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

Phase 3

Completed

• Conditions: HIV
• Interventions: Drug: triple therapy; Drug: dual therapy

• Registration Number: NCT02302547
• Lead Sponsor: University Hospital, Tours

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-10-14
• Study First Submitted QC: 2014-11-26
• Study First Posted: 2014-11-27
• Study Start: 2014-12
• Primary Completion: 2017-08-23
• Study Completion: 2018-09-21
• Status Verified: 2018-11
• Last Update Submitted: 2018-11-30
• Last Update Posted: 2018-12-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 224

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
triple therapy	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).
dual therapy	dual therapy	Truvada®"245mg":oral administration Tenofovir Disoproxil Fumarate (nucleotide reverse transcriptase inhibitor) + Emtricitabine (nucleoside reverse transcriptase inhibitor)

Primary Outcome Measures

Name	Time	Method
Viral Load at 48 weeks	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®).

Secondary Outcome Measures

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

Trial Locations

Locations (16)

CHU de NANCY; 🇫🇷 Nancy, France

Service Universitaire des Maladies Infectieuses et du Voyageur, CH DRON; 🇫🇷 Tourcoing, France

Service d'Immunologie Clinique centre de Vaccination anti- VIH ANRS Hopital Henri- Mondor; 🇫🇷 Creteil, France

Service de Médecine Interne et Maladies Infectieuses, Groupe Hospitalier La Rochelle, Cedex 01; 🇫🇷 La Rochelle, France

Centre de diagnostic et thérapeutique, Hopital Hotel Dieu; 🇫🇷 Paris, France

Maladies Infectieuses, CHU de ROUEN; 🇫🇷 Rouen, France

Service des maladies Infectieuses et tropicales, CH GEORGES RENON; 🇫🇷 Niort, France

Médecine Interne, Hôpital FOCH; 🇫🇷 Suresnes, France

Unité des Maladies Infectieuses, CHU de CAEN; 🇫🇷 Caen, France

Service de Pneumologie, centre Hospitalier Fontenoy, CH de CHARTRES; 🇫🇷 Le Coudray, France

Service de Médecine Interne, CH de SAINTONGE- BP 326; 🇫🇷 Saintes, France

Hospital Tenon; 🇫🇷 Paris, France

Consultation Maladies Infectieuses, Chu de Poitiers, Cedex; 🇫🇷 Poitiers, France

Service de Medecine Interne et Maladies Infectieuses, CHRU BRETONNEAU, TOURS CEDEX9; 🇫🇷 Tours, France

Service des Maladies Infectieuses, CHR Orléans La Source, ORLEANS CEDEX 2; 🇫🇷 CHR d'ORLEANS, France

Service des Maladies Infectieuses et tropicales, APHP SAINT LOUIS; 🇫🇷 Paris, France