Evaluation of the Efficacy and Safety Between Two Antiretroviral Regimens, in HIV-1-infected Treatment-naïve Subjects With Low CD4 Counts

Study Overview
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Brief Summary
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A phase IV, prospective, multicenter , randomized open label, 48 weeks study to evaluate the antiretroviral efficacy and safety of atazanavir/ritonavir or darunavir/ritonavir, each in combination with a fixed dose of tenofovir disoproxil fumarate- emtricitabine in HIV-1-infected treatment-naïve subjects with CD4 counts below 200 µL.

Detailed Description
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Principal objective To evaluate the virological efficacy and safety at week 48 of 2 regimens atazanavir/ritonavir (ATZ/r) 300/100 mg or darunavir/ritonavir (DRV/r) 800/100 mg, each in combination with a fixed-dose of tenofovir/emtracitabine in HIV-1 treatment-naïve subjects with CD4 counts below 200 µL. Secondary objectives Proportion of subjets with virologic efficacy at week 24 Proportion of subjects with confirmed virologic failure at week 24 or later Proportion of patients with virologic mutations Evaluate the virologic effect in seminal fluid To evaluate immunological response over time up to week 48 To assess plasma and seminal pharmacokinetics of the drugs in the treatment regimen at week 4, 24, and 48 Correlate the pharmacokinetic properties of the drugs with virologic outcome in plasma and semen at week 4 and 48 Correlate the free fraction (not bound to protein) of atazanavir and darunavir in plasma and semen to virologic outcome Evaluate the relationship of bilirubinemia with atazanavir Change from baseline in fasting lipids, fasting glucose and insulin over time in the 2 arms Compare adherence patient satisfaction and sexual behaviour between the regimens Methodology This is a 48 week, multicentre, prospective, open label, phase IV, randomized. non comparative, study. Inclusion criteria Male or female, aged > 18 years of age. HIV-1 infection determined by a positive ELISA and confirmed by Western blot Plasma HIV-RNA > 1 000 c/mL CD4+T cell count < =200 cells/mm3 at the time of screening, or < =250 cells/mm3 if the CD4 count was <200 cells/mm3 12 weeks before screening. Women of childbearing potential must agree to use an effective method of barrier contraception or have documented sterility. Subjects must have medical insurance throught the Securite Sociale Ability to understand and provide written informed consent. Non-inclusion criteria Acute opportunistic infection within the past two weeks HIV-2 infection pregnant woman Any subject with drug resistance mutations at screening Any subject with a grade 3 or greater clinical or laboratory adverse event at screening Any subject who has received antiretoviral therapy except for prevention of mother to child transmission and patients who has received post exposure prophylaxis for a a month or less calculated creatinine clearance < 60/mL as estimated by the Cockcroft- Gault equation Patients in the opinion of the investigator that are unlikley to be able to follow study instructions Any subject unable to take antiretroviral medication for whatever reason Any subject taking a treatment or medication that is contraindicated when co-administered with any arm or drug in the treatment. Treatment: Group 1 : ATV + TDF/FTC (or Abacavir/Lamivudine, [ABC/3TC], if TDF/FTc contre-indicated atazanavir/ritonavir 300/100mg/day and TDF/FTC 245 /200 mg by day, 3 pills once a day, during 48 weeks during a meal Group 2 : DRV+ TDF/FTC (or ABC/3TC if TDF/FTc contre-indicated) darunavir/ritonavir 800/100mg/day and TDF/FTC 245 /200 mg by day, 4 pills once a day, during 48 weeks during a meal Primary Endpoints : Proportion of patients with HIV-1 plasma viral load below 50 copies/mL at week 48 while receiving their initial regimen Proportion of patients experiencing grade 2-4 adverse clinical and laboratory events including hematology, chemistry, lipids (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides), glucose and insulin by week 48. Secondary endpoints: Proportion of patients with plasma HIV RNA below 50 cp/mL at week 24 Proportion of patients with HIV RNA> 50 cp/mL at week 24 or later confirmed by a second HIV RNA at least 14 days after the first test Development of resistance mutations in subjects who have virologic failure testing at 24 weeks or later tested by a genotypic resistance test Evaluate the virologic effect in seminal fluid at baseline, W4 and W48 by change in HIV RNA concentrations in semen over time To evaluate immunological response over time up to week 48 in the 2 arms by CD4 cell count ( W-4, W2,W4, W12, W36 and W48), differenciation and activation in T CD4 ( W2,W4, W12, W24 and W48); Change in lymphocyte subset reconsistution at week 48 compared to baseline. ; Change in immunolgic markers of inflammations at weeks 2, 4, 12, 24, 48 To assess plasma and seminal pharmacokinetics of the drugs in the treatment regimen at week 4, 24, and 48 through residual concentrations ( C min) of antiretroviral drugs at W4, W24, and W48 Atazanavir and darunavir (plasma and seminal) drug concentrations and coorelation with adverse clinical and laboratory events. Evaluate the relationship of bilirubinemia with atazanavir pharmacokinetics (Cmin) Evolution of lipid, glucose and insulin parameters from baseline to weeks 24 and 48 Adherence to regimen, patient satisfaction and sexual behaviour between the regimens at W2,W24 and W48 mesured by ( mettre ref) Evolution of anthropomorphic measurements from baseline to weeks 24, 48. Substudies Brief description (2 lines maximum) and person in charge of the substudy Immunologic substudy ( Pr Brigitte Autran) : Change in immunolgic markers of inflammations at weeks 2, 4, 12, 24, 48 and change in lymphocyte subset reconsistution at week 48 compared to baseline. Pharmacologic substudy ( Dr Gilles Peytavin) : To assess plasma and seminal pharmacokinetics of the drugs in the treatment regimen at week 4, 24, and 48 through residual concentrations ( C min) of antiretroviral drugs at W4, W24, and W48 Virologic substudy ( Dr Anne Geneviève Marcelin) : Evaluate the virologic effect in seminal fluid at baseline, W4 and W48 Behaviour substudy ( Dr France Lert) : Compare adherence patient satisfaction and sexual behaviour between the regimens at W2,W24 and W48 Estimated enrolment: 120 subjects (60 per group) randomly assigned 1:1

Official Title
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A Phase IV, Prospective, Multicenter , Randomized Open Label, 48 Weeks Study to Evaluate the Antiretroviral Efficacy and Safety of Atazanavir or Darunavir,Each in Combination With a Fixed Dose of Tenofovir Emtricitabine in HIV-1-infected Treatment-naïve Subjects With CD4counts Below 200 µL.

Conditions
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HIV-1 Infection, Immunosuppression-related Infectious Disease

Intervention / Treatment
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* Drug: DARUNAVIR
* Drug: ATAZANAVIR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Male or female, aged > 18 years of age HIV-1 infection determined by a positive ELISA and confirmed by Western blot Plasma HIV-RNA > 1 000 c/mL CD4+T cell count < =200 cells/mm3 at the time of screening, or < =250 cells/mm3 if the CD4 count was <200 cells/mm3 12 weeks before screening Women of childbearing potential must agree to use an effective method of barrier contraception or have documented sterility Subjects must have medical insurance throught the Securite Sociale Ability to understand and provide written informed consent Exclusion Criteria Acute opportunistic infection within the past two weeks HIV-2 infection Pregnant woman Any subject with drug resistance mutations at screening Any subject with a grade 3 or greater clinical or laboratory adverse event at screening Any subject who has received antiretoviral therapy except for prevention of mother to child transmission and patients who has received post exposure prophylaxis for a a month or less Calculated creatinine clearance < 60/mL as estimated by the Cockcroft- Gault equation Patients in the opinion of the investigator that are unlikley to be able to follow study instructions Any subject unable to take antiretroviral medication for whatever reason Any subject taking a treatment or medication that is contraindicated when co-administered with any arm or drug in the treatment

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 |
| --- | --- |
| Experimental: ATAZANAVIR<br>The patient included in this Group 1 will receive their first antiretroviral regimen included : ATV + TDF/FTC (or Abacavir/Lamivudine, [ABC/3TC], if contre indicated of TDF/FTC) The dose : atazanavir/ritonavir 300/100mg/day and TDF/FTC 245 /200 mg day, 3 pills once a day, during 48 weeks during a meal | Drug: ATAZANAVIR<br>* The patient included will receive their first antiretroviral regimen included the atazanavir treatment in combination with 2 others molecules<br>* Other names: REYATAZ;|
| Experimental: DARUNAVIR<br>The patients included in this Group 2 will receive their first antiretroviral regimen included Group 2 : DRV+ TDF/FTC (or ABC/3TC if contre-indicated of TDF/FTC) The dose : darunavir/ritonavir 800/100mg/day and TDF/FTC 245 /200 mg day, 4 pills once a day, during 48 weeks during a meal | Drug: DARUNAVIR<br>* The patient included will receive their first antiretroviral regimen included the darunavir treatment in combination with 2 others molecules<br>* Other names: Prezista;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Viral load of HIV-1 < 50 cp/ml | To evaluate the virological efficacy and safety at week 48 of 2 regimens atazanavir/ritonavir (ATZ/r) 300/100 mg or darunavir/ritonavir (DRV/r) 800/100 mg, each in combination with a fixed-dose of tenofovir/emtracitabine in HIV-1 treatment-naïve subjects with CD4 counts below 200 µL | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| • Proportion of subjets with virologic efficacy | • Proportion of subjets with virologic efficacy (viral load of HIV-1 <50 cp/ml) | 24 weeks | 
| • Proportion of subjects with confirmed virologic failure | • Proportion of subjects with confirmed virologic failure (viral load > 50 cp/ml on 2 consecutive mesures) | 24 weeks | 
| Viral lod of HIV-1 on seminal fluid | • Evaluate the viral load of HIV-1 at week 0, week 4 and week 48 on the seminal fluid (substudy) | W00,W4 et W48 | 
| Immunologic response | • Evaluate the immunologic response by the CD4 mesearement at W-4,W2,W4,W12,W24 and W48 | W-4,W2,W4,W12,W24 and W48 | 
| Differenciation and activation of lymphocytes | At the end of the study, in a central lab, we will measure some inflammation and activation markers (CD69, HLA-DR, CD38, annexine V, IL-6, CD14s, IL-7 plasma) of lymphocytes CD4 and CD8(with the plasmatheque collected during the study) | W0,W2,W4,W12,W24 and W48 | 
| Pharmacokinetics evaluation of the drugs in plasma | Measure of drugs (atazanir and darunavir) concentration (24 hours after taking treatment)in plasma at week 4, 24, and 48 | W4,W24 and W48 | 
| Pharmacokinetic evaluation of the drugs in semen | Measure of drugs (atazanir and darunavir) concentration (24 hours after taking treatment)in semen at week 4 and 48 | W4 and W48 | 
| • Evaluate the relationship of bilirubinemia with atazanavir | Evaluate the relationship of the evolution of the measure of bilirubinemia (collected during study) with the concentration of atazanavir in blood | W4 and W48 | 
| Fasting glucose, lipids and insulin | • Change from baseline in fasting lipids, fasting glucose and insulin over time in the 2 arms | W48 | 
| Clinic and biologic tolerance | Evaluate the clinic and biologic tolerance between the 2 regimens (adverse event and some biologic measure will be collected for this evaluation). We will see in two arms if there are more adverse event or biological event. | W48 | 
| Sexual behaviour | • Compare sexual behaviour between the regimens (substudy with a questionnary) | W0,W24 et W48 | 
| Adherence patient satisfaction | • Compare adherence patient satisfaction between the regimens (with questionnary) | W2,W24 et W48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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naives, CD4 < 200 cell/mm3, Atazanavir, Darunavir