Optimizing Pediatric HIV-1 Treatment, Nairobi, Kenya

• Sponsor: University of Washington (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00428116
• Collaborator: Fred Hutchinson Cancer Center (Other), University of Nairobi (Other), National Institutes of Health (NIH) (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Enrollment: 140
• Arms: 2
• Duration (Months): 87

Study Details

Study Description

Brief Summary

Given the high mortality associated with infant HIV-1 and the fact that surrogate markers are poorly predictive of mortality risk,empiric highly active antiretroviral therapy (HAART) initiation is started 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 who initiated HAART at <13 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).

Condition or Disease	Intervention/Treatment	Phase
HIV Infections	Drug: HAART	N/A

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 13 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 13 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 (<13 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 (<13 months) newly initiating HAART and HIV-1 infected infants already receiving HAART who initiated HAART at age <13 months 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))

Study Design

• Study Type: Interventional
• Actual Enrollment: 140 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Optimizing Pediatric HIV-1 Treatment, Nairobi, Kenya (0-4.5 Month Randomized Controlled Trial)
• Study Start Date: Sep 1, 2007
• Actual Primary Completion Date: Jul 1, 2013
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Interrupted HAART After 24 months of treatment with HAART, half the eligible infants will be randomized to interrupted treatment and followed for 18 months.
Active Comparator: Continued HAART After 24 months of treatment with HAART, half the eligible infants will be randomized to continued treatment with HAART for 18 months.	Drug: HAART; Combination first line antiretrovirals as previously described.

Outcome Measures

Primary Outcome Measures

1. Growth at 18 Months Post-randomization [18 months of post-randomization follow-up]

   Weight and height will be transformed to the weight-for-age Z-score (i.e., WAZ) and height-for-age Z-score (i.e., HAZ) using World Health Organization Child Growth Standards, taking into account the infant's age and gender.

Secondary Outcome Measures

1. Morbidity [18 months post-randomization]

   severe adverse events including death, pneumonia, diarrhea, and other adverse events

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 54 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Infants newly initiating HAART

• Less than 13 months 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

1. Infants already receiving HAART

• Initiated HAART at <13 months of age

• Records confirming HIV positive status

• Documentation of CD4% and weight prior to HAART initiation

• Must be on 1st line drug regimen

Eligibility for randomization:

• Completed 24 months of treatment with HAART

• Normalized growth: weight for height z-score (WHZ) > -0.5; 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.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• University of Washington
• Fred Hutchinson Cancer Center
• University of Nairobi
• National Institutes of Health (NIH)
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Dalton Wamalwa, MMed, MPH, Department of Paediatrics and Child Health, Kenyatta National Hospital, University of Nairobi
• Principal Investigator: Grace C John-Stewart, MD, PhD, University of Washington

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Grace John-Stewart, Professor, University of Washington
• ClinicalTrials.gov Identifier: NCT00428116
• Other Study ID Numbers: STUDY00001675; R01HD023412
• First Posted: Jan 29, 2007
• Last Update Posted: Jul 26, 2018
• Last Verified: Jun 1, 2018

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Grace John-Stewart, Professor, University of Washington: HIV-1; Pediatric; HAART; Treatment Naive
• Additional relevant MeSH terms: HIV Infections

Study Results

Participant Flow

Recruitment Details	Infants were identified from Nairobi City Council clinics, the Kenyatta National Hospital (KNH) wards, and the HIV treatment clinic. Recruitment occurred from 2007-2009.
Pre-assignment Detail	Of 140 infants enrolled, 37 infants died, 11 were lost, and 7 were withdrawn. Of 75 infants who completed 2 years ART pre-randomization, 33 were ineligible for randomization and 42 were randomized.

Arm/Group Title	Continued HAART	Interrupted HAART
Arm/Group Description	After 24 months of HAART, infants were continued on HAART.	After 24 months of treatment with HAART, half the eligible infants will be randomized to interrupted treatment and followed for 18 months.
Period Title: Overall Study
STARTED	21	21
COMPLETED	18	21
NOT COMPLETED	3	0

Baseline Characteristics

Arm/Group Title	Continued HAART	Interrupted HAART	Total
Arm/Group Description	After 24 months of treatment with HAART, half the eligible infants will be randomized to continued treatment with HAART for 18 months.	After 24 months of treatment with HAART, half the eligible infants will be randomized to interrupted treatment and followed for 18 months.	Total of all reporting groups
Overall Participants	21	21	42
Age (Count of Participants)
<=18 years	21 100%	21 100%	42 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (months) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [months]	29	30.0	30.0
Sex: Female, Male (Count of Participants)
Female	15 71.4%	8 38.1%	23 54.8%
Male	6 28.6%	13 61.9%	19 45.2%
Region of Enrollment (participants) [Number]
Kenya	21 100%	21 100%	42 100%
CD4% (percent) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percent]	33	34	33
Log10 HIV RNA level (copies/ml) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [copies/ml]	2.18	2.18	2.18

Outcome Measures

1. Primary Outcome

Title	Growth at 18 Months Post-randomization
Description	Weight and height will be transformed to the weight-for-age Z-score (i.e., WAZ) and height-for-age Z-score (i.e., HAZ) using World Health Organization Child Growth Standards, taking into account the infant's age and gender.
Time Frame	18 months of post-randomization follow-up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Continued HAART	Interrupted HAART
Arm/Group Description	After 24 months of treatment with HAART, half the eligible infants will be randomized to continued treatment with HAART for 18 months.	After 24 months of treatment with HAART, half the eligible infants will be randomized to interrupted treatment and followed for 18 months.
Measure Participants	21	21
WAZ (z-score)	-0.57	-0.17
HAZ (z-score)	-1.04	-0.78

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Continued HAART, Interrupted HAART
	Comments	WAZ-score comparison at 18 months
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.15
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Continued HAART, Interrupted HAART
	Comments	HAZ score at 18 months
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.45
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Morbidity
Description	severe adverse events including death, pneumonia, diarrhea, and other adverse events
Time Frame	18 months post-randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Continue HAART	Interrupted HAART
Arm/Group Description	After 24 months of treatment with HAART, half the eligible infants will be randomized to continued treatment with HAART for 18 months.	After 24 months of treatment with HAART, half the eligible infants will be randomized to interrupted treatment and followed for 18 months.
Measure Participants	21	21
Severe adverse events	2 9.5%	1 4.8%
Pneumonia	4 19%	3 14.3%
Diarrhea	7 33.3%	12 57.1%
Death	1 4.8%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Continued HAART, Interrupted HAART
	Comments	SAEs
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.39
	Comments
	Method	log rank or Cox regression
	Comments	incidence with Cox regression utilized Anderson-Gill method to handle recurrent events

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Continued HAART, Interrupted HAART
	Comments	Pneumonia
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.60
	Comments
	Method	Cox regression Anderson Gill
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Continued HAART, Interrupted HAART
	Comments	Pneumonia
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.60
	Comments
	Method	Regression, Cox
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Continued HAART, Interrupted HAART
	Comments	Diarrhea
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.77
	Comments
	Method	Regression, Cox
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Continued HAART, Interrupted HAART
	Comments	Death
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.29
	Comments
	Method	Log Rank
	Comments

Adverse Events

Time Frame	18 months post-randomization
Arm/Group Title	Continued HAART		Interrupted HAART
Arm/Group Description	After 24 months of treatment with HAART, half the eligible infants will be randomized to continued treatment with HAART for 18 months.		After 24 months of treatment with HAART, half the eligible infants will be randomized to interrupted treatment and followed for 18 months.
All Cause Mortality
	Continued HAART		Interrupted HAART
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Continued HAART		Interrupted HAART
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/21 (9.5%)		1/21 (4.8%)
Hepatobiliary disorders
Hepatotoxicity	1/21 (4.8%)		1/21 (4.8%)
Infections and infestations
Death	1/21 (4.8%)	1	0/21 (0%)	0
Skin and subcutaneous tissue disorders
Cellulitis	0/21 (0%)		1/21 (4.8%)
Other (Not Including Serious) Adverse Events
	Continued HAART		Interrupted HAART
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/21 (100%)		21/21 (100%)
Blood and lymphatic system disorders
Lymphadenopathy	5/21 (23.8%)		14/21 (66.7%)
Anemia	12/21 (57.1%)		16/21 (76.2%)
Gastrointestinal disorders
Diarrhea	7/21 (33.3%)		12/21 (57.1%)
Metabolism and nutrition disorders
High cholesterol	10/21 (47.6%)		4/21 (19%)
Respiratory, thoracic and mediastinal disorders
Upper respiratory infection	21/21 (100%)		20/21 (95.2%)
Pneumonia	4/21 (19%)		3/21 (14.3%)
Skin and subcutaneous tissue disorders
Rash	11/21 (52.4%)		11/21 (52.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.