4 Consecutive Days on Treatment Followed by 3 Days Off Treatment, in HIV Patients (ANRS162-4D)

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.

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).

Study Overview

• Status: Completed
• Conditions: HIV-1 Infection
• Intervention / Treatment: Drug: Four consecutive days on treatment and 3 days off

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Bobigny, France, 93000
    • Hôpital Avicenne
  • Caen, France, 14033
    • CHU Côte de Nacre
  • Corbeil Essonnes, France, 91100
    • Centre Hospitalier Sud Francilien
  • Dijon, France, 21079
    • Hôpital Le Bocage
  • Garches, France, 92380
    • Hopital Raymond Poincare
  • Kremlin Bicetre, France, 94275
    • Hôpital Bicêtre
  • Montpellier, France, 34295
    • Hopital Gui de Chauliac
  • Paris, France, 75015
    • Hôpital Européen Georges Pompidou
  • Paris, France, 75012
    • Hopital Saint-Antoine
  • Paris, France, 75020
    • Hopital Tenon
  • Paris, France, 75015
    • Hopital Necker
  • Paris, France, 75013
    • Hôpital Pitié-Salpêtrière
  • Paris, France, 75018
    • Hôpital Bichat
  • Suresnes, France, 92151
    • Hopital Foch
  • Toulouse, France, 31059
    • Hopital Purpan
  • Tours, France, 37044
    • Hopital Bretonneau
  • Martinique
    • Fort-de-france, Martinique, France, 97261
      • Hôpital Meynard

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 :

    1. NRTI : tenofovir, emtricitabine, abacavir, lamivudine
    2. PI/r : lopinavir/r, darunavir/r or atazanavir/r
    3. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Four consecutive days on treatment and 3 days off; 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; 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; Other Names: tenofovir,; emtricitabine,; abacavir,; lamivudine,; efavirenz,; rilpivirine,; etravirine,; lopinavir/r,; darunavir/r,; atazanavir/r

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: ANRS, Emerging Infectious Diseases
• Investigators: Principal Investigator: Christian PERRONNE, MD-PHD, Hopital Raymond Poincare; Principal Investigator: Jean-Claude MELCHIOR, MD-PHD, Hopital Raymond Poincare; Principal Investigator: Damien LE DU, MD, Hopital Raymond Poincare

Publications and helpful links

General Publications

• de Truchis P, Assoumou L, Landman R, Mathez D, Le Du D, Bellet J, Amat K, Katlama C, Gras G, Bouchaud O, Duracinsky M, Abe E, Alvarez JC, Izopet J, Saillard J, Melchior JC, Leibowitch J, Costagliola D, Girard PM, Perronne C; ANRS 162-4D Study Group. Four-days-a-week antiretroviral maintenance therapy in virologically controlled HIV-1-infected adults: the ANRS 162-4D trial. J Antimicrob Chemother. 2018 Mar 1;73(3):738-747. doi: 10.1093/jac/dkx434.

Study record dates

Study Major Dates

• Study Start: July 1, 2014
• Primary Completion (ACTUAL): January 1, 2016
• Study Completion (ACTUAL): January 1, 2016

Study Registration Dates

• First Submitted: May 21, 2014
• First Submitted That Met QC Criteria: June 2, 2014
• First Posted (ESTIMATE): June 6, 2014

Study Record Updates

• Last Update Posted (ESTIMATE): January 27, 2016
• Last Update Submitted That Met QC Criteria: January 26, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: HIV-1; simplification,; treatment discontinuation; virological success; four days a week
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Protease Inhibitors; Viral Protease Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Tenofovir; Emtricitabine; Lopinavir; Lamivudine; Darunavir; Etravirine; Atazanavir Sulfate; Efavirenz; Rilpivirine; Abacavir
• Other Study ID Numbers: ANRS162-4D; 2014-000146-29 (EUDRACT_NUMBER)