Overview

This trial is active, not recruiting.

Condition hiv infections
Treatments lamivudine, lopinavir/ritonavir, nevirapine, zidovudine
Phase phase 2
Sponsor International Maternal Pediatric Adolescent AIDS Clinical Trials Group
Collaborator National Institute of Allergy and Infectious Diseases (NIAID)
Start date December 2005
End date October 2010
Trial size 452 participants
Trial identifier NCT00307151, IMPAACT P1060, U01AI068632

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Cohort I: Previously received single dose nevirapine (SD NVP). Randomly assigned to receive an NNRTI-based regimen.
lamivudine 3TC
4 mg/kg twice daily
nevirapine NVP
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
zidovudine ZDV
180 mg/m^2 twice daily
(Experimental)
Cohort I: Previously received SD NVP. Randomly assigned to receive a PI-based regimen.
lamivudine 3TC
4 mg/kg twice daily
lopinavir/ritonavir LPV/r
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
zidovudine ZDV
180 mg/m^2 twice daily
(Experimental)
Cohort II: Did not previously receive SD NVP. Randomly assigned to receive an NNRTI-based regimen
lamivudine 3TC
4 mg/kg twice daily
nevirapine NVP
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
zidovudine ZDV
180 mg/m^2 twice daily
(Experimental)
Cohort II: Did not previously receive SD NVP. Randomly assigned to receive a PI-based regimen
lamivudine 3TC
4 mg/kg twice daily
lopinavir/ritonavir LPV/r
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
zidovudine ZDV
180 mg/m^2 twice daily

Primary Outcomes

Measure
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
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)

Secondary Outcomes

Measure
Time From Randomization to Treatment Failure, Defined as Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment
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)
Percent of Participants Experiencing Virologic Failure
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)
Time From Randomization to Virologic Failure
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)
Time From Start of Study Treatment to First New Grade >=3 Lab Abnormality, Sign or Symptom Occurring on 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)
Number of Participants Developing New NRTI, NNRTI or PI-resistant Virus
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)
Change in CD4 Percent From Entry to Week 48
time frame: 48 weeks if before date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010)
Time From Randomization to HIV-related Disease Progression 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)
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)

Eligibility Criteria

Male or female participants from 2 months up to 36 months old.

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 Exclusion Criteria for Cohort I: - History of or currently breastfeeding. Breastfed infants with a positive HIV test or who had experienced an AIDS-defining illness by WHO criteria at 60 days of age or younger were not excluded Exclusion Criteria for Cohort II: - Exposure to any maternal NVP or other NNRTI prior to or during the pregnancy or while breastfeeding - Exposure of infant to NVP at any time including during the first week of life

Additional Information

Official title Phase II, Parallel, Randomized, Clinical Trials Comparing the Responses to Initiation of NNRTI-Based Versus PI-Based Antiretroviral Therapy in HIV Infected Infants Who Have and Have Not Previously Received Single Dose Nevirapine for Prevention of Mother-to-Child HIV Transmission
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. Adverse event summaries use all follow-up while on the randomized study treatment regimen in both Cohorts until October 27, 2010. >> >> Version 5.0 of the protocol (March 21, 2011) extends follow-up on all subjects for an additional 5 years to March 2016. The purpose of the extension is 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 will not receive any medications through the study, but instead through their local clinics. Clinic visits will take place every 3 months. >> >>
Trial information was received from ClinicalTrials.gov and was last updated in September 2013.
Information provided to ClinicalTrials.gov by International Maternal Pediatric Adolescent AIDS Clinical Trials Group.