Clinical trial NCT05852301: Optimising Cohorts for HIV Cure Interventions
Official title: Optimising Cohorts for HIV Cure Interventions: the Role of Very High CD4 T Cell Counts: HI-ART Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: HIV-1-infection
Lead sponsor: Bayside Health
Sponsor class: OTHER_GOV
Collaborators: name: The Peter Doherty Institute for Infection and Immunity
First posted: 2023-05-10
Enrollment: 112
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: HIV-DNA
timeFrame: at baseline
Secondary outcomes:
measure: Reservoir measurements
timeFrame: at baseline
measure: Reservoir measurements
timeFrame: at baseline
measure: Reservoir measurements
timeFrame: at baseline
measure: HIV-specific T-cell responses
timeFrame: at baseline
measure: Decay of reservoir
timeFrame: at 12 months
measure: Decay of reservoir
timeFrame: at 24 months
Other outcomes:
Locations:
city: Prahran
country: Australia
facility: Alfred Health
state: Victoria
Study officials:
affiliation: The Alfred
name: Jillian Lau, MBBS
role: PRINCIPAL_INVESTIGATOR
References: