4 Consecutive Days on Treatment Followed by 3 Days Off Treatment, in HIV Patients

Study Overview
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Brief Summary
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Evaluate after 48 weeks, the capacity of a weekly strategy of 4 consecutive days on treatment followed by 3 days off treatment, in HIV-1 treated patients with undetectable viral load for at least 12 months and continuous antiretroviral regimen unchanged for at least 4 months, to maintain a therapeutic success defined by the absence of virological failure (2 consecutive viral loads > 50 cp/mL) and the absence of interruption of therapeutic strategy (interruption or change of the  4 days on / 3 days off  strategy for a time longer than 30 consecutive days).

Detailed Description
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Methods: Open-label, multicentric, prospective, non-randomized, non-controlled trial to evaluate at 48 weeks, the capacity of a weekly strategy of 4 consecutive days on treatment followed by 3 days off treatment, in HIV-1 treated patients with undetectable viral load for at least 12 months and continuous antiretroviral regimen unchanged for at least 4 months, to maintain a therapeutic success defined by the absence of virological failure (2 consecutive viral loads > 50 cp/mL) and the absence of interruption of therapeutic strategy (interruption or change of the  4 days on / 3 days off  strategy for a time longer than 30 consecutive days). Allocation: Non-randomized Endpoint Classification: Safety/Efficacy Study Primary Purpose: Treatment Enrollment: 100 patients

Official Title
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Evaluation of the Capacity of a Weekly Strategy of 4 Consecutive Days on Treatment Followed by 3 Days Off Treatment, in HIV-1 Infected Patients With Undetectable Viral Load for at Least 12 Months, to Maintain a Virological Success With This Intermittent Maintenance Therapy After a Successful Continuous Induction Therapy.

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Four consecutive days on treatment and 3 days off


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • HIV-1 documented infection Age 18 years or older HIV-1 viral load always ≤ 50 cp/mL for at least 12 months (with a minimum of 3 measures in the last 12 months, including screening) CD4+ lymphocytes count > 250/mm3, for at least 6 months Treatment with a stable regimen for at least 4 months prior to screening, containing 2 nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTI) combined with, either 1 non-nucleoside reverse transcriptase inhibitor (NNRTI), or 1 ritonavir-boosted protease inhibitor (PI/r). The list of accepted antiretroviral drugs is limited to : NRTI : tenofovir, emtricitabine, abacavir, lamivudine PI/r : lopinavir/r, darunavir/r or atazanavir/r NNRTI : efavirenz, rilpivirine or etravirine. Exclusive antiretroviral 3 drug-therapy (no 4 drug-therapy) A least one genotypic resistance test available (reverse transcriptase and/or protease amino acid sequence, according to on-going antiretroviral drugs) ; on each genotypic resistance test(s) available in medical history, susceptibility to every on-going antiretroviral drugs must be demonstrated Clearance of the creatinine > 60 mL/min (MDRD) ASAT and ALAT < 3 ULN Hemoglobin > 10 g/dl Platelets count > 100 000/mm3 Negative pregnancy test for potential child-bearing women and mechanical contraception for sexual intercourses Patient living in France and affiliated to a social security system Written informed consent Exclusion Criteria: • HIV-2 infection HBV infection (positive HBs antigen) or isolated positive HBc antibody HCV infection requiring specific treatment during the 51 weeks of the trial At least one known resistance to one of on-going antiretroviral drugs Exclusive antiretroviral 3 drug-therapy (no 4 drug-therapy) No genotypic resistance test available On-going either interferon, interleukin treatment, or every immuno- / chemo-therapy Progressive opportunistic infection, on-going treatment for opportunistic infection or tuberculosis Patient with irregular follow-up or with treatment adherence problems Any condition (alcohol, drug abuse…) compromising treatment adherence, treatment safety, and/or study adherence Progressive neurological disorders (meningitis, encephalitis, myelitis…) related to HIV infection or not Medical history of severe neuropsychiatric disorder, with insufficient treatment efficacy Subject under legal guardianship or incapacitation

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Four consecutive days on treatment and 3 days off<br>All patients will take a combination of three HIV treatment with a weekly strategy of 4 consecutive days on treatment followed by 3 days off treatment | Drug: Four consecutive days on treatment and 3 days off<br>* All patients will take a combination of three of these treatment with a weekly strategy of 4 consecutive days on treatment followed by 3 days off treatment<br>* Other names: atazanavir/r;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Capacity to maintain a therapeutic success with 4 days on treatment followed 3 days off treatment | To evaluate after 48 weeks, the capacity of a weekly strategy of 4 consecutive days on treatment followed by 3 days off treatment, in HIV-1 treated patients with undetectable viral load for at least 12 months and continuous antiretroviral regimen unchanged for at least 4 months, to maintain a therapeutic success defined by the absence of virological failure (2 consecutive viral loads > 50 cp/mL) and the absence of interruption of therapeutic strategy (interruption or change of the  4 days on / 3 days off  strategy for a time longer than 30 consecutive days). | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virological success | The HIV-1 viral load at week 48 must be inferior to 50 copies/mL | Week 48 | 
| The time of virological failure occurrence | Measure the delay between week 0 and the date of the different virologic failure | Week 0, Week 4, Week 8, Week 12, Week 16, Week 24, Week 32, Week 40, Week 48, Week 51 | 
| The blips | Number of blips (viral load detectable on 1 sample) during the study | Week 0, Week 4, Week 8, Week 12, Week 16, Week 24, Week 32, Week 40, Week 48, Week 51 | 
| The low viral loads (between 20 - 50 cp/mL) | Measurement of the low viral loads (between 20 - 50 cop/mL) | Week 0, Week 4, Week 8, Week 12, Week 16, Week 24, Week 32, Week 40, Week 48, Week 51 | 
| Detected signal on viral quantification | The presence or not of detected signal when no quantification is possible on viral loads | Week 0, Week 4, Week 8, Week 12, Week 16, Week 24, Week 32, Week 40, Week 48, Week 51 | 
| Mutations resistance | The profile of new resistance mutations in case of virological failure | Week 0, Week 4, Week 8, Week 12, Week 16, Week 24, Week 32, Week 40, Week 48, Week 51 | 
| Evaluation CD4, CD8 and CD4/CD8 ratios | Measurement of the CD4 cell count, CD8 cell count, and CD4/CD8 ratio | Week 0, week 8, week 16, week 24, week 24, week 32, week 40 and week 48 | 
| HIV proviral DNA | The evolution of HIV proviral DNA in the peripheral blood mononuclear cells (PBMC) | Week 0, Week 24 and Week 48 | 
| Clinical events related to HIV infection | Clinical events related to HIV infection, according to the US CDC classification | Week 0, Week 4, Week 8, Week 12, Week 16, Week 24, Week 32, Week 40, Week 48, Week 51 | 
| Adverse events | Collect all clinical and biological adverse events | Week 0, Week 4, Week 8, Week 12, Week 16, Week 24, Week 32, Week 40, Week 48, Week 51 | 
| Interruption or modification of the therapeutic strategy | Every interruption or modification of the therapeutic strategy for more than 30 days | Week 0, Week 4, Week 8, Week 12, Week 16, Week 24, Week 32, Week 40, Week 48, Week 51 | 
| Renal parameters | The evolution of creatinin and clearance of creatinin between week 0 and Week 48. | Week 0, week 8, week 16, week 24, week 32, week 40 and week 48 | 
| Inflammation and immune activation | The evolution of inflammation and immune activation parameters (IL-6, CRP-US, CD14s, IP-10 and MIG-1). The measurement will be done at the end of the study in a central lab on the biobank | Week 0, week 24 and Week 48 | 
| Antiretrovirals Pharmacokinetic | The evolution of pharmacokinetic parameters, for protease inhibitors (lopinavir, darunavir or atazanavir) or non-nucleoside reverse transcriptase inhibitors (efavirensz, etravirine or rilpivirine) The measurment will be done on the sample bank at the end of the study in a central lab | Week 0, week 24 and week 48 | 
| Antiretrovirals pharmacokinetic | Measurment of Residual plasmatic concentrations of protease inhibitors (lopinavir/r - darunavir/r - atazanavir/r ) or non-nucleoside reverse transcriptase inhibitors (efavirenz or rilpivirine or etravirine), at the end of the 3-days off, from Day 0 to week 48. The measurment will be done on the sample bank at the end of the study in a central lab | week 4, week8, week 12, week 24, week 32 and week 48 | 
| Quality of life | selfquestionnary to measure the quality of life (PRO-QOL HIV and felt symptoms ) | week 0, week 24 and week 48 | 
| Adherence | Measurement of treatment adherence (questionnaire, self-survey book, pharmacological measures of antiretroviral drugs, medication event monitoring system) | Week 0, Week 4, Week 8, Week 12, Week 16, Week 24, Week 32, Week 40, Week 48, Week 51 | 
| Hepatitis parameters | Measurment of AST, SGOT, CGT | Week 0, week 8, week 16, week 24, week 32, week 40 and week 48 | 
| Glucidolipidics parameters | Measurement of Glycemia, Triglycerids, total cholesterol, HDL and LDL | Week 0, week 24 and week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-1, simplification,, treatment discontinuation, virological success, four days a week