Clinical trial NCT05419024: Imaging and Biopsy of People With HIV-1 Undergoing Analytic Treatment Interruption
Official title: Imaging and Biopsy of People With HIV-1 Undergoing Analytic Treatment Interruption
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: HIV
Keywords: Human Immunodeficiency Virus
Antiretroviral Therapy
FDG-PET
Reservoir
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2022-06-15
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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.

Primary outcomes:
measure: 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
timeFrame: Up to day 90
Secondary outcomes:
measure: 1.Levels of HIV DNA and integration site analysis to assess clonal distribution at different biopsy sites, semen, vaginal swabs, and PBMCs.
timeFrame: Up to Month 6
measure: 2.Correlation between regional and overall change in PET SUV with HIV DNA and RNA sequencing characteristics pre-ATI to post ATI
timeFrame: Up to Month 6
measure: 3.Cytokine and T-cell profiles during suppression and after ATI criteria for treatment resumption are met.
timeFrame: Up to Month 6
measure: 4.HIV RNA and DNA sequence analyses for genetic studies and potential for replication competence.
timeFrame: Up to Month 6
measure: 5.Correlation of HIV RNA levels and cytokine and T-cell profiles
timeFrame: Up to Month 6
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Chuen-Yen C Lau, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.