Monitored Antiretroviral Pause in Chronic HIV-Infected Subjects With Long-Lasting Suppressed Viremia

Study Overview
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Brief Summary
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Prospective, open-label, single arm, non-randomized, proof-of-concept study. Eligible patients will sign a written informed consent and will be followed-up at screening, baseline (ART interruption) and at 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption. The study visits will include: general clinical assessment, routine laboratory tests including: creatinine, phosphorus, calcium, alkaline phosphatase, AST, ALT, fasting glucose, total cholesterol, HDL- and LDL-cholesterol, triglycerides, CD4+ cell count and CD4+/CD8+ ratio. Additional 30 mL of peripheral blood will be withdrawn at study visits for further virological, and immunological investigations and for bio-banking purposes. During follow-up, the occurrence of two consecutive HIV-1 RNA values >50 copies/mL or the occurrence of stage B or C AIDS-defining events or any serious non-AIDS clinical event at least potentially related to treatment interruption will be criteria for ART resumption. All patients with HIV-RNA<50 copies/mL at week 48 (end of the study) will resume their baseline ART regimen. The main demographic, clinical and therapy information will be accurately recorded at the study visits in an electronic Case Report Form.

Detailed Description
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The aim of this proof-of-concept study on adult (>18 and <65 years old), chronically HIV-1 infected individuals with undetectable viremia for ≥10 years, undetectable HIV-DNA, CD4+≥500 cells/µL and no evidence of detectable residual viremia for ≥5 years is to evaluate the frequency of spontaneous control of virus replication after ART pausing for up to 12 months and to identify the virological and immunological markers associated with spontaneous control of viral replication. Prospective, open-label, single arm, non-randomized, proof-of-concept study. Eligible patients will sign a written informed consent and will be followed-up at screening, baseline (ART interruption) and at 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption. The clinical assessment (study visit) will include: the evaluation of CDC stage, height, weight, systolic and diastolic blood pressure and smoking status, routine laboratory tests [including creatinine, phosphorus, calcium, alkaline phosphatase, AST, ALT, fasting glucose, total cholesterol, HDL- and LDL-cholesterol, triglycerides, CD4+ cell count and CD4+/CD8+ ratio, urine analysis]. Additional 30 mL of peripheral blood will be withdrawn at study visits and stored in a biobank for further investigations. During follow-up, the occurrence of two consecutive HIV-1 RNA values >50 copies/mL or the occurrence of stage B or C AIDS-defining events will be criteria for ART resumption or any serious non-AIDS clinical event at least potentially related to treatment interruption. All patients with HIV-RNA<50 copies/mL at week 48 (end of the study) will resume their baseline ART regimen. The main demographic, clinical and therapy information will be accurately recorded at the study visits in an electronic Case Report Form (eCRF).

Official Title
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Monitored Antiretroviral Pause in Chronic HIV-Infected Subjects With Long-Lasting Suppressed Viremia (APACHE Study)

Conditions
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HIV Seropositivity

Intervention / Treatment
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* Other: Stop of ART


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The study will include HIV-1 infected: men and non-pregnant women, ≥18 and <65 years-old, asking to stop therapy, with HIV-1 RNA<50 copies/mL for ≥10 years, current CD4+≥500 cells/µL, HIV-DNA<100 copies/106PBMCs, no evidence of detectable residual viremia for ≥5 years . Exclusion Criteria: The study will exclude HIV-1 infected subjects: significant risk of HIV transmission during IMAP (including evidence of not adopting effective contraception methods and women who wish to be pregnant) in the opinion of the investigator, pregnancy and breastfeeding, a documented pre-ART HIV-1 RNA<200 copies/mL, reactive Hepatitis B virus (HBV) surface antigen, positive HCV-RNA at the time of screening, current AIDS defining event as defined in category C of the 'Centers for disease control and prevention (CDC)' clinical classification, previous diagnosis of diabetes, a previous diagnosis of cancer or major adverse cardiac events (MACE) and currently receiving chemotherapy or immuno-modulating agents at the time of screening, history of HIV-related thrombocytopenia, active renal disease defined as a glomerular filtration rate (calculated by MDRD equation) below 50 mL/min or the presence of HIV associated nephropathy in the past medical history, any condition, including psychiatric or psychological disorders that might interfere with adherence to study requirements or safety of the participant, prior use of any HIV vaccine and/or non-established experimental therapy, active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Interruption of antiretroviral therapy<br>Patients willing to stop antiretroviral therapy will stop ART.The occurrence of two consecutive HIV-1 RNA values >50 copies/mL or the occurrence of stage B or C AIDS-defining events will be criteria for ART resumption or any serious non-AIDS clinical event at least potentially related to treatment interruption. | Other: Stop of ART<br>* Patients willing to stop antiretroviral therapy will stop ART.The occurrence of two consecutive HIV-1 RNA values >50 copies/mL or the occurrence of stage B or C AIDS-defining events will be criteria for ART resumption or any serious non-AIDS clinical event at least potentially related to treatment interruption.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients who will not resume antiretroviral regimen | Cumulative proportion of patients who will not resume ART 12 months after IMAP (Monitored Antiretroviral Pause) due to the occurrence of two consecutive HIV-1 RNA values >50 copies/mL or the occurrence of stage B or C AIDS-defining events or any serious non-AIDS clinical event at least potentially related to treatment interruption. | 12 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in plasma viremia | Change in plasma viremia | 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption. | 
| Change in plasma HIV-DNA | Change in plasma HIV-DNA | 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption. | 
| Change in CD4+ | Change in CD4+ | 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption. | 
| Change in CD4+/CD8+ ratio | Change in CD4+/CD8+ ratio | 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption. | 
| Change in virological biomarkers | Change in virological biomarkers prior to ART interruption and/or at ART resumption | 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption. | 
| Change in immunological biomarkers | Change in immunological biomarkers prior to ART interruption and/or at ART resumption | 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48 weeks thereafter or at ART resumption. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-1