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

July 27, 2018 updated by: Grace John-Stewart, University of Washington

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).

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

34

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Kenya
      • Nairobi, Kenya
        • Kenyatta National Hospital, University of Nairobi

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 years to 2 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: NVP-containing
Infants randomized to this arm will receive nevirapine-containing HAART regimen
Drug: AZT/3TC/NVP (zidovudine/lamivudine/nevirapine)
First line regimen
Drug: d4T/3TC/NVP (stavudine/lamivudine/nevirapine)
First line regimen
Drug: ABC/3TC/NVP (abacavir/lamivudine/nevirapine)
First line regimen
Active Comparator: NVP-sparing
Infants randomized to this arm will receive nevirapine-sparing HAART
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of Mortality
Time Frame: 2 years
Death during follow-up
2 years
Immunologic Failure
Time Frame: 2 years
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
Time Frame: 2 years
Virologic treatment failure was defined as follow-up (at least 24 weeks after enrollment date) viral load > 400 copies.
2 years

Secondary Outcome Measures

Outcome Measure
Time Frame
Incidence of Severe Adverse Events (Excluding Mortality)
Time Frame: 2 years
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Washington

Collaborators

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

Investigators

  • 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

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2007

Primary Completion (Actual)

May 1, 2009

Study Completion (Actual)

December 1, 2009

Study Registration Dates

First Submitted

January 22, 2007

First Submitted That Met QC Criteria

January 26, 2007

First Posted (Estimate)

January 29, 2007

Study Record Updates

Last Update Posted (Actual)

August 27, 2018

Last Update Submitted That Met QC Criteria

July 27, 2018

Last Verified

July 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STUDY00002049
  • 2R01HD023412-16 (U.S. NIH Grant/Contract)
  • 06-1886-D 02

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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