IMPAACT P1092: Steady State PK in Malnourished HIV Infected Children

Phase 4

Completed

Conditions: HIV Positive
Malnourished

Interventions: Drug: ZDV+3TC+LPV/r

Registration Number: NCT01818258

Lead Sponsor: International Maternal Pediatric Adolescent AIDS Clinical Trials Group

Brief Summary: 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.

Detailed 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 52

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Severe Malnutrition	ZDV+3TC+LPV/r	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
Normal Nutrition/Mild Malnutrition	ZDV+3TC+LPV/r	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

Primary Outcome Measures

Name	Time	Method
Steady-state Lopinavir Area Under the Curve	0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry	Steady-state area under the curve (AUC) for Lopinavir (LPV)
Plasma Clearance of Lopinavir	0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry	Steady-state plasma clearance (CL/F) of LPV
Grade 3 or Higher Adverse Events Through 24 Weeks	From week 0 to week 24	Number (percent) of participants with at least one grade 3 or higher adverse event (AE) regardless of the relationship to study drugs.
Grade 3 or Higher Adverse Events Related to Study Drugs Through Week 24	From week 0 to week 24	Number (percent) of participants with at least one Grade 3 or higher adverse event related to study drugs
Plasma Clearance of Ritonavir	0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry	Steady-state plasma clearance (CL/F) of RTV
Plasma Clearance of Lamivudine	0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry	Steady-state plasma clearance (CL/F) of Lamivudine (3TC)
Plasma Clearance of Zidovudine	0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry	Steady-state plasma clearance (CL/F) of Zidovudine (ZDV)
Steady-state Ritonavir Area Under the Curve	0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry	Steady-state area under the curve (AUC) for Ritonavir (RTV)
Steady-state Zidovudine Area Under the Curve	0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry	Steady-state area under the curve (AUC) of zidovudine (ZDV)
Steady-state Lamivudine Area Under the Curve	0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry	Steady-state area under the curve (AUC) of Lamivudine (3TC)

Secondary Outcome Measures

Name	Time	Method
Change in HIV Viral Load From Baseline	Weeks 0, 12, 24, 36 and 48	Change from baseline in plasma HIV RNA viral load
Change in Mid-upper Arm Circumference	Weeks 0, 24, and 48	Change in mid-upper arm circumference (MUAC) from entry
Free Fraction of LPV at Hour 2 Post Dose	Weeks 1, 12 and 24	Free fraction of steady-state lopinavir at 2 hours post dose
HIV Viral Load <400 Copies/mL	Baseline and weeks 12, 24, and 48	Count (%) of participants with plasma HIV RNA viral load \<400 copies/mL
Change in CD4 Percent	Weeks 0, 12, 24, 36 and 48	Change in CD4 percent from baseline
Minimum Trough Concentration (Ctrough) of Lopinavir	Measured 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 4, 8, 12, 16, 24, 36 and 48 weeks following study entry	Count (%) of participants with minimum trough concentration (Ctrough) of steady-state Lopinavir \>= 1 ug/mL
Change in WHO Weight-for-height Z-score	Weeks 0, 24, and 48	Change in WHO weight-for-height Z-score from entry. A Z-score indicates the number of standard deviations the measurement is away from the mean. A Z-score of 0 is equal to the mean of the reference population. Negative numbers indicate values lower than the reference population and positive numbers indicate values higher than the reference population. The reference population was determined by the World Health Organization for children from 0 up to 5 years.

Trial Locations

Locations (5): Blantyre CRS (30301)
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Blantyre, Malawi
Makerere University-Johns Hopkins University (MUJHU) Research Collaboration (30293)
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Kampala, Uganda
Malawi CRS (12001)
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Lilongwe, Malawi
Harare Family Care (31890)
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Harare, Zimbabwe
Kilimanjaro Christian Medical Centre (5118)
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Moshi, Tanzania