Optimizing Pediatric HIV-1 Treatment, Nairobi, Kenya

Condition(s) targeted: HIV Infections

Intervention: AZT/3TC/NVP (zidovudine/lamivudine/nevirapine) (Drug); d4T/3TC/NVP (stavudine/lamivudine/nevirapine) (Drug); AZT/3TC/ABC (zidovudine/lamivudine/abacavir) (Drug); d4T/3TC/ABC (stavudine/lamivudine/abacavir) (Drug); ddl/ABC/LPV/r (didanosine/abacavir/lopinavir-ritonavir) (Drug); AZT/3TC/ LPV/r (zidovudine/lamivudine/ lopinavir-ritonavir) (Drug); - ABC/ddI or TDF/NVP or EFV (abacavir/didanosine or tenofovir/nevirapine or efavirenz) (Drug); ABC/3TC/NVP (abacavir/lamivudine/nevirapine) (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: University of Washington

Official(s) and/or principal investigator(s):
Dalton Wamalwa, MMed, MPH, Principal Investigator, Affiliation: Department of Paediatrics and Child Health, Kenyatta National Hospital, University of Nairobi
Grace C John-Stewart, MD, PhD, Principal Investigator, Affiliation: University of Washington

Overall contact:
Grace C John-Stewart, MD, PhD, Phone: 206-543-4278, Email: gjohn@u.washington.edu

Given the high mortality associated with infant HIV-1 and the fact that surrogate markers are poorly predictive of mortality risk, some experts recommend empiric highly active antiretroviral therapy (HAART) initiation in infants younger than 12 months. A problem with this approach is that it obligates infants to life-long therapy, which may be associated with cumulative drug toxicity, poor adherence, and treatment failure. Early HAART for prevention of mortality during the first 2 years of life has potential to salvage immune function and alter viral set-point, allowing withdrawal of therapy, perhaps for several years, until subsequent CD4% decline requires it. This untested approach is attractive because it combines the survival benefits of early pediatric HAART therapy with the benefits of antiretroviral deferral.

One hundred and fifty infants less than or equal to 4 months of age will be treated with HAART regimen for 24 months after which those who have immune reconstitution and adequate growth (~100) will be randomized to continued versus deferred therapy. Clinical outcomes, growth, and toxicity will be compared in these children to determine if interruption is a safe and beneficial strategy. Follow-up in this studies will be closely monitored by an external Data Safety and Monitoring Board (DSMB).

Official title: Optimizing Pediatric HIV-1 Treatment, Nairobi, Kenya (0-4.5 Month RCT)

Study design: Treatment, Randomized, Open Label, Placebo Control, Parallel Assignment, Efficacy Study

Primary outcome: Growth will be compared in continuous and interrupted therapy arms at every monthly follow-up visits after randomization

Secondary outcome: Incidence of morbidities, specifically, pneumonia, diarrhea, and hospitalization.

Detailed description: Hypothesis: Deferring antiretroviral therapy in infants who have immune reconstitution and adequate growth following early therapy of primary infection (initiated HAART during primary infection at less than 4 months of age) will not compromise clinical status or growth and may spare antiretroviral toxicity.

Specific Aim/Primary Objective: To compare growth and morbidity in infants (who initiated HAART during primary infection at less than or equal to 4 months of age with subsequently normalized CD4% and growth following 24 months of HAART) randomized to deferred versus continuous therapy and followed for an additional 18 months.

Secondary Aim/Secondary Objective: To determine predictors of non-progression of HIV among the infants, including: age, adherence, HIV-1 specific immune responses, baseline HIV-1 RNA, CD4 percent and immune activation.

Design: Randomized clinical trial involving HIV-1 treatment of infants (0-4 months old) for 24 months, followed by randomization and 18 months follow-up of children randomized to continued versus deferred treatment. This trial is unblinded.

Population: HIV-1 infected infants (0-4 months) meeting eligibility will be enrolled. After 24 months of treatment follow-up, children with CD4% > 25% and normalized growth will be retained in the study and randomized.

Sample size: 150 infants will be enrolled of which 100 are expected to be eligible for randomization (50 in each arm).

Treatment: All infants will be treated with HAART according to WHO and Kenyan national guidelines. The specific regimens that will be used as a part of this study are:

First line regimen

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

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

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

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

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

Second line regimen

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

For infants with prior exposure to nevirapine as part of PMTCT:

First line regimen - AZT/3TC/LPV/r (zidovudine/lamivudine/lopinavir-ritonavir (kaletra))

Second line regimen

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

Minimum age: N/A. Maximum age: 4 Months. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Less than 4 months and 2 weeks of age

- HIV-1 DNA detection with confirmation (positive on two HIV-1 DNA filter paper tests)

- Caregiver of infant plans to reside in Nairobi for at least 3 years (reported by

caregiver)

- Caregiver is able to provide sufficient location information

Exclusion Criteria:

- Infant has not have received any prior antiretroviral therapy (except for PMTCT

drugs) (reported by caregiver)

Eligibility for randomization:

- Completed 24 months of treatment with HAART

- Normalized growth (weight for age within normal range): Child's weight must be above

the 5th weight-for-age percentile and the weight curve must not be flat or falling (i. e. cross 2 major percentile lines or more over the past 3 months)

- CD4% >= 25

- Children who recently initiated or who require anti-tuberculosis treatment at the

time of randomization will be ineligible for randomization.

Grace C John-Stewart, MD, PhD, Phone: 206-543-4278, Email: gjohn@u.washington.edu

Kenyatta National Hospital, University of Nairobi, Nairobi, Kenya; Recruiting
Agnes Langat, MMed (Paeds), Phone: 254-020-2731498, Email: langat2004@yahoo.com
Dalton Wamalwa, MMed, MPH, Principal Investigator
Dorothy Mbori-Ngacha, MMed, MPH, Sub-Investigator
Ruth Nduati, MMed, MPH, Sub-Investigator
Elizabeth Obimbo, MMed, MPH, Sub-Investigator

Starting date: September 2007
Ending date: June 2012
Last updated: September 18, 2009