Antiretroviral Treatment Taken 4 Days Per Week Versus Continuous Therapy 7/7 Days Per Week in HIV-1 Infected Patients

Study Overview
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Brief Summary
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The trial is an open-label, multicenter, prospective, randomized trial in 2 parallel groups, evaluating at W48, the non-inferiority of antiretroviral treatment taken 4 consecutive days a week versus continuous therapy, in HIV infected patients with controlled viral load for at least 12 months and stable antiretroviral treatment since 4 months.

Detailed Description
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Open-label, multicenter, prospective, randomized trial in 2 parallel groups, evaluating at W48, the non-inferiority of antiretroviral treatment taken 4 consecutive days a week versus continuous therapy, in HIV infected patients with controlled viral load for at least 12 months and stable antiretroviral treatment since 4 months. The non-inferiority margin (delta) is 5%. The randomization will be stratified according to the family of the third antiretroviral agent (II, PI, and NNRTI). A minimum of 200 patients will be included in the integrase inhibitor strata to provide a sufficient power to assess the efficacy of strategy in this population. At W48, all patients with virological success in the continuous therapy group will switch to the 4/7 days therapy.

Official Title
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Randomized, Open-label and Multicentric Trial Evaluating the Non-inferiority of Antiretroviral Treatment Taken 4 Consecutive Days Per Week Versus Continuous Therapy 7/7 Days Per Week in HIV-1 Infected Patients With Controlled Viral Load Under Antiretroviral Therapy

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Treatment discontinuation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection, coinfection HIV-1/HIV-2 possible Age≥18 years old Current therapy unchanged for the last 4 months Receiving tritherapy with 2 nucleoside reverse transcriptase inhibitor+protease inhibitors or 2 nucleoside reverse transcriptase inhibitor+non-nucleoside reverse transcriptase inhibitors or 2 nucleoside reverse transcriptase inhibitor+integrase inhibitors. Allowed treatment drugs are : 1. nucleoside analogs : tenofovir (TDF ou TAF), emtricitabine, abacavir, lamivudine 2. protease inhibitors : lopinavir/r, darunavir/r ou atazanavir/r 3. Non nucleoside reverse transcriptase inhibitors : efavirenz, rilpivirine ou etravirine 4. integrase inhibitors : dolutegravir, elvitegravir/cobicistat ou raltegravir Viruses susceptible to all antiretroviral drugs present in the ongoing tritherapy (AC11-ANRS algorithm). If a genotype is available in the patient medical history; viruses must be susceptible to all ongoing antiretroviral drugs If no RNA genotype available, a genotype will be performed on DNA at screening and will not have to show any resistance to the ongoing antiretroviral drugs Viral load (VL) < 50 cp/mL in the past year, with at least 3 VL measurements including screening; only one episode of viral blip < 200 copies/mL is authorized in the last year CD4 T cells > 250/mm3 at the screening visit Estimated glomerular filtration rate > 60 mL/min (Chronic Kidney Disease - Epidemiology Collaboration method) Transaminases : aspartate aminotransférase et alanine aminotransférase < 3N Haemoglobin > 10 g/dL Platelets > 100 000/mm3 For women of childbearing age, negative pregnancy test at screening; agree to use mechanical contraception during the study Social security system coverage Informed consent form signed by patient and investigator Exclusion Criteria: Infection by HIV-2 Chronic and active Viral B Hepatitis with positive antigen HBs Chronic and active Viral C Hepatitis with treatment expected in the next 98 weeks Concomitant treatment using interferon, interleukins, any other immune-therapy or chemotherapy, antivitaminK for patients on ARVT using a booster Concomitant prophylactic or curative treatment for an opportunistic infection All conditions (use of alcohol, drugs, etc.) judged by the investigator to possibly interfere with study protocol compliance, observance and/or study treatment tolerance Pregnant or breast feeding women Subjects under sauvegarde de justice (judicial protection due to temporarily and slightly diminished mental or physical faculties), or under legal guardianship

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open-label, randomized trial in 2 parallel groups
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 4 days / 7<br>Patients included in this arm will take their ARV treatment 4 consecutive days per week during 98 weeks | Drug: Treatment discontinuation<br>* • Receiving tritherapy. Allowed treatment drugs are : nucleoside analogs : tenofovir (TDF ou TAF), emtricitabine, abacavir, lamivudine protease inhibitors : lopinavir/r, darunavir/r ou atazanavir/r non nucleoside reverse transcriptase inhibitors : efavirenz, rilpivirine ou etravirine integrase inhibitors : dolutegravir, elvitegravir/cobicistat ou raltegravir<br>|
| Active Comparator: 7 days / 7<br>Patients included in this arm will continue their ARV therapy 7 days per weeks during 48 weeks and after W48, they will take their ARV treatment 4 days per week until W98 | Drug: Treatment discontinuation<br>* • Receiving tritherapy. Allowed treatment drugs are : nucleoside analogs : tenofovir (TDF ou TAF), emtricitabine, abacavir, lamivudine protease inhibitors : lopinavir/r, darunavir/r ou atazanavir/r non nucleoside reverse transcriptase inhibitors : efavirenz, rilpivirine ou etravirine integrase inhibitors : dolutegravir, elvitegravir/cobicistat ou raltegravir<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with therapeutic success at Week 48. | To evaluate after 48 weeks the therapeutic success of a weekly strategy of 4 consecutive days on treatment followed by 3 days off treatment, defined by : absence of virological failure : a measure of the viral load will be done, this measure have to be < 50 cp/mL. If it's > 50 cp/mL, a second measure will be done at 2 to 4 weeks apart. If it's still > 50 cp/mL, it's a virological failure no discontinuation or modification of the study strategy for more than 30 consecutive days. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with therapeutic success at Week 96 | To evaluate after 96 weeks the therapeutic success of a weekly strategy of 4 consecutive days on treatment followed by 3 days off treatment, defined by : absence of virological failure : a measure of the viral load will be done, this measure have to be < 50 cp/mL. If it's > 50 cp/mL, a second measure will be done at 2 to 4 weeks apart. If it's still > 50 cp/mL, it's a virological failure no discontinuation or modification of the study strategy for more than 30 consecutive days. | Week 96 | 
| Virological success | The HIV-1 viral load at week 48 must be inferior to 50 copies/mL | Week 48 and Week 96 | 
| Number of virological  blips  | viral load > 50 copies/mL followed by a control value ≤ 50 cp/mL | between Week 0 and Week 48, and between Week 0 and Week 96 | 
| Percentage of patients with a viral load signal detected | (subgroup of patients tested with Roche-Taqman, threshold<20 copies/mL) | between Week 0 and Week 48 and Week 0 and Week 96 | 
| Proportion of patients with acquisition of drugs resistance mutations in case of virological failure detected by Sanger and by next generation sequencing |  | Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 96 (if it's necessary) | 
| Frequency of minority resistant variants archived in DNA at Week 0 and their impact on virological failure (2 consecutive VL> 50 copies / mL) and on the acquisition of drugs resistance mutations |  | Week 0 | 
| Evolution of ultra sensitive viral load and total DNA in the peripheral blood mononuclear cells at Week 0, Week 24, Week 48 and Week 96; evolution of viral genotypic sequence between Week 0, Week 48 and Week 96 (subgroup of 120 patients) | Immuno-viro-pharmacological sub-study of 120 patients | between Week 0, Week 48 and Week 96 | 
| Description of the factors associated with virological rebound (viral load >50 cp/mL). | (viral load >50 cp/mL). | Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 96 (if it's necessary) | 
| Evolution of T cluster of differentiation 4 and cluster of differentiation 8 cells count, and T cluster of differentiation 4 /cluster of differentiation 8 ratio | Measurement of T cluster of differentiation 4 cell count, T cluster of differentiation 8 cell count, and T cluster of differentiation 4 /T cluster of differentiation 8 ratio | from Week-4 to Week 48 and Week 96 | 
| Evolution of fasting metabolic parameters | Measurement of total cholesterol total, LDL-C, HDL-C, Triglycerides and glycemia | until Week 48 and Week 96 | 
| Evolution of inflammation and immune activation parameters | Measurement of sCD14, sCD163, IP-10, C-reactive protein, interleukin-6 et D-dimerus, soluble TNF receptor 1, soluble TNF receptor 2 Immuno-viro-Pharmacological Sub-study in 120 patients | from Week 0 to Week 24 and Week 48 | 
| HIV RNA viral load in semen | Sperm sub-study (120 patients) | Week 0, Week 24 and Week 48 | 
| Residual plasmatic concentrations of the third antiretroviral agent | Measurement of the third antiretroviral agent plasmatic concentration (protease inhibitors or non-nucleoside reverse transcriptase inhibitors or integrase inhibitors) | Week 0, Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84 and Week 96 | 
| Residual plasmatic concentrations of tenofovir (TDF or TAF) | Measurement of tenofovir plasmatic concentration | Week 0, Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84 and Week 96 | 
| Residual intracellular concentrations of the third antiretroviral agents | Immuno-viro-Pharmacological sub-study (120 patients) Measurement of the third antiretroviral agent intracellular concentration (protease inhibitors or non-nucleoside reverse transcriptase inhibitors or integrase inhibitors) | Week 0, Week 24 and Week 48 | 
| Treatment adherence | Evaluation by a self-reported questionnaire | Week 0, Week 12, Week 24, Week 36, Week 48, Week 72,and Week 96 | 
| Quality of life | Evaluation by a self-reported questionnaire | Week-4, Week 0, Week 48 and Week 96 | 
| Patient satisfaction | Evaluation by a self-reported questionnaire | Week 0, Week 12, Week 48 and Week 96 | 
| Pharmaco-economic aspects of the strategy | Assessment and comparison of cost essay between each arm. | Between Week 0 and Week 98 | 
| Median time to virologic failure | Measure the delay between week 0 and the date of different virologic failure | Between week 0 and 98 | 
| Frequency of grade 3 or more adverse events, adverse effects, drug-modifying adverse events, drug-related adverse events and serious adverse events (SAE) | according to the sponsor's grading scale | Between Week 0 and Week 98 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Controlled, virological and therapeutic success, treatment discontinution, 4 days per week