Clinical trial NCT02302547: Trial to Evaluate the Interest of a Reductive Anti Retroviral Strategy Using Dual Therapy Inspite of Triple Therapy
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV
Keywords: HIV-DNA
dual therapy
NRTI
virological control
truvada®
Lead sponsor: University Hospital, Tours
Sponsor class: OTHER
Collaborators: name: HOSPITAL, ORLEANS
name: Poitiers University Hospital
name: Centre Hospitalier de La Rochelle
name: HOSPITAL, SAINTES
name: HOSPITAL, FOCH
name: HOSPITAL, CAEN
name: Henri Mondor University Hospital
name: HOSPITAL, HOTEL DIEU
name: HOSPITAL, CHARTRES
name: HOSPITAL, SAINT LOUIS
name: Tourcoing Hospital
name: Central Hospital, NIORT
name: Tenon Hospital, Paris
name: Central Hospital, Nancy, France
name: University Hospital, Rouen
First posted: 2014-11-27
Enrollment: 224
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Viral Load at 48 weeks
timeFrame: 48 weeks
Secondary outcomes:
measure: Change from week 4 in Viral load at 48 weeks
timeFrame: between 4 weeks and 48 weeks
measure: CD 4 level in each arm
timeFrame: 48 weeks
measure: Change from day 0 in HIV - DNA at week 48
timeFrame: day 0 and 48 weeks
measure: RNA and DNA viral load (sub study)
timeFrame: Time Frame: Week 24 to Week 48
Other outcomes:
Locations:
city: Caen
country: France
facility: Unité des Maladies Infectieuses, CHU de CAEN
city: CHR d'ORLEANS
country: France
facility: Service des Maladies Infectieuses, CHR Orléans La Source, ORLEANS CEDEX 2
city: Creteil
country: France
facility: Service d'Immunologie Clinique centre de Vaccination anti- VIH ANRS Hopital Henri- Mondor
city: La Rochelle
country: France
facility: Service de Médecine Interne et Maladies Infectieuses, Groupe Hospitalier La Rochelle, Cedex 01
city: Le Coudray
country: France
facility: Service de Pneumologie, centre Hospitalier Fontenoy, CH de CHARTRES
city: Nancy
country: France
facility: CHU de NANCY
city: Niort
country: France
facility: Service des maladies Infectieuses et tropicales, CH GEORGES RENON
city: Paris
country: France
facility: Service des Maladies Infectieuses et tropicales, APHP SAINT LOUIS
city: Paris
country: France
facility: Hospital Tenon
city: Paris
country: France
facility: Centre de diagnostic et thérapeutique, Hopital Hotel Dieu
city: Poitiers
country: France
facility: Consultation Maladies Infectieuses, Chu de Poitiers, Cedex
city: Rouen
country: France
facility: Maladies Infectieuses, CHU de ROUEN
city: Saintes
country: France
facility: Service de Médecine Interne, CH de SAINTONGE- BP 326
city: Suresnes
country: France
facility: Médecine Interne, Hôpital FOCH
city: Tourcoing
country: France
facility: Service Universitaire des Maladies Infectieuses et du Voyageur, CH DRON
city: Tours
country: France
facility: Service de Medecine Interne et Maladies Infectieuses, CHRU BRETONNEAU, TOURS CEDEX9
Study officials:
affiliation: CHRU de TOURS
name: LOUIS BERNARD, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Poitiers University Hospital
name: GWENAEL LE MOAL, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: CH de LA ROCHELLE
name: MARIAM RONCATO- SABERAN, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: CH de SAINTES
name: THIERRY PASDELOUPS, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: HOPITAL de FOCH
name: DAVID ZUCMAN, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Caen
name: RENAUD VERDON, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU d'HENRI MONDOR
name: SEBASTIEN GALLIEN, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: CH d'HOTEL DIEU
name: JEAN - PAUL VIARD, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: CH de CHARTRES
name: MARC LESTELLE, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU SAINT LOUIS
name: JEAN - MICHEL MOLINA, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: CH de TOURCOING
name: FAÏZA AJANA, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: CH de NIORT
name: SIMON SUNDER, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: HOSPITAL TENON
name: Gilles PIALOUX, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Central Hospital, Nancy, France
name: Thierry MAY, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Rouen
name: Manuel ETIENNE, Dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.