Antiviral Responses to a Nevirapine-Based Regimen Versus a Lopinavir/Ritonavir-Based Regimen in HIV Infected Infants Who Have or Have Not Received Single Dose Nevirapine for the Prevention of Mother-to-Child Transmission of HIV - Full Text View

Sponsors and Collaborators:	National Institute of Allergy and Infectious Diseases (NIAID) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by:	National Institute of Allergy and Infectious Diseases (NIAID)
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 shown to be an effective way of reducing the rate of mother-to-child transmission (MTCT) of HIV. The purpose of this study is to compare the effectiveness of a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen versus a protease inhibitor (PI)-based regimen in HIV infected infants who have or have not been exposed to SD NVP.

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

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver), Active Control, Parallel Assignment, Efficacy Study
Official Title:	Phase II, Parallel, Randomized, Clinical Trial 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:

MedlinePlus related topics: AIDS

Drug Information available for: Zidovudine Nevirapine Lamivudine Ritonavir Lopinavir

U.S. FDA Resources

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:

Treatment failure, defined as a confirmed viral load less than 1 log10 copies/ml below study entry value [ Time Frame: Weeks 12 to 24 following treatment ] [ Designated as safety issue: No ]
Treatment failure, defined as a permanent discontinuation of the NNRTI or PI component of study treatment [ Time Frame: At or prior to Week 24 ] [ Designated as safety issue: No ]
Treatment failure, defined as a confirmed viral load greater than 400 copies/ml [ Time Frame: At Week 24 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Time from randomization to treatment failure, defined as specified in primary outcome measures [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Time from randomization to virologic failure, defined as specified in primary outcome measures [ Time Frame: After Week 24 ] [ Designated as safety issue: Yes ]
Tolerability and safety of drug regimens, as determined by protocol outcome-related measurements [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
Development of new circulating nucleoside reverse transcriptase inhibitor (NRTI)-, NNRTI-, or PI-resistant virus as determined by standard composite (bulk) genotyping [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Change over time in CD4 percentage (CD4%) from study entry [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Time from randomization to HIV-related disease progression (progression to World Health Organization [WHO] Clinical Stage 3 or 4) or death [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
Time from randomization to death [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	452
Study Start Date:	September 2006
Estimated Study Completion Date:	October 2009
Estimated Primary Completion Date:	October 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Active Comparator Previously received single dose nevirapine (SD NVP); randomly assigned to receive an NNRTI-based regimen. Now closed to enrollment. Lopinavir/ritonavir is now available to participants who achieved a virologic endpoint in this group.	Drug: Lamivudine 4 mg/kg twice daily Drug: Nevirapine 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 Drug: Zidovudine 180 mg/m^2 twice daily
2: Active Comparator Previously received SD NVP; randomly assigned to receive a PI-based regimen. Now closed to enrollment.	Drug: Lamivudine 4 mg/kg twice daily Drug: Nevirapine 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 Drug: Zidovudine 180 mg/m^2 twice daily
3: Active Comparator Have not previously received SD NVP; randomly assigned to receive an NNRTI-based regimen	Drug: Lamivudine 4 mg/kg twice daily 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 Drug: Zidovudine 180 mg/m^2 twice daily
4: Active Comparator Have not previously received SD NVP; randomly assigned to receive a PI-based regimen	Drug: Lamivudine 4 mg/kg twice daily 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 Drug: Zidovudine 180 mg/m^2 twice daily

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 is to compare and evaluate the virologic responses to an NNRTI-based regimen versus a protease inhibitor (PI)-based regimen in HIV infected infants who have or have not been exposed to SD NVP intrapartum and after birth.

This study will last between 6 months and 4 years. Participants will be divided into two cohorts (Cohorts I and II); Cohort I participants previously received SD NVP, and Cohort II participants have not previously received SD NVP. Participants in both cohorts will be randomly assigned to receive either an NNRTI- or a PI-based regimen.

The NNRTI-based regimen will include NVP, zidovudine (ZDV) and lamivudine (3TC); the PI-based regimen will include lopinavir/ritonavir (LPV/r), ZDV and 3TC. If participants have adverse reactions to ZDV, stavudine (d4T) may be substituted, but may not be supplied by the study, depending on medication access within the site country.

There will be at least nine study visits. A physical exam, blood collection, and assessments of HIV-related symptoms will occur at all visits.

Based on a review of safety data in April 2009, enrollment in Cohort I was ended. Data from this and another, similar study (A5208) indicate that a PI-based regimen is clearly more effective for infants who received SD NVP.

Cohort II remains open for enrollment. Participants who were enrolled in Cohort I will continue to be followed.

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:

HIV infected
Viral load greater than 5,000 copies/ml within 60 days of study entry
Treatment naive. Participants who have taken antiretrovirals (ARVs) to prevent MTCT of HIV are eligible.
Eligible for treatment according to WHO pediatric algorithm. Participants with active opportunistic infections are not eligible for this study until they have been treated and are clinically stable.
Parent or legal guardian willing to provide signed informed consent
There are no CD4 count or CD4% restrictions on children younger than 12 months of age
For children from 12 to 35 months of age: CD4% must be less than 20% or CD4 count must be less than 750 cells/mm^3, or there must be history of AIDS-defining conditions or AIDS-defining opportunistic infections

Inclusion Criteria for Cohort I: Closed to Enrollment

Documentation of maternal or infant NVP exposure. Infant exposure to SD NVP with supporting written clinic/hospital documentation is required.
Use of ARVs 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 while younger than 60 days of age.

Confirmation of HIV infection may be made after 60 days of age.

Inclusion Criteria for Cohort II:

Use of ARVs during pregnancy.
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 is shown in these records or if these records are not available for review, then a verbal report that is considered to be highly reliable by the study nurse is acceptable.

AND one or more of the following:

A. Study subject was born before single dose NVP was available for prevention of MTCT of HIV in the location of birth of study subject

B. Study subject was born before the biological mother's first positive HIV test

C. Site staff have another reason to believe the subject has 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) are excluded.
Acute serious infections requiring treatment
Receiving chemotherapy for an active tumor
History of a cardiac conduction abnormality and underlying structural heart disease
Requires certain medications

Exclusion Criteria for Cohort I: Closed to Enrollment

History of or currently breastfeeding. Breastfed infants with a positive HIV test or who have experienced an AIDS-defining illness at 60 days of age or younger will not be excluded.

Exclusion Criteria for Cohort II:

Exposure to any maternal NVP or other NNRTI prior to or during the pregnancy or while breastfeeding
Exposure to NVP at any time including during the first week of life

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00307151

Locations

India, Maharashtra
BJ Medical College CRS	Recruiting
Pune, Maharashtra, India, 411001
Contact: Nishi Suryavanshi, PhD 91-020-26052419 nishi@jhumitpune.com
Principal Investigator: Gowri Sastry, MD, MPH
Malawi, Lilongwe
University of North Carolina Lilongwe CRS	Recruiting
Mzimba Road, Lilongwe, Malawi
Contact: Kimberly Reynolds 265-1-755954 kreynolds@unclilongwe.org.mw
Principal Investigator: Francis Martinson, MPH, PhD, MB ChB
South Africa
University of Stellenbosch-Tygerberg Hospital, South Africa	Recruiting
Cape Town, South Africa, 7700
Contact: Joan Coetzee, CPN 278-327-59577 joan@sun.ac.za
Harriet Shezi Clinic at Chris Hani Baragwanath Hospital	Recruiting
Soweto, South Africa, Bertsha
Contact: Angela Oosthuizen +27 (0) 11-933-9630 oosthuizenan@paedshiv.wits.ac.za
South Africa, Durban
Nelson R. Mandela School of Medicine, University of Kwazulu	Recruiting
Natal, Durban, South Africa, 50202
Contact: Enbavani Pillay 270-312-604729 Pillaye1@ukzn.ac.za
Principal Investigator: Raziya Bobat, MD
Tanzania, Moshi
Kilimanjaro Christian Medical CRS	Recruiting
IDC Research Offices, Moshi, Tanzania
Contact: Julieta Giner 255-786-882498 giner001@mc.duke.edu
Principal Investigator: John A Crump, MB, ChB, DTM&H
Zambia
George Clinic CRS	Recruiting
Lusaka, Zambia
Contact: Allison V. Verbe, MD allison@cidrz.org
Principal Investigator: Benjamin Chi, MD

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

Study Chair:

Paul Palumbo, MD

Division of Infectious Diseases and International Health, Dartmouth-Hitchcock Medical Center

More Information

Additional Information:

Click here for more information about lamivudine This link exits the ClinicalTrials.gov site

Click here for more information about lopinavir/ritonavir This link exits the ClinicalTrials.gov site

Click here for more information about nevirapine This link exits the ClinicalTrials.gov site

Click here for more information about zidovudine This link exits the ClinicalTrials.gov site

Click here for more information on after birth care for HIV positive women and their babies This link exits the ClinicalTrials.gov site

Click here for more information on medication regimens for HIV positive pregnant women This link exits the ClinicalTrials.gov site

Haga clic aquí para ver información sobre este ensayo clínico en español. This link exits the ClinicalTrials.gov site

Publications:

Arrive E, Newell ML, Ekouevi DK, Chaix ML, Thiebaut R, Masquelier B, Leroy V, Perre PV, Rouzioux C, Dabis F. 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 May 28; [Epub ahead of print]

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):957-964.

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. 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. 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. Epub 2007 May 16.

Responsible Party:	DAIDS ( Rona Siskind )
Study ID Numbers:	IMPAACT P1060, PACTG P1060
Study First Received:	March 24, 2006
Last Updated:	September 1, 2009
ClinicalTrials.gov Identifier:	NCT00307151 History of Changes
Health Authority:	United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

Treatment Naive
Pregnancy
Perinatal Transmission

Vertical Transmission
Mother-To-Child Transmission
MTCT

Study placed in the following topic categories:

Antimetabolites
Anti-Infective Agents
HIV Protease Inhibitors
Sexually Transmitted Diseases, Viral
Anti-HIV Agents
Acquired Immunodeficiency Syndrome
Zidovudine
Lamivudine
Antiviral Agents
Immunologic Deficiency Syndromes

Protease Inhibitors
Reverse Transcriptase Inhibitors
Virus Diseases
Nevirapine
Anti-Retroviral Agents
Lopinavir
HIV Infections
Ritonavir
Sexually Transmitted Diseases
Retroviridae Infections

Additional relevant MeSH terms:

Antimetabolites
Anti-Infective Agents
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Molecular Mechanisms of Pharmacological Action
Zidovudine
Lamivudine
Infection
Reverse Transcriptase Inhibitors
Lopinavir
Anti-Retroviral Agents
Therapeutic Uses
Retroviridae Infections
Nucleic Acid Synthesis Inhibitors
HIV Protease Inhibitors

RNA Virus Infections
Anti-HIV Agents
Immune System Diseases
Acquired Immunodeficiency Syndrome
Enzyme Inhibitors
Antiviral Agents
Immunologic Deficiency Syndromes
Pharmacologic Actions
Protease Inhibitors
Virus Diseases
Nevirapine
HIV Infections
Ritonavir
Sexually Transmitted Diseases
Lentivirus Infections

ClinicalTrials.gov processed this record on September 11, 2009