evaluation of the efficacy and safety between two antiretroviral regimens, in hiv-1-infected treatment-naïve subjects with low cd4 counts

Conditions: HIV-1 Infection; Immunosuppression-related Infectious Disease

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.

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

Keywords: naives, cd4 < 200 cell/mm3, atazanavir, darunavir