Analytical Treatment Interruption in HIV Positive Patients (ISALA)

• ClinicalTrials.gov Identifier: NCT02590354
• Recruitment Status: Completed
• First Posted: October 29, 2015
• Results First Posted: September 24, 2019
• Last Update Posted: September 24, 2019
• Sponsor: Institute of Tropical Medicine, Belgium
• Collaborators: University Hospital, Ghent; Universitair Ziekenhuis Brussel; Saint-Pierre University Hospital; Agentschap voor Innovatie door Wetenschap en Technologie
• Information provided by (Responsible Party): Institute of Tropical Medicine, Belgium

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
HIV-1 Infection	Other: ART interruption	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 114 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Analytical Treatment Interruption in HIV Positive Patients With Low Viral Reservoir to Evaluate the Potential of a Functional Cure
• Actual Study Start Date: January 25, 2016
• Actual Primary Completion Date: June 22, 2018
• Actual Study Completion Date: June 22, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment interruption; The ART treatment in patients with a very low viral reservoir will be interrupted.	Other: ART interruption

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: 48 weeks after treatment interruption ]
   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.

Secondary Outcome Measures :

1. 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 [ Time Frame: 23 months ]
   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).
2. 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). [ Time Frame: At screening, baseline, week 2, week 4, week 6, week 8 and at 12 weeks after relapse ]
   Assessment of the viral reservoir magnitude on cryopreserved Peripheral Blood Mononuclear Cells (PBMCs) prior and after treatment interruption by means of Total HIV DNA.
3. 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). [ Time Frame: At screening, baseline, week 2, week 4, week 6, week 8 and at 12 weeks after relapse ]
   Assessment of the viral reservoir magnitude on cryopreserved Peripheral Blood Mononuclear Cells (PBMCs) prior and after treatment interruption by means of unspliced RNA.
4. Assessment of the Kinetics of HIV Viral Load Rebound After Treatment Interruption Based on the Repetitive Plasma Viral Load Measurements. [ Time Frame: At screening, baseline, week 2, week 4, week 6, week 8, End of Intervention (relapse), 4 weeks after relapse and 12 weeks after relapse ]
   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).

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 64 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Belgium

Institute of Tropical Medicine

Antwerp, Belgium, 2000

Saint-Pierre University Hospital

Brussels, Belgium, 1000

Brussels University Hospital

Brussels, Belgium, 1090

Ghent University Hospital

Ghent, Belgium, 9000

Sponsors and Collaborators

Institute of Tropical Medicine, Belgium

University Hospital, Ghent

Universitair Ziekenhuis Brussel

Saint-Pierre University Hospital

Agentschap voor Innovatie door Wetenschap en Technologie

Investigators

• Principal Investigator: Eric Florence, Dr; Institute of Tropical Medicine

  Study Documents (Full-Text)

Documents provided by Institute of Tropical Medicine, Belgium:

Statistical Analysis Plan  [PDF] July 4, 2018

Study Protocol  [PDF] May 23, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Pannus P, Rutsaert S, De Wit S, Allard SD, Vanham G, Cole B, Nescoi C, Aerts J, De Spiegelaere W, Tsoumanis A, Couttenye MM, Herssens N, De Scheerder MA, Vandekerckhove L, Florence E. Rapid viral rebound after analytical treatment interruption in patients with very small HIV reservoir and minimal on-going viral transcription. J Int AIDS Soc. 2020 Feb;23(2):e25453. doi: 10.1002/jia2.25453.

• Responsible Party: Institute of Tropical Medicine, Belgium
• ClinicalTrials.gov Identifier: NCT02590354
• Other Study ID Numbers: ITM0714
• First Posted: October 29, 2015
• Results First Posted: September 24, 2019
• Last Update Posted: September 24, 2019
• Last Verified: September 2019

Keywords provided by Institute of Tropical Medicine, Belgium:

Treatment interruption; functional cure

Additional relevant MeSH terms:

HIV Seropositivity; HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases