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
NCT ID: NCT00307151
Last Updated: 2017-04-13
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2
452 participants
INTERVENTIONAL
2005-12-31
2016-12-31
Brief Summary
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\>\> A five year follow up has been added to the study.
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Detailed Description
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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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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Coh I: NVP
Cohort I: Previously received single dose nevirapine (SD NVP). Randomly assigned to receive an NNRTI-based regimen.
Lamivudine
4 mg/kg twice daily
Nevirapine
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
180 mg/m\^2 twice daily
Coh I: LPV/r
Cohort I: Previously received SD NVP. Randomly assigned to receive a PI-based regimen.
Lamivudine
4 mg/kg twice daily
Lopinavir/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
Zidovudine
180 mg/m\^2 twice daily
Coh II: NVP
Cohort II: Did not previously receive SD NVP. Randomly assigned to receive an NNRTI-based regimen
Lamivudine
4 mg/kg twice daily
Nevirapine
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
180 mg/m\^2 twice daily
Coh II: LPV/r
Cohort II: Did not previously receive SD NVP. Randomly assigned to receive a PI-based regimen
Lamivudine
4 mg/kg twice daily
Lopinavir/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
Zidovudine
180 mg/m\^2 twice daily
Interventions
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Lamivudine
4 mg/kg twice daily
Lopinavir/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
Nevirapine
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
180 mg/m\^2 twice daily
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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\>\>
* 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. \>\>
* 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\>\>
Exclusion Criteria
* 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\>\>
* 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\>\>
* 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
2 Months
36 Months
ALL
No
Sponsors
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National Institute of Allergy and Infectious Diseases (NIAID)
NIH
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
NIH
International Maternal Pediatric Adolescent AIDS Clinical Trials Group
NETWORK
Responsible Party
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Principal Investigators
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Paul Palumbo, MD
Role: STUDY_CHAIR
Division of Infectious Diseases and International Health, Dartmouth-Hitchcock Medical Center
Avy Violari, MD
Role: STUDY_CHAIR
Perinatal HIV Research Unit, University of Witwatersrand
Locations
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BJ Medical College CRS
Pune, Maharashtra, India
University of North Carolina Lilongwe CRS
Mzimba Road, Lilongwe, Malawi
Nelson R. Mandela School of Medicine, University of Kwazulu
Natal, Durban, South Africa
University of Stellenbosch-Tygerberg Hospital, South Africa
Cape Town, , South Africa
Harriet Shezi Clinic at Chris Hani Baragwanath Hospital
Johannesburg, , South Africa
Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital
Johannesburg, , South Africa
Kilimanjaro Christian Medical CRS
IDC Research Offices, Moshi, Tanzania
Makerere University
Kampala, , Uganda
George Clinic CRS
Lusaka, , Zambia
UZ-College of Health Sciences
Harare, , Zimbabwe
Countries
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References
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Arrive E, Newell ML, Ekouevi DK, Chaix ML, Thiebaut R, Masquelier B, Leroy V, Perre PV, Rouzioux C, Dabis F; Ghent Group on HIV in Women and Children. Prevalence of resistance to nevirapine in mothers and children after single-dose exposure to prevent vertical transmission of HIV-1: a meta-analysis. Int J Epidemiol. 2007 Oct;36(5):1009-21. doi: 10.1093/ije/dym104. Epub 2007 May 28.
Chi BH, Sinkala M, Stringer EM, Cantrell RA, Mtonga V, Bulterys M, Zulu I, Kankasa C, Wilfert C, Weidle PJ, Vermund SH, Stringer JS. Early clinical and immune response to NNRTI-based antiretroviral therapy among women with prior exposure to single-dose nevirapine. AIDS. 2007 May 11;21(8):957-64. doi: 10.1097/QAD.0b013e32810996b2.
Eshleman SH, Hoover DR, Hudelson SE, Chen S, Fiscus SA, Piwowar-Manning E, Jackson JB, Kumwenda NI, Taha TE. Development of nevirapine resistance in infants is reduced by use of infant-only single-dose nevirapine plus zidovudine postexposure prophylaxis for the prevention of mother-to-child transmission of HIV-1. J Infect Dis. 2006 Feb 15;193(4):479-81. doi: 10.1086/499967. Epub 2006 Jan 11.
White PD. What causes prolonged fatigue after infectious mononucleosis: and does it tell us anything about chronic fatigue syndrome? J Infect Dis. 2007 Jul 1;196(1):4-5. doi: 10.1086/518615. Epub 2007 May 24. No abstract available.
Sankatsing RR, Wit FW, Pakker N, Vyankandondera J, Mmiro F, Okong P, Kastelein JJ, Lange JM, Stroes ES, Reiss P. Effects of nevirapine, compared with lamivudine, on lipids and lipoproteins in HIV-1-uninfected newborns: the stopping infection from mother-to-child via breast-feeding in Africa lipid substudy. J Infect Dis. 2007 Jul 1;196(1):15-22. doi: 10.1086/518248. Epub 2007 May 16.
Palumbo P, Lindsey JC, Hughes MD, Cotton MF, Bobat R, Meyers T, Bwakura-Dangarembizi M, Chi BH, Musoke P, Kamthunzi P, Schimana W, Purdue L, Eshleman SH, Abrams EJ, Millar L, Petzold E, Mofenson LM, Jean-Philippe P, Violari A. Antiretroviral treatment for children with peripartum nevirapine exposure. N Engl J Med. 2010 Oct 14;363(16):1510-20. doi: 10.1056/NEJMoa1000931.
Palumbo P, Violari A, Lindsey J, Hughes M, Jean-Philippe P, Mofenson L, Purdue L, Eshleman S for the IMPAACT P1060 Study Team. Nevirapine vs Lopinavir-ritonavir-based antiretroviral therapy in single dose Nevirapine-exposed HIV-infected infants: preliminary results from the IMPAACT P1060 Trial. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Capetown, July, 2009.
Palumbo P, Violari A, Lindsey J, Hughes M, Jean-Philippe P, Mofenson L, Bwakura-Dangarembizi M, Kamthunzi P, Eshleman S and Prudue L for the IMPAACT P1060 Team. Nevirapine (NVP)-vs. Lopinavir-Ritonavir (LPV/r)-based antiretroviral therapy (ART) among HIV-infected infants in resource-limited settings: The IMPAACT P1060 Trial. 18th Conference on Retroviruses and Opportunistic Infections, Boston, February, 2011.
Patel K, Lindsey J, Angelidou K, Aldrovandi G, Palumbo P; IMPAACT P1060 Study Team. Metabolic effects of initiating lopinavir/ritonavir-based regimens among young children. AIDS. 2018 Oct 23;32(16):2327-2336. doi: 10.1097/QAD.0000000000001980.
Angelidou K, Palumbo P, Lindsey J, Violary A, Archary M, Barlow L, Claggett B, Hughes M, Wei LJ; International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) P1060 Study Team. Defining Study Outcomes That Better Reflect Individual Response to Treatment. Pediatr Infect Dis J. 2018 Mar;37(3):258-262. doi: 10.1097/INF.0000000000001766.
Barlow-Mosha L, Angelidou K, Lindsey J, Archary M, Cotton M, Dittmer S, Fairlie L, Kabugho E, Kamthunzi P, Kinikar A, Mbengeranwa T, Msuya L, Sambo P, Patel K, Barr E, Jean-Phillipe P, Violari A, Mofenson L, Palumbo P, Chi BH. Nevirapine- Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy in HIV-Infected Infants and Young Children: Long-term Follow-up of the IMPAACT P1060 Randomized Trial. Clin Infect Dis. 2016 Oct 15;63(8):1113-1121. doi: 10.1093/cid/ciw488. Epub 2016 Jul 20.
Lindsey JC, Hughes MD, Violari A, Eshleman SH, Abrams EJ, Bwakura-Dangarembizi M, Barlow-Mosha L, Kamthunzi P, Sambo PM, Cotton MF, Moultrie H, Khadse S, Schimana W, Bobat R, Zimmer B, Petzold E, Mofenson LM, Jean-Philippe P, Palumbo P; P1060 Study Team. Predictors of virologic and clinical response to nevirapine versus lopinavir/ritonavir-based antiretroviral therapy in young children with and without prior nevirapine exposure for the prevention of mother-to-child HIV transmission. Pediatr Infect Dis J. 2014 Aug;33(8):846-54. doi: 10.1097/INF.0000000000000337.
Violari A, Lindsey JC, Hughes MD, Mujuru HA, Barlow-Mosha L, Kamthunzi P, Chi BH, Cotton MF, Moultrie H, Khadse S, Schimana W, Bobat R, Purdue L, Eshleman SH, Abrams EJ, Millar L, Petzold E, Mofenson LM, Jean-Philippe P, Palumbo P. Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. N Engl J Med. 2012 Jun 21;366(25):2380-9. doi: 10.1056/NEJMoa1113249.
Other Identifiers
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IMPAACT P1060
Identifier Type: -
Identifier Source: org_study_id
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