taken from lymph nodes. They may also opt to provide semen samples or vaginal fluid. They may have samples taken of bone marrow or the fluid inside their spinal column....

Detailed Description

Study Description:

HIV persistence during antiretroviral therapy (ART) is the principal obstacle preventing cure from the infection, and new studies are essential to understand mechanisms and sources of persistence. Lymphoid tissue is a well-described compartment for HIV, but the mechanisms of HIV persistence during ART and rebound when ART is interrupted are not well understood. Metabolic activity in lymphoid tissue of participants on long-term ART is relatively low, and increases when ART is stopped. Such an increase in metabolic activity can be detected by 18fluorodeoxyglucose (FDG)-positron emission tomography (PET). It is not known whether this increase in metabolic activity represents sites of HIV replication or reflects immune activation in response to HIV replication. We will use FDG-PET imaging to identify areas of high and low metabolic uptake in lymphoid tissue of individuals undergoing long-term ART. Tissue samples will be collected by biopsy. Participants will then be randomized 1:1 to either continue ART or to interrupt ART in an analytic treatment interruption (ATI). Image-guided biopsy will be repeated 10 days after initiation of ATI. ATI will be continued until ART restart criteria are achieved, or a maximum of 90 days of ATI, and image-guided biopsy will be repeated for the ATI group after viral suppression is re-achieved. Participants who continue ART will have a second FDG-PET and collection of lymphoid biopsies 12 to 16 weeks after the first collection. During the study, participants will undergo assessments of genetic characteristics of HIV populations (diversity, phylogenetics, and clonal structure) in areas of high and low FDG uptake. In addition to investigating HIV in lymphoid tissue, optional assessments of non-lymphoid anatomic compartments, including cerebrospinal fluid (CSF) obtained by lumbar puncture (LP), may be performed to evaluate different reservoirs characteristics, which need to be addressed in cure strategies.

Primary Objective:

To evaluate if changes in glucose metabolism (as measured by FDG-PET standard uptake value, SUV) correlate with changes in levels of HIV RNA in lymphoid tissue before and after ATI.

Secondary Objectives:

1. Characterize HIV populations (sequences) in sampled tissues, peripheral blood mononuclear cells (PBMCs), and plasma prior to and following ATI, and after ART resumption.
2. Assess relationship between changes in PET SUV and genetic characteristics (eg, diversity, phylogenetics, and clonality) of HIV populations prior to, during, and after ATI.
3. Assess relationship between changes in soluble and cellular immune parameters and imaging findings during viral rebound.
4. Estimate replication competence of HIV variants from different anatomic compartments (sample tissues, PBMCs, plasma, semen, vaginal fluid, and CSF).
5. Compare kinetics of viral rebound after ATI with changes in immune activation markers.

Tertiary/Exploratory Objectives:

1. Evaluate interaction of host characteristics, HIV population characteristics, and immune profiles.
2. Investigate HIV reactivation in other anatomic locations (CSF, semen, vaginal fluid or bone marrow) in individuals who elect to undergo optional LP, semen or vaginal fluid collection, or bone marrow biopsy.
3. Evaluate the relationship between FDG-PET SUV and immunologic activity.
4. Investigate impact of ATI-associated changes in drug levels with changes in viral and immunologic characteristics.

Primary Endpoint:

Proportion of participants who have a 3-fold increase in HIV RNA levels at tissue sites identified by imaging as having increased SUV on FDG-PET.

Secondary Endpoints:

1. Levels of HIV DNA and integration site analysis to assess clonal distribution at different biopsy sites, semen, vaginal fluid, and PBMCs.
2. Correlation between regional and overall change in PET SUV with HIV DNA and RNA sequencing characteristics pre-ATI to post-ATI.
3. Cytokine and T-cell profiles during suppression and after ATI criteria for treatment resumption are met.
4. HIV RNA and DNA sequence analyses for genetic studies and potential for replication competence.
5. Correlation of HIV RNA levels and cytokine and T-cell profiles.

Tertiary/Exploratory Endpoints:

1. Correlations between HIV population markers, lymphocyte phenotype parameters, and participant characteristics.
2. Comparative analysis of HIV DNA and RNA, levels of inflammatory markers, cytokine profiles, and antibody levels at different sites.
3. Correlation between regional and overall change in PET SUV with changes in cytokine and T-cell profiles pre-ATI and post-ATI.
4. Correlations of viral population changes, HIV DNA levels, HIV RNA levels, and immune markers with drug levels.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Outcomes Assessor); Primary Purpose: Basic Science
• Condition: HIV

Intervention

Other: Acute Treatment Interruption

Participants randomized to ATI will halt their ART medications starting 2 weeks (more or less 3 days) after the first imaging visit. This plan will be discussed with participants during the baseline visit. Patients will be contacted 1-3 days prior to ATI initiation. ATI may be delayed or cancelled if there are new safety concerns. HIV plasma viral levels and CD4 counts will be monitored every week during the ATI phase. If a participant meets any of the ART restart criteria during the ATI phase, then they will discontinue ATI and restart ART. Participants who do not meet restart criteria will remain off ART and continue to be monitored weekly until they have been on ATI for 90 days, and then will restart ART.

Study Arms

• Experimental: ATI
  Participants randomized to ATI will halt their ART medications starting 2 weeks (more or less 3 days) after the first imaging visit. This plan will be discussed with participants during the baseline visit. Patients will be contacted 1-3 days prior to ATI initiation. ATI may be delayed or cancelled if there are new safety concerns. HIV plasma viral levels and CD4 counts will be monitored every week during the ATI phase. If a participant meets any of the ART restart criteria during the ATI phase, then they will discontinue ATI and restart ART. Participants who do not meet restart criteria will remain off ART and continue to be monitored weekly until they have been on ATI for 90 days, and then will restart ART.
  Intervention: Other: Acute Treatment Interruption
• No Intervention: Continue ART
  Participants will continue on their pre-study ART throughout the trial.

Publications *

• Lau CY, Adan MA, Maldarelli F. Why the HIV Reservoir Never Runs Dry: Clonal Expansion and the Characteristics of HIV-Infected Cells Challenge Strategies to Cure and Control HIV Infection. Viruses. 2021 Dec 14;13(12):2512. doi: 10.3390/v13122512.
• Lau CY, Adan MA, Earhart J, Seamon C, Nguyen T, Savramis A, Adams L, Zipparo ME, Madeen E, Huik K, Grossman Z, Chimukangara B, Wulan WN, Millo C, Nath A, Smith BR, Ortega-Villa AM, Proschan M, Wood BJ, Hammoud DA, Maldarelli F. Imaging and biopsy of HIV-infected individuals undergoing analytic treatment interruption. Front Med (Lausanne). 2022 Aug 22;9:979756. doi: 10.3389/fmed.2022.979756. eCollection 2022.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 14, 2022): 50
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 1, 2026
• Estimated Primary Completion Date: August 1, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

• INCLUSION CRITERIA:

Participants must meet all of the following criteria to be eligible for this study:

1. Aged >=18 years.
2. People with HIV-1 documented using US Food and Drug Administration-approved screening and confirmatory or supplemental assays in Centers for Disease Control and Prevention (CDC)-recommended testing strategies.
3. Established medical care outside NIH.
4. Able to provide informed consent.
5. Willing to allow samples to be stored for future research.
6. Willing to allow genetic testing.
7. Undergoing cART using recommended, alternative, or other regimens as defined by Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV.
8. Viral RNA <40 copies/mL plasma by conventional assay for at least 3 years (blips [transient increases within 6 weeks] of <200 copies/mL are allowable when succeeding viral levels return to <40 copies/mL on subsequent testing).
9. CD4 cell count >=350 cells/microliter.
10. Willing to interrupt ART for up to 90 days.
11. Willing to use a barrier method of contraception, such as condoms or dental dams, when engaging in sexual activity, or remain abstinent during ATI and after re-initiating ART until viral re-suppression is achieved, to prevent pregnancy and transmission of HIV.

EXCLUSION CRITERIA:

Participants who meet any of the following criteria will be excluded from this study:

1. Active intercurrent illness or infection, including fever >38 degrees Celsius.
2. Known history of initiating ART during the first year of infection with HIV. Participants will be considered to have initiated ART within 1 year of infection as defined by documented screening/confirmatory seroconversion (positive testing within one year of non-reactive HIV enzyme-linked immunosorbent assay).
3. Pregnant.
4. Breastfeeding.
5. Currently undergoing therapy with drugs that, in the judgment of the investigators, may interfere with biodistribution of FDG, including prednisolone, valproate carbamazepine, phenytoin, phenobarbital, and catecholamines.
6. Undergoing ART that is incompatible with an ATI.
7. Has undergone PET/CT within the last 6 months.
8. History of poorly controlled diabetes that, in the judgement of the investigators, would prevent completion of PET/CT scan.
9. Vaccination within the previous 4 weeks.
10. History of ATI within the past 1 year.
11. Has comorbid illness for which, in the judgment of the investigators, an ATI will represent elevated risk.
12. Active opportunistic infection as defined by the Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV.
13. Significant active substance abuse or psychiatric illness that may, in the judgment of the investigator, interfere with study visits or procedures.
14. Allergy to planned anesthetic agents that are expected to be used. For local anesthetics, this is lidocaine. For sedation, this is midazolam and fentanyl.
15. Currently undergoing chronic systemic steroid therapy (corticosteroid nasal spray or inhaler and topical steroid use are acceptable).
16. Contraindication to use of IV contrast.
17. History of developing keloids.
18. Renal impairment: HIV-related kidney disease or estimated glomerular filtration rate (eGFR) CKD-EPI equation <60 mL/min/1.73 m^2. For individuals undergoing therapy with cobicistat or integrase strand inhibitors, GFR may be estimated using cystatin C or creatinine.
19. Active or chronic hepatitis B virus infection, with detectable hepatitis B surface antigen, hepatitis B virus DNA, or both.
20. Active hepatitis C virus infection, with detectable virus RNA.
21. History of HIV-associated dementia or progressive multifocal leukoencephalopathy.
22. Documented ARV drug resistance that, in the judgment of the investigator, would pose a risk of virologic failure should additional mutations develop during the study.
23. History of cardiovascular event or at high risk of an event (eg, atherosclerotic cardiovascular disease score >20%) (https://tools.acc.org/ascvd-risk-estimatorplus/#!/calculate/estimate/).
24. History of AIDS-defining illness according to CDC criteria within the past 3 years.
25. Hepatic impairment: alanine transaminase >2.5 X the upper limit of normal or documented history of cirrhosis.
26. Any condition that, in the judgment of the investigator, contraindicates participation in this study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 100 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Chuen-Yen C Lau, M.D.; (240) 858-7088; lauc@mail.nih.gov

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05419024
• Other Study ID Numbers: 10000277; 000277-C
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: .There are only a few patients are being studied in this protocol. Data sharing might make it easier to identify participants.

• Current Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
• Original Responsible Party: Same as current
• Current Study Sponsor: National Cancer Institute (NCI)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Chuen-Yen C Lau, M.D.; National Cancer Institute (NCI)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: May 8, 2024