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

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.

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

Eligibility Criteria:
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