Antiviral Responses to NNRTI-Based vs. PI-Based ARV Therapy in HIV Infected Infants Who Have or Have Not Received Single Dose NVP for Prevention of Mother-to-Child Transmission of HIV

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

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.

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>> A five year follow up has been added to the study.

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.

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>> 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).

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>> 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.

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>> 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.

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>> 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.

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>> 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.

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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