HIV Infections
Conditions
Keywords
Dose-Response Relationship, Drug, Drug Therapy, Combination, Drug Administration Schedule, HIV Protease Inhibitors, Reverse Transcriptase Inhibitors, Anti-HIV Agents, Pharmacokinetics, Treatment Experienced, Treatment Naive
Brief summary
The purpose of this study was to find a safe and tolerable dose of the protease inhibitor (PI) atazanavir (ATV), with or without a low-dose boost of the PI ritonavir (RTV), when taken with other anti-HIV drugs in HIV infected infants, children, and adolescents. Advancements in anti-HIV drugs for HIV infected children and adolescents have been hard to make, in part because these patients often do not take the drugs as prescribed. ATV may be a better option because it is available in the form of powder which children and adolescents may be more willing to take regularly. Using a low dose of RTV as a boosting agent for ATV may also increase the chances of virologic response of highly active antiretroviral treatment (HAART)-experienced patients. This study aimed to find safe and tolerable doses of ATV with or without low-dose RTV boost in infants, children, and adolescents. For this study, participants were enrolled in the United States and South Africa.
Detailed description
Advancements in HAART for HIV-infected children and adolescents are hindered by patient nonadherence. The availability of a powder formulation and the once-daily dosing schedule make ATV an attractive agent for improved adherence in pediatric treatment regimens. This study was designed to provide pharmacokinetic (PK) data to guide dosing recommendations for ATV, when given concurrently with or without low-dose RTV boost, in infants, children, and adolescents. During the study, the safety and tolerance of ATV (with or without low-dose RTV) were closely monitored, and virologic efficacy data were obtained. There were two parts to this study. Step I took place in the United States and South Africa, and were further divided into two sets of groups, Parts A and B. Part A participants received ATV only and Part B participants received ATV with low-dose RTV boost. All participants received ATV once a day with 2 other antiretroviral drugs (not provided by the study). In Part B only, participants received ATV with a low dose of RTV. Participants were placed into 1 of 8 groups (Groups 1 to 4 for Part A; Groups 5 to 8 for Part B) with respect to age and study drug formulation. Participants in Groups 1 and 5 were infants between ages 3 months and 1 day (91 days) and 2 years (less than or exactly 730 days) and took ATV in powder form. Participants in Groups 2, 3, 6, and 7 were children between 2 years and 1 day (731 days) old and 13 years old. Groups 2 and 6 received ATV in powder form, while Groups 3 and 7 received the capsule form. Patients in Groups 4 and 8 were adolescents between 13 years and 1 day old and 21 years old (not including the 22nd birthday) and took ATV in capsule form. As of 01/02/2008 a new group, 5A was opened for enrollment. Participants in Group 5A were between 3 months and 6 months old and took ATV in powder form plus a low-dose RTV booster. For each group, enrollment started with five participants per group. All participants were evaluated for PK and safety criteria, adjusting the dose of ATV until one was found that passes both sets of criteria. Then five additional participants were enrolled, with enrollment continuing for each group once all participants within that group meet the PK criteria. For groups receiving RTV (Groups 5 to 8), additional criteria must be met for each dose of ATV studied. In addition to the PK and safety evaluations, 24-hour post-dose concentrations (Cmin) were monitored in the first 10 participants enrolled for a dose of ATV before more participants were enrolled and studied at that same dose. Note that in Protocol Version 5.0, South African (S.A.) sites were allowed to enroll patients in study groups 3,4,5,6,7,8. As a result, the study design has been modified to further stratify study groups 3, 4, 5, 6, 7, 8 (at the final recommended dose), by country, i.e., U.S.A. versus S.A., such that 10 evaluable study subjects will be accrued in parallel to each study group-country cohort. Clinic visits will be every 4 weeks through Week 48, then every 8 weeks until the last participant to enroll in the study has reached Week 96 of his/her treatment. If, after 56 weeks, a participant has a toxic reaction to a nucleoside/tide reverse transcriptase inhibitor (NRTI) in their medication regimen, the regimen may be changed to a different NRTI. At every visit, participants will undergo a complete medical history and physical exam, cardiac conduction evaluation, and urine and blood collection. Participants of childbearing age will have a pregnancy test performed at each visit. Step II will only be open to South African subjects who are virologically responding to treatment when the last enrollee into either part of Step I (Part A or Part B) has completed 96 weeks of treatment (end of Step I) . All such participants will be given ATV in capsule form at the same dose they received at the end of Step I, as well as the other antiretrovirals they were receiving during Step I. Step II will continue until ATV is approved in South Africa and readily available by individual prescription, and participants will have a study visit every 12 weeks. Note that the following ATV doses were independently evaluated for each group during the dose-finding stage based on the description above: Group 1 ATV Powder (310mg/m\^2, 620mg/m\^2); Group 2 ATV Powder (310mg/m\^2, 620mg/m\^2); Group 3 ATV Capsule (310mg/m\^2, 415mg/m\^2, 520mg/m\^2); Group 4 ATV Capsule (310mg/m\^2, 520mg/m\^2, 620mg/m\^2); Group 5 ATV Powder + RTV (310mg/m\^2); Group 6 ATV Powder +RTV (310mg/m\^2); Group 7 ATV Capsule + RTV (310mg/m\^2, 205mg/m\^2); Group 8 ATV Capsule + RTV (310mg/m\^2, 205mg/m\^2); Group 5A ATV Powder + RTV (310mg/m\^2). All these dosing groups are presented in Participant Flow groups to show the total number of participants enrolled, but only the participants enrolled at the final group doses are presented in the subsequent results. The following groups satisfied the safety and PK guidelines specified in the protocol: Groups 3,4,6,7,8. Groups 5 and 5A did not satisfy the protocol-defined pharmacokinetic criteria. There was considerable inter-subject variability in systemic exposures in this age group, such that a dose escalation to 415mg/m\^2 may have resulted in ATV exposures greater than 90,000 ng\*hr/mL in some children. Thus, a further dose increase in Groups 5 and 5A was not attempted. These are the final dose for each group: Groups 1 and 2 (Final dose was not established); Group 3 ATV Capsule (520mg/m\^2); Group 4 ATV Capsule (620mg/m\^2); Group 5 ATV Powder (310mg/m\^2) + RTV; Group 6 ATV Powder (310mg/m\^2) +RTV; Group 7 ATV Capsule (205mg/m\^2) + RTV; Group 8 ATV Capsule (205mg/m\^2) + RTV; Group 5A ATV Powder (310mg/m\^2) + RTV.
Interventions
DRUGATV
Participants received varying doses of ATV, depending on their age and weight. The medication was administered as 50 mg, 100 mg, or 200 mg capsules or a powder formulation, depending on which study arm participants were in.
DRUGRitonavir
Administered as 100 mg capsules or oral solution.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
International Maternal Pediatric Adolescent AIDS Clinical Trials Group
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
91 Days to 21 Years
Healthy volunteers
No
Inclusion criteria
for Step I: * Age: 91 days to 21 years of age (not including the 22nd birthday). * A confirmed diagnosis of HIV infection defined by the current definition of the IMPAACT Virology Core Laboratory Committee. More information about this criterion can be found in the protocol. * Viral load greater than or equal to 5,000 copies/mL * Any CDC clinical classification and immune status * Antiretroviral treatment-naïve or -experienced study candidates must be able to add two new NRTIs as part of their new therapy in this protocol, or have genotypic evidence of sensitivity to two NRTIs (the NRTIs must be used in combinations recommended in the Guidelines for the Use of Antiretroviral Agents in Pediatric and Adolescent HIV Infection). More information about this criterion can be found in the protocol. * Study candidates must show evidence of retained phenotypic sensitivity to ATV (resistance index ratio of less than 10) when the subject has failed (after at least 12 weeks of therapy) two or more courses of PI containing regimens. More information about this criterion can be found in the protocol. * Demonstrated ability and willingness to swallow study medications * Study candidate, parent, or legal guardian must be able and willing to provide signed informed consent * Female participants who are sexually active and able to become pregnant must use two methods of birth control. More information about this criterion can be found in the protocol. * Males participating in the study must not attempt to impregnate a female, or participate in sperm donation programs. Males engaging in sexual activity that could lead to pregnancy must use a condom. * Study candidates with a history of undefined syncope will require a complete cardiac conduction evaluation at screening \[e.g., ECG, 24-hour monitoring (Holter), and exercise test (if age appropriate)\]. This evaluation must rule-out any cardiac conduction abnormalities.
Exclusion criteria
for Step I: * Active hepatitis * Presence of an acute serious/invasive infection requiring therapy at the time of enrollment * Hypersensitivity to any component of the formulation of ATV * Chemotherapy for active malignancy * Pregnant or breastfeeding * Any clinically significant diseases (other than HIV infection) or clinically significant findings during the screening medical history or physical examination that, in the clinician's opinion, would compromise the outcome of this study * Any laboratory or clinical toxicity greater than Grade 2 at entry * Documented history of cardiac conduction abnormalities or significant cardiac dysfunction * History of undefined syncope that cannot be ruled out as related to cardiac conduction abnormalities * Family history of prolonged QTc-interval syndrome, Brugada syndrome, or right-ventricular (RV) dysplasia * Corrected QTc-Interval greater than 440 msec at screening * Prolonged PR-Interval greater than 0.200 seconds (200 ms) on ECG at screening (study candidates greater than or equal to 13 years of age) * PR-Interval greater than 98th percentile on ECG at screening (study candidates less than 13 years of age) * Cardiac rhythm abnormalities: 1. A type I second-degree atrioventricular (AV) block (Mobitz type I heart-block) occurring during waking hours on ECG at screening 2. A type II second-degree AV-block (Mobitz type II heart-block) at any time on ECG at screening 3. A complete AV-block at any time on ECG at screening 4. A heart rate less than the 2nd percentile for age of the normal heart rate range on ECG at screening * Prolonged therapy with intravenous pentamidine for acute Pneumocystis Carinii Pneumonia (PCP) within three months of entry Inclusion Criteria for Step II: * Any South African subject enrolled into either part of Step I, who is virologically successful by Week 96 of when the last study participant enrolled into the respective part of Step I * Female participants who are sexually active and able to become pregnant must continue using two methods of birth control. More information about this criterion can be found in the protocol. * Males who continue participation in the study must not attempt to impregnate a woman, or participate in sperm donation programs. Males engaging in sexual activity that could lead to pregnancy must use a condom.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | From study entry up to week 96 | Total Bilirubin \>= 5.1xULN, ECG Events and Other Grade 3+ toxicities attributed to study treatment. The AEs were graded by the clinicians according to the Division of AIDS (DAIDS) Toxicity Table (see references in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening, Grade 5=Death. Relationship to study treatment was determined by the study team. |
| Number of Participants Who Died | From study entry up to week 96 | — |
| Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC24h) | Week 1 (Day 7) Intensive PK-24hr (Pre-Dose, 1, 2, 3, 4, 6, 8, and 12 hours post-dose and the following day at 24-hours post-dose) | Pharmacokinetics were determined by non-compartmental analysis and AUC0-24hr calculated by the linear trapezoidal method. |
| Pharmacokinetic (PK) Parameter: Minimum Plasma Concentration (C24) | Week 1 (Day 7) Intensive PK-24hr (Pre-dose, 1, 2, 3, 4, 6, 8, and 12 hours post-dose and the following day at 24-hours post-dose) | Pharmacokinetics were determined by non-compartmental analysis. C24 determined visually, except in the instance when the patient re-dosed the study medication prior to the 24 hour blood draw or the 24 hour level was not obtained, in which case the C24 was calculated from the elimination rate (ke) and the last measured concentration. |
| Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) | Week 1 (Day 7) Intensive PK-24 hr (Pre-dose, 1, 2, 3, 4, 6, 8, and 12 hours post-dose and the following day at 24-hours post-dose) | Pharmacokinetics were determined by non-compartmental analysis and Maximum concentration (Cmax) was determined visually. |
| Pharmacokinetic (PK) Parameter: Clearance (CL/F) | Week 1 (Day 7) Intensive PK-24 hr (Pre-dose, 1, 2, 3, 4, 6, 8, and 12 hours post-dose and the following day at 24-hours post-dose) | Pharmacokinetics were determined by non-compartmental analysis and Apparent oral clearance (CL/F) was calculated as ATV dose divided by AUC0-24hr. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in CD4 Percent From Baseline to Week 20 | Baseline, Week 20 | — |
| Percentage of Participants With HIV RNA <400 Copies/mL at Week 24 | Week 24 | Over the duration of the protocol, the assay used to determine Plasma HIV RNA levels was transitioned from the Amplicor HIV-1 Assay to the Amplicor HIV-1 Monitor 1.5 UltraSensitive Assay (Roche Molecular Systems, Branchburg, NJ) to finally the Abbott Real time HIV-1 RNA assay. The assays were performed according to the manufacturer's instructions in a laboratory accredited by the College of American Pathologists and certified by the NIH Virology Quality Assurance (VQA) in the United States, and VQA certified in South Africa. |
| Change in CD4 Percent From Baseline to Week 96 | Baseline, Week 96 | — |
| Change in CD4 Percent From Baseline to Week 48 | Baseline, Week 48 | — |
| Percentage of Participants With HIV RNA <400 Copies/mL at Week 48 | Week 48 | Over the duration of the protocol, the assay used to determine Plasma HIV RNA levels was transitioned from the Amplicor HIV-1 Assay to the Amplicor HIV-1 Monitor 1.5 UltraSensitive Assay (Roche Molecular Systems, Branchburg, NJ) to finally the Abbott Real time HIV-1 RNA assay. The assays were performed according to the manufacturer's instructions in a laboratory accredited by the College of American Pathologists and certified by the NIH Virology Quality Assurance (VQA) in the United States, and VQA certified in South Africa. |
| Percentage of Participants With HIV RNA <400 Copies/mL at Week 96 | Week 96 | Over the duration of the protocol, the assay used to determine Plasma HIV RNA levels was transitioned from the Amplicor HIV-1 Assay to the Amplicor HIV-1 Monitor 1.5 UltraSensitive Assay (Roche Molecular Systems, Branchburg, NJ) to finally the Abbott Real time HIV-1 RNA assay. The assays were performed according to the manufacturer's instructions in a laboratory accredited by the College of American Pathologists and certified by the NIH Virology Quality Assurance (VQA) in the United States, and VQA certified in South Africa. |
| Change in CD4 Count (Cells/mm^3) From Baseline to Week 20 | Baseline, Week 20 | — |
| Change in CD4 Count (Cells/mm^3) From Baseline to Week 48 | Baseline, Week 48 | — |
| Change in CD4 Count (Cells/mm^3) From Baseline to Week 96 | Baseline, Week 96 | — |
Countries
Puerto Rico, South Africa, United States
Participant flow
Recruitment details
Date of First Enrollment: 16 November 2000; Date of Last Enrollment: 22 December 2009
Participants by arm
| Arm | Count |
|---|---|
| Step I: Group 3 (ATV Final Dose: 520mg/m^2 Capsule) Group 3 enrolled participants between 2 years and 1 day of age and 13 years of age. They received ATV (capsule) and two NRTIs.
ATV: Participants received varying doses of ATV, depending on their age and weight. The medication was administered as 50 mg, 100 mg, or 200 mg capsules or a powder formulation, depending on which study arm participants were in.
ATV Final Recommended Dose: 520mg/m\^2 | 21 |
| Step I: Group 4 (ATV Final Dose: 620mg/m^2 Capsule) Group 4 enrolled participants between 13 years and 1 day of age and 21 years of age. They received ATV (capsule) and two NRTIs.
ATV: Participants received varying doses of ATV, depending on their age and weight. The medication was administered as 50 mg, 100 mg, or 200 mg capsules or a powder formulation, depending on which study arm participants were in.
ATV Final Recommended Dose: 620mg/m\^2 | 25 |
| Step I: Group 5 (ATV Final Dose: 310mg/m^2 Powder + RTV) Group 5 enrolled participants between 91 days of age and 2 years of age. They received ATV (powder), ritonavir, and two NRTIs.
ATV: Participants received varying doses of ATV, depending on their age and weight. The medication was administered as 50 mg, 100 mg, or 200 mg capsules or a powder formulation, depending on which study arm participants were in.
Ritonavir: Administered as 100 mg capsules or oral solution.
ATV Final Recommended Dose: 310mg/m\^2 | 21 |
| Step I: Group 5a (ATV Final Dose: 310mg/m^2 Powder + RTV) Group 5a enrolled participants between 91 days of age and 180 days of age. They received ATV (powder), ritonavir, and two NRTIs.
ATV: Participants received varying doses of ATV, depending on their age and weight. The medication was administered as 50 mg, 100 mg, or 200 mg capsules or a powder formulation, depending on which study arm participants were in.
Ritonavir: Administered as 100 mg capsules or oral solution.
ATV Final Recommended Dose: 310mg/m\^2 | 11 |
| Step I: Group 6 (ATV Final Dose: 310mg/m^2 Powder + RTV) Group 6 enrolled participants between 2 years and 1 day of age and 13 years of age. They received ATV (powder), ritonavir, and two NRTIs.
ATV: Participants received varying doses of ATV, depending on their age and weight. The medication was administered as 50 mg, 100 mg, or 200 mg capsules or a powder formulation, depending on which study arm participants were in.
Ritonavir: Administered as 100 mg capsules or oral solution.
ATV Final Recommended Dose: 310mg/m\^2 | 26 |
| Step I: Group 7 (ATV Final Dose: 205mg/m^2 Capsule + RTV) Group 7 enrolled participants between 2 years and 1 day of age and 13 years of age. They received ATV (capsule), ritonavir, and two NRTIs.
ATV: Participants received varying doses of ATV, depending on their age and weight. The medication was administered as 50 mg, 100 mg, or 200 mg capsules or a powder formulation, depending on which study arm participants were in.
Ritonavir: Administered as 100 mg capsules or oral solution.
ATV Final Recommended Dose: 205mg/m\^2 | 24 |
| Step I: Group 8 (ATV Final Dose: 205mg/m^2 Capsule + RTV) Group 8 enrolled participants between 13 years and 1 day of age and 21 years of age. They received ATV (capsule), ritonavir, and two NRTIs.
ATV: Participants received varying doses of ATV, depending on their age and weight. The medication was administered as 50 mg, 100 mg, or 200 mg capsules or a powder formulation, depending on which study arm participants were in.
Ritonavir: Administered as 100 mg capsules or oral solution.
ATV Final Recommended Dose: 205mg/m\^2 | 14 |
| Total | 142 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 1 | 3 |
| Overall Study | Met study objective - no further FU | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
| Overall Study | Other Reason | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Randomization entry error-no RX, no FU | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Severe debilitation, unable to continue | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 | 0 | 5 | 0 | 2 | 1 | 0 | 2 | 0 | 0 |
| Overall Study | Site closing | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 1 |
| Overall Study | Subj/Parent not able to get to clinic | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 1 | 2 | 1 | 1 | 1 | 3 | 0 | 0 |
| Overall Study | Subj/parent not willing to adhere to req | 0 | 0 | 1 | 3 | 0 | 0 | 3 | 1 | 0 | 6 | 3 | 0 | 0 | 2 | 3 | 3 | 4 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 2 | 0 | 1 | 2 | 2 | 0 | 1 | 3 | 2 | 0 | 1 | 2 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Step I: Group 5 (ATV Final Dose: 310mg/m^2 Powder + RTV) | Step I: Group 5a (ATV Final Dose: 310mg/m^2 Powder + RTV) | Step I: Group 6 (ATV Final Dose: 310mg/m^2 Powder + RTV) | Step I: Group 3 (ATV Final Dose: 520mg/m^2 Capsule) | Step I: Group 4 (ATV Final Dose: 620mg/m^2 Capsule) | Step I: Group 7 (ATV Final Dose: 205mg/m^2 Capsule + RTV) | Step I: Group 8 (ATV Final Dose: 205mg/m^2 Capsule + RTV) | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 1.2 years | 0.4 years | 4.4 years | 8.6 years | 14.3 years | 9 years | 17 years | 7 years |
| CD4 Count | 1306 cells/mm^3 | 2125 cells/mm^3 | 466 cells/mm^3 | 374 cells/mm^3 | 286 cells/mm^3 | 540 cells/mm^3 | 334 cells/mm^3 | 457 cells/mm^3 |
| CD4 Percent | 19 percentage of total lymphocytes | 35 percentage of total lymphocytes | 16 percentage of total lymphocytes | 18 percentage of total lymphocytes | 14 percentage of total lymphocytes | 21 percentage of total lymphocytes | 19 percentage of total lymphocytes | 18 percentage of total lymphocytes |
| HIV-RNA | 5 log10 copies/ml | 5 log10 copies/ml | 4.8 log10 copies/ml | 4.4 log10 copies/ml | 4.7 log10 copies/ml | 4.5 log10 copies/ml | 4.3 log10 copies/ml | 4.8 log10 copies/ml |
| Race/Ethnicity, Customized Black Non-Hispanic | 18 participants | 10 participants | 18 participants | 14 participants | 17 participants | 17 participants | 8 participants | 102 participants |
| Race/Ethnicity, Customized Hisp-Regardless of Race | 2 participants | 1 participants | 7 participants | 3 participants | 7 participants | 5 participants | 5 participants | 30 participants |
| Race/Ethnicity, Customized More than one race | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Unavailable | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized White Non-Hispanic | 0 participants | 0 participants | 1 participants | 4 participants | 0 participants | 0 participants | 0 participants | 5 participants |
| Sex: Female, Male Female | 8 Participants | 6 Participants | 12 Participants | 11 Participants | 18 Participants | 11 Participants | 9 Participants | 75 Participants |
| Sex: Female, Male Male | 13 Participants | 5 Participants | 14 Participants | 10 Participants | 7 Participants | 13 Participants | 5 Participants | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 21 / 21 | 25 / 25 | 21 / 21 | 26 / 26 | 24 / 24 | 14 / 14 | 11 / 11 |
| serious Total, serious adverse events | 10 / 21 | 15 / 25 | 12 / 21 | 14 / 26 | 15 / 24 | 8 / 14 | 5 / 11 |
Outcome results
Primary
Number of Participants Who Died
Time frame: From study entry up to week 96
Population: Participants accrued at the final recommended dose for each group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Number of Participants Who Died | Death attributed to ATV | 0 participants |
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Number of Participants Who Died | Death not attributed to ATV | 0 participants |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Number of Participants Who Died | Death attributed to ATV | 0 participants |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Number of Participants Who Died | Death not attributed to ATV | 1 participants |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Died | Death not attributed to ATV | 1 participants |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Died | Death attributed to ATV | 0 participants |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Died | Death not attributed to ATV | 1 participants |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Died | Death attributed to ATV | 0 participants |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Died | Death attributed to ATV | 0 participants |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Died | Death not attributed to ATV | 0 participants |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Number of Participants Who Died | Death not attributed to ATV | 0 participants |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Number of Participants Who Died | Death attributed to ATV | 0 participants |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Number of Participants Who Died | Death attributed to ATV | 0 participants |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Number of Participants Who Died | Death not attributed to ATV | 0 participants |
Primary
Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV
Total Bilirubin \>= 5.1xULN, ECG Events and Other Grade 3+ toxicities attributed to study treatment. The AEs were graded by the clinicians according to the Division of AIDS (DAIDS) Toxicity Table (see references in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening, Grade 5=Death. Relationship to study treatment was determined by the study team.
Time frame: From study entry up to week 96
Population: Patients accrued at the final recommended dose for each group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Heart Rate-Grade 2 | 2 participants |
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Total Bilirubin >= 5.1xULN | 1 participants |
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Other Grade 3+ Toxicities | 0 participants |
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in PR Interval-Grade 1 | 11 participants |
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in QTc Interval-Grade 3 | 1 participants |
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in PR Interval-Grade 2 | 1 participants |
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Heart Rate-Grade 3 | 1 participants |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Total Bilirubin >= 5.1xULN | 4 participants |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in PR Interval-Grade 1 | 4 participants |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in QTc Interval-Grade 3 | 0 participants |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Heart Rate-Grade 3 | 0 participants |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Heart Rate-Grade 2 | 1 participants |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in PR Interval-Grade 2 | 1 participants |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Other Grade 3+ Toxicities | 3 participants |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in PR Interval-Grade 2 | 0 participants |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Other Grade 3+ Toxicities | 0 participants |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in PR Interval-Grade 1 | 3 participants |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Total Bilirubin >= 5.1xULN | 0 participants |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in QTc Interval-Grade 3 | 0 participants |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Heart Rate-Grade 2 | 3 participants |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Heart Rate-Grade 3 | 1 participants |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Heart Rate-Grade 2 | 1 participants |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Total Bilirubin >= 5.1xULN | 0 participants |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in PR Interval-Grade 1 | 1 participants |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in PR Interval-Grade 2 | 0 participants |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Heart Rate-Grade 3 | 0 participants |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in QTc Interval-Grade 3 | 1 participants |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Other Grade 3+ Toxicities | 2 participants |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Other Grade 3+ Toxicities | 0 participants |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Total Bilirubin >= 5.1xULN | 0 participants |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Heart Rate-Grade 2 | 1 participants |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in PR Interval-Grade 2 | 0 participants |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in PR Interval-Grade 1 | 4 participants |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in QTc Interval-Grade 3 | 1 participants |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Heart Rate-Grade 3 | 0 participants |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Other Grade 3+ Toxicities | 1 participants |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Total Bilirubin >= 5.1xULN | 4 participants |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in PR Interval-Grade 1 | 5 participants |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Heart Rate-Grade 3 | 0 participants |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in QTc Interval-Grade 3 | 0 participants |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Heart Rate-Grade 2 | 4 participants |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in PR Interval-Grade 2 | 0 participants |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Heart Rate-Grade 2 | 0 participants |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Heart Rate-Grade 3 | 0 participants |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in PR Interval-Grade 1 | 1 participants |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in QTc Interval-Grade 3 | 0 participants |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Total Bilirubin >= 5.1xULN | 4 participants |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Other Grade 3+ Toxicities | 0 participants |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Number of Participants Who Experienced a Safety Endpoint of Interest Attributed to ATV | Increase in PR Interval-Grade 2 | 0 participants |
Primary
Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC24h)
Pharmacokinetics were determined by non-compartmental analysis and AUC0-24hr calculated by the linear trapezoidal method.
Time frame: Week 1 (Day 7) Intensive PK-24hr (Pre-Dose, 1, 2, 3, 4, 6, 8, and 12 hours post-dose and the following day at 24-hours post-dose)
Population: Participants with intensive pharmacokinetic (PK) results at the final recommended dose for each group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC24h) | 40653 ng*hr/mL |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC24h) | 51781 ng*hr/mL |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC24h) | 44243 ng*hr/mL |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC24h) | 38928 ng*hr/mL |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC24h) | 52199 ng*hr/mL |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC24h) | 45680 ng*hr/mL |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC24h) | 42835 ng*hr/mL |
Primary
Pharmacokinetic (PK) Parameter: Clearance (CL/F)
Pharmacokinetics were determined by non-compartmental analysis and Apparent oral clearance (CL/F) was calculated as ATV dose divided by AUC0-24hr.
Time frame: Week 1 (Day 7) Intensive PK-24 hr (Pre-dose, 1, 2, 3, 4, 6, 8, and 12 hours post-dose and the following day at 24-hours post-dose)
Population: Participants with intensive pharmacokinetic (PK) results at the final recommended dose for each group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Pharmacokinetic (PK) Parameter: Clearance (CL/F) | 12.8 L/hr/m^2 |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Pharmacokinetic (PK) Parameter: Clearance (CL/F) | 11.4 L/hr/m^2 |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Pharmacokinetic (PK) Parameter: Clearance (CL/F) | 7.9 L/hr/m^2 |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Pharmacokinetic (PK) Parameter: Clearance (CL/F) | 8.3 L/hr/m^2 |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Pharmacokinetic (PK) Parameter: Clearance (CL/F) | 5.3 L/hr/m^2 |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Pharmacokinetic (PK) Parameter: Clearance (CL/F) | 4.7 L/hr/m^2 |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Pharmacokinetic (PK) Parameter: Clearance (CL/F) | 4.8 L/hr/m^2 |
Primary
Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax)
Pharmacokinetics were determined by non-compartmental analysis and Maximum concentration (Cmax) was determined visually.
Time frame: Week 1 (Day 7) Intensive PK-24 hr (Pre-dose, 1, 2, 3, 4, 6, 8, and 12 hours post-dose and the following day at 24-hours post-dose)
Population: Participants with intensive pharmacokinetic (PK) results at the final recommended dose for each group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) | 6463 ng/mL |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) | 7006 ng/mL |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) | 6501 ng/mL |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) | 4952 ng/mL |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) | 5593 ng/mL |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) | 5013 ng/mL |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) | 4095 ng/mL |
Primary
Pharmacokinetic (PK) Parameter: Minimum Plasma Concentration (C24)
Pharmacokinetics were determined by non-compartmental analysis. C24 determined visually, except in the instance when the patient re-dosed the study medication prior to the 24 hour blood draw or the 24 hour level was not obtained, in which case the C24 was calculated from the elimination rate (ke) and the last measured concentration.
Time frame: Week 1 (Day 7) Intensive PK-24hr (Pre-dose, 1, 2, 3, 4, 6, 8, and 12 hours post-dose and the following day at 24-hours post-dose)
Population: Participants with intensive pharmacokinetic (PK) results at the final recommended dose for each group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Pharmacokinetic (PK) Parameter: Minimum Plasma Concentration (C24) | 173 ng/mL |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Pharmacokinetic (PK) Parameter: Minimum Plasma Concentration (C24) | 510 ng/mL |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Pharmacokinetic (PK) Parameter: Minimum Plasma Concentration (C24) | 482 ng/mL |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Pharmacokinetic (PK) Parameter: Minimum Plasma Concentration (C24) | 596 ng/mL |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Pharmacokinetic (PK) Parameter: Minimum Plasma Concentration (C24) | 947 ng/mL |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Pharmacokinetic (PK) Parameter: Minimum Plasma Concentration (C24) | 575 ng/mL |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Pharmacokinetic (PK) Parameter: Minimum Plasma Concentration (C24) | 885 ng/mL |
Secondary
Change in CD4 Count (Cells/mm^3) From Baseline to Week 20
Time frame: Baseline, Week 20
Population: Participants accrued at the final recommended dose for each group (with evaluable CD4 data).~CD4 changes from baseline were calculated in an 'as-treated' analysis' such that only patients who tolerated the study treatment, and who had evaluable data were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Change in CD4 Count (Cells/mm^3) From Baseline to Week 20 | 120 Cells/mm^3 |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Change in CD4 Count (Cells/mm^3) From Baseline to Week 20 | 184 Cells/mm^3 |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Change in CD4 Count (Cells/mm^3) From Baseline to Week 20 | 286 Cells/mm^3 |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Change in CD4 Count (Cells/mm^3) From Baseline to Week 20 | -294 Cells/mm^3 |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Change in CD4 Count (Cells/mm^3) From Baseline to Week 20 | 312 Cells/mm^3 |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Change in CD4 Count (Cells/mm^3) From Baseline to Week 20 | 176 Cells/mm^3 |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Change in CD4 Count (Cells/mm^3) From Baseline to Week 20 | 139 Cells/mm^3 |
Secondary
Change in CD4 Count (Cells/mm^3) From Baseline to Week 48
Time frame: Baseline, Week 48
Population: Patients accrued to the final recommended dose for each group (with evaluable CD4 data).~CD4 changes from baseline were calculated in an 'as-treated' analysis' such that only patients who tolerated the study treatment, and who had evaluable data were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Change in CD4 Count (Cells/mm^3) From Baseline to Week 48 | 164 Cells/mm^3 |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Change in CD4 Count (Cells/mm^3) From Baseline to Week 48 | 140 Cells/mm^3 |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Change in CD4 Count (Cells/mm^3) From Baseline to Week 48 | 74 Cells/mm^3 |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Change in CD4 Count (Cells/mm^3) From Baseline to Week 48 | -232 Cells/mm^3 |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Change in CD4 Count (Cells/mm^3) From Baseline to Week 48 | 324 Cells/mm^3 |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Change in CD4 Count (Cells/mm^3) From Baseline to Week 48 | 157 Cells/mm^3 |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Change in CD4 Count (Cells/mm^3) From Baseline to Week 48 | 135 Cells/mm^3 |
Secondary
Change in CD4 Count (Cells/mm^3) From Baseline to Week 96
Time frame: Baseline, Week 96
Population: Patients accrued to the final recommended dose for each group (with evaluable CD4 data).~CD4 changes from baseline were calculated in an 'as-treated' analysis' such that only patients who tolerated the study treatment, and who had evaluable data were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Change in CD4 Count (Cells/mm^3) From Baseline to Week 96 | 366 cells/mm^3 |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Change in CD4 Count (Cells/mm^3) From Baseline to Week 96 | 233 cells/mm^3 |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Change in CD4 Count (Cells/mm^3) From Baseline to Week 96 | 340 cells/mm^3 |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Change in CD4 Count (Cells/mm^3) From Baseline to Week 96 | -600 cells/mm^3 |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Change in CD4 Count (Cells/mm^3) From Baseline to Week 96 | 317 cells/mm^3 |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Change in CD4 Count (Cells/mm^3) From Baseline to Week 96 | 260 cells/mm^3 |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Change in CD4 Count (Cells/mm^3) From Baseline to Week 96 | 293 cells/mm^3 |
Secondary
Change in CD4 Percent From Baseline to Week 20
Time frame: Baseline, Week 20
Population: Patients accrued to the final recommended dose for each group (with evaluable CD4 data).~CD4 changes from baseline were calculated in an 'as-treated' analysis' such that only patients who tolerated the study treatment, and who had evaluable data were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Change in CD4 Percent From Baseline to Week 20 | 8 percentage of total lymphocytes |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Change in CD4 Percent From Baseline to Week 20 | 6 percentage of total lymphocytes |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Change in CD4 Percent From Baseline to Week 20 | 8 percentage of total lymphocytes |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Change in CD4 Percent From Baseline to Week 20 | 6 percentage of total lymphocytes |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Change in CD4 Percent From Baseline to Week 20 | 11 percentage of total lymphocytes |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Change in CD4 Percent From Baseline to Week 20 | 7 percentage of total lymphocytes |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Change in CD4 Percent From Baseline to Week 20 | 3 percentage of total lymphocytes |
Secondary
Change in CD4 Percent From Baseline to Week 48
Time frame: Baseline, Week 48
Population: Patients accrued to the final recommended dose for each group (with evaluable CD4 data).~CD4 changes from baseline were calculated in an 'as-treated' analysis' such that only patients who tolerated the study treatment, and who had evaluable data were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Change in CD4 Percent From Baseline to Week 48 | 7 percentage of total lymphocytes |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Change in CD4 Percent From Baseline to Week 48 | 9 percentage of total lymphocytes |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Change in CD4 Percent From Baseline to Week 48 | 10 percentage of total lymphocytes |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Change in CD4 Percent From Baseline to Week 48 | 0 percentage of total lymphocytes |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Change in CD4 Percent From Baseline to Week 48 | 12 percentage of total lymphocytes |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Change in CD4 Percent From Baseline to Week 48 | 8 percentage of total lymphocytes |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Change in CD4 Percent From Baseline to Week 48 | 5 percentage of total lymphocytes |
Secondary
Change in CD4 Percent From Baseline to Week 96
Time frame: Baseline, Week 96
Population: Patients accrued to the final recommended dose for each group (with evaluable CD4 data).~CD4 changes from baseline were calculated in an 'as-treated' analysis' such that only patients who tolerated the study treatment, and who had evaluable data were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Change in CD4 Percent From Baseline to Week 96 | 14 percentage of total lymphocytes |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Change in CD4 Percent From Baseline to Week 96 | 9 percentage of total lymphocytes |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Change in CD4 Percent From Baseline to Week 96 | 10 percentage of total lymphocytes |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Change in CD4 Percent From Baseline to Week 96 | -0.5 percentage of total lymphocytes |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Change in CD4 Percent From Baseline to Week 96 | 15 percentage of total lymphocytes |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Change in CD4 Percent From Baseline to Week 96 | 10 percentage of total lymphocytes |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Change in CD4 Percent From Baseline to Week 96 | 9 percentage of total lymphocytes |
Secondary
Percentage of Participants With HIV RNA <400 Copies/mL at Week 24
Over the duration of the protocol, the assay used to determine Plasma HIV RNA levels was transitioned from the Amplicor HIV-1 Assay to the Amplicor HIV-1 Monitor 1.5 UltraSensitive Assay (Roche Molecular Systems, Branchburg, NJ) to finally the Abbott Real time HIV-1 RNA assay. The assays were performed according to the manufacturer's instructions in a laboratory accredited by the College of American Pathologists and certified by the NIH Virology Quality Assurance (VQA) in the United States, and VQA certified in South Africa.
Time frame: Week 24
Population: Participants accrued at the final recommended dose for each group (with evaluable HIV-RNA data).~Virologic response, defined as achieving HIV-RNA \< 400 copies/mL and remaining on treatment, was analyzed using an 'intent-to-treat' (ITT) approach, in which children who discontinued study treatment for any reason were considered failures.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Percentage of Participants With HIV RNA <400 Copies/mL at Week 24 | 67 percentage of participants |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Percentage of Participants With HIV RNA <400 Copies/mL at Week 24 | 44 percentage of participants |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Percentage of Participants With HIV RNA <400 Copies/mL at Week 24 | 57 percentage of participants |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Percentage of Participants With HIV RNA <400 Copies/mL at Week 24 | 44 percentage of participants |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Percentage of Participants With HIV RNA <400 Copies/mL at Week 24 | 85 percentage of participants |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Percentage of Participants With HIV RNA <400 Copies/mL at Week 24 | 67 percentage of participants |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Percentage of Participants With HIV RNA <400 Copies/mL at Week 24 | 38 percentage of participants |
Secondary
Percentage of Participants With HIV RNA <400 Copies/mL at Week 48
Over the duration of the protocol, the assay used to determine Plasma HIV RNA levels was transitioned from the Amplicor HIV-1 Assay to the Amplicor HIV-1 Monitor 1.5 UltraSensitive Assay (Roche Molecular Systems, Branchburg, NJ) to finally the Abbott Real time HIV-1 RNA assay. The assays were performed according to the manufacturer's instructions in a laboratory accredited by the College of American Pathologists and certified by the NIH Virology Quality Assurance (VQA) in the United States, and VQA certified in South Africa.
Time frame: Week 48
Population: Participants accrued at the final recommended dose for each group (with evaluable HIV-RNA data).~Virologic response, defined as achieving HIV-RNA \< 400 copies/mL and remaining on treatment, was analyzed using an 'intent-to-treat' (ITT) approach, in which children who discontinued study treatment for any reason were considered failures.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Percentage of Participants With HIV RNA <400 Copies/mL at Week 48 | 62 percentage of participants |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Percentage of Participants With HIV RNA <400 Copies/mL at Week 48 | 32 percentage of participants |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Percentage of Participants With HIV RNA <400 Copies/mL at Week 48 | 71 percentage of participants |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Percentage of Participants With HIV RNA <400 Copies/mL at Week 48 | 55 percentage of participants |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Percentage of Participants With HIV RNA <400 Copies/mL at Week 48 | 85 percentage of participants |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Percentage of Participants With HIV RNA <400 Copies/mL at Week 48 | 63 percentage of participants |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Percentage of Participants With HIV RNA <400 Copies/mL at Week 48 | 29 percentage of participants |
Secondary
Percentage of Participants With HIV RNA <400 Copies/mL at Week 96
Over the duration of the protocol, the assay used to determine Plasma HIV RNA levels was transitioned from the Amplicor HIV-1 Assay to the Amplicor HIV-1 Monitor 1.5 UltraSensitive Assay (Roche Molecular Systems, Branchburg, NJ) to finally the Abbott Real time HIV-1 RNA assay. The assays were performed according to the manufacturer's instructions in a laboratory accredited by the College of American Pathologists and certified by the NIH Virology Quality Assurance (VQA) in the United States, and VQA certified in South Africa.
Time frame: Week 96
Population: Participants accrued at the final recommended dose for each group (with evaluable HIV-RNA data).~Virologic response, defined as achieving HIV-RNA \< 400 copies/mL and remaining on treatment, was analyzed using an 'intent-to-treat' (ITT) approach, in which children who discontinued study treatment for any reason were considered failures.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Step I: Group 3: ATV Dose: 520mg/m^2 Capsule | Percentage of Participants With HIV RNA <400 Copies/mL at Week 96 | 48 percentage of participants |
| Step I: Group 4: ATV Dose: 620mg/m^2 Capsule | Percentage of Participants With HIV RNA <400 Copies/mL at Week 96 | 20 percentage of participants |
| Step I: Group 5: ATV Dose: 310mg/m^2 Powder + RTV | Percentage of Participants With HIV RNA <400 Copies/mL at Week 96 | 75 percentage of participants |
| Step I: Group 5a: ATV Dose: 310mg/m^2 Powder + RTV | Percentage of Participants With HIV RNA <400 Copies/mL at Week 96 | 20 percentage of participants |
| Step I: Group 6: ATV Dose: 310mg/m^2 Powder + RTV | Percentage of Participants With HIV RNA <400 Copies/mL at Week 96 | 73 percentage of participants |
| Step I: Group 7: ATV Dose: 205mg/m^2 Capsule + RTV | Percentage of Participants With HIV RNA <400 Copies/mL at Week 96 | 63 percentage of participants |
| Step I: Group 8: ATV Dose: 205mg/m^2 Capsule + RTV | Percentage of Participants With HIV RNA <400 Copies/mL at Week 96 | 14 percentage of participants |