DATA: Evaluation of the Efficacy and Safety Between Two Antiretroviral Regimens, in HIV-1-infected Treatment-naïve Subjects With Low CD4 Counts
Study Details
Study Description
Brief 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 4 |
Detailed 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
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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
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Evaluate the virologic effect in seminal fluid
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To evaluate immunological response over time up to week 48
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To assess plasma and seminal pharmacokinetics of the drugs in the treatment regimen at week 4, 24, and 48
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Correlate the pharmacokinetic properties of the drugs with virologic outcome in plasma and semen at week 4 and 48
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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
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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
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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
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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
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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.
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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
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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
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: ATAZANAVIR 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
The patient included will receive their first antiretroviral regimen included the atazanavir treatment in combination with 2 others molecules
Other Names:
|
| Experimental: DARUNAVIR 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
The patient included will receive their first antiretroviral regimen included the darunavir treatment in combination with 2 others molecules
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Viral load of HIV-1 < 50 cp/ml [48 weeks]
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 Outcome Measures
- • Proportion of subjets with virologic efficacy [24 weeks]
• Proportion of subjets with virologic efficacy (viral load of HIV-1 <50 cp/ml)
- • Proportion of subjects with confirmed virologic failure [24 weeks]
• Proportion of subjects with confirmed virologic failure (viral load > 50 cp/ml on 2 consecutive mesures)
- Viral lod of HIV-1 on seminal fluid [W00,W4 et W48]
• Evaluate the viral load of HIV-1 at week 0, week 4 and week 48 on the seminal fluid (substudy)
- Immunologic response [W-4,W2,W4,W12,W24 and W48]
• Evaluate the immunologic response by the CD4 mesearement at W-4,W2,W4,W12,W24 and W48
- Differenciation and activation of lymphocytes [W0,W2,W4,W12,W24 and W48]
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)
- Pharmacokinetics evaluation of the drugs in plasma [W4,W24 and W48]
Measure of drugs (atazanir and darunavir) concentration (24 hours after taking treatment)in plasma at week 4, 24, and 48
- Pharmacokinetic evaluation of the drugs in semen [W4 and W48]
Measure of drugs (atazanir and darunavir) concentration (24 hours after taking treatment)in semen at week 4 and 48
- • Evaluate the relationship of bilirubinemia with atazanavir [W4 and W48]
Evaluate the relationship of the evolution of the measure of bilirubinemia (collected during study) with the concentration of atazanavir in blood
- Fasting glucose, lipids and insulin [W48]
• Change from baseline in fasting lipids, fasting glucose and insulin over time in the 2 arms
- Clinic and biologic tolerance [W48]
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.
- Sexual behaviour [W0,W24 et W48]
• Compare sexual behaviour between the regimens (substudy with a questionnary)
- Adherence patient satisfaction [W2,W24 et W48]
• Compare adherence patient satisfaction between the regimens (with questionnary)
Eligibility Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Hopital Zobda Quitman | Fort De France | Martinique | France | 97261 |
| 2 | Centre Hospitalier D'Argenteuil | Argenteuil | France | 95107 | |
| 3 | Hopital Saint-Jacques | Besancon | France | 25000 | |
| 4 | Hopital Avicenne | Bobigny | France | 93000 | |
| 5 | Hopital Jean Verdier | Bondy | France | 93143 | |
| 6 | Hopital Saint-Andre | Bordeaux | France | 33075 | |
| 7 | Chu Cote de Nacre | Caen | France | 14033 | |
| 8 | Hopital Louis Mourier | Colombes | France | 92700 | |
| 9 | Hopital Le Bocage | Dijon | France | 21034 | |
| 10 | Hopital Raymond Poincare | Garches | France | 92380 | |
| 11 | C.H.D de Vendee | La Roche Sur Yon | France | 85925 | |
| 12 | Hopital Dupuytren | Limoges | France | 87000 | |
| 13 | Hopital Sainte-Marguerite | Marseille | France | 13274 | |
| 14 | Centre Hospitalier de Melun | Melun | France | 77011 | |
| 15 | Hopital L'Archet | Nice | France | 06202 | |
| 16 | Hopital Lariboisiere | Paris | France | 75010 | |
| 17 | Hopital Saint Antoine | Paris | France | 75012 | |
| 18 | Hopital Pitie-Salpetriere | Paris | France | 75013 | |
| 19 | Hopital Necker | Paris | France | 75015 | |
| 20 | Hopital Bichat | Paris | France | 75018 | |
| 21 | Hopital Tenon | Paris | France | 75020 | |
| 22 | Hopital Pitie-Salpetriere | Paris | France | 75651 | |
| 23 | Hopital Cochin | Paris | France | 75674 | |
| 24 | Hopital Europeen Georges Pompidou | Paris | France | 75908 | |
| 25 | Hopital Saint-Jean Roussillon | Perpignan | France | 66046 | |
| 26 | Hopital Rene Dubos | Pontoise | France | 95303 | |
| 27 | C.H.R.A | Pringy | France | 74374 | |
| 28 | Hopital Civil | Strasbourg | France | 67000 | |
| 29 | Hopital Gustave Dron | Tourcoing | France | 59208 | |
| 30 | Hopital Bretonneau | Tours | France | 37044 |
Sponsors and Collaborators
- Institut de Médecine et d'Epidémiologie Appliquée - Fondation Internationale Léon M'Ba
Investigators
- Principal Investigator: Laurence LS SLAMA, PhD, Hospital TENON
- Principal Investigator: Roland RL LANDMAN, PhD, Institut de Médecine et d'Epidémiologie Appliquée - Fondation Internationale Léon M'Ba
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- IMEA 040-DATA