HIV Infections
Conditions
Keywords
Treatment Naive, Mother-To-Child Transmission, MTCT, Pediatrics, Viral resistance
Brief summary
A single dose of nevirapine (SD NVP) given to an HIV infected pregnant woman followed by a single dose to her infant has been shown to be an effective way of reducing the risk of mother-to-child transmission (MTCT) of HIV. The purpose of this study was to compare the effectiveness of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral regimen versus a protease inhibitor (PI)-based regimen in HIV infected infants who had or had not been exposed to SD NVP for prevention of MTCT. \>\> \>\> A five year follow up has been added to the study.
Detailed description
Single dose nevirapine (SD NVP) has greatly reduced the rate of mother-to-child transmission (MTCT) of HIV. Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens are recommended for use by the World Health Organization (WHO) in resource-limited settings. However, research suggests that mothers and infants exposed to SD NVP experience higher virologic failure rates when treated with NNRTI-based regimens than their unexposed counterparts. Data show that the use of SD NVP is associated with NNRTI resistance in HIV infected women and infants. The purpose of this trial was to compare and evaluate virologic responses to an NNRTI-based regimen versus a protease-inhibitor (PI)-based regimen in HIV infected infants who had or had not been exposed to SD NVP intrapartum and after birth. \>\> \>\> Participants were enrolled into one of two Cohorts with proposed enrollment into each Cohort of 288 participants. Cohort I participants must have received SD NVP for prevention of MTCT. Cohort II participants and their mothers must not have previously received NVP or any other NNRTIs. Participants in both Cohorts were randomly assigned to receive either an NNRTI (Coh I:NVP and Coh II: NVP) or PI (Coh I: LPV/r and Coh II: LPV/r) -based regimen. The NNRTI-based regimen included NVP, zidovudine (ZDV) and lamivudine (3TC). The PI-based regimen included lopinavir/ritonavir (LPV/r), ZDV and 3TC. If participants experienced adverse reactions to ZDV, stavudine (d4T) could be substituted. Randomization was stratified by age (6-\<12 months vs. \>=12 months, with the 2-\<6 month stratum added in protocol version 4.0 when the lower age limit was decreased from 6 months to 2 months). \>\> \>\> Study visits were scheduled at entry, weeks 2, 4, 8, 12, 16, 24 and then every 24 weeks. A physical exam, blood collection, and assessments of HIV-related symptoms occurred at all visits. \>\> \>\> Based on a Data Safety and Monitoring Committee (DSMB) review of study data on April 20 2009, enrollment to Cohort I was closed and interim results released. Data from this and another similar study (AIDS Clinical Trials Group (ACTG) A5208) conducted in mothers, showed that the PI-based regimen was more effective than the NNRTI-based regimen in infants who had received SD NVP for prevention of MTCT. Cohort II was allowed to remain open for enrollment and the lower age limit for enrollment reduced from 6 months to 2 months. \>\> \>\> In June 2010, follow-up for all subjects was extended from the original 24 weeks beyond enrollment of the last subject to 48 weeks. On October 27 2010, the DSMB conducted a final review of Cohort II data, and recommended results be unblinded and released. As found in Cohort I, the PI-based regimen was more effective than the NNRTI-based regimen in infants who had not been previously exposed to SD NVP for PMTCT. Primary and secondary outcome results for Cohort I include all follow-up until April 20, 2009 and for Cohort II, all follow-up until October 27, 2010. \>\> \>\> Version 5.0 of the protocol (March 21, 2011) extended follow-up on all subjects for an additional 5 years to December 2016. The purpose of the extension was to collect long term safety and virologic efficacy data in this study population and to pilot administration of a series of neuropsychological tests. During the extension, participants did not receive any medications through the study, but instead through their local clinics. Clinic visits took place every 3 months. Adverse event summaries use all follow-up in both Cohorts until December, 2016. \>\> \>\>
Interventions
DRUGLamivudine
4 mg/kg twice daily
DRUGLopinavir/ritonavir
16/4 mg/kg twice daily for participants 2 months of age to less than 6 months of age; 12/3 mg/kg twice daily for participants at least 6 months of age and weighing less than 15 kg; 10/2.5 mg/kg twice daily for participants at least 6 months of age and weighing between 15 kg and 40kg; 400/100 mg twice daily for participants weighing more than 40 kg
DRUGNevirapine
Initially: 4 mg/kg for 14 days, then 7 mg/kg twice daily. In protocol version 2.0, Letter of Amendment 1 (September 2007), NVP dose increased to conform with WHO guidelines to: 160 to 200 mg/m\^2/dose to max 200 mg once daily for 14 days, then 160 to 200 mg/m\^2/dose to max 200 mg twice daily
DRUGZidovudine
180 mg/m\^2 twice daily
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
International Maternal Pediatric Adolescent AIDS Clinical Trials Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Months to 36 Months
Healthy volunteers
No
Inclusion criteria
for All Participants:\>\> * age \>=6 months to \< 36 months (decreased to 2 months in protocol version 4.0)\>\> * HIV infected\>\> * Viral load greater than 5,000 copies/ml within 60 days of study entry\>\> * Treatment naive except for antiretrovirals (ARV) used to prevent MTCT (infant ARV use for \<=1 week postpartum for prevention of MTCT allowed) \>\> * Eligible for treatment according to WHO pediatric algorithm (updated in protocol version 1.0, Letter of amendment (LOA)#1) and protocol version 2.0, LOA#3). Subjects with active opportunistic infections were not eligible for study participation until they had been treated and were clinically stable \>\> * Parent or legal guardian willing to provide signed informed consent\>\> Inclusion Criteria for Cohort I:\>\> * Documentation of maternal or infant NVP exposure or a highly reliable verbal report. (Updated in protocol version 2.0, LOA#3 to require written clinic/hospital documentation of infant exposure to SD NVP)\>\> * Use of maternal ARV, including NVP, permitted during pregnancy\>\> * One or more of the following: strict formula feeding, initial infant HIV diagnosis occurring while younger than 60 days of age, or an initial AIDS-defining illness diagnosis by WHO criteria while younger than 60 days of age. \>\> Inclusion Criteria for Cohort II:\>\> * Use of maternal ARVs, excluding NNRTIs, permitted during pregnancy\>\> * Evidence of lack of prior NVP exposure (added in protocol version 2.0, LOA#3) by review of maternal and child medical records or health card (or other written documentation) for evidence of NVP exposure to mother or infant during pregnancy, labor, and delivery. If no written documentation showing lack of NVP use was shown in these records or if these records were not available for review, then a verbal report considered to be highly reliable by the study nurse was acceptable AND one or more of the following: \>\> 1. Study subject born before single dose NVP was available for prevention of MTCT of HIV in the location of birth of study subject\>\> 2. Study subject born before the biological mother's first positive HIV test\>\> 3. Site staff had another reason to believe the subject had not been exposed to NVP \>\> \>\>
Exclusion criteria
for All Participants:\>\> * Grade 2 or higher aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at study screening\>\> * Grade 3 or higher laboratory toxicity at study screening\>\> * Received ARVs for anything other than the prevention of intrapartum MTCT. Infants who received ARVs after the first week of life (e.g., for the prevention of MTCT of HIV through breastfeeding) were excluded \>\> * Acute serious infections requiring active treatment. Subjects could be receiving treatment for active TB if it did not include rifamycin drugs\>\> * Receiving chemotherapy for an active tumor\>\> * History of a cardiac conduction abnormality and underlying structural heart disease\>\> * Required certain medications\>\> \>\>
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With Treatment Failure, Defined as a Confirmed Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment | Earlier of 24 weeks or date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010) | Treatment failure is defined as a confirmed plasma HIV-1 RNA level that is \<1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level \>400 copies/mL at 24 weeks OR permanent discontinuation of the randomized NNRTI or PI component of study treatment at or prior to 24 weeks of treatment for any reason including death. Results report percent of participants reaching a treatment failure endpoint by week 24 calculated using the Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants Experiencing Virologic Failure | Earlier of 24 weeks or date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010) | Virologic failure is defined as a confirmed plasma HIV-1 RNA level that is \<1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level \>400 copies/mL at 24 weeks OR death on or before 24 weeks. Results report percent of participants reaching a virologic failure endpoint by week 24 calculated using the Kaplan-Meier method. |
| Time From Randomization to Virologic Failure | Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks) | Virologic failure is defined as the earlier of a confirmed plasma HIV-1 RNA level that is \<1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level \>400 copies/mL at 24 weeks OR a confirmed viral rebound \>4000 copies/mL after week 24 OR death. |
| Time From Start of Study Treatment to First New Grade >=3 Lab Abnormality, Sign or Symptom Occurring on Study Treatment | On randomized NNRTI or PI component of study treatment and until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010) | Safety events include lab abnormalities, signs or symptoms of grade 3 or higher. Events were graded according to the Division of AIDS Table for Grading Severity of Adult and Pediatric Adverse Events, Version 1.0. Events defined as new if first occurrence was after initiation of study treatment or if severity increased from entry and while on the NNRTI or PI component of study treatment. |
| Time From Randomization to Treatment Failure, Defined as Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment | Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks) | Treatment failure is defined as a confirmed plasma HIV-1 RNA level that is \<1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level \>400 copies/mL at 24 weeks OR a confirmed viral rebound \>4000 copies/mL after week 24 OR permanent discontinuation of the randomized NNRTI or PI component of study treatment for any reason including death. |
| Change in CD4 Percent From Entry to Week 48 | 48 weeks if before date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010) | Change was calculated as CD4 percent at week 48 minus entry CD4 percent (last CD4 percent before randomization date). Only subjects who reached 48 weeks of follow-up before DSMB decisions to unblind each Cohort were included in summary. |
| Time From Randomization to HIV-related Disease Progression or Death | Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks) | HIV-related disease progression was defined as progression in WHO clinical stage from stage at entry or death. For subjects in WHO Stage IV at entry, disease progression was defined as death. |
| Time From Randomization to Death | Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks) | Results report 2nd percentile of time from randomization to death |
| Number of Participants Developing New NRTI, NNRTI or PI-resistant Virus | Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks) | Numbers of participants developing new NRTI, NNRTI or PI-resistant virus after reaching a virologic failure endpoint |
Countries
India, Malawi, South Africa, Tanzania, Uganda, Zambia, Zimbabwe
Participant flow
Recruitment details
Study participants were recruited at 10 study sites, 4 in South Africa and 1 each in Uganda, Zimbabwe, Zambia, Malawi, Tanzania and India between November 9, 2006 and March 19, 2010.
Pre-assignment details
Infants and children 6 - 36 months of age (lower age limit changed to 2 months in Protocol Version 4.0) were stratified by age (2-\<6 months, 6-\<12 months and \>=12 months) and randomly assigned to receive either AZT/3TC/NVP or AZT/3TC/LPV/r. One subject was randomized but never started study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Coh I: NVP Cohort I: Previously received single dose nevirapine (SD NVP). Randomly assigned to receive an NNRTI-based regimen. | 82 |
| Coh I: LPV/r Cohort I: Previously received SD NVP. Randomly assigned to receive a PI-based regimen. | 82 |
| Coh II: NVP Cohort II: Did not previously receive SD NVP. Randomly assigned to receive an NNRTI-based regimen | 147 |
| Coh II: LPV/r Cohort II: Did not previously receive SD NVP. Randomly assigned to receive a PI-based regimen | 140 |
| Total | 451 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Clinic unable to contact subject | 3 | 3 | 1 | 1 |
| Overall Study | Death | 4 | 3 | 10 | 3 |
| Overall Study | Not willing to adhere to study reqs | 2 | 0 | 2 | 2 |
| Overall Study | Severe debilitation, unable to continue | 1 | 0 | 0 | 0 |
| Overall Study | Subject unable to get to clinic | 1 | 0 | 6 | 2 |
| Overall Study | Withdrew consent | 0 | 1 | 1 | 3 |
Baseline characteristics
| Characteristic | Coh I: LPV/r | Total | Coh II: LPV/r | Coh II: NVP | Coh I: NVP |
|---|---|---|---|---|---|
| Age, Customized <12 months | 63 participants | 200 participants | 36 participants | 41 participants | 60 participants |
| Age, Customized >=12 months | 19 participants | 251 participants | 104 participants | 106 participants | 22 participants |
| CD4 Percent <15 Percent | 21 participants | 187 participants | 69 participants | 73 participants | 24 participants |
| CD4 Percent 15 Percent - < 25 Percent | 37 participants | 188 participants | 54 participants | 60 participants | 37 participants |
| CD4 Percent >= 25 Percent | 24 participants | 75 participants | 17 participants | 13 participants | 21 participants |
| CD4 Percent Missing | 0 participants | 1 participants | 0 participants | 1 participants | 0 participants |
| Documentation of SD NVP use at birth Born before NVP available/mother known to have HIV | 0 participants | 220 participants | 104 participants | 116 participants | 0 participants |
| Documentation of SD NVP use at birth Found to have received SD NVP | 0 participants | 4 participants | 2 participants | 2 participants | 0 participants |
| Documentation of SD NVP use at birth Medical record review | 63 participants | 147 participants | 12 participants | 10 participants | 62 participants |
| Documentation of SD NVP use at birth Verbal evidence only | 19 participants | 80 participants | 22 participants | 19 participants | 20 participants |
| Ever breastfed No | 63 participants | 184 participants | 25 participants | 29 participants | 67 participants |
| Ever breastfed Yes | 19 participants | 267 participants | 115 participants | 118 participants | 15 participants |
| HIV-1 RNA 100,000 - < 750,000 copies/ml | 34 participants | 184 participants | 53 participants | 70 participants | 27 participants |
| HIV-1 RNA <100,000 copies/ml | 5 participants | 58 participants | 27 participants | 20 participants | 6 participants |
| HIV-1 RNA >=750,000 copies/ml | 43 participants | 209 participants | 60 participants | 57 participants | 49 participants |
| NVP resistance No | 62 participants | 331 participants | 91 participants | 110 participants | 68 participants |
| NVP resistance Not available | 9 participants | 97 participants | 45 participants | 36 participants | 7 participants |
| NVP resistance Yes | 11 participants | 23 participants | 4 participants | 1 participants | 7 participants |
| Race/Ethnicity, Customized Black African | 81 participants | 428 participants | 134 participants | 132 participants | 81 participants |
| Race/Ethnicity, Customized Coloured | 1 participants | 5 participants | 2 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Native of India | 0 participants | 16 participants | 4 participants | 12 participants | 0 participants |
| Race/Ethnicity, Customized Not available | 0 participants | 2 participants | 0 participants | 2 participants | 0 participants |
| Region of Enrollment India | 0 participants | 16 participants | 4 participants | 12 participants | 0 participants |
| Region of Enrollment Malawi | 0 participants | 38 participants | 20 participants | 16 participants | 2 participants |
| Region of Enrollment South Africa | 65 participants | 213 participants | 36 participants | 41 participants | 71 participants |
| Region of Enrollment Tanzania | 0 participants | 17 participants | 7 participants | 8 participants | 2 participants |
| Region of Enrollment Uganda | 4 participants | 45 participants | 20 participants | 20 participants | 1 participants |
| Region of Enrollment Zambia | 4 participants | 38 participants | 18 participants | 14 participants | 2 participants |
| Region of Enrollment Zimbabwe | 9 participants | 84 participants | 35 participants | 36 participants | 4 participants |
| Sex: Female, Male Female | 41 Participants | 237 Participants | 72 Participants | 78 Participants | 46 Participants |
| Sex: Female, Male Male | 41 Participants | 214 Participants | 68 Participants | 69 Participants | 36 Participants |
| WHO Stage I | 18 participants | 79 participants | 25 participants | 29 participants | 7 participants |
| WHO Stage II | 22 participants | 98 participants | 27 participants | 26 participants | 23 participants |
| WHO Stage III | 38 participants | 234 participants | 77 participants | 80 participants | 39 participants |
| WHO Stage IV | 4 participants | 40 participants | 11 participants | 12 participants | 13 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 82 | 3 / 82 | 10 / 147 | 6 / 140 |
| other Total, other adverse events | 81 / 82 | 82 / 82 | 146 / 147 | 140 / 140 |
| serious Total, serious adverse events | 23 / 82 | 19 / 82 | 65 / 147 | 47 / 140 |
Outcome results
Primary
Percent of Participants With Treatment Failure, Defined as a Confirmed Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment
Treatment failure is defined as a confirmed plasma HIV-1 RNA level that is \<1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level \>400 copies/mL at 24 weeks OR permanent discontinuation of the randomized NNRTI or PI component of study treatment at or prior to 24 weeks of treatment for any reason including death. Results report percent of participants reaching a treatment failure endpoint by week 24 calculated using the Kaplan-Meier method.
Time frame: Earlier of 24 weeks or date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010)
Population: Analysis uses intent to treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Coh I: NVP | Percent of Participants With Treatment Failure, Defined as a Confirmed Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment | 39.6 Percent of participants |
| Coh I: LPV/r | Percent of Participants With Treatment Failure, Defined as a Confirmed Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment | 21.7 Percent of participants |
| Coh II: NVP | Percent of Participants With Treatment Failure, Defined as a Confirmed Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment | 40.8 Percent of participants |
| Coh II: LPV/r | Percent of Participants With Treatment Failure, Defined as a Confirmed Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment | 19.3 Percent of participants |
p-value: 0.01595% CI: [3.7, 33.6]t-test, 2 sided
p-value: <0.00195% CI: [11.2, 31.8]t-test, 2 sided
Secondary
Change in CD4 Percent From Entry to Week 48
Change was calculated as CD4 percent at week 48 minus entry CD4 percent (last CD4 percent before randomization date). Only subjects who reached 48 weeks of follow-up before DSMB decisions to unblind each Cohort were included in summary.
Time frame: 48 weeks if before date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010)
Population: Analysis uses intent to treat population. Change reported if subject followed at least 48 weeks before DSMB unblinding of results for each Cohort
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Coh I: NVP | Change in CD4 Percent From Entry to Week 48 | 13.9 Percent of CD4 |
| Coh I: LPV/r | Change in CD4 Percent From Entry to Week 48 | 12.0 Percent of CD4 |
| Coh II: NVP | Change in CD4 Percent From Entry to Week 48 | 15.2 Percent of CD4 |
| Coh II: LPV/r | Change in CD4 Percent From Entry to Week 48 | 14.3 Percent of CD4 |
Secondary
Number of Participants Developing New NRTI, NNRTI or PI-resistant Virus
Numbers of participants developing new NRTI, NNRTI or PI-resistant virus after reaching a virologic failure endpoint
Time frame: Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks)
Population: Results included for any participant who was a virologic failure as defined in secondary outcome 4 and who had results available at study entry and virologic failure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Coh I: NVP | Number of Participants Developing New NRTI, NNRTI or PI-resistant Virus | 16 participants |
| Coh I: LPV/r | Number of Participants Developing New NRTI, NNRTI or PI-resistant Virus | 1 participants |
| Coh II: NVP | Number of Participants Developing New NRTI, NNRTI or PI-resistant Virus | 10 participants |
| Coh II: LPV/r | Number of Participants Developing New NRTI, NNRTI or PI-resistant Virus | 4 participants |
Secondary
Percent of Participants Experiencing Virologic Failure
Virologic failure is defined as a confirmed plasma HIV-1 RNA level that is \<1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level \>400 copies/mL at 24 weeks OR death on or before 24 weeks. Results report percent of participants reaching a virologic failure endpoint by week 24 calculated using the Kaplan-Meier method.
Time frame: Earlier of 24 weeks or date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010)
Population: Analysis uses intent to treat population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Coh I: NVP | Percent of Participants Experiencing Virologic Failure | 27.4 Percent of participants |
| Coh I: LPV/r | Percent of Participants Experiencing Virologic Failure | 10.4 Percent of participants |
| Coh II: NVP | Percent of Participants Experiencing Virologic Failure | 28.6 Percent of participants |
| Coh II: LPV/r | Percent of Participants Experiencing Virologic Failure | 12.9 Percent of participants |
Secondary
Time From Randomization to Death
Results report 2nd percentile of time from randomization to death
Time frame: Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks)
Population: Analysis uses intent to treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Coh I: NVP | Time From Randomization to Death | 11 Weeks |
| Coh I: LPV/r | Time From Randomization to Death | 3 Weeks |
| Coh II: NVP | Time From Randomization to Death | 2 Weeks |
| Coh II: LPV/r | Time From Randomization to Death | 83 Weeks |
Secondary
Time From Randomization to HIV-related Disease Progression or Death
HIV-related disease progression was defined as progression in WHO clinical stage from stage at entry or death. For subjects in WHO Stage IV at entry, disease progression was defined as death.
Time frame: Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks)
Population: Analysis uses intent to treat population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Coh I: NVP | Time From Randomization to HIV-related Disease Progression or Death | 5th percentile | 11 Weeks |
| Coh I: NVP | Time From Randomization to HIV-related Disease Progression or Death | 10th percentile | 17 Weeks |
| Coh I: LPV/r | Time From Randomization to HIV-related Disease Progression or Death | 10th percentile | 4 Weeks |
| Coh I: LPV/r | Time From Randomization to HIV-related Disease Progression or Death | 5th percentile | 2 Weeks |
| Coh II: NVP | Time From Randomization to HIV-related Disease Progression or Death | 5th percentile | 8 Weeks |
| Coh II: NVP | Time From Randomization to HIV-related Disease Progression or Death | 10th percentile | 35 Weeks |
| Coh II: LPV/r | Time From Randomization to HIV-related Disease Progression or Death | 5th percentile | 35 Weeks |
| Coh II: LPV/r | Time From Randomization to HIV-related Disease Progression or Death | 10th percentile | 132 Weeks |
Secondary
Time From Randomization to Treatment Failure, Defined as Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment
Treatment failure is defined as a confirmed plasma HIV-1 RNA level that is \<1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level \>400 copies/mL at 24 weeks OR a confirmed viral rebound \>4000 copies/mL after week 24 OR permanent discontinuation of the randomized NNRTI or PI component of study treatment for any reason including death.
Time frame: Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks)
Population: Analysis uses intent to treat population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Coh I: NVP | Time From Randomization to Treatment Failure, Defined as Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment | 25th percentile | 16 Weeks |
| Coh I: NVP | Time From Randomization to Treatment Failure, Defined as Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment | 10th percentile | 12 Weeks |
| Coh I: LPV/r | Time From Randomization to Treatment Failure, Defined as Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment | 10th percentile | 4 Weeks |
| Coh I: LPV/r | Time From Randomization to Treatment Failure, Defined as Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment | 25th percentile | 36 Weeks |
| Coh II: NVP | Time From Randomization to Treatment Failure, Defined as Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment | 25th percentile | 16 Weeks |
| Coh II: NVP | Time From Randomization to Treatment Failure, Defined as Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment | 10th percentile | 4 Weeks |
| Coh II: LPV/r | Time From Randomization to Treatment Failure, Defined as Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment | 25th percentile | 36 Weeks |
| Coh II: LPV/r | Time From Randomization to Treatment Failure, Defined as Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment | 10th percentile | 14 Weeks |
Secondary
Time From Randomization to Virologic Failure
Virologic failure is defined as the earlier of a confirmed plasma HIV-1 RNA level that is \<1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level \>400 copies/mL at 24 weeks OR a confirmed viral rebound \>4000 copies/mL after week 24 OR death.
Time frame: Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks)
Population: Analysis uses intent to treat population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Coh I: NVP | Time From Randomization to Virologic Failure | 5th percentile | 12 Weeks |
| Coh I: NVP | Time From Randomization to Virologic Failure | 10th percentile | 12 Weeks |
| Coh I: LPV/r | Time From Randomization to Virologic Failure | 10th percentile | 24 Weeks |
| Coh I: LPV/r | Time From Randomization to Virologic Failure | 5th percentile | 16 Weeks |
| Coh II: NVP | Time From Randomization to Virologic Failure | 10th percentile | 16 Weeks |
| Coh II: NVP | Time From Randomization to Virologic Failure | 5th percentile | 12 Weeks |
| Coh II: LPV/r | Time From Randomization to Virologic Failure | 5th percentile | 16 Weeks |
| Coh II: LPV/r | Time From Randomization to Virologic Failure | 10th percentile | 24 Weeks |
Secondary
Time From Start of Study Treatment to First New Grade >=3 Lab Abnormality, Sign or Symptom Occurring on Study Treatment
Safety events include lab abnormalities, signs or symptoms of grade 3 or higher. Events were graded according to the Division of AIDS Table for Grading Severity of Adult and Pediatric Adverse Events, Version 1.0. Events defined as new if first occurrence was after initiation of study treatment or if severity increased from entry and while on the NNRTI or PI component of study treatment.
Time frame: On randomized NNRTI or PI component of study treatment and until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010)
Population: Uses follow-up from start of NVP or LPV/r component of study treatment until component switched or date of DSMB decision to unblind results, whichever occurred first
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Coh I: NVP | Time From Start of Study Treatment to First New Grade >=3 Lab Abnormality, Sign or Symptom Occurring on Study Treatment | 10th percentile | 4 Weeks |
| Coh I: NVP | Time From Start of Study Treatment to First New Grade >=3 Lab Abnormality, Sign or Symptom Occurring on Study Treatment | 25th percentile | 24 Weeks |
| Coh I: LPV/r | Time From Start of Study Treatment to First New Grade >=3 Lab Abnormality, Sign or Symptom Occurring on Study Treatment | 25th percentile | 36 Weeks |
| Coh I: LPV/r | Time From Start of Study Treatment to First New Grade >=3 Lab Abnormality, Sign or Symptom Occurring on Study Treatment | 10th percentile | 8 Weeks |
| Coh II: NVP | Time From Start of Study Treatment to First New Grade >=3 Lab Abnormality, Sign or Symptom Occurring on Study Treatment | 10th percentile | 3 Weeks |
| Coh II: NVP | Time From Start of Study Treatment to First New Grade >=3 Lab Abnormality, Sign or Symptom Occurring on Study Treatment | 25th percentile | 4 Weeks |
| Coh II: LPV/r | Time From Start of Study Treatment to First New Grade >=3 Lab Abnormality, Sign or Symptom Occurring on Study Treatment | 10th percentile | 4 Weeks |
| Coh II: LPV/r | Time From Start of Study Treatment to First New Grade >=3 Lab Abnormality, Sign or Symptom Occurring on Study Treatment | 25th percentile | 12 Weeks |