Predictors of Time to Viremia With an Analytic Treatment Interruption

This is a two-center study of 30 HIV-infected participants who have been on antiretroviral therapy (ART) for at least two years.

Participants will be asked to undergo LN and GALT biopsies both before and after a closely monitored analytic treatment interruption (ATI).

Study Overview

• Status: Withdrawn
• Conditions: HIV
• Intervention / Treatment: Other: Blood Testing

Detailed Description

The HIV field has made a dramatic shift to an emphasis on finding a cure for HIV.

However, there is no agreed upon test of cure, or even what the definition of a cure might be. The investigator believes the most reliable test of cure will be an analytic treatment interruption (ATI) with time to viremia as a standard measure of the impact of an intervention on the degree to which the reservoir has been depleted. This is rational as modeling studies utilizing ATI data point to reservoir size as an important predictor of time to viremia(1) and other studies have shown that levels of HIV DNA(2) and cell associated HIV RNA(3) prior to starting antiretroviral therapy (ART) are associated with time-to-rebound. However, these studies used a limited sampling strategy to determine when viremia rebounded and it is likely that greater sensitivity in measures of time-to rebound will be needed to accurately assess the impact of an intervention. The investigators have tested an ATI strategy where plasma HIV is sampled three times each week and ART is resumed once the virus becomes detectable. In this small, pilot study, the investigators sampled lymph nodes, GALT, plasma, and PBMC before, during, and after the ATI and found the time-to-rebound was 14 days (range 5 to 30 days) and that total years of ART exposure was associated with the time-to-rebound (4). The investigators propose a similar study that includes more intensive blood and lymphoid tissue sampling to identify factors that predict time to-rebound to provide a necessary foundation for future studies that utilize a treatment interruption as a test of efficacy for curative interventions.

• Study Type: Observational

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States
      • University of California
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

30 HIV-infected participants who have been on antiretroviral therapy (ART) for at least two years.

Description

Inclusion Criteria:

1. HIV-infected individuals who have been on ART therapy for at least two years
2. Male or Female, aged 18 years or older
3. Documented evidence of CD4+ T cell count ≥ 300 cells/µl for 12 months prior to study entry
4. BMI ≤ 30 or evidence by ultrasound or physical exam of peripheral inguinal lymph node(s) that is/are surgically accessible
5. Documented plasma HIV RNA levels below level of quantification <20 to <40 copies RNA/mL depending on the assay) ≥ 24 months (a single measurement above the level of detection but < 200 copies/ml will be allowed)
6. Willing to switch to an ART regimen consisting of dolutegravir and either tenofovir/emtricitabine or abacavir/lamivudine to avoid drugs with a long-half life that would expose the participant to a period of mono-therapy when the drugs are stopped.
7. Women of child bearing potential and men with partners of child bearing potential must agree to use effective contraception during protocol
8. Able to provide voluntary written consent.

Exclusion Criteria

1. ART was initiated during acute infection (within first 6 months of infection)
2. Planning or current pregnancy or breastfeeding
3. History and/or presence of any clinically significant disease or disorder, such as cardiovascular, pulmonary, renal, hepatic, neurological, gastrointestinal and psychiatric/mental disease/disorder, which, in the opinion of the enrolling physician, may put the participant at risk because of participation in the study, influence the results of the study, or affect the participant's ability to participate in the study.
4. Inability to comply with study procedures per enrolling physician discretion.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
HIV-infected on antiretroviral therapy 2 years; HIV-infected participants who have been on antiretroviral therapy (ART) for at least two years.	Other: Blood Testing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to viremia	Time to viremia	Baseline to 14 days
Change in vRNA+ and vDNA+ cells	measured by in situ hybridization and using quantitative image analysis to determine the frequency of + cell/gram lymphoid tissue	Baseline to 14 days
SCA (Single Copy Assay)	performed as described in the protocol and reported as number of cells/ml plasma.	Baseline to 14 days
Change in markers of immune activation	All measurements are the same IL1B, TNF, IL4, IL13, IL17, IL21,IL22, IL6, IL10	Baseline to 14 days
Change in CD4		Baseline to 14 days
Change in CD4/CD8 ratio		Baseline to 14 days
Polyadenylation-RT-ddPCR assay for total transcripts (TAR)	transcripts/million cells	Baseline to 14 days
ddPCR assays for read-through, elongated, polyadenylated, and multiply-spliced (Tat-Rev) transcripts	reported as transcripts/million cells	Baseline to 14 days

Collaborators and Investigators

• Sponsor: University of Minnesota
• Investigators: Principal Investigator: Timothy Schacker, MD, University of Minnesota

Study record dates

Study Major Dates

• Study Start: July 1, 2016
• Primary Completion (Anticipated): January 1, 2019
• Study Completion (Anticipated): January 1, 2019

Study Registration Dates

• First Submitted: October 7, 2016
• First Submitted That Met QC Criteria: January 25, 2017
• First Posted (Estimate): January 26, 2017

Study Record Updates

• Last Update Posted (Actual): December 4, 2017
• Last Update Submitted That Met QC Criteria: December 1, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Keywords: HIV
• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Viremia
• Other Study ID Numbers: 24777

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided