Clinical trial NCT03256422: Antiretroviral Treatment Taken 4 Days Per Week Versus Continuous Therapy 7/7 Days Per Week in HIV-1 Infected Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: HIV Infections
Keywords: Controlled, virological and therapeutic success, treatment discontinution, 4 days per week
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: IMEA Leon M'Ba Foundation
name: INSERM UMR S 1136
First posted: 2017-08-22
Enrollment: 640
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open-label, randomized trial in 2 parallel groups
Primary purpose: TREATMENT

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.

Eligibility criteria: 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).

  1. If a genotype is available in the patient medical history; viruses must be susceptible to all ongoing antiretroviral drugs
  2. 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

Primary outcomes:
measure: Proportion of patients with therapeutic success at Week 48.
timeFrame: Week 48
Secondary outcomes:
measure: Proportion of patients with therapeutic success at Week 96
timeFrame: Week 96
measure: Virological success
timeFrame: Week 48 and Week 96
measure: Number of virological " blips "
timeFrame: between Week 0 and Week 48, and between Week 0 and Week 96
measure: Percentage of patients with a viral load signal detected
timeFrame: between Week 0 and Week 48 and Week 0 and Week 96
measure: Proportion of patients with acquisition of drugs resistance mutations in case of virological failure detected by Sanger and by next generation sequencing
timeFrame: Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 96 (if it's necessary)
measure: 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
timeFrame: Week 0
measure: 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)
timeFrame: between Week 0, Week 48 and Week 96
measure: Description of the factors associated with virological rebound (viral load >50 cp/mL).
timeFrame: Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 96 (if it's necessary)
measure: 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
timeFrame: from Week-4 to Week 48 and Week 96
measure: Evolution of fasting metabolic parameters
timeFrame: until Week 48 and Week 96
measure: Evolution of inflammation and immune activation parameters
timeFrame: from Week 0 to Week 24 and Week 48
measure: HIV RNA viral load in semen
timeFrame: Week 0, Week 24 and Week 48
measure: Residual plasmatic concentrations of the third antiretroviral agent
timeFrame: Week 0, Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84 and Week 96
measure: Residual plasmatic concentrations of tenofovir (TDF or TAF)
timeFrame: Week 0, Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84 and Week 96
measure: Residual intracellular concentrations of the third antiretroviral agents
timeFrame: Week 0, Week 24 and Week 48
measure: Treatment adherence
timeFrame: Week 0, Week 12, Week 24, Week 36, Week 48, Week 72,and Week 96
measure: Quality of life
timeFrame: Week-4, Week 0, Week 48 and Week 96
measure: Patient satisfaction
timeFrame: Week 0, Week 12, Week 48 and Week 96
measure: Pharmaco-economic aspects of the strategy
timeFrame: Between Week 0 and Week 98
measure: Median time to virologic failure
timeFrame: Between week 0 and 98
measure: Frequency of grade 3 or more adverse events, adverse effects, drug-modifying adverse events, drug-related adverse events and serious adverse events (SAE)
timeFrame: Between Week 0 and Week 98
Other outcomes:
Locations:
city: Pointe-à-Pitre
country: France
facility: CHU Pointe-à-Pitre
state: Guadeloupe
city: Fort-de-France
country: France
facility: Hôpital La Meynard Zobda Quitman
state: Martinique
city: Argenteuil
country: France
facility: Centre hospitalier Victor Dupouy
city: Avignon
country: France
facility: Hôpital Henri Duffaut
city: Besançon
country: France
facility: CHRU Jean Minjoz
city: Bobigny
country: France
facility: Avicenne
city: Bondy
country: France
facility: Jean Verdier
city: Bordeaux
country: France
facility: Hôpital Saint-André
city: Bordeaux
country: France
facility: Hôpital Pellegrin
city: Boulogne-Billancourt
country: France
facility: Hôpital Ambroise Paré
city: Caen
country: France
facility: Hôpital de la Côte de Nacre
city: Chartres
country: France
facility: Hôpital Louis Pasteur
city: Clamart
country: France
facility: Antoine Beclère
city: Clermont-Ferrand
country: France
facility: Hôpital Gabriel Montpied
city: Corbeil-Essonnes
country: France
facility: Centre hospitalier sud francilien
city: Créteil
country: France
facility: CHI de Créteil
city: Créteil
country: France
facility: Hôpital Henri Mondor
city: Dijon
country: France
facility: Hôpital du Bocage
city: Garches
country: France
facility: Hôpital Raymond Poincaré
city: Grenoble
country: France
facility: Hôpital Michallon
city: Kremlin Bicêtre
country: France
facility: Bicêtre
city: La Roche-sur-Yon
country: France
facility: CHD de la Roche Sur Yon
city: Le Mans
country: France
facility: Centre Hospitalier du Mans
city: Levallois-Perret
country: France
facility: Institut hospitalier franco-britannique
city: Limoges
country: France
facility: Hôpital Dupuytren
city: Lyon
country: France
facility: Hôpital de la Croix Rousse
city: Lyon
country: France
facility: Hôpital Edouard Herriot
city: Marseille
country: France
facility: Hôpital Sainte Marguerite
city: Marseille
country: France
facility: Hôpital Européen
city: Montpellier
country: France
facility: Hôpital Gui de Chauliac
city: Mulhouse
country: France
facility: Hôpital Emile Müller
city: Nantes
country: France
facility: Hôpital de l'Hôtel Dieu
city: Nice
country: France
facility: Hôpital de l'Archet
city: Nîmes
country: France
facility: Hôpital Carémeau
city: Orléans
country: France
facility: Hôpital de La Source
city: Paris
country: France
facility: Hôpital Saint-Antoine
city: Paris
country: France
facility: Hôpital Necker
city: Paris
country: France
facility: Hôpital Bichat
city: Paris
country: France
facility: Hôpital de l'Hôtel Dieu
city: Paris
country: France
facility: Hôtel-Dieu
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Paris
country: France
facility: Lariboisière
city: Paris
country: France
facility: Hôpital Pitié-Salpêtrière
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
city: Paris
country: France
facility: Tenon
city: Perpignan
country: France
facility: Centre Hospitalier de Perpignan
city: Pontoise
country: France
facility: Centre Hospitalier René Dubos
city: Pringy
country: France
facility: Centre hospitalier Annecy Genevois
city: Reims
country: France
facility: Hôpital Robert Debré
city: Rennes
country: France
facility: Hôpital Pontchaillou
city: Saint-Brieuc
country: France
facility: Centre Hospitalier de Saint-Brieuc
city: Saint-Denis
country: France
facility: Hôpital Delafontaine
city: Saint-Nazaire
country: France
facility: Centre Hospitalier Général de Saint Nazaire
city: Saint-Étienne
country: France
facility: Hôpital Nord
city: Strasbourg
country: France
facility: Hôpital Civil
city: Suresnes
country: France
facility: Hôpital Foch
city: Toulouse
country: France
facility: Hôpital La Grave
city: Toulouse
country: France
facility: Hôpital Purpan
city: Tourcoing
country: France
facility: Hôpital Gustave Dron
city: Tours
country: France
facility: Hôpital Bretonneau
city: Vandoeuvre les Nancy cedex
country: France
facility: Hôpital de Brabois
city: Versailles
country: France
facility: Hôpital André Mignot
city: Villeneuve-Saint-Georges
country: France
facility: Centre Hospitalier Intercommunal
Study officials:
affiliation: Hôpital Raymond Poincaré
name: Pierre De Truchis, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Landman R, de Truchis P, Assoumou L, Lambert S, Bellet J, Amat K, Lefebvre B, Allavena C, Katlama C, Yazdanpanah Y, Molina JM, Petrov-Sanchez V, Gibowski S, Alvarez JC, Leibowitch J, Capeau J, Fellahi S, Duracinsky M, Morand-Joubert L, Costagliola D, Alvarez JC, Girard PM; ANRS 170 QUATUOR study group. A 4-days-on and 3-days-off maintenance treatment strategy for adults with HIV-1 (ANRS 170 QUATUOR): a randomised, open-label, multicentre, parallel, non-inferiority trial. Lancet HIV. 2022 Feb;9(2):e79-e90. doi: 10.1016/S2352-3018(21)00300-3.