IMPAACT P1092: Steady State PK in Malnourished HIV Infected Children

IMPAACT 1092: Phase IV Evaluation Of The Steady State Pharmacokinetics Of Zidovudine, Lamivudine, and Lopinavir/Ritonavir in Severely Malnourished HIV-1-Infected Children

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.

Study Overview

• Status: Completed
• Conditions: HIV Positive; Malnourished
• Intervention / Treatment: Drug: ZDV+3TC+LPV/r

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.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 4

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 months to 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Severe Malnutrition; 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	Drug: ZDV+3TC+LPV/r; Other Names: Lopinavir/ritonavir; Kaletra; Epivir; Retrovir; Lamivudine; Zidovudine
Active Comparator: Normal Nutrition/Mild Malnutrition; 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	Drug: ZDV+3TC+LPV/r; Other Names: Lopinavir/ritonavir; Kaletra; Epivir; Retrovir; Lamivudine; Zidovudine

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Minimum Trough Concentration (Ctrough) of Lopinavir	Count (%) of participants with minimum trough concentration (Ctrough) of steady-state Lopinavir >= 1 ug/mL	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
Free Fraction of LPV at Hour 2 Post Dose	Free fraction of steady-state lopinavir at 2 hours post dose	Weeks 1, 12 and 24
Change in HIV Viral Load From Baseline	Change from baseline in plasma HIV RNA viral load	Weeks 0, 12, 24, 36 and 48
HIV Viral Load <400 Copies/mL	Count (%) of participants with plasma HIV RNA viral load <400 copies/mL	Baseline and weeks 12, 24, and 48
Change in CD4 Percent	Change in CD4 percent from baseline	Weeks 0, 12, 24, 36 and 48
Change in WHO Weight-for-height Z-score	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.	Weeks 0, 24, and 48
Change in Mid-upper Arm Circumference	Change in mid-upper arm circumference (MUAC) from entry	Weeks 0, 24, and 48

Collaborators and Investigators

• Sponsor: International Maternal Pediatric Adolescent AIDS Clinical Trials Group
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH)
• Investigators: Study Chair: Maxensia O Owor, MBChB, MMED, MPH, International Maternal Pediatric Adolescent AIDS Clinical Trials Group

Publications and helpful links

General Publications

• Owor M, Tierney C, Ziemba L, Browning R, Moye J, Graham B, Reding C, Costello D, Norman J, Wiesner L, Hughes E, Whalen ME, Purdue L, Mmbaga BT, Kamthunzi P, Kawalazira R, Nathoo K, Bradford S, Coletti A, Aweeka F, Musoke P. Pharmacokinetics and Safety of Zidovudine, Lamivudine, and Lopinavir/Ritonavir in HIV-infected Children With Severe Acute Malnutrition in Sub-Saharan Africa: IMPAACT Protocol P1092. Pediatr Infect Dis J. 2021 May 1;40(5):446-452. doi: 10.1097/INF.0000000000003055.

Helpful Links

• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010
• Signs/symptoms, laboratory events, and diagnoses were graded using the Division of AIDS (DAIDS) Table for Grading Severity of Adult and Pediatric Adverse Events, Corrected Version 2.0, November 2014.

Study record dates

Study Major Dates

• Study Start (Actual): October 26, 2015
• Primary Completion (Actual): April 11, 2017
• Study Completion (Actual): September 29, 2017

Study Registration Dates

• First Submitted: January 14, 2013
• First Submitted That Met QC Criteria: March 21, 2013
• First Posted (Estimate): March 26, 2013

Study Record Updates

• Last Update Posted (Actual): August 12, 2021
• Last Update Submitted That Met QC Criteria: July 19, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: HIV; Children; HAART; Malnourished
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Nutrition Disorders; HIV Infections; HIV Seropositivity; Malnutrition; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Lopinavir; Lamivudine; Zidovudine
• Other Study ID Numbers: IMPAACT P1092; U01AI068632 (U.S. NIH Grant/Contract); 11689 (Other Identifier: DAIDS Study ID)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the IMPAACT Network.; For what types of analyses? To achieve aims in the proposal approved by the IMPAACT Network.; By what mechanism will data be made available? Researchers may submit a request for access to data using the IMPAACT "Data Request" form at: https://www.impaactnetwork.org/studies/submit-research-proposal. Researchers of approved proposals will need to sign an IMPAACT Data Use Agreement before receiving the data."