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

NCT00427297 | Terminated Phase 3 Results DMC FDA Drug

• 3 other identifiers: STUDY000020492R01HD023412-1606-1886-D 02
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

HIV Infections

Keywords

HIV-1; Pediatric; nevirapine; HAART; Resistance; Treatment Naive

Outcome Measures

Primary Outcomes (3)

• Incidence of Mortality

  Death during follow-up

  2 years

• Immunologic Failure

  Immunologic treatment failure was defined as CD4% dropping below 15%, after a previous result greater than or equal to 15% (following along WHO Guidelines).

  2 years

• Viral Failure

  Virologic treatment failure was defined as follow-up (at least 24 weeks after enrollment date) viral load \> 400 copies.

  2 years

Secondary Outcomes (1)

• Incidence of Severe Adverse Events (Excluding Mortality)

  2 years

Study Arms (2)

NVP-containing

EXPERIMENTAL

Infants randomized to this arm will receive nevirapine-containing HAART regimen

Drug: AZT/3TC/NVP (zidovudine/lamivudine/nevirapine); Drug: d4T/3TC/NVP (stavudine/lamivudine/nevirapine); Drug: ABC/3TC/NVP (abacavir/lamivudine/nevirapine)

NVP-sparing

ACTIVE COMPARATOR

Infants randomized to this arm will receive nevirapine-sparing HAART

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)

Interventions

AZT/3TC/NVP (zidovudine/lamivudine/nevirapine) DRUG

First line regimen

NVP-containing

d4T/3TC/NVP (stavudine/lamivudine/nevirapine) DRUG

First line regimen

NVP-containing

AZT/3TC/ABC (zidovudine/lamivudine/abacavir) DRUG

First line regimen

NVP-sparing

d4T/3TC/ABC (stavudine/lamivudine/abacavir) DRUG

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

NVP-sparing

ddI/ABC/LPV/r (didanosine/abacavir/lopinavir-ritonavir) DRUG

Second line regimen

NVP-sparing

ABC/ ddI or TDF / NVP or EFV (abacavir / didanosine or tenofovir / nevirapine or efavirenz) DRUG

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.

NVP-sparing

ABC/3TC/NVP (abacavir/lamivudine/nevirapine) DRUG

First line regimen

NVP-containing

Eligibility Criteria

• Age: 6 Months - 18 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Washington: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

Kenyatta National Hospital, University of Nairobi

Nairobi, Kenya

Location

MeSH Terms

Conditions

HIV Infections

Interventions

Zidovudine; Stavudine; abacavir, lamivudine drug combination; Didanosine; abacavir; Nevirapine; efavirenz; Tenofovir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Thymidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Dideoxynucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Inosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Ribonucleosides; Pyridines; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine

Limitations and Caveats

The study team suggested discontinuation of the trial and the DSMB concurred based on slow accrual and based on new data that emerged after the RCT was initiated which made the trial question less relevant.

Results Point of Contact

• Title: Grace John-Stewart
• Organization: University of Washington

gjohn@uw.edu

206 5434278

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, Global Health, Medicine, Epidemiology, Pediatrics

Study Record Dates

• First Submitted: January 22, 2007
• First Posted: January 29, 2007
• Study Start: September 1, 2007
• Primary Completion: May 1, 2009
• Study Completion: December 1, 2009
• Last Updated: August 27, 2018
• Results First Posted: August 27, 2018

Record last verified: 2018-07

Locations

KE (1)