Trial to Evaluate the Interest of a Reductive Anti Retroviral Strategy Using Dual Therapy Inspite of Triple Therapy (TRULIGHT)

Randomized Clinical Trial to Evaluate the Interest of a Down-scaled Treatment Strategy Using Dual Therapy (Nucleoside Analogs) in HIV Infected Patients Already Being Treated Using Triple Therapy, Who Present With a Successful Virological Control and for Which the HIV Reservoir is Low to Moderate

In the early 2000s, the "TRILEGE©" study was realized to determine if the reductive anti retroviral strategy from an initial triple therapy (based on a protease inhibitor as the third agent) towards a dual therapy of nucleoside analogs (in particular the association of "zidovudine +lamivudine") for patients infected by HIV and stabilized for at least 3 months at a threshold value of 400 copies/ml, would allow to obtain a well-controlled plasmatic viral load, with an aim to reduce the long-term side effects of the treatment.

The afore mentioned study showed that the reductive anti retroviral strategy was a failure. No study has as yet to revaluate this strategy, in particular in the current context of antiretroviral treatments.

Indeed, modern nucleoside inhibitors (Kivexa®, Truvada®) have extended half-lives as well as a superior intrinsic power as compared to treatments proposed in the initial "TRILEGE©" study. Furthermore, the better quality of current triple therapy (as compared to that used 10 years ago) has lead to substantial viral reservoir reduction.

Currently, a small number of patients is being successfully treated in the long-term (viral load < 20 copies/ml) using nucleoside analog dual therapy. The particular characteristics of these patients have yet to be thoroughly investigated.

The patients concerned were all treated prematurely before ever passing below 200 lymphocytes T CD4/mm3. It occurred that all these patients presented a low viral reservoir as measured by HIV DNA quantification (< 2,7 log copies/106 PBMC).

Therefore, by targeting patients who have (1) a strong immune restoration, (2) a low HIV DNA value and (3) a very good observance, the investigators emit the hypothesis that, reductive anti retroviral strategy that would consist in changing from a conventional triple therapy towards a Nucleoside reverse-transcriptase inhibitors dual therapy, could allow for durable control of viral replication with the concomitant benefice of reduced antiretroviral side effects and cost.

Study Overview

• Status: Completed
• Conditions: HIV
• Intervention / Treatment: Drug: triple therapy; Drug: dual therapy

• Study Type: Interventional
• Enrollment (Actual): 224
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • CHR d'ORLEANS, France, 45067
    • Service des Maladies Infectieuses, CHR Orléans La Source, ORLEANS CEDEX 2
  • Caen, France, 14033
    • Unité des Maladies Infectieuses, CHU de CAEN
  • Creteil, France, 94010
    • Service d'Immunologie Clinique centre de Vaccination anti- VIH ANRS Hopital Henri- Mondor
  • La Rochelle, France, 17019
    • Service de Médecine Interne et Maladies Infectieuses, Groupe Hospitalier La Rochelle, Cedex 01
  • Le Coudray, France, 28630
    • Service de Pneumologie, centre Hospitalier Fontenoy, CH de CHARTRES
  • Nancy, France, 54035
    • Chu de Nancy
  • Niort, France, 79021
    • Service des maladies Infectieuses et tropicales, CH GEORGES RENON
  • Paris, France, 75475
    • Service des Maladies Infectieuses et tropicales, APHP SAINT LOUIS
  • Paris, France, 75970
    • Hospital Tenon
  • Paris, France, 94010
    • Centre de diagnostic et thérapeutique, Hopital Hotel Dieu
  • Poitiers, France, 86021
    • Consultation Maladies Infectieuses, Chu de Poitiers, Cedex
  • Rouen, France, 76031
    • Maladies Infectieuses, CHU de ROUEN
  • Saintes, France, 17108
    • Service de Médecine Interne, CH de SAINTONGE- BP 326
  • Suresnes, France, 92151
    • Médecine Interne, Hôpital FOCH
  • Tourcoing, France, 59200
    • Service Universitaire des Maladies Infectieuses et du Voyageur, CH DRON
  • Tours, France, 37044
    • Service de Medecine Interne et Maladies Infectieuses, CHRU BRETONNEAU, TOURS CEDEX9

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 infected patient
• Initial TT ARV started above (or equal to) 150 / mm3 LT CD4, and 18 months prior to inclusion in the study
• Ongoing antiretroviral therapy combining tenofovir + emtricitabine + a 3rd agent (IP / r, IP, NNRTI, II, Inhibitors) with at least one undetectable viral load (CV <50 copies / mL) after introduction of the latter treatment.
• Patient in virological success: CV <50 copies / mL for at least 12 months, including visit to selection.
• Absence of previous therapeutic failure: no viral load ≥ 200 copies / mL (after 6 months of treatment) (Except in the case of a justified therapeutic interruption: travel, stock-out ...) and of obtaining success Virologic after introduction of treatment, without concept of genotypic resistance known to the ARVs used.
• Cellular DNA-HIV <2.7 log copies / 106 PBMC
• Zenith RNA-HIV <150,000 copies / ml (excluding viral load values during primary infection if it is documented)
• No genotypic resistance to currently used and known ARVs
• Patient who has given written informed consent
• Affiliate or beneficiary of a social security scheme
• Patient followed on an outpatient basis, age ≥ 18 years.

Exclusion Criteria:

• Non-compliant patient
• Subject is pregnant, or lactating, or of childbearing potential and without contraception
• Active opportunistic infections
• Major overweight (BMI ≥ 40)
• Severe renal pathology (creatinine clearance < 30ml/min)
• Cirrhosis or severe liver failure (factor V < 50%)
• Prognosis threatened within 6 months
• Circumstances that may impair judgment or understanding of the information given to the patient
• Malabsorption syndromes

• The following laboratory criteria:

  • Serum ASAT,ALAT > 5 x upper limit of normal (ULN)
  • Thrombocytopenia with platelet count < 50.000/ml
  • Anemia with hemoglobin < 8g/dl
  • Polynuclear neutrophil count < 500/mm3

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: triple therapy; Tenofovir Disoproxil Fumarate (nucleotide reverse transcriptase inhibitor) + Emtricitabine (nucleoside reverse transcriptase inhibitor) + third agent (boosted protease inhibitor or unboosted protease inhibitor or integrase inhibitor or celsentri or non-nucleoside reverse transcriptase inhibitor).	Drug: triple therapy; Dosage treatment and usual prescription; Other Names: Tenofovir+Emtricitabine+Third agent (Including a non nucleoside reverse transcriptase inhibitor: efavirenz or nevirapine or etravirine or rilpivirine; Tenofovir+Emtricitabine+Third agent (Including a ritonavir-boosted protease inhibitor : saquinavir or indinavir or fosamprenavir or tipranavir or darunavir or atazanavir or lopinavir; Tenofovir+Emtricitabine+Third agent (Including an unboosted protease inhibitor: atazanavir or indinavir; Tenofovir+Emtricitabine+Third agent (Including an integrase inhibitor raltegravir or dolutegravir or cobicistat-boosted elvitegravir; Tenofovir+Emtricitabine+Third agent (Including a fusion inhibitor: enfuvirtide or a CCR5 antagonist :maraviroc
Experimental: dual therapy; Truvada®"245mg":oral administration Tenofovir Disoproxil Fumarate (nucleotide reverse transcriptase inhibitor) + Emtricitabine (nucleoside reverse transcriptase inhibitor)	Drug: dual therapy; 1 tablet (200mg/245mg) daily for 48 weeks; Other Names: Truvada®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Viral Load at 48 weeks	Percentage of patient having a viral load < 50 copies/ml in each arm reductive anti retroviral strategy from an original backbone of 2 Nucleoside reverse transcriptase inhibitors (Tenofovir Disoproxil Fumarate+ Emtricitabine) coupled to a third agent, towards a therapeutic strategy containing the backbone therapy alone (Truvada®).	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from week 4 in Viral load at 48 weeks	percentage of patients having a viral load between 50 and 400 copies/ml between week 4 and week 48	between 4 weeks and 48 weeks
CD 4 level in each arm	delta CD 4 measurement in each arm	48 weeks
Change from day 0 in HIV - DNA at week 48	HIV DNA evolution between day 0 and week 48 in each arm	day 0 and 48 weeks
RNA and DNA viral load (sub study)	RNA and DNA viral load in the genital tract (cervico-vaginal secretions or sperm): comparison between arms	Time Frame: Week 24 to Week 48

Collaborators and Investigators

• Sponsor: University Hospital, Tours
• Collaborators: University Hospital, Rouen; Central Hospital, Nancy, France; Poitiers University Hospital; Tourcoing Hospital; Henri Mondor University Hospital; Tenon Hospital, Paris; Centre Hospitalier de La Rochelle; HOSPITAL, ORLEANS; HOSPITAL, SAINTES; HOSPITAL, FOCH; HOSPITAL, CAEN; HOSPITAL, HOTEL DIEU; HOSPITAL, CHARTRES; HOSPITAL, SAINT LOUIS; Central Hospital, NIORT
• Investigators: Principal Investigator: LOUIS BERNARD, Pr, CHRU de Tours; Principal Investigator: GWENAEL LE MOAL, Dr, Poitiers university hospital; Principal Investigator: MARIAM RONCATO- SABERAN, Dr, CH de la Rochelle; Principal Investigator: THIERRY PASDELOUPS, Dr, CH de SAINTES; Principal Investigator: DAVID ZUCMAN, Dr, HOPITAL de FOCH; Principal Investigator: RENAUD VERDON, Pr, University Hospital, Caen; Principal Investigator: SEBASTIEN GALLIEN, Pr, CHU d'HENRI MONDOR; Principal Investigator: JEAN - PAUL VIARD, Pr, CH d'HOTEL DIEU; Principal Investigator: MARC LESTELLE, Dr, CH de Chartres; Principal Investigator: JEAN - MICHEL MOLINA, Pr, CHU Saint Louis; Principal Investigator: FAÏZA AJANA, Dr, CH de Tourcoing; Principal Investigator: SIMON SUNDER, Dr, CH de Niort; Principal Investigator: Gilles PIALOUX, Pr, Hospital Tenon; Principal Investigator: Thierry MAY, Dr, Chu de Nancy; Principal Investigator: Manuel ETIENNE, Dr, CHU de Rouen

Publications and helpful links

General Publications

• Hocqueloux L, Gubavu C, Prazuck T, De Dieuleveult B, Guinard J, Seve A, Mille C, Gardiennet E, Lopez P, Rouzioux C, Lefeuvre S, Avettand-Fenoel V. Genital Human Immunodeficiency Virus-1 RNA and DNA Shedding in Virologically Suppressed Individuals Switching From Triple- to Dual- or Monotherapy: Pooled Results From 2 Randomized, Controlled Trials. Clin Infect Dis. 2020 Apr 15;70(9):1973-1979. doi: 10.1093/cid/ciz511.
• Prazuck T, Verdon R, Le Moal G, Ajana F, Bernard L, Sunder S, Roncato-Saberan M, Ponscarme D, Etienne M, Viard JP, Pasdeloup T, Darasteanu I, Pialoux G, de la Blanchardiere A, Avettand-Fenoel V, Parienti JJ, Hocqueloux L; TRULIGHT Study Team. Tenofovir disoproxil fumarate and emtricitabine maintenance strategy in virologically controlled adults with low HIV-1 DNA: 48 week results from a randomized, open-label, non-inferiority trial. J Antimicrob Chemother. 2021 May 12;76(6):1564-1572. doi: 10.1093/jac/dkab038.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2014
• Primary Completion (Actual): August 23, 2017
• Study Completion (Actual): September 21, 2018

Study Registration Dates

• First Submitted: October 14, 2014
• First Submitted That Met QC Criteria: November 26, 2014
• First Posted (Estimate): November 27, 2014

Study Record Updates

• Last Update Posted (Actual): December 4, 2018
• Last Update Submitted That Met QC Criteria: November 30, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: dual therapy; virological control; NRTI; HIV-DNA; truvada®
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Integrase Inhibitors; Viral Protease Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; CCR5 Receptor Antagonists; Cytochrome P-450 CYP2C19 Inhibitors; Tenofovir; Emtricitabine; Cobicistat; Nevirapine; Raltegravir Potassium; Ritonavir; Lopinavir; Indinavir; Protease Inhibitors; Maraviroc; Tipranavir; Enfuvirtide; Reverse Transcriptase Inhibitors; Darunavir; Etravirine; Atazanavir Sulfate; Efavirenz; Dolutegravir; Rilpivirine; Fosamprenavir; Saquinavir; Elvitegravir; HIV Protease Inhibitors; Integrase Inhibitors
• Other Study ID Numbers: PHAO13-TP/TRULIGHT