Pharmacokinetics of Atazanavir/Ritonavir in HIV-1 Infected Pregnant Women

Study Overview
=================
Brief Summary
-----------------
To determine what dosing regimen of atazanavir (ATV) / ritonavir (RTV) produces adequate drug exposure during pregnancy compared to drug exposure in historical data in human immunodeficiency virus (HIV) infected participants.

Official Title
-----------------
A Study of the Pharmacokinetics of Atazanavir (ATV)/Ritonavir(RTV) Administered as Part of Highly Active Antiretroviral Therapy (HAART) in HIV-1 Infected Pregnant Women

Conditions
-----------------
HIV Infection

Intervention / Treatment
-----------------
* Drug: Atazanavir + Ritonavir + Combivir


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: HIV-infected pregnant women > 18 years of age Between week 12 and 32 gestation CD4 > 200 cells/mm³ Treatment-naive with HIV RNA > 400 c/mL, on HAART with HIV RNA <50 c/mL, or previously treated with ATV (< 3 weeks) with HIV RNA>400 c/mL

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br> | Drug: Atazanavir + Ritonavir + Combivir<br>* Capsules, tablets, Oral, initially ATV 300 mg + RTV 100 mg + ZDV/3TC 300/150 mg, dose escalated to ATV 400 mg + RTV 100 mg + ZDV/3TC 300/150 mg, ATV and RTV once daily, lamivudine (ZDV) / zidovudine (3TC) twice daily (BID), up to 36 weeks<br>* Other names: BMS-232632;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infant Gestational Age at Delivery |  | At the time of delivery | 
| Infant Gender |  | At the time of delivery | 
| Infant Race |  | At the time of delivery | 
| Mean ATV Maximum Plasma Concentration (Cmax) in One Dosing Interval | Cmax = maximum observed plasma concentration of atazanavir at specified time points. | Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum | 
| Mean RTV Maximum Plasma Concentration (Cmax) in One Dosing Interval | Cmax = maximum observed plasma concentration of ritonavir at specified time points. | Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum | 
| Mean ATV Area Under the Concentration Curve (AUC TAU) | AUC = area under the concentration curve (AUC [TAU]) of atazanavir in one dosing interval from time zero to 24 hours. | Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum | 
| Mean RTV Area Under the Concentration Curve (AUC TAU) | AUC = area under the concentration curve (AUC [TAU]) of ritonavir in one dosing interval. | Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum | 
| Mean ATV Trough Plasma Concentration (Cmin) 24 Hours Following the Daily Dose | Cmin = plasma concentration 24 hours post dose of atazanavir at specified time points. | Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum at 24 hours following the daily dose. | 
| Mean RTV Trough Plasma Concentration (Cmin) 24 Hours Following the Daily Dose | Cmin = plasma concentration 24 hours post dose of ritonavir at specified time points. | Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum at 24 hours following the daily dose. | 
| Mean ATV Terminal Elimination Half Life (T 1/2) | T 1/2 = terminal elimination half life of atazanavir at specified time points. | Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum | 
| Mean RTV Terminal Elimination Half Life (T 1/2) | T 1/2 = terminal elimination half life of ritonavir at specified time points. | Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum | 
| Mean ATV Time of Maximum Observed Plasma Concentration (Tmax) | Tmax = time to reach maximum observed plasma concentration of atazanavir at specified time points. | Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum | 
| Mean RTV Time of Maximum Observed Plasma Concentration (Tmax) | Tmax = time to reach the maximum observed plasma concentration of ritonavir at specified time points. | Pregnancy Weeks 12 to 28, Weeks 28 to 36, and 4-6 Weeks Postpartum | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maternal HIV Ribonucleic Acid (RNA) Level on Day of Delivery | The maternal HIV RNA level is assessed by the Roche Amplicor® Ultrasensitive Assay Version 1.5. | Day of Delivery ± 2 Days | 
| Median Change From Baseline to Day of Delivery in Maternal HIV RNA Level | The maternal HIV RNA level was determined at baseline and the day of delivery ± 2 days using VR-OC. The maternal HIV RNA level is assessed by the Roche Amplicor® Ultrasensitive Assay Version 1.5. | Baseline, Day of Delivery ± 2 Days | 
| Mean HIV RNA Level at Baseline |  | Baseline | 
| Median Change From Baseline to Day of Delivery in Maternal Cluster of Differentiation 4 (CD4) Cell Count | The median CD4 cell count change from baseline was calculated for all treated mothers at the time of delivery ± 2 days. Maternal CD4 cell counts were assessed by the Roche Amplicor® Ultrasensitive Assay Version 1.5. | Baseline, Day of Delivery ± 2 Days | 
| Mean CD4 Cell Count at Baseline |  | Baseline | 
| Infant HIV Status | The neonatal HIV-1 status are assessed by the Roche Amplicor HIV-1 DNA Assay Version 1.5 (Roche Molecular Systems). | Birth Through 6 Months on Study | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. SAE =any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event. | During study period and 30 days post-study. | 
| Number of Participants With Grade 2 to Grade 4 AEs and SAEs | AEs and SAEs considered possibly, probably, or certainly related to study treatment, were graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death). Hyperbilirubinemia (Grade 1=1.1 to 1.5 upper limit of normal [ULN] [mild], Grade 2=1.6 to 2.5 ULN [moderate], Grade 3=2.6 to 5.0 ULN [severe], Grade 4= > 5.0 ULN [potentially life threatening]). | During Study Period and 30 Days Post-Study. | 
| SAEs in Enrolled Mothers | SAEs were evaluated for all treated and untreated participants. An SAE was defined as an untoward medical occurrence that results in death, is life-threatening (defined as an event in which the participant was at risk of death at the time of the event); might have caused death if it were more severe, required inpatient hospitalization or prolongation of existing hospitalization, in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, an important medical event that required intervention to prevent serious outcomes. | During Study Period and 30 Days Post-Study. | 
| SAEs in Enrolled Infants | SAEs were evaluated for all treated and untreated participants. An SAE was defined as an untoward medical occurrence that results in death, is life-threatening (defined as an event in which the participant was at risk of death at the time of the event); might have caused death if it were more severe, required inpatient hospitalization or prolongation of existing hospitalization, in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, an important medical event that required intervention to prevent serious outcomes. | Birth Through Week 16 of Life | 
| Mean Atazanavir Maternal Plasma Concentration and Neonatal Cord Blood Concentration | Mean atazanavir maternal plasma concentration and neonatal cord blood concentration as measured at the time of delivery. | At Time of Delivery | 
| Median Infant Total Bilirubin Level | Median infant total bilirubin level as measured at specified time points. | Birth (Day 1), Day 3, Day 5, and Day 7 of Life | 
| Mean Atazanavir Plasma Protein Binding | Atazanavir Plasma Protein Binding Percentage measured at specified time points. | Pregnancy Weeks 28 to Delivery at 3 Hours Postdose and 24 Hours Postdose, and Time of Delivery | 
| Multicenter AIDS Cohort Study (MACS) Participant Adherence to Regimen and Drug Components for ATV 300 mg / RTV 100 mg Test Dose | The MACS was administered to evaluate participant adherence to each drug and the adherence to the regimen. The MACS adherence questionnaire asks patients how many medication doses they missed during the previous day, 2 days, 3 days and 4 days. Drug-specific questions included adherence with dose and frequency. Adherence was defined as taking all doses and numbers of pills as prescribed for each medication. This strict adherence cut-off was based on the guidelines stating that anything less than excellent adherence may result in a virus breakthrough and development of resistance. | Study Week 2, Pregnancy Weeks 20 to Weeks 28, Pregnancy Weeks 28 to Delivery, Week 2 Postpartum, Week 4 Postpartum | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV-1 infected pregnant women, either treatment naive or on ATV/RTV combined with ZDV/3TC