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

HIV-1 Infection Clinical Trial

Official title: 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.

Status Completed

Clinical Trial Summary

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.

Clinical Trial Description

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 ;

Related Conditions & MeSH terms

• Communicable Diseases
• HIV-1 Infection
• Immunosuppression-related Infectious Disease
• Infection

• NCT number: NCT01928407
• Study type: Interventional
• Source: Institut de Médecine et d'Epidémiologie Appliquée - Fondation Internationale Léon M'Ba
• Status: Completed
• Phase: Phase 4
• Start date: February 23, 2011
• Completion date: January 7, 2013