IMPAACT P1092: Steady State PK in Malnourished HIV Infected Children

International Maternal Pediatric Adolescent AIDS Clinical Trials Group

Status and phase

Completed

Phase 4

Conditions

Malnourished

HIV Positive

Treatments

Drug: ZDV+3TC+LPV/r

Study type

Interventional

Funder types

NETWORK

NIH

Identifiers

NCT01818258

U01AI068632 (U.S. NIH Grant/Contract)

IMPAACT P1092

11689 (Other Identifier)

Details and patient eligibility

About

Children living with HIV from sub-Saharan Africa often present with severe malnutrition. In severe malnutrition, metabolic and/or gut structural derangement may lead to inadequate antiretroviral (ARV) absorption and/or erratic drug levels. The greater surface area to weight ratio in severely malnourished children could also place them at higher risk of under dosing compared to children with mild to moderate malnutrition. However, limited data are available on the pharmacokinetics of ARVs in severely malnourished children. This study addressed this critical gap in knowledge by evaluating the PK of zidovudine (ZDV), lamivudine (3TC), and lopinavir/ritonavir (LPV/r) in severely malnourished children living with HIV, compared to children with normal nutrition to mild malnutrition living with HIV.

Full description

P1092 was a prospective, non-randomized Phase IV open label study of antiretroviral drugs zidovudine (ZDV), lamivudine (3TC), and ritonavir boosted lopinavir (LPV/r) in children living with HIV aged 6 to less than 36 months grouped by nutritional status. The study's primary objectives were to characterize the pharmacokinetics (PK), safety, and tolerability of antiretroviral (ARV) regimens in severely acute malnourished (SAM) children following the initiation of nutritional rehabilitation and compare results to mildly malnourished or normally nourished children in order to determine if current recommended doses are optimal in severely malnourished children.

Two cohorts of children were enrolled based on nutritional status at screening: severely acute malnourished children and children with mild malnutrition or normal nutrition (non-SAM cohort). SAM participants were recruited from nutritional rehabilitation clinics while non-SAM participants were enrolled from HIV treatment centers. SAM participants were required to complete a 10 to 18 day nutritional rehabilitation program before entering the study. A World Health Organization (WHO, 2013) approach to management of SAM was used. All participants were to receive an antiretroviral regimen of ZDV+3TC+LPV/r. ARVs were dosed based on WHO weight band dosing and were to be administered twice per day in a pediatric liquid formulation. ZDV was allowed to be replaced with abacavir at the discretion of the site investigator/clinician in cases of grade 3 or higher hematologic toxicity on a ZDV-inclusive regimen or ZDV intolerance. Participants were followed for 48 weeks.

Enrollment

52 patients

Sex

All

Ages

6 to 36 months old

Volunteers

No Healthy Volunteers

Inclusion criteria

Documentation of HIV-1 infection defined as positive results from two samples collected at different time points, using protocol-specified tests
Meets WHO classification for severe malnutrition, normal nutrition status, or mild malnutrition
Eligible for HAART defined by WHO 2013 pediatric guidelines
Parent or legal guardian able and willing to provide signed informed consent, remain within the study area during the study period and agree to have subject followed at the clinical site
Qualifying hematology and chemistry laboratory values obtained from specimens collected within the study-specific screening period
For severely malnourished children: An inpatient in a nutrition rehabilitation unit. Clinical improvement after 10-18 days on nutrition rehabilitation defined as: Appetite returned and eating better - child shows interest in food even if does not complete amount given:
No further weight loss
Normalized sodium and potassium defined as severity grade 1 or lower
No evidence of cardiac failure
Loss of apathy and starting to play
No hypothermia or pyrexia - temperature stable at >35.0 to <38.0° C (non-axillary) or >34.4 to <37.4° C (axillary)

For children with normal - mild malnutrition, clinical stability will be indicated by:

Good appetite
Normalized sodium and potassium defined as severity grade 1 or lower
No hypothermia or pyrexia - temperature stable at >35.0 to <38.0° C (non-axillary) or >34.4 to <37.4° C (axillary)

Exclusion criteria

Edematous malnutrition at the time of study entry
≥ Grade 3 respiratory distress or presence of cardio respiratory compromise within 3 days prior to entry
Chemotherapy for malignancy
Acute infection for which the child has received appropriate antimicrobial treatment for <5 days
Tuberculosis disease
Clinic hepatitis as evidenced by jaundice and hepatomegaly
Taking any disallowed medications
Any condition, situation, or clinical finding that in the opinion of the investigator would place the child at an unacceptable level of risk for injury, or render the child/caregiver(s) unable to meet the requirements of the study, interfere with study participation, or in the interpretation of study results.

Trial design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

52 participants in 2 patient groups

Severe Malnutrition

Active Comparator group

Description:

ZDV+3TC+LPV/r Zidovudine (ZDV, Retrovir®) 10 mg/ml oral syrup administered twice daily at WHO weight band dose for 48 weeks; Lamivudine (Epivir®, 3TC) 10 mg/ml for oral solution administered twice daily at WHO weight band dose for 48 weeks; Lopinavir/ritonavir (Kaletra®, LPV/r) 80/20 mg/ml oral solution administered twice daily at the WHO weight band dose for 48 weeks

Treatment:

Drug: ZDV+3TC+LPV/r

Normal Nutrition/Mild Malnutrition

Active Comparator group

Description:

Treatment:

Drug: ZDV+3TC+LPV/r

Trial documents