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Optimizing Pediatric HIV-1 Treatment in Infants With Prophylactic Exposure to Nevirapine, Nairobi, Kenya

This study has been terminated.
(There is no longer equipoise.)
Sponsor:
Collaborator:
Information provided by:
University of Washington
ClinicalTrials.gov Identifier:
NCT00427297
First received: January 22, 2007
Last updated: March 16, 2010
Last verified: March 2010

January 22, 2007
March 16, 2010
September 2007
May 2009   (final data collection date for primary outcome measure)
  • Incidence of mortality will be compared in NVP-containing and NVP-sparing arms at every monthly visit following randomization [ Time Frame: Over 24 months of post-randomization follow-up ] [ Designated as safety issue: No ]
  • CD4% will be compared in NVP-containing and NVP-sparing arms at every 3-monthly intervals following randomization [ Time Frame: Over 24 months of post-randomization follow-up ] [ Designated as safety issue: No ]
  • Viral suppression in NVP-containing and NVP-sparing arms will be compared at 3, 6 and then every 6 monthly intervals following randomization [ Time Frame: Over 24 months of post-randomization follow-up ] [ Designated as safety issue: No ]
  • WHO stage of AIDS will be compared in NVP-containing and NVP-sparing arms at every monthly visit following randomization
  • CD4% will be compared in NVP-containing and NVP-sparing arms at every 3-monthly intervals following randomization
  • Viral suppression in NVP-containing and NVP-sparing arms will be compared at 3, 6 and then every 6 monthly intervals following randomization
  • weight-for-height z-scores will be compared in NVP-containing and NVP-sparing arms at every monthly visit following randomization
Complete list of historical versions of study NCT00427297 on ClinicalTrials.gov Archive Site
  • Incidence of severe adverse events will be compared in NVP-containing and NVP-sparing arms at every monthly visit following randomization [ Time Frame: Over 24 months of post-randomization follow-up ] [ Designated as safety issue: Yes ]
  • Correlates of toxicities will be compared in NVP-containing and NVP-sparing arms at every monthly visit following randomization [ Time Frame: Over 24 months of post-randomization follow-up ] [ Designated as safety issue: Yes ]
  • Predictors of non-progression of HIV among infants;
  • Age at initiation of HAART
  • time since nevirapine-exposure
  • Adherence to HAART
  • HIV-1 specific immune responses
  • Baseline HIV-1 RNA level
  • Baseline CD4%
  • Baseline immune activation markers
Not Provided
Not Provided
 
Optimizing Pediatric HIV-1 Treatment in Infants With Prophylactic Exposure to Nevirapine, Nairobi, Kenya
Optimizing Pediatric HIV-1 Treatment in Infants With Prophylactic Exposure to Nevirapine, Nairobi, Kenya (6-12 Month RCT)

Globally, children who acquire HIV-1 increasingly do so in the context of maternal antiretroviral prophylaxis. It is important to determine whether maternal antiretroviral prophylaxis should alter infant treatment regimens. Nevirapine (NVP) is commonly used for PMTCT and is also a commonly used first-line drug for treatment of pediatric HIV-1. Approximately half of infants exposed to NVP have detectable NVP resistance early in infancy, with loss of detectable resistance over time. Thus, if an HIV-1 infected child was exposed to single-dose NVP prophylaxis, the question remains whether NVP or any NNRTI can be used effectively in therapeutic regimens. Alternative PI-based regimens are associated with heat-lability, poor palatability, cumulative toxicity, and fewer salvage options. This poses challenges for pediatric PI-based highly active antiretroviral therapy (HAART) in settings without refrigeration and limited antiretroviral repertoire. It is plausible that in older NVP-exposed infants (older than 6 months since exposure) who are genotypically NVP-susceptible, that nevirapine will be effective and useful.

We propose to study resistance in a pediatric HIV-1 clinical trial involving 100 children. Among children enrolled at between 6 and 18 months of age, we will provide real-time field-based genotypic NVP-resistance testing, and randomize 100 NVP-susceptible children to NVP-containing versus NVP-sparing HAART to compare therapeutic response, adverse events, and morbidity in the 2 arms during 2-year follow-up. Follow-up in these studies will be closely monitored by an external Data Safety and Monitoring Board (DSMB).

Hypotheses

  1. Infants older than 6 months who do not have detectable nevirapine resistance on genotypic testing will respond equivalently to a nevirapine-sparing or a nevirapine-containing HAART regimen, despite previous single-dose nevirapine exposure.
  2. Genotypic drug resistance levels may predict response to therapy and clinical progression.

Specific Aims/Primary Objectives

  1. To compare response to therapy (viral levels, CD4%, growth, and morbidity) in infants without detectable nevirapine-resistance on population-based sequencing who are randomized to nevirapine-containing versus nevirapine-sparing HAART.
  2. To develop methods to detect and quantify nevirapine resistance mutations present at low frequency in the virus population in order to examine the relationship between the copy number of such variants and virologic failure of infants treated with nevirapine-containing HAART.

Secondary Aim/Secondary Objective: To determine predictors of non-progression in these studies, including: age, time since nevirapine-exposure, adherence, HIV-1 specific immune responses, baseline HIV-1 RNA, CD4 percent, and immune activation.

Design: Randomized clinical trial in which infant 6-18 months of age will be randomized to nevirapine containing versus nevirapine sparing HAART regimen and followed for 24 months.

Population: HIV-1 infected infants (6-12 months) meeting eligibility will be enrolled. Infants who were exposed to nevirapine in-utero or following delivery, with no detectable resistance to nevirapine will be eligible for enrollment.

Sample size: 100 infants will be enrolled (50 infants in each arm).

Treatment: All infants will be treated with NVP containing or sparing HAART. The regimen will be prescribed according to WHO and Kenyan national guidelines on dosage and combination of antiretroviral drugs. The HAART regimen that will be used in this study are:

First line regimen:

For infants on NVP containing HAART

  • AZT/3TC/NVP (zidovudine/lamivudine/nevirapine)
  • d4T/3TC/NVP (stavudine/lamivudine/nevirapine)
  • ABC/3TC/NVP (abacavir/lamivudine/nevirapine)

For infants on NVP sparing HAART

  • AZT/3TC/ABC (zidovudine/lamivudine/abacavir)
  • d4T/3TC/ABC (stavudine/lamivudine/abacavir)

For children who have anaemia (Hb of <8g/dl), AZT will be substituted for d4T.

Second line regimen:

  • ddI/ABC/LPV/r (didanosine/abacavir/lopinavir-ritonavir (kaletra))
  • ABC / ddI or TDF / NVP or EFV (abacavir / didanosine or tenofovir / nevirapine or efavirenz) Among children randomized to NVP sparing HAART, who will be initiated on a regimen containing lopinavir/ritonavir, zidovudine and lamivudine will be substituted with abacavir and didanosine or tenofovir (TDF) and lopinavir/ ritonavir will be replaced with nevirapine or efavirenz (EFV) in case of treatment failure of the LPV/r containing regimen.
Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
HIV Infections
  • Drug: AZT/3TC/NVP (zidovudine/lamivudine/nevirapine)
    First line regimen
  • Drug: d4T/3TC/NVP (stavudine/lamivudine/nevirapine)
    First line regimen
  • Drug: AZT/3TC/ABC (zidovudine/lamivudine/abacavir)
    First line regimen
  • Drug: d4T/3TC/ABC (stavudine/lamivudine/abacavir)
    First line regimen For children who have anaemia(Hb of<8g/dl), AZT will be substituted for d4T.
  • Drug: ddI/ABC/LPV/r (didanosine/abacavir/lopinavir-ritonavir)
    Second line regimen
  • Drug: ABC/ ddI or TDF / NVP or EFV (abacavir / didanosine or tenofovir / nevirapine or efavirenz)
    Second line regimen - Among children randomized to NVP sparing HAART, who will be initiated on a regimen containing lopinavir/ritonavir, zidovudine and lamivudine will be substituted with abacavir and didanosine or tenofovir (TDF) and lopinavir/ ritonavir will be replaced with nevirapine or efavirenz (EFV) in case of treatment failure of the LPV/r containing regimen.
  • Drug: ABC/3TC/NVP (abacavir/lamivudine/nevirapine)
    First line regimen
  • Experimental: NVP-containing
    Infants randomized to this arm will receive nevirapine-containing HAART regimen
    Interventions:
    • Drug: AZT/3TC/NVP (zidovudine/lamivudine/nevirapine)
    • Drug: d4T/3TC/NVP (stavudine/lamivudine/nevirapine)
    • Drug: ABC/3TC/NVP (abacavir/lamivudine/nevirapine)
  • Active Comparator: NVP-sparing
    Infants randomized to this arm will receive nevirapine-sparing HAART
    Interventions:
    • Drug: AZT/3TC/ABC (zidovudine/lamivudine/abacavir)
    • Drug: d4T/3TC/ABC (stavudine/lamivudine/abacavir)
    • Drug: ddI/ABC/LPV/r (didanosine/abacavir/lopinavir-ritonavir)
    • Drug: ABC/ ddI or TDF / NVP or EFV (abacavir / didanosine or tenofovir / nevirapine or efavirenz)
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
34
December 2009
May 2009   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • 6-18 months age
  • HIV-1 DNA detection with confirmation (positive on two HIV-1 DNA filter paper tests)
  • Mother exposed to NVP-containing PMTCT regimen during currently ended pregnancy and/or infant received NVP-containing PMTCT regimen
  • Infant susceptible to NVP (i.e. no detectable NVP resistance on genotypic testing)
  • Caregiver of infant plans to reside in Nairobi for at least 3 years
  • Caregiver is able to provide sufficient location information

Exclusion Criteria:

  • Infant has received any prior antiretroviral therapy (expect prophylaxis for PMTCT)
  • Infant has evidence of active tuberculosis
  • Mother currently receiving NVP-containing HAART and breastfeeding the infant
Both
6 Months to 18 Months
No
Contact information is only displayed when the study is recruiting subjects
Kenya
 
NCT00427297
30200-D, 2 RO1 HD023412-16;, 06-1886-D 02
Yes
Grace John-Stewart, University of Washington
University of Washington
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Principal Investigator: Grace C John-Stewart, MD, PhD University of Washington
Principal Investigator: Dalton Wamalwa, MMed, MPH Department of Paediatrics and Child Health, Kenyatta National Hospital, University of Nairobi
University of Washington
March 2010

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP