Analytical Treatment Interruption in HIV Positive Patients

Study Overview
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Brief Summary
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HIV-1 infected patients with normal peripheral blood CD4+ T-cell counts and undetectable viral load will be recruited in four Belgian HIV reference centers. Selected patients will undergo a two-step screening in which a viral reservoir measurement will be performed and among those with a very low viral reservoir an analytical treatment interruption of their longstanding antiretroviral therapy (ART). There is no randomization foreseen. Patients will receive an intense clinical and laboratory follow-up during 48 weeks followed by 12 weeks post intervention.

Official Title
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Analytical Treatment Interruption in HIV Positive Patients With Low Viral Reservoir to Evaluate the Potential of a Functional Cure

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Other: ART interruption


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to provide written informed consent Men and women age ≥ 18 and < 65 years. Confirmed HIV-1 infection at any time prior to study entry. Infected with HIV-1 subtype A, B, C, D, CRF01_AE or CRF02_AG virus Participant should take ART for at least 2 years before baseline with no changes in the ART regimen for at least 90 days prior to study entry. ART regimen is defined as mono- or bi-therapy or a combination of three or more active antiretroviral drugs CD4 T-cell count is >= 500/μl for a period of at least 3 months prior study entry Nadir CD4+ T-cell count is ≥300/μl. A lower nadir CD4+ T-cell count will be allowed if measured at time of acute infection as far as the relative CD4+ count remains above 20%. An acute infection is defined as an association of a clinical picture of retroviral syndrome together with a seroconversion in HIV serology or an incomplete confirmation test. Plasma viral load < 50 copies/ml for at least 2 years before baseline. (Occasional blips will be permitted if it happened more than six months before study entry. An occasional blip is defined as an intermittent viremic episode with a viral load above detection level but below 200 copies/ml and a return to an undetectable level in a next control). Willingness to complete scheduled assessments and participant visits. Adequate peripheral vein access to perform leukapheresis All female participants of childbearing potential should have a negative pregnancy test. These women and their partner should use double barrier contraception during the study. Females of reproductive potential will need a negative serum or urine pregnancy test at screening. They are defined as those who have not reached menopause or been post-menopausal for at least 24 consecutive months, who have had menses within the preceding 24 months, or women who have not undergone surgical sterilization, specifically hysterectomy, or bilateral oophorectomy or tubal ligation) . NOTE: Acceptable documentation of hysterectomy and bilateral oophorectomy, bilateral salpingectomy, tubal micro-inserts, partner who has undergone vasectomy, and menopause is participant-reported history. All participants must agree not to participate in a conception process (e.g., active attempt to become pregnant, sperm donation, or in vitro fertilization). Exclusion Criteria: Previous or current history of AIDS defining event as defined in category C of the 'Centers for disease control and prevention (CDC)' clinical classification . Any acute infection or serious medical illness within 60 days prior to study entry. Participants will be excluded from this study for a serious illness (requiring systemic treatment and/or admission) until the subject either completes therapy or is clinically stable on therapy, in the opinion of the Investigator, for at least 14 days prior to study entry History of resistance to antiretroviral drugs, documented by genotyping. Active hepatitis B or C virus infection: as defined with a positive serology for either disease with signs of active viral replication? Significant risk of HIV transmission during treatment interruption in the opinion of the investigator. This includes evidence for unsafe sexual contacts. Current or past history of cardiomyopathy or significant ischemic or cerebrovascular disease. 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. Current or known history of cancer (with the exception of in situ cervix carcinoma or squamous cell carcinoma of the skin) within five years prior to screening. Pregnancy and breastfeeding. Any condition, including psychiatric and 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 Any of the following laboratory test results at screening: 1. Confirmed hemoglobin <11g/dl for women and <12 g//dl for men 2. Confirmed platelet count < 90,000/μl 3. Confirmed neutrophil count <1200/μl 4. Confirmed AST and/or ALT > 5 x upper limit on normal range (ULN). One retest within 14 days is allowed. Receipt of any immune modulator or suppressor within 30 days prior study entry, including, but not limited to drugs such as corticosteroids (with the exception of corticosteroids used for topical use), granulocyte-macrophage colony-stimulating factor, interleukin (IL)-2, IL-7 and IL-15. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. Participation in other interventional studies involving investigational drug.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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: Treatment interruption<br>The ART treatment in patients with a very low viral reservoir will be interrupted. | Other: ART interruption<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of the Number of Participants With a HIV Plasma Viral Load Below the Lower Limit of Detection 48 Weeks Following Interruption of Antiretroviral Treatment | The number of post treatment controllers (PTC - i.e. patients under ART at baseline that show low peripheral blood proviral DNA and still will show sustained viral suppression at 48 weeks after treatment interruption) will be determined. The assessment will be based on the plasma viral load (expressed in copies/ml) measured two-weekly (or four-weekly after W12) until W48 after treatment interruption. Patients below the lower limit of detection (<50 HIV RNA copies/ml plasma) at 48 weeks after treatment interruption will be considered as PTC. | 48 weeks after treatment interruption | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With and the Severity of Adverse Events That Are Related to the Study Intervention, Graded According to NCI CTCAE Version 4.0 | Confirmation of the safety of a treatment interruption strategy in selected patients will be based on the number and intensity of AEs graded according to the NCI Common Terminology Criteria for Adverse Events v4.0 (CTCAE) on a five-point scale (Grade 1 to 5: Mild, Moderate, Severe, Life-threatening and Death). | 23 months | 
| Evaluation of the Reservoir Replenishment Upon Interruption of Antiretroviral Treatment (TI) by Quantifying the Viral Reservoir at Baseline (i.e. Just Before TI) and at Viral Rebound (Total HIV DNA). | Assessment of the viral reservoir magnitude on cryopreserved Peripheral Blood Mononuclear Cells (PBMCs) prior and after treatment interruption by means of Total HIV DNA. | At screening, baseline, week 2, week 4, week 6, week 8 and at 12 weeks after relapse | 
| Evaluation of the Reservoir Replenishment Upon Interruption of Antiretroviral Treatment (TI) by Quantifying the Viral Reservoir at Baseline (i.e. Just Before TI) and at Viral Rebound (Unspliced RNA). | Assessment of the viral reservoir magnitude on cryopreserved Peripheral Blood Mononuclear Cells (PBMCs) prior and after treatment interruption by means of unspliced RNA. | At screening, baseline, week 2, week 4, week 6, week 8 and at 12 weeks after relapse | 
| Assessment of the Kinetics of HIV Viral Load Rebound After Treatment Interruption Based on the Repetitive Plasma Viral Load Measurements. | The kinetics will be on the plasma viral load (expressed in copies/ml) measured two-weekly (or four-weekly after W12) until W48 after treatment interruption. A viral load of 19 means <20 copies/mL (lower limit of detection). | At screening, baseline, week 2, week 4, week 6, week 8, End of Intervention (relapse), 4 weeks after relapse and 12 weeks after relapse | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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functional cure, Treatment interruption