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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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HIV

Intervention / Treatment
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* Drug: triple therapy
* Drug: dual therapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: triple therapy<br>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<br>* Dosage treatment and usual prescription<br>* Other names: Tenofovir+Emtricitabine+Third agent (Including a fusion inhibitor: enfuvirtide or a CCR5 antagonist :maraviroc;|
| Experimental: dual therapy<br>Truvada®245mg:oral administration Tenofovir Disoproxil Fumarate (nucleotide reverse transcriptase inhibitor) + Emtricitabine (nucleoside reverse transcriptase inhibitor) | Drug: dual therapy<br>* 1 tablet (200mg/245mg) daily for 48 weeks<br>* Other names: Truvada®;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-DNA, dual therapy, NRTI, virological control, truvada®