Antiretroviral Treatment Taken 4 Days Per Week Versus Continuous Therapy 7/7 Days Per Week in HIV-1 Infected Patients
- Conditions
- HIV Infections
- Interventions
- Drug: Treatment discontinuation
- Registration Number
- NCT03256422
- Lead Sponsor
- ANRS, Emerging Infectious Diseases
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 640
- 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 :
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description 4 days / 7 Treatment discontinuation Patients included in this arm will take their ARV treatment 4 consecutive days per week during 98 weeks 7 days / 7 Treatment discontinuation 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
- Primary Outcome Measures
Name Time Method Proportion of patients with therapeutic success at Week 48. 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.
- Secondary Outcome Measures
Name Time Method Virological success Week 48 and Week 96 The HIV-1 viral load at week 48 must be inferior to 50 copies/mL
Number of virological " blips " between Week 0 and Week 48, and between Week 0 and Week 96 viral load \> 50 copies/mL followed by a control value ≤ 50 cp/mL
Percentage of patients with a viral load signal detected between Week 0 and Week 48 and Week 0 and Week 96 (subgroup of patients tested with Roche-Taqman, threshold\<20 copies/mL)
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 Proportion of patients with therapeutic success at Week 96 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.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) Description of the factors associated with virological rebound (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) (viral load \>50 cp/mL).
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 from Week-4 to Week 48 and Week 96 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
Evolution of fasting metabolic parameters until Week 48 and Week 96 Measurement of total cholesterol total, LDL-C, HDL-C, Triglycerides and glycemia
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) between Week 0, Week 48 and Week 96 Immuno-viro-pharmacological sub-study of 120 patients
Evolution of inflammation and immune activation parameters from Week 0 to Week 24 and Week 48 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
HIV RNA viral load in semen Week 0, Week 24 and Week 48 Sperm sub-study (120 patients)
Residual plasmatic concentrations of the third antiretroviral agent Week 0, Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84 and Week 96 Measurement of the third antiretroviral agent plasmatic concentration (protease inhibitors or non-nucleoside reverse transcriptase inhibitors or integrase inhibitors)
Residual plasmatic concentrations of tenofovir (TDF or TAF) Week 0, Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84 and Week 96 Measurement of tenofovir plasmatic concentration
Residual intracellular concentrations of the third antiretroviral agents Week 0, Week 24 and Week 48 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)
Treatment adherence Week 0, Week 12, Week 24, Week 36, Week 48, Week 72,and Week 96 Evaluation by a self-reported questionnaire
Quality of life Week-4, Week 0, Week 48 and Week 96 Evaluation by a self-reported questionnaire
Patient satisfaction Week 0, Week 12, Week 48 and Week 96 Evaluation by a self-reported questionnaire
Pharmaco-economic aspects of the strategy Between Week 0 and Week 98 Assessment and comparison of cost essay between each arm.
Median time to virologic failure Between week 0 and 98 Measure the delay between week 0 and the date of different virologic failure
Frequency of grade 3 or more adverse events, adverse effects, drug-modifying adverse events, drug-related adverse events and serious adverse events (SAE) Between Week 0 and Week 98 according to the sponsor's grading scale
Trial Locations
- Locations (62)
CHU Pointe-à-Pitre
🇫🇷Pointe-à-Pitre, Guadeloupe, France
Hôpital Henri Mondor
🇫🇷Créteil, France
Centre hospitalier Victor Dupouy
🇫🇷Argenteuil, France
Hôpital Ambroise Paré
🇫🇷Boulogne-Billancourt, France
Centre hospitalier sud francilien
🇫🇷Corbeil-Essonnes, France
Hôpital La Meynard Zobda Quitman
🇫🇷Fort-de-France, Martinique, France
Hôpital du Bocage
🇫🇷Dijon, France
Bicêtre
🇫🇷Kremlin Bicêtre, France
Centre Hospitalier du Mans
🇫🇷Le Mans, France
Hôpital Henri Duffaut
🇫🇷Avignon, France
Avicenne
🇫🇷Bobigny, France
Hôpital Saint-André
🇫🇷Bordeaux, France
Hôpital Louis Pasteur
🇫🇷Chartres, France
Hôpital Michallon
🇫🇷Grenoble, France
Antoine Beclère
🇫🇷Clamart, France
Hôpital Gabriel Montpied
🇫🇷Clermont-Ferrand, France
Hôpital Pellegrin
🇫🇷Bordeaux, France
Hôpital de la Côte de Nacre
🇫🇷Caen, France
CHD de la Roche Sur Yon
🇫🇷La Roche-sur-Yon, France
Hôpital Edouard Herriot
🇫🇷Lyon, France
Hôpital Saint-Antoine
🇫🇷Paris, France
Hôpital Pontchaillou
🇫🇷Rennes, France
Hôpital de la Croix Rousse
🇫🇷Lyon, France
CHI de Créteil
🇫🇷Créteil, France
Hôpital Raymond Poincaré
🇫🇷Garches, France
Institut hospitalier franco-britannique
🇫🇷Levallois-Perret, France
Hôpital Dupuytren
🇫🇷Limoges, France
Hôpital Européen
🇫🇷Marseille, France
Hôpital Emile Müller
🇫🇷Mulhouse, France
Hôpital de l'Archet
🇫🇷Nice, France
Hôpital de La Source
🇫🇷Orléans, France
Hôpital de l'Hôtel Dieu
🇫🇷Paris, France
Hôpital Necker
🇫🇷Paris, France
Hôpital Bichat
🇫🇷Paris, France
Hôtel-Dieu
🇫🇷Paris, France
Hôpital Saint-Louis
🇫🇷Paris, France
Lariboisière
🇫🇷Paris, France
Tenon
🇫🇷Paris, France
Centre Hospitalier René Dubos
🇫🇷Pontoise, France
Hôpital Pitié-Salpêtrière
🇫🇷Paris, France
Hôpital Européen Georges Pompidou
🇫🇷Paris, France
Centre Hospitalier de Perpignan
🇫🇷Perpignan, France
Hôpital Robert Debré
🇫🇷Reims, France
Hôpital Nord
🇫🇷Saint-Étienne, France
Hôpital Civil
🇫🇷Strasbourg, France
Hôpital de Brabois
🇫🇷Vandoeuvre les Nancy cedex, France
CHRU Jean Minjoz
🇫🇷Besançon, France
Jean Verdier
🇫🇷Bondy, France
Hôpital Sainte Marguerite
🇫🇷Marseille, France
Hôpital Gui de Chauliac
🇫🇷Montpellier, France
Hôpital Carémeau
🇫🇷Nîmes, France
Hôpital Delafontaine
🇫🇷Saint-Denis, France
Centre hospitalier Annecy Genevois
🇫🇷Pringy, France
Hôpital La Grave
🇫🇷Toulouse, France
Centre Hospitalier de Saint-Brieuc
🇫🇷Saint-Brieuc, France
Hôpital Foch
🇫🇷Suresnes, France
Centre Hospitalier Général de Saint Nazaire
🇫🇷Saint-Nazaire, France
Hôpital Bretonneau
🇫🇷Tours, France
Hôpital Gustave Dron
🇫🇷Tourcoing, France
Hôpital André Mignot
🇫🇷Versailles, France
Hôpital Purpan
🇫🇷Toulouse, France
Centre Hospitalier Intercommunal
🇫🇷Villeneuve-Saint-Georges, France