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
Condition: HIV Infections
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 2

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).

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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.

      >>

      >> 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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      >>
    

Intervention name(s): Lamivudine; Lopinavir/ritonavir; Nevirapine; Zidovudine
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 4 mg/kg twice daily; 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; 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; 180 mg/m^2 twice daily
Other intervention name(s): 3TC; Epivir; LPV/r; Kaletra; LPV/RTV; NVP; Viramune; ZDV; AZT; Retrovir
Intervention MeSH terms: Ritonavir; Lopinavir; Lamivudine; Zidovudine; Nevirapine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Treatment Naive; Mother-To-Child Transmission; MTCT; Pediatrics; Viral resistance