The Italian Cohort (ITACO) and the Analytical Antiretroviral Treatment Interruption Italian Cohort (ITACO-ATI) study guided by molecular HIV-1 reservoir profiling

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ospedale Pediatrico Bambino Gesu

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

8 Aug 2023 → 2 Apr 2026

Decision date (initial)

2025-01-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

NIH (Johns Hopkins University)

External identifiers

EU CT number

2024-518694-33-00

EudraCT number

2022-001437-36

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

ITACO AIMS:
Quantify the susceptibility of the proviral reservoir to reactivation through the establishment of a predictive platform to early-select promising immune-targeted strategies to reverse HIV-1 latency in perinatal infection.
2. To select patients within the ITACO cohort according to the predictive platform (PredictHIV) built by data source obtained by aim 1), to be eligible for analytical antiretroviral treatment interruption (ITACO-ATI)
ITACO-ATI AIMS:
1. Determine whether chromosomal integration of intact HIV-1 proviruses in repressive chromatin regions, obtained by the analysis produced in ITACO analysis, predicts delayed viral rebound during an ATI.
2. To evaluate changes in intact proviral reservoir configuration during ATI and after re-initiation of ART.
3. To evaluate innate and adaptive immune cell frequency and function during ATI and their association with the viral reservoir and viral rebound kinetics.

Conditions and MedDRA coding

perinatally HIV infection

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. ITACO eligibility criteria Inclusion Criteria 1. Males and females ≥ 12 years old 2. HIV-1 infection 3. Written informed consent by adult patients or caregivers 4. Laboratory values at screening that meet the following criteria: a. Hemoglobin > 11.5 g/dL b. Absolute neutrophil count ≥ 1000/mm3 c. Platelet count ≥ 100,000/mm3
2. ITACO-ATI eligibility criteria Inclusion criteria 1. Subjects who completed ITACO 2. Males and females ≥12 years old 3. Written informed consent by adult patients or caregivers 4. Subjects currently on the same regimen of 3 or more antiretroviral drugs for at least 1 year. 5. Evaluation of intact proviruses explored in ITACO within 24 months prior to Visit 1 revealing absence of intact proviruses isolated from at least 20 million peripheral blood mononuclear cells (PBMCs) or intact proviruses which are located in heterochromatin positions, which include (i) all non-genic positions, (ii) positions in ZNF genes on chromosome 19, which display extensive binding to heterochromatin proteins and are associated with repressive histone modifications. Testing for chromosomal locations of intact proviruses will be performed using an established assay termed MIP-Seq (matched integration site and proviral sequencing). 6. CD4+ cell count ≥200 cells/mm3 at study entry. 7. One documented plasma HIV-1 RNA that is below the limit of detection of an FDA-approved assay between 12 and 24 months prior to the screening HIV-1 RNA and one documented HIV-RNA that is below the limit of detection of an FDA-approved assay collected fewer than 12 months prior to the screening HIV-1 RNA. 8. Willingness to interrupt ART from the patient if an adult or both caregiver and adolescents NOTE: These participants will be counseled again regarding the requirement to use barrier protection for all sexual exposures while on study.

Exclusion criteria 2

1. ITACO eligibility criteria Exclusion Criteria 1. History of advanced coronary artery disease, myocardial infarction, severe Chronic obstructive pulmonary disease, chronic renal failure, decompensated cirrhosis, seizure disorder, or any other condition that in the opinion of the investigator will compromise ability to participate in the study. 2. Subject taking any of the following medications: systemic steroids (inhaled, nasal, or topical steroid therapy is permitted), interleukins, systemic interferons (e.g. local injection of interferon alpha or use of topical immune modulators for the treatment of HPV is permitted) or systemic chemotherapy. 3. Use of any immunomodulatory agents within 30 days prior to the study procedure. 4. Antibiotic use within 1 week of study procedures. 5. Recipient of a live vaccine within 2 weeks of study procedures. 6. Unwilling or unable to comply with study visit requirements. 7. Patients weighting <35kg. 8. Female subject who is pregnant as determined by urine pregnancy test or less than eight weeks post partum NOTE: Critical values to be considered for chronic renal failure are estimated glomerular filtration rate (eGFR) < or = 59mL/min/1,73m2. Chemistry values to be considered for decompensated cirrhosis are AST > 5 or /and ALT > 5 times the upper limit.
2. ITACO-ATI eligibility criteria Exclusion criteria 1. Cannot or unwilling to attend visits required for the study 2. Unwilling to restart antiretroviral treatment (ART) if CD4 percent or count indicates this is necessary 3. Most recent two plasma HIV-1 RNA viral load > 1000 copies/ml (at least 1 month apart) 4. Most recent two CD4% <20% (at least 1 month apart) 5. 1. History of advanced coronary artery disease, myocardial infarction, severe Chronic obstructive pulmonary disease, chronic renal failure, decompensated cirrhosis, seizure disorder, or any other condition that in the opinion of the investigator will compromise ability to participate in the study. 6. S-Creatinine >1.5 times the upper limit of normal. 7. Currently breastfeeding or plans on breastfeeding during the course of the study or is pregnant. 8. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. 9. Acute or serious illness, in the opinion of the site investigator, requiring systemic treatment and/or hospitalization within 60 days prior to entry. 10. Receipt of any study-defined prohibited medication within 6 months prior to entry (see point 4 of paragraph 3.7.2). 11. Significant pre-existing resistance to protease inhibitors and integrase inhibitors based on a review of pre-existing antiretroviral drug resistance testing data - according to the Stanford University HIV drug resistance database https://hivdb.stanford.edu/ 12. Latent hepatitis B infection. Note: If a patient is hepatitis B core antibody-positive, s/he must be both hepatitis B surface antigen AND hepatitis B DNA negative. If a patient is hepatitis B core antibody negative, s/he must also be hepatitis B surface antigen negative. Critical values to be considered for chronic renal failure are estimated glomerular filtration rate (eGFR) < or = 59mL/min/1,73m2. Chemistry values to be considered for decompensated cirrhosis are AST > 5 or /and ALT > 5 times the upper limit.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 1. ITACO cohort: Proportion of patients with absence or HIV intact proviruses, isolated from at least 20 million peripheral blood mononuclear cells (PBMCs), located in heterochromatin positions, which include (i) all non-genic positions, (ii) positions in ZNF genes on chromosome 19, which display extensive binding to heterochromatin proteins and associated with repressive histone modifications (PredictHIV negative) 2. ITACO-ATI cohort: Proportion of patients “PredictHIV negative” who underwent A

Secondary endpoints 1

1. 1. ITACO cohort: • Proportion of patients with virus inducibility (TILDA assay) in the whole cohort and with distinct latency reversal agents (LRAs) in vitro • Proportion of patients with GALT with absence of intact HIV provirus • Adverse events and serious adverse events 2. ITACO-ATI cohort: • Time from ART discontinuation (start of ATI) to HIV RNA rebound to ≥ 1,000 copies/mL. • Time from ART discontinuation to meeting criteria for ART re-initiation. • Proteomic and In Vitro Gene Expre

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 9

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ospedale Pediatrico Bambino Gesu

Sponsor organisation

Ospedale Pediatrico Bambino Gesu

Address

Piazza Di Sant'onofrio 4

City

Rome

Postcode

00165

Country

Italy

Scientific contact point

Organisation

Ospedale Pediatrico Bambino Gesu

Contact name

Paolo Palma

Public contact point

Organisation

Ospedale Pediatrico Bambino Gesu

Contact name

Paolo Palma

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 20 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications