Capacity of the Dual Combination Raltegravir/Etravirine to Maintain Virological Success in HIV-1 Infected Patients of at Least 45 Years of Age- ANRS 163 ETRAL

Study Overview
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Brief Summary
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This multicenter, international, non randomized (single arm), open, phase II trial aims to evaluate the capacity of the dual combination raltegravir/etravirine to maintain virological success in virologically suppressed HIV-1 infected patients, of at least 45 years of age, switching from a boosted PI-containing regimen. Patients will be followed for 96 weeks. The primary endpoint was the proportion of participants with virological success at 48 weeks. Virological success is defined as the absence of 2 consecutive plasma viral load >50 copies/mL within 2 to 4 weeks apart. The study was designed to show an efficacy >90%, assuming a success rate >95%, with a power of 80% and a 5%type-1 error. A total of 160 individuals was required to achieve the objective. The principal secondary endpoint is the proportion of patients in therapeutic success up to week 48 and 96.

Official Title
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Dual Therapy Combining Raltegravir With Etravirine Maintains a High Level of Viral Suppression Over 96 Weeks in Long-term Experienced HIV-infected Individuals Over 45 Years on a PI-based Regimen: Results From the Phase II ANRS 163 ETRAL Study

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: raltegravir and etravirine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented HIV-1 infection Age ≥ 45 years Naïve to integrase inhibitor and etravirine At least 6 months of stable antiretroviral therapy (ART) including a boosted protease inhibitor, whatever the number of combined drugs HIV-RNA plasma VL ≤ 50 copies/mL during the last 24 months prior to screening visit (Week-6/Week-4), documented by at least 4 time-points with no more than one blip in HIV-RNA plasma viral load between 51 and 200 copies/mL HIV-RNA plasma VL ≤ 50 copies/mL at screening visit (Week-6/Week-4) A genotype is available (on amplified DNA at Week-6/Week-4 Visit and/or on RNA in the medical history of the patient) and shows a virus sensitive to ETR OR no genotype is available (amplification failure on DNA at Week-6/Week-4 Visit and no genotype in the medical history of the patient), there are no virological failure on NNRTI in the medical history CD4+ lymphocytes > 200 cells/mm3 Creatinine < 2.5 x ULN CPK (Creatine Phospho Kinase) < 6 ULN (Upper Limit of Normal) AST (Aspartate Aminotransferase), ALT (Alanine Aminotransferase) < 5 ULN Hemoglobin > 10 g/dL Platelets > 100 000/mm3 Negative urinary pregnancy test and use of efficient contraception for women of childbearing potential For French participants only: subject enrolled in or a beneficiary of a Social Security programme (State Medical Aid or AME is not a Social Security programme), article L1121-11 of the Public health code Patients with a coverage from a social health Signed informed consent Exclusion Criteria: Previous exposure to raltegravir or etravirine Presence of any documented integrase inhibitor mutation on DNA genotype at Week-6/Week-4 and/or on RNA in the medical history of the patient Positive hepatitis B HBsAg or Positive HBc Ac and negative HBs Ac HIV-2 infection Active viral hepatitis C requiring a specific treatment during the 24 months of the trial Patient with a history of non-compliance or irregular follow-up Initiation of a concomitant anti-hypercholesterolemia (e.g. statins) or antidiabetic treatment within the last 3 months prior the screening visit (Week-6 /Week-4) Patient using: Clopidogrel (Plavix®), Prasugrel (Effient®), Ticagrelor (Brilinta®), Ticlopidine (Ticlid®), Flurbiprofen (Antadys® - Cebutid®), Rifampin (Rifampicin® - Rifadin® - RofactMC - Rifater®), Rifapentine (Priftin®), St John's wort, Carbamazepine (Tegretol®), Phenobarbital, Phenytoin (Dilantin®),Avanafil (Stendra™), Triazolam (Halcion®) Concomitant treatment using interferon, interleukins or any other immunotherapy or chemotherapy Concomitant prophylactic or curative treatment for an opportunistic infection All conditions (use of alcohol, drugs, etc.) judged by the investigator to possibly interfere with trial protocol compliance, adherence and/or trial treatment tolerance Subjects under judicial protection due to temporarily and slightly diminished mental or physical faculties, or under legal guardianship Subjects participating in another clinical trial evaluating different therapies and including an exclusion period that is still in force during the screening phase Pregnant women or breastfeeding women

Ages Eligible for Study
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Minimum Age: 45 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: raltegravir and etravirine<br> | Drug: raltegravir and etravirine<br>* Raltegravir (RAL, ISENTRESS®) 400 mg tablets will be administered as one 400 mg oral tablet PO twice daily (800 mg per day) after a meal. Etravirine (ETR, INTELENCE®) 200 mg tablets will be administered as one 200 mg oral tablet PO twice daily (400 mg per day) after a meal.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Successful Virological Suppression at Weeks 48 and 96 | Virological success is defined as the absence of 2 consecutive plasma viral loads (VL) > 50 copies/mL within 2 to 4 weeks of a dual raltegravir/etravirine regimen. The proportion of patients who maintained viral suppression under raltegravir plus etravirine was 99.4% (95% confidence interval (95% CI:95.6 -99.9) at week 48 and 98.7% (95% CI: 95.0 -99.7) at week 96 | at week48 and at week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Therapeutic Success at Week 48 and Week 96 | Therapeutic success was defined as the absence of virological failure (i.e. 2 consecutive plasma viral loads (VL) > 50 copies/mL within 2 to 4 weeks) and the absence of treatment interruption due to adverse event judged by DSMB as related to the study treatment or procedure | weeks 48 and 96 | 
| Percentage of Patients With Trial Treatment Interruption at Week 48 and Week 96 |  | weeks 48 and 96 | 
| Percentage of Patients With With Grade Virological Failure (HIV-RNA Plasma VL Between 51 and 200 Copies/mL) |  | weeks 48 and 96 | 
| Median Time of Virological Failure | Time between the date of the study treatment initiation and the date of virological failure | week 96 | 
| Percentage of Patients With High Grade of Virological Failure Defined as HIV RNA > 200 Copies/mL |  | weeks 48 and 96 | 
| Number of Patients With RAL and/or ETR Resistance Mutations Among Those With Virological Failure |  | week 96 | 
| Factors Associated With the Occurrence of Plasma HIV-RNA Viral Load > 50 Copies/mL |  | week 96 | 
| Evolution of Total Cell-associated HIV-DNA |  | from day 0 to week 48 and week 96 | 
| Evolution of CD4+, CD8+ T Cells Counts and CD4/CD8 Ratio |  | from day 0 to week 48 and week 96 | 
| Number of Participants Experiencing Adverse Events and Effects | Number of all clinical and biological adverse events effects. Number of grade 3 or 4 clinical and biological adverse events and effects. | From day 0 to week 48 and week 96 | 
| Evolution of Metabolic Parameters (Fasting Triglycerides, Total Cholesterol, HDL-cholesterol, LDL-cholesterol and Fasting Glycemia) |  | from day 0 to week 96 | 
| Evolution of the Calibrated 5-year Framingham Risk Score | The Framingham risk score is expressed as a percentage. Higher scores mean a worse outcome and lower scores mean better outcome. Median percent change expressed as median (interquartile range (IQR)) | from day 0 to week 48 and at week 96 | 
| Percent Change of Renal Function | Percent change of the estimated Glomerular Filtration Rate (eGFR) calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration Calculator) formula | from day 0 to week 96 | 
| Evolution of Body Fat Distribution From Day 0 to W96 (DXA Scan Sub-study, 80 Patients) | Evolution of total fat mass, limb fat and trunk fat from day 0 to week 96 | from day 0 to week 96 | 
| Sub-study: Bone Mineral Density | • Evolution of bone mineral density (BMD) measured by DXA scans (DXA scan sub-study, 81 patients) Lumbar spine BMD, mg/cm2 Total hip BMD, mg/cm2 | from day 0, to week 48 and week 96 | 
| Percentage of Participants With Detectable Seminal HIV-RNA Viral Load at Week 48 | • Assessment of HIV-RNA viral load in human male genital compartment (20 patients) at week 48 | week 48 | 
| Inflammatory Parameters | • Evolution of the inflammation markers (IL-6hs, sCD14, sCD163, D-Dimers, IP-10, IgG, CRPus and insulin) on frozen plasma aliquots | from day 0 to week 96 | 
| Percentage of Participants Reporting a Very Good or an Excellent Quality of Life at Day 0, Weeks 48 and 96 |  | day 0 and weeks 48 and 96 | 
| Percentage of Participants Compliant With Treatment Program. | The compliance rate was estimated as the number of pills consumed (recorded using the self-reported 90 questionnaire) divided by the number of pills theoretically consumed, classified as low (80%), medium (80%-95%) or high (95%). | at week 0, week 48, and week 96 | 
| Evolution of the Ovarian Reserve From D0 to W48 Measured by AMH on Frozen Aliquots | We measured the Anti-mullerian Hormone (AMH) level to evaluate the ovarian reserve (from D0 to W48) | from day 0, to week 48 | 
| Evolution of the Level of MCP1 From D0 to W48 on Frozen Samples |  | from day 0, to week 48 | 
| Sub-study in Women : Comparison of the Metabolic/Inflammatory Profile in Women According to Their Ovarian Reserve and Menopausal Status at D0 and Its Evolution up to Week 96 | Metabolic markers measures are total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides. Inflammatory and innate immune activation markers measures are: IL-6hs, sCD14, sCD163, D-Dimers, IP-10, IgG, hsCRP and Insulin. Ovarian reserve measure is AMH | from day 0, to week 96 | 
| Sub-study in Women : Comparison of the Evolution Fat Distribution Measured by DXA Scan and Body Weight According to AMH Status | BMI, Hip circumference, Waist circumference, waist/hip ratio, Limb fat, Trunk fat, Total fat, Limb lean, Trunk lean, and Total lean | from day 0, to week 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Raltegravir, Etravirine, aged, 45 and over, Viral load, Efficacy, Safety