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
- Conditions
- HIV Infections
- Interventions
- Registration Number
- NCT00307151
- Lead Sponsor
- International Maternal Pediatric Adolescent AIDS Clinical Trials Group
- 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.
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\>\> 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.
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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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Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 452
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Coh I: NVP Lamivudine Cohort I: Previously received single dose nevirapine (SD NVP). Randomly assigned to receive an NNRTI-based regimen. Coh II: LPV/r Lopinavir/ritonavir Cohort II: Did not previously receive SD NVP. Randomly assigned to receive a PI-based regimen Coh II: LPV/r Zidovudine Cohort II: Did not previously receive SD NVP. Randomly assigned to receive a PI-based regimen Coh I: LPV/r Zidovudine Cohort I: Previously received SD NVP. Randomly assigned to receive a PI-based regimen. Coh I: LPV/r Lopinavir/ritonavir Cohort I: Previously received SD NVP. Randomly assigned to receive a PI-based regimen. Coh I: NVP Nevirapine Cohort I: Previously received single dose nevirapine (SD NVP). Randomly assigned to receive an NNRTI-based regimen. Coh I: LPV/r Lamivudine Cohort I: Previously received SD NVP. Randomly assigned to receive a PI-based regimen. Coh I: NVP Zidovudine Cohort I: Previously received single dose nevirapine (SD NVP). Randomly assigned to receive an NNRTI-based regimen. Coh II: NVP Lamivudine Cohort II: Did not previously receive SD NVP. Randomly assigned to receive an NNRTI-based regimen Coh II: NVP Nevirapine Cohort II: Did not previously receive SD NVP. Randomly assigned to receive an NNRTI-based regimen Coh II: NVP Zidovudine Cohort II: Did not previously receive SD NVP. Randomly assigned to receive an NNRTI-based regimen Coh II: LPV/r Lamivudine Cohort II: Did not previously receive SD NVP. Randomly assigned to receive a PI-based regimen
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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.
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.
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 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.
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
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
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.
Trial Locations
- Locations (10)
George Clinic CRS
🇿🇲Lusaka, Zambia
UZ-College of Health Sciences
🇿🇼Harare, Zimbabwe
BJ Medical College CRS
🇮🇳Pune, Maharashtra, India
University of Stellenbosch-Tygerberg Hospital, South Africa
🇿🇦Cape Town, South Africa
Kilimanjaro Christian Medical CRS
🇹🇿IDC Research Offices, Moshi, Tanzania
Harriet Shezi Clinic at Chris Hani Baragwanath Hospital
🇿🇦Johannesburg, South Africa
University of North Carolina Lilongwe CRS
🇲🇼Mzimba Road, Lilongwe, Malawi
Makerere University
🇺🇬Kampala, Uganda
Nelson R. Mandela School of Medicine, University of Kwazulu
🇿🇦Natal, Durban, South Africa
Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital
🇿🇦Johannesburg, South Africa