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 - Full Text View

Sponsor:	International Maternal Pediatric Adolescent AIDS Clinical Trials Group
Collaborators:	National Institute of Allergy and Infectious Diseases (NIAID) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):	International Maternal Pediatric Adolescent AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:	NCT00307151

Purpose

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.

Condition	Intervention	Phase
HIV Infections	Drug: Lamivudine Drug: Lopinavir/ritonavir Drug: Nevirapine Drug: Zidovudine	Phase II

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
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

Resource links provided by NLM:

Genetics Home Reference related topics: complement factor I deficiency

MedlinePlus related topics: HIV/AIDS

Drug Information available for: Zidovudine Nevirapine Lamivudine Ritonavir Lopinavir

U.S. FDA Resources

Further study details as provided by International Maternal Pediatric Adolescent AIDS Clinical Trials Group:

Primary Outcome Measures:

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) ] [ Designated as safety issue: No ]
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:

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) ] [ Designated as safety issue: No ]
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.
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) ] [ Designated as safety issue: No ]
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 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) ] [ Designated as safety issue: No ]
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.
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) ] [ Designated as safety issue: Yes ]
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 [ 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) ] [ Designated as safety issue: No ]
Numbers of participants developing new NRTI, NNRTI or PI-resistant virus after reaching a virologic failure endpoint
Change in CD4% 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) ] [ Designated as safety issue: No ]
Change was calculated as CD4% at week 48 minus entry CD4% (last CD4% 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 [ 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) ] [ Designated as safety issue: No ]
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.
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) ] [ Designated as safety issue: Yes ]
Results report 2nd percentile of time from randomization to death

Enrollment:	452
Study Start Date:	December 2005
Estimated Study Completion Date:	April 2016
Primary Completion Date:	October 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Coh I: NVP Cohort I: Previously received single dose nevirapine (SD NVP). Randomly assigned to receive an NNRTI-based regimen.	Drug: Lamivudine 4 mg/kg twice daily Other Names: 3TC Epivir Drug: 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 Other Names: NVP Viramune Drug: Zidovudine 180 mg/m^2 twice daily Other Names: ZDV AZT Retrovir
Experimental: Coh I: LPV/r Cohort I: Previously received SD NVP. Randomly assigned to receive a PI-based regimen.	Drug: Lamivudine 4 mg/kg twice daily Other Names: 3TC Epivir Drug: 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 Other Names: LPV/r Kaletra LPV/RTV Drug: Zidovudine 180 mg/m^2 twice daily Other Names: ZDV AZT Retrovir
Experimental: Coh II: NVP Cohort II: Did not previously receive SD NVP. Randomly assigned to receive an NNRTI-based regimen	Drug: Lamivudine 4 mg/kg twice daily Other Names: 3TC Epivir Drug: 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 Other Names: NVP Viramune Drug: Zidovudine 180 mg/m^2 twice daily Other Names: ZDV AZT Retrovir
Experimental: Coh II: LPV/r Cohort II: Did not previously receive SD NVP. Randomly assigned to receive a PI-based regimen	Drug: Lamivudine 4 mg/kg twice daily Other Names: 3TC Epivir Drug: 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 Other Names: LPV/r Kaletra LPV/RTV Drug: Zidovudine 180 mg/m^2 twice daily Other Names: ZDV AZT Retrovir

Show Detailed Description

Eligibility

Ages Eligible for Study:	2 Months to 36 Months
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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
  
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2. Study subject born before the biological mother's first positive HIV test
  
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3. Site staff had another reason to believe the subject had not been exposed to NVP
  
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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

United States, Massachusetts
Boston Medical Center Ped. HIV Program NICHD CRS (5011)
Boston, Massachusetts, United States, 02118
India
BJ Medical College CRS
Pune, Maharashtra, India, 411001
Malawi
University of North Carolina Lilongwe CRS
Mzimba Road, Lilongwe, Malawi
South Africa
Nelson R. Mandela School of Medicine, University of Kwazulu
Natal, Durban, South Africa, 50202
University of Stellenbosch-Tygerberg Hospital, South Africa
Cape Town, South Africa, 7700
Harriet Shezi Clinic at Chris Hani Baragwanath Hospital
Johannesburg, South Africa, 2013
Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital
Johannesburg, South Africa
Tanzania
Kilimanjaro Christian Medical CRS
IDC Research Offices, Moshi, Tanzania
Uganda
Makerere University
Kampala, Uganda
Zambia
George Clinic CRS
Lusaka, Zambia
Zimbabwe
UZ-College of Health Sciences
Harare, Zimbabwe

Study Chair:	Paul Palumbo, MD	Division of Infectious Diseases and International Health, Dartmouth-Hitchcock Medical Center
Study Chair:	Avy Violari, MD	Perinatal HIV Research Unit, University of Witwatersrand

Responsible Party:	International Maternal Pediatric Adolescent AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:	NCT00307151 History of Changes
Other Study ID Numbers:	IMPAACT P1060, U01AI068632, PACTG P1060
Study First Received:	March 24, 2006
Results First Received:	July 5, 2011
Last Updated:	November 14, 2011
Health Authority:	United States: Federal Government