Optimising Cohorts for HIV Cure Interventions (HI-ART)

Optimising Cohorts for HIV Cure Interventions: the Role of Very High CD4 T Cell Counts: HI-ART Study

In a recent international substudy of START (Study of Initiation of ART in Early HIV Infection), we found that people with HIV (PHIV) who initiate ART with CD4+ T cells > 800 cells/μL achieve a substantially smaller HIV reservoir on ART, as measured by the frequency of CD4+ T cells containing HIV DNA, compared to individuals who commence ART with CD4 counts between 500-599 and 600-799 cells/µL. We have termed these individuals 'HI-ARTs' (very High CD4 prior to ART).

Smaller reservoirs have also been noted in PHIV who achieve a CD4 count greater than 1000 cells/µL within 48 months of initiation of ART who are referred to as 'Hypers'.

This study will establish a prospective cohort of HI-ARTs and Hypers at Alfred Health and our clinical partners. It will characterise the HIV reservoir and HIV-specific immune responses in these individuals and compare these to age-matched HIV positive controls from the Alfred HIV clinic, who have CD4+ T cells between 500-800 cells/uL, or who do not reconstitute their CD4+ T cells to greater than 1000 cells/uL within 48 months.

Participants will be asked to donate a blood sample at baseline, and pending initial analyses, again at month 12 and 24.

Study Overview

• Status: Recruiting
• Conditions: HIV-1-infection
• Intervention / Treatment: Other: no intervention

Detailed Description

In individuals who commence ART in early HIV infection (within 6 months of acquiring HIV) compared to those who initiate ART in later infection, the frequency of cells containing intact and replication competent HIV DNA is reduced and HIV-specific immune responses are better preserved.

Previous studies in humans and infected macaque models have demonstrated that smaller reservoirs (measured by HIV DNA levels) predicted a longer time to viral rebound when ART was interrupted. These individuals are difficult to identify, and specialist research laboratories are required to conduct HIV DNA assays. There is therefore an urgent need to develop simple and efficient processes to identify PHIV with small HIV reservoirs who may best respond to cure interventions aiming to control virus without the need for regular ART.

In a recent international substudy of the START study (Initiation of ART in Early HIV Infection), our group showed that PHIV who initiate ART with CD4 T cells > 800 cells/μL achieve a substantially smaller HIV reservoir on ART compared to individuals who commence ART with CD4 counts between 500-800 cells/μL. We have termed these individuals 'Hi-ARTs' (High CD4 prior to ART). Smaller reservoirs have also been noted in PHIV who reach a CD4 count above 1000 cells/μL within 48 months of ART initiation who are referred to as 'Hypers'.

The immunological mechanisms by which latently infected cells are more efficiently eliminated or diluted by uninfected CD4 T cells in these patient groups are not understood. It is also unclear whether cells containing genetically-intact (or replication competent) HIV are eliminated at the same rate as cells harbouring HIV with extensive mutations/deletions ('defective'). The distinction between cells harbouring intact or defective HIV is important as only intact virus can cause viral rebound in the absence of ART and there are now assays to distinguish between the two.

Blood on enrolment and yearly for 2 years. Plasma and peripheral blood mononuclear cells (PBMC) will be assessed to determine the reservoir size and HIV-specific immune responses using validated assays including total HIV DNA and Intact Proviral DNA (IPDA), cell associated unspliced HIV-RNA (transcriptional activity), plasma HIV RNA, and intracellular cytokine staining in response to Gag and Nef stimulation using antibodies against IFN-g, TNF-a, and CD107a. Outcome measures will be compared and age- and sex- matched controls from The Alfred Hospital HIV clinic.

• Study Type: Observational
• Enrollment (Anticipated): 112

Contacts and Locations

• Study Contact: Name: Jillian Lau, MBBS; Phone Number: 613 90766908; Email: Jillian.Lau@monash.edu

Study Locations

• Australia
  • Victoria
    • Prahran, Victoria, Australia, 3181
      • Recruiting
      • Alfred Health
      • Contact: Jillian Lau

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

Individuals who are HIV antibody positive; have very high CD4 counts on ART initiation (>800 cells/uL , known as HI-ARTs), or reconstitute their CD4 counts to >1000 cells/μL within 48 months of commencing ART (Hypers) will be eligible for inclusion.

The study will recruit people with HIV into 4 cohorts based on CD4+ T cell criteria.

• CD4+ T cells > 800 c/uL on ART initiation (HI-ARTs)
• CD4+ T cells between 350-800 c/uL on ART initiation (HI-ART controls)
• CD4+ T cells <800 c/μL on ART initiation, but increase to >1000c/μL within 48 months of ART initiation (Hypers)
• CD4+ T cells reconstituted to 500-1000c/μL within 48 months (Hyper controls)

The study consists of three study visits over 24 months with study visits and blood sampling at months 0, 12 and 24.

Description

Inclusion Criteria:

• Aged 18 years or older
• Able to give written informed consent;
• Documented HIV infection (antibody positive);
• Taking continuous ART for at least 2 years prior to study enrolment;

Exclusion Criteria:

• Unwillingness to follow protocol requirements;
• HIV negative;
• Not meeting study definition for HI-ART or Hyper (except for control group);
• Medicare ineligible

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
HI-ART; People living with HIV with CD4+ T cells > 800 c/uL on ART initiation	Other: no intervention; no intervention, observational study only
HI-ART control; People living with HIV with CD4+ T cells between 500-800 c/uL on ART initiation	Other: no intervention; no intervention, observational study only
Hyper; People living with HIV with CD4+ T cells >800 c/μL on ART initiation, but increase to >1000c/μL within 48 months of ART initiation	Other: no intervention; no intervention, observational study only
Hyper control; People living with HIV with CD4+ T cells <500 c/μL on ART initiation and reconstituted to 500-1000c/μL within 48 months of ART initiation	Other: no intervention; no intervention, observational study only

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HIV-DNA	Quantitative DNA measurements in CD4+ T cells by PCR	at baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reservoir measurements	Quantitative HIV RNA/DNA measurements in CD4+ T cells by PCR	at baseline
Reservoir measurements	flow cytometry	at baseline
Reservoir measurements	proviral sequencing	at baseline
HIV-specific T-cell responses	HIV-specific T-cell immunity by intracellular cytokine staining (ICS) to measure the frequency of responding cells producing multiple effector cytokines including IFN-γ, TNF-α, and IL-2.	at baseline
Decay of reservoir	Compare changes in intact/defective HIV DNA by PCR from baseline	at 12 months
Decay of reservoir	Compare changes in intact/defective HIV DNA by PCR from baseline	at 24 months

Collaborators and Investigators

• Sponsor: Bayside Health
• Collaborators: The Peter Doherty Institute for Infection and Immunity
• Investigators: Principal Investigator: Jillian Lau, MBBS, The Alfred

Study record dates

Study Major Dates

• Study Start (Actual): March 16, 2023
• Primary Completion (Anticipated): June 30, 2025
• Study Completion (Anticipated): December 31, 2025

Study Registration Dates

• First Submitted: April 17, 2023
• First Submitted That Met QC Criteria: May 1, 2023
• First Posted (Actual): May 10, 2023

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: May 1, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Other Study ID Numbers: 413.22

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No