HIV Infections
Conditions
Brief summary
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used as part of combination antiretroviral therapy (ART) for infants and children, but NNRTI resistance is increasing, leading to treatment failure. This study tested the safety, tolerability, and dosing levels of etravirine (ETR), a new NNRTI.
Detailed description
Use of NNRTI-based regimens as initial therapy for HIV-infected children is increasing, especially in areas where newborns exposed to HIV-1 receive single-dose nevirapine (NVP) as part of prevention of mother-to-child transmission (PMTCT) regimens and/or daily NVP for prevention of transmission through breastfeeding. First-generation NNRTIs have a low genetic barrier to the development of resistance; in two of the most widely used NNRTIs, NVP and efavirenz (EFV), even a single amino acid mutation in the virus can lead to a reduction in the drug's effectiveness. Even short-term use of these NNRTIs, including only a single dose of NVP, can cause NNRTI resistance. Second-generation NNRTIs are needed as part of ARV regimens for newly diagnosed infants and children who have been exposed to single-dose NVP or who have failed their current antiretroviral (ARV) regimens. In this study, the second-generation NNRTI ETR was tested for safety, tolerability, and appropriate dosing. Children were assigned to one of three cohorts based on age: * Cohort I: At least 2 but younger than 6 years of age * Cohort II: At least 1 but younger than 2 years of age * Cohort III: At least 2 months but younger than 1 year of age Children in all three cohorts were treatment experienced, defined as being on a failing combination ARV regimen (containing at least 3 ARVs) for at least 8 weeks or having a treatment interruption of at least 4 weeks with a history of virologic failure while on a combination ARV regimen (containing at least 3 ARVs). Children received ETR together with an optimized background regimen (OBR) consisting of at least 2 active agents (a boosted protease inhibitor \[PI\] and at least 1 additional active ARV drug). OBR were based on clinical status, treatment history, resistance data, and availability of appropriate pediatric dosing and formulations. The children received an oral dose of ETR twice daily. Most children had 11 visits: at screening, entry (Day 0), Day 14 (intensive pharmacokinetic \[PK\] visit), and at Weeks 4, 8, 12, 16, 24, 32, 40, and 48. Most visits included a physical exam, giving a medical history, discussion of adherence, and blood and urine collection. The screening and intensive PK visits also included an electrocardiogram (ECG). During the intensive PK visit, the child had blood drawn approximately 7 times over 12 hours. After the Week 48 visit, children entered the long-term follow-up phase of the study and have a visit every 12 weeks for up to 5 years. These follow-up visits included giving a medical history and undergoing a physical exam and blood draw.
Interventions
DRUGEtravirine (ETR)
ETR was administered as 25-mg scored tablets and/or 100-mg tablets swallowed whole or dispersed in an appropriate liquid vehicle following a meal. Children took the specified dose orally twice daily within 30 minutes following a meal. Dose was decided according to dosing tables in protocol.
Sponsors
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
2 Months to 6 Years
Healthy volunteers
No
Inclusion criteria
* Confirmed HIV-1 infection as described in the protocol * NOTE: Children who were born at or sooner than 37 weeks gestational age must be at least 12 weeks of age and at least 46 weeks post-conceptual age at study entry. * HIV-1 RNA viral load greater than 1,000 copies/mL (within the previous 90 days prior to screening) and an HIV-1 RNA viral load greater than 1,000 copies/mL at screening * Treatment-experienced children on a failing combination antiretroviral (ARV) regimen (containing at least three ARVs) for at least 8 weeks; OR, treatment-experienced children on a treatment interruption of at least 4 weeks with a history of virologic failure while on a combination ARV regimen (containing at least three ARVs) * Ability to swallow etravirine (ETR) whole or dispersed in an appropriate liquid * Parent or legal guardian able and willing to provide signed informed consent and to have the child followed at the clinic site * Availability of sufficient active ARV drugs to create an optimized background regimen (OBR) consistent with protocol requirements
Exclusion criteria
* Evidence of phenotypic resistance to ETR at screening (phenotypic cutoffs of greater than 10 for loss of sensitivity for cohorts I, II, III) * Known history of HIV-2 infection in child or child's mother * Diagnosis of a new Centers for Disease Control (CDC) Stage C (per 1994 Revised Classification System for Human Immunodeficiency Virus Infection in Children Less than 13 Years of Age) criteria or opportunistic or bacterial infection diagnosed within 30 days prior to screening and not considered clinically stable * Prior history of malignancy * Any clinically significant diseases (other than HIV infection) or clinically significant findings during the screening medical history or physical examination that in the investigator's opinion would place the child at an unacceptable risk of injury, render the child unable to meet the requirements of the protocol, compromise the outcome of this study, or lead to the child being ineligible for participation * Current Grade 3 or higher of any of the following laboratory toxicities at screening: neutrophil count, hemoglobin, platelets, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lipase, or serum creatinine. * Current or anticipated use of any disallowed medications (listed in the protocol) * Child's family is unlikely to adhere to the study procedures or keep appointments or is planning to relocate to a non-IMPAACT study site during the study * History of nonadherence with ARV medications that in the investigator's opinion could affect the ability of the child to comply with the protocol/procedures * Child is currently participating, or has participated within the previous 30 days prior to screening, in a study with a compound or device that is not commercially available * Grade 3 or higher QTc or PR interval prolongation from the electrocardiogram (ECG) at screening. More information on this criterion can be found in the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Termination From Treatment Due to a Suspected Adverse Drug Reaction (SADR) | From baseline to occurrence of event, up to Week 48. | Number (%) of participants who discontinued treatment due to a suspected adverse drug reaction (SADR) by Cohort. |
| Adverse Events (AEs) of Grade 3 or Higher Severity | From baseline to occurrence of event, up to Week 48. | Number (%) of participants who experienced a Grade 3 or higher severity adverse event through Week 48 by Cohort, with Clopper-Pearson confidence intervals. |
| Death | From baseline to occurrence of event, up to Week 48. | Number (%) of deaths on study by Cohort. |
| Area Under the Plasma Concentration-Time Curve Over 12 Hours of ETR | Pre-dose, 1, 2, 4, 6, 9, and 12 hours post-dose measured at intensive PK visit (within 7-10 days after last dose of study drug administration) | Geometric Mean (Standard Deviation) of the area under the plasma concentration-time curve over 12 hours (AUC12h) of ETR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Optimized Background Regimen Due to Virologic Failure | Measured at entry and at Weeks 8, 12, 24, and 48 | Number (%) of participants who initiated a change in their optimized background regimen (OBR) due to virologic failure, by Cohort. |
| AEs of Grade 3 or Higher Severity Judged to be at Least Possibly Attributable to the Study Medications | From baseline to occurrence of event, up to Week 48. | Number (%) of Participants with AEs of Grade 3 or higher severity judged, by the Study Team, to be at least possibly attributable to the study medications by Cohort, including Clopper-Pearson confidence intervals. |
| New Onset Opportunistic Infection (OI) or AIDS Diagnosis | From baseline to occurrence of event, up to Week 48. | Number (%) of participants with a new onset opportunistic infection (OI) or AIDS diagnosis, by Cohort. |
| Decline in Absolute CD4 Percent of Greater Than 5 Percent Any Time After 12 Weeks of Therapy | Measured at baseline and at Weeks 12, 24, and 48 | Number (%) of participants with a \>5% decline in absolute CD4 percent from baseline at weeks 12, 24, and 48, by Cohort, including Clopper-Pearson confidence intervals. |
| HIV-1 RNA Virologic Failure Status at Weeks 24 and 48 | Baseline, Week 24, and Week 48 | Number (%) of participants with confirmed Virologic Failure, defined as: failure to suppress plasma HIV-1 RNA to fewer than 400 copies/ml and failure to achieve at least a 2-log10 reduction (from baseline) in HIV-1 RNA at Weeks 24 or 48, by Cohort, with Clopper-Pearson confidence intervals. The initial HIV-1 RNA results that met the Virologic Failure definition were each confirmed by a second result obtained within 1 to 4 weeks of the initial result obtained at Week 24 and/or 48. |
| Treatment Discontinued Due to Toxicity or Virologic Failure | From baseline to occurrence of event, up to Week 48. | Number (%) of participants who discontinued study treatment (ETR) due to a toxicity or Virologic Failure (VF), by Cohort. |
Countries
Brazil, South Africa, United States
Participant flow
Recruitment details
The first participant was enrolled March 2013, and the final participant was enrolled June 2017. Participants were accrued from a total of 11 sites across Brazil, South Africa, and the USA.
Pre-assignment details
Participants were stratified into the 3 Cohorts by age group and not randomized. There were no eligibility violations or errors to cohort assignments.
Participants by arm
| Arm | Count |
|---|---|
| Cohort I: Treatment Experienced, 2 to 6 Years of Age Children in this arm were at least 2 but younger than 6 years of age; they received the study drug etravirine (ETR) together with an optimized background regimen (OBR) consisting of one active boosted protease inhibitor (PI) and at least one other active antiretroviral (ARV) drug.
Etravirine (ETR): ETR was administered as 25-mg scored tablets and/or 100-mg tablets swallowed whole or dispersed in an appropriate liquid vehicle following a meal. Children took the specified dose orally twice daily within 30 minutes following a meal. Dose was decided according to dosing tables in protocol. | 11 |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age Children in this arm were at least 1 but younger than 2 years of age; they received ETR together with an OBR consisting of one active boosted PI and at least one other active ARV drug.
Etravirine (ETR): ETR was administered as 25-mg scored tablets and/or 100-mg tablets swallowed whole or dispersed in an appropriate liquid vehicle following a meal. Children took the specified dose orally twice daily within 30 minutes following a meal. Dose was decided according to dosing tables in protocol. | 4 |
| Cohort III: Treatment Experienced, 2 Months to 1 Year of Age Children in this arm were at least 2 months but younger than 1 year of age; they received ETR together with an OBR consisting of one active boosted PI and at least one other active ARV drug.
Etravirine (ETR): ETR was administered as 25-mg scored tablets and/or 100-mg tablets swallowed whole or dispersed in an appropriate liquid vehicle following a meal. Children took the specified dose orally twice daily within 30 minutes following a meal. Dose was decided according to dosing tables in protocol. | 0 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort II: Treatment Experienced, 1 to 2 Years of Age | Total | Cohort I: Treatment Experienced, 2 to 6 Years of Age |
|---|---|---|---|
| Age, Continuous | 1 years | 3.5 years | 4 years |
| CD4 Count 200 - <350 cells/mm^3 | 0 Participants | 1 Participants | 1 Participants |
| CD4 Count 350 - <500 cells/mm^3 | 1 Participants | 2 Participants | 1 Participants |
| CD4 Count >=500 cells/mm^3 | 3 Participants | 11 Participants | 8 Participants |
| CD4 Count 50 - <200 cells/mm^3 | 0 Participants | 1 Participants | 1 Participants |
| CD4 Percent <= 14 % | 1 Participants | 2 Participants | 1 Participants |
| CD4 Percent >14 - <25 % | 1 Participants | 6 Participants | 5 Participants |
| CD4 Percent >= 25 % | 2 Participants | 7 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 5 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 4 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 6 Participants | 4 Participants |
| Plasma HIV RNA 10,000 - < 25,000 copies/ml | 1 Participants | 3 Participants | 2 Participants |
| Plasma HIV RNA 25,000 - < 50,000 copies/ml | 1 Participants | 2 Participants | 1 Participants |
| Plasma HIV RNA 400 - <5,000 copies/ml | 1 Participants | 5 Participants | 4 Participants |
| Plasma HIV RNA <400 copies/ml | 0 Participants | 0 Participants | 0 Participants |
| Plasma HIV RNA >=50,000 copies/ml | 1 Participants | 5 Participants | 4 Participants |
| Plasma HIV RNA 5,000 - <10,000 copies/ml | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 12 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Brazil | 1 participants | 4 participants | 3 participants |
| Region of Enrollment South Africa | 2 participants | 8 participants | 6 participants |
| Region of Enrollment United States | 1 participants | 3 participants | 2 participants |
| Sex: Female, Male Female | 1 Participants | 7 Participants | 6 Participants |
| Sex: Female, Male Male | 3 Participants | 8 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 6 |
| other Total, other adverse events | 20 / 20 | 6 / 6 |
| serious Total, serious adverse events | 5 / 20 | 3 / 6 |
Outcome results
Primary
Adverse Events (AEs) of Grade 3 or Higher Severity
Number (%) of participants who experienced a Grade 3 or higher severity adverse event through Week 48 by Cohort, with Clopper-Pearson confidence intervals.
Time frame: From baseline to occurrence of event, up to Week 48.
Population: Analysis population is defined as having been treated exclusively on the final dose determined to be optimal for a given cohort without adjustments and having either completed 48 weeks of exposure to the study drug or been classified as a safety failure, due to a study drug related adverse event occurring during the first 48 weeks of treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | Adverse Events (AEs) of Grade 3 or Higher Severity | Experienced a grade 3+ AE | 4 Participants |
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | Adverse Events (AEs) of Grade 3 or Higher Severity | Did not experience a grade 3+ AE | 7 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | Adverse Events (AEs) of Grade 3 or Higher Severity | Experienced a grade 3+ AE | 4 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | Adverse Events (AEs) of Grade 3 or Higher Severity | Did not experience a grade 3+ AE | 0 Participants |
95% CI: [10.9, 69.2]
95% CI: [39.8, 100]
Primary
Area Under the Plasma Concentration-Time Curve Over 12 Hours of ETR
Geometric Mean (Standard Deviation) of the area under the plasma concentration-time curve over 12 hours (AUC12h) of ETR.
Time frame: Pre-dose, 1, 2, 4, 6, 9, and 12 hours post-dose measured at intensive PK visit (within 7-10 days after last dose of study drug administration)
Population: Analysis population is defined as having been treated exclusively on the final dose determined to be optimal for a given cohort without adjustments and having either completed 48 weeks of exposure to the study drug or been classified as a safety failure. They must also be considered PK evaluable by the study team; 1 Participant in Cohort 1 is not.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | Area Under the Plasma Concentration-Time Curve Over 12 Hours of ETR | 5512.85 ng*h/mL | Standard Deviation 3615.36 |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | Area Under the Plasma Concentration-Time Curve Over 12 Hours of ETR | 4821.76 ng*h/mL | Standard Deviation 3167.11 |
Primary
Death
Number (%) of deaths on study by Cohort.
Time frame: From baseline to occurrence of event, up to Week 48.
Population: Analysis population is defined as having been treated exclusively on the final dose determined to be optimal for a given cohort without adjustments and having either completed 48 weeks of exposure to the study drug or been classified as a safety failure, due to a study drug related adverse event occurring during the first 48 weeks of treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | Death | Deaths | 0 Participants |
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | Death | Live participants | 11 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | Death | Deaths | 0 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | Death | Live participants | 4 Participants |
Primary
Termination From Treatment Due to a Suspected Adverse Drug Reaction (SADR)
Number (%) of participants who discontinued treatment due to a suspected adverse drug reaction (SADR) by Cohort.
Time frame: From baseline to occurrence of event, up to Week 48.
Population: Analysis population is defined as having been treated exclusively on the final dose determined to be optimal for a given cohort without adjustments and having either completed 48 weeks of exposure to the study drug or been classified as a safety failure, due to a study drug related adverse event occurring during the first 48 weeks of treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | Termination From Treatment Due to a Suspected Adverse Drug Reaction (SADR) | Discontinued treatment due to a SADR | 1 Participants |
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | Termination From Treatment Due to a Suspected Adverse Drug Reaction (SADR) | Did not discontinue treatment due to a SADR | 10 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | Termination From Treatment Due to a Suspected Adverse Drug Reaction (SADR) | Discontinued treatment due to a SADR | 0 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | Termination From Treatment Due to a Suspected Adverse Drug Reaction (SADR) | Did not discontinue treatment due to a SADR | 4 Participants |
Secondary
AEs of Grade 3 or Higher Severity Judged to be at Least Possibly Attributable to the Study Medications
Number (%) of Participants with AEs of Grade 3 or higher severity judged, by the Study Team, to be at least possibly attributable to the study medications by Cohort, including Clopper-Pearson confidence intervals.
Time frame: From baseline to occurrence of event, up to Week 48.
Population: Analysis population is defined as having been treated exclusively on the final dose determined to be optimal for a given cohort without adjustments and having either completed 48 weeks of exposure to the study drug or been classified as a safety failure, due to a study drug related adverse event occurring during the first 48 weeks of treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | AEs of Grade 3 or Higher Severity Judged to be at Least Possibly Attributable to the Study Medications | Had a grade 3+ AE related to study drug | 2 Participants |
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | AEs of Grade 3 or Higher Severity Judged to be at Least Possibly Attributable to the Study Medications | Had no grade 3+ AE related to study drug | 9 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | AEs of Grade 3 or Higher Severity Judged to be at Least Possibly Attributable to the Study Medications | Had a grade 3+ AE related to study drug | 0 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | AEs of Grade 3 or Higher Severity Judged to be at Least Possibly Attributable to the Study Medications | Had no grade 3+ AE related to study drug | 4 Participants |
95% CI: [2.5, 51.8]
95% CI: [0, 60.2]
Secondary
Change in Optimized Background Regimen Due to Virologic Failure
Number (%) of participants who initiated a change in their optimized background regimen (OBR) due to virologic failure, by Cohort.
Time frame: Measured at entry and at Weeks 8, 12, 24, and 48
Population: Analysis population is defined as having been treated exclusively on the final dose determined to be optimal for a given cohort without adjustments and having either completed 48 weeks of exposure to the study drug or been classified as a safety failure, due to a study drug related adverse event occurring during the first 48 weeks of treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | Change in Optimized Background Regimen Due to Virologic Failure | Changed OBR due to Virologic Failure | 0 Participants |
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | Change in Optimized Background Regimen Due to Virologic Failure | Did not change OBR due to Virologic Failure | 11 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | Change in Optimized Background Regimen Due to Virologic Failure | Changed OBR due to Virologic Failure | 0 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | Change in Optimized Background Regimen Due to Virologic Failure | Did not change OBR due to Virologic Failure | 4 Participants |
Secondary
Decline in Absolute CD4 Percent of Greater Than 5 Percent Any Time After 12 Weeks of Therapy
Number (%) of participants with a \>5% decline in absolute CD4 percent from baseline at weeks 12, 24, and 48, by Cohort, including Clopper-Pearson confidence intervals.
Time frame: Measured at baseline and at Weeks 12, 24, and 48
Population: Analysis population is defined as having been treated exclusively on the final dose determined to be optimal for a given cohort without adjustments and having either completed 48 weeks of exposure to the study drug or been classified as a safety failure, due to a study drug related adverse event occurring during the first 48 weeks of treatment.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | Decline in Absolute CD4 Percent of Greater Than 5 Percent Any Time After 12 Weeks of Therapy | Week 12 | >5% decline in CD4 % from baseline | 1 Participants |
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | Decline in Absolute CD4 Percent of Greater Than 5 Percent Any Time After 12 Weeks of Therapy | Week 12 | Increase or <5% decline in CD4 % from baseline | 10 Participants |
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | Decline in Absolute CD4 Percent of Greater Than 5 Percent Any Time After 12 Weeks of Therapy | Week 24 | >5% decline in CD4 % from baseline | 1 Participants |
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | Decline in Absolute CD4 Percent of Greater Than 5 Percent Any Time After 12 Weeks of Therapy | Week 24 | Increase or <5% decline in CD4 % from baseline | 10 Participants |
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | Decline in Absolute CD4 Percent of Greater Than 5 Percent Any Time After 12 Weeks of Therapy | Week 48 | >5% decline in CD4 % from baseline | 2 Participants |
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | Decline in Absolute CD4 Percent of Greater Than 5 Percent Any Time After 12 Weeks of Therapy | Week 48 | Increase or <5% decline in CD4 % from baseline | 9 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | Decline in Absolute CD4 Percent of Greater Than 5 Percent Any Time After 12 Weeks of Therapy | Week 48 | >5% decline in CD4 % from baseline | 2 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | Decline in Absolute CD4 Percent of Greater Than 5 Percent Any Time After 12 Weeks of Therapy | Week 12 | >5% decline in CD4 % from baseline | 2 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | Decline in Absolute CD4 Percent of Greater Than 5 Percent Any Time After 12 Weeks of Therapy | Week 24 | Increase or <5% decline in CD4 % from baseline | 3 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | Decline in Absolute CD4 Percent of Greater Than 5 Percent Any Time After 12 Weeks of Therapy | Week 12 | Increase or <5% decline in CD4 % from baseline | 2 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | Decline in Absolute CD4 Percent of Greater Than 5 Percent Any Time After 12 Weeks of Therapy | Week 48 | Increase or <5% decline in CD4 % from baseline | 2 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | Decline in Absolute CD4 Percent of Greater Than 5 Percent Any Time After 12 Weeks of Therapy | Week 24 | >5% decline in CD4 % from baseline | 1 Participants |
Comparison: Week 12 time point.95% CI: [0.2, 41.3]
Comparison: Week 12 time point.95% CI: [6.8, 93.2]
Comparison: Week 24 time point.95% CI: [0.2, 41.3]
Comparison: Week 24 time point.95% CI: [0.6, 80.6]
Comparison: Week 48 time point.95% CI: [2.3, 51.8]
Comparison: Week 48 time point.95% CI: [6.8, 93.2]
Secondary
HIV-1 RNA Virologic Failure Status at Weeks 24 and 48
Number (%) of participants with confirmed Virologic Failure, defined as: failure to suppress plasma HIV-1 RNA to fewer than 400 copies/ml and failure to achieve at least a 2-log10 reduction (from baseline) in HIV-1 RNA at Weeks 24 or 48, by Cohort, with Clopper-Pearson confidence intervals. The initial HIV-1 RNA results that met the Virologic Failure definition were each confirmed by a second result obtained within 1 to 4 weeks of the initial result obtained at Week 24 and/or 48.
Time frame: Baseline, Week 24, and Week 48
Population: Analysis population is defined as having been treated exclusively on the final dose determined to be optimal for a given cohort without adjustments and having either completed 48 weeks of exposure to the study drug or been classified as a safety failure, due to a study drug related adverse event occurring during the first 48 weeks of treatment.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | HIV-1 RNA Virologic Failure Status at Weeks 24 and 48 | Week 24 | Virologic Failure | 2 Participants |
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | HIV-1 RNA Virologic Failure Status at Weeks 24 and 48 | Week 24 | No Virologic Failure | 9 Participants |
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | HIV-1 RNA Virologic Failure Status at Weeks 24 and 48 | Week 48 | Virologic Failure | 3 Participants |
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | HIV-1 RNA Virologic Failure Status at Weeks 24 and 48 | Week 48 | No Virologic Failure | 8 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | HIV-1 RNA Virologic Failure Status at Weeks 24 and 48 | Week 48 | No Virologic Failure | 1 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | HIV-1 RNA Virologic Failure Status at Weeks 24 and 48 | Week 24 | Virologic Failure | 1 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | HIV-1 RNA Virologic Failure Status at Weeks 24 and 48 | Week 48 | Virologic Failure | 3 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | HIV-1 RNA Virologic Failure Status at Weeks 24 and 48 | Week 24 | No Virologic Failure | 3 Participants |
Comparison: Week 24 time point.95% CI: [2.3, 51.8]
Comparison: Week 24 time point.95% CI: [0.6, 80.6]
Comparison: Week 48 time point.95% CI: [6, 61]
Comparison: Week 48 time point.95% CI: [19.4, 99.4]
Secondary
New Onset Opportunistic Infection (OI) or AIDS Diagnosis
Number (%) of participants with a new onset opportunistic infection (OI) or AIDS diagnosis, by Cohort.
Time frame: From baseline to occurrence of event, up to Week 48.
Population: Analysis population is defined as having been treated exclusively on the final dose determined to be optimal for a given cohort without adjustments and having either completed 48 weeks of exposure to the study drug or been classified as a safety failure, due to a study drug related adverse event occurring during the first 48 weeks of treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | New Onset Opportunistic Infection (OI) or AIDS Diagnosis | Had a new OI | 0 Participants |
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | New Onset Opportunistic Infection (OI) or AIDS Diagnosis | Had no new OIs | 11 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | New Onset Opportunistic Infection (OI) or AIDS Diagnosis | Had a new OI | 0 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | New Onset Opportunistic Infection (OI) or AIDS Diagnosis | Had no new OIs | 4 Participants |
Secondary
Treatment Discontinued Due to Toxicity or Virologic Failure
Number (%) of participants who discontinued study treatment (ETR) due to a toxicity or Virologic Failure (VF), by Cohort.
Time frame: From baseline to occurrence of event, up to Week 48.
Population: Analysis population is defined as having been treated exclusively on the final dose determined to be optimal for a given cohort without adjustments and having either completed 48 weeks of exposure to the study drug or been classified as a safety failure, due to a study drug related adverse event occurring during the first 48 weeks of treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | Treatment Discontinued Due to Toxicity or Virologic Failure | Discontinued Treatment due to VF | 1 Participants |
| Cohort I: Treatment Experienced, 2 to 6 Years of Age | Treatment Discontinued Due to Toxicity or Virologic Failure | Did not discontinue treatment due to VF | 10 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | Treatment Discontinued Due to Toxicity or Virologic Failure | Discontinued Treatment due to VF | 0 Participants |
| Cohort II: Treatment Experienced, 1 to 2 Years of Age | Treatment Discontinued Due to Toxicity or Virologic Failure | Did not discontinue treatment due to VF | 4 Participants |