Pharmacokinetics and Safety of Zidovudine, Lamivudine, and Lopinavir/Ritonavir in HIV-infected Children With Severe Acute Malnutrition in Sub-Saharan Africa: IMPAACT Protocol P1092

Maxensia Owor, Camlin Tierney, Lauren Ziemba, Renee Browning, John Moye, Bobbie Graham, Christina Reding, Diane Costello, Jennifer Norman, Lubbe Wiesner, Emma Hughes, Meghan E Whalen, Lynette Purdue, Blandina Theophil Mmbaga, Portia Kamthunzi, Rachel Kawalazira, Kusum Nathoo, Sarah Bradford, Anne Coletti, Francesca Aweeka, Philippa Musoke, Maxensia Owor, Camlin Tierney, Lauren Ziemba, Renee Browning, John Moye, Bobbie Graham, Christina Reding, Diane Costello, Jennifer Norman, Lubbe Wiesner, Emma Hughes, Meghan E Whalen, Lynette Purdue, Blandina Theophil Mmbaga, Portia Kamthunzi, Rachel Kawalazira, Kusum Nathoo, Sarah Bradford, Anne Coletti, Francesca Aweeka, Philippa Musoke

Abstract

Background: Severe acute malnutrition (SAM) may alter the pharmacokinetics (PK), efficacy, and safety of antiretroviral therapy. The phase IV study, IMPAACT P1092, compared PK, safety, and tolerability of zidovudine (ZDV), lamivudine (3TC), and lopinavir/ritonavir (LPV/r) in children with and without SAM.

Materials and methods: Children living with HIV 6 to <36 months of age with or without World Health Organization (WHO)-defined SAM received ZDV, 3TC, and LPV/r syrup for 48 weeks according to WHO weight band dosing. Intensive PK sampling was performed at weeks 1, 12, and 24. Plasma drug concentrations were measured using liquid chromatography tandem mass spectrometry. Steady-state mean area under the curve (AUC0-12h) and clearance (CL/F) for each drug were compared. Grade ≥3 adverse events were compared between cohorts.

Results: Fifty-two children were enrolled across 5 sites in Africa with 44% (23/52) female, median age 19 months (Q1, Q3: 13, 25). Twenty-five children had SAM with entry median weight-for-height Z-score (WHZ) -3.4 (IQR -4.0, -3.0) and 27 non-SAM had median WHZ -1.0 (IQR -1.8, -0.1). No significant differences in mean AUC0-12h or CL/F were observed (P ≥ 0.09) except for lower 3TC AUC0-12h (GMR, 0.60; 95% CI, 0.4-1.0; P = 0.047) at week 12, higher ZDV AUC0-12h (GMR, 1.52; 1.2-2.0; P = 0.003) at week 24 in the SAM cohort compared with non-SAM cohort. Treatment-related grade ≥3 events did not differ significantly between cohorts (24.0% vs. 25.9%).

Conclusion: PK and safety findings for ZDV, 3TC, and LPV/r support current WHO weight band dosing of syrup formulations in children with SAM.

Trial registration: ClinicalTrials.gov NCT01818258.

Conflict of interest statement

The authors have no conflicts of interest to disclose.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.

Figures

FIGURE 1.
FIGURE 1.
A, Plasma concentration—time profile of LPV and RTV in children with severe malnutrition (blue) and mild malnutrition/normal nutrition (red) for study weeks 1, 12, and 24. Data are reported as median (25th and 75th percentile). B, Plasma concentration—time profile of 3TC and ZDV in children with severe malnutrition (blue) and mild malnutrition/normal nutrition (red) for study weeks 1, 12, and 24. Data are reported as median (25th and 75th percentile). 3TC indicates lamivudine; LPV, lopinavir; RTV, ritonavir; ZDV, zidovudine.

References

    1. UNAIDS. UNAIDS data 2019 (updated 2018 data). 2019. Available at: . Accessed November 16, 2019.
    1. Cross Continents Collaboration for Kids (3Cs4kids) Analysis and Writing Committee. Markers for predicting mortality in untreated HIV-infected children in resource-limited settings: a meta-analysis. AIDS. 2008; 22:97–105.
    1. Walker AS, Mulenga V, Sinyinza F, et al. ; CHAP Trial Team. Determinants of survival without antiretroviral therapy after infancy in HIV-1-infected Zambian children in the CHAP Trial. J Acquir Immune Defic Syndr. 2006; 42:637–645.
    1. Fergusson P, Tomkins A. HIV prevalence and mortality among children undergoing treatment for severe acute malnutrition in sub-Saharan Africa: a systematic review and meta-analysis. Trans R Soc Trop Med Hyg. 2009; 103:541–548.
    1. Muenchhoff M, Healy M, Singh R, et al. . Malnutrition in HIV-infected children is an indicator of severe disease with an impaired response to antiretroviral therapy. AIDS Res Hum Retroviruses. 2018; 34:46–55.
    1. Krishnaswamy K. Drug metabolism and pharmacokinetics in malnourished children. Clin Pharmacokinet. 1989; 17suppl 168–88.
    1. Gilman RH, Partanen R, Brown KH, et al. . Decreased gastric acid secretion and bacterial colonization of the stomach in severely malnourished Bangladeshi children. Gastroenterology. 1988; 94:1308–1314.
    1. Falcon RW, Kakuda TN. Drug interactions between HIV protease inhibitors and acid-reducing agents. Clin Pharmacokinet. 2008; 47:75–89.
    1. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. 2013. Available at: . Accessed June 16, 2020.
    1. World Health Organization. Antiretroviral Therapy for HIV Infection in Infants and Children: Recommendations for a Public Health Approach 2010 Revision. 2010, World Health Organization; 206.
    1. Division of AIDS. DAIDS AE Grading table Version 2.0 dated November 2014. 2014. Available at: . Accessed November 16, 2019.
    1. World Health Organization. Guideline: Updates on the management of severe acute malnutrition in infants and children. 2013.World Health Organization
    1. Capparelli E, Pinto J, Robbins B, et al. . Lopinavir pharmacokinetic (PK) maturational changes and variability in HIV-infected infants beginning Kaletra (LPV/r) therapy at <6 weeks (WK) of age. 2008. In: Conference on Retroviruses and Opportunistic Infections, Boston, 2008
    1. Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Bioanalytical Method Validation. 2013. FDA. Available at: . Accessed November 16, 2019.
    1. European Medicines Agency. Guideline on Bioanalytical Method Validation. 2011. EMA. Available at: . Accessed November 16, 2019.
    1. DiFrancesco R, Rosenkranz SL, Taylor CR, et al. . Clinical pharmacology quality assurance program: models for longitudinal analysis of antiretroviral proficiency testing for international laboratories. Ther Drug Monit. 2013; 35:631–642.
    1. Bartelink IH, Savic RM, Dorsey G, et al. . The effect of malnutrition on the pharmacokinetics and virologic outcomes of lopinavir, efavirenz and nevirapine in food insecure HIV-infected children in Tororo, Uganda. Pediatr Infect Dis J. 2015; 34:e63–e70.
    1. Yang J, Nikanjam M, Best BM, et al. . Population pharmacokinetics of lopinavir/ritonavir: changes across formulations and human development from infancy through adulthood. J Clin Pharmacol. 2018; 58:1604–1617.
    1. Kasirye P, Kendall L, Adkison KK, et al. ; ARROW Trial Team. Pharmacokinetics of antiretroviral drug varies with formulation in the target population of children with HIV-1. Clin Pharmacol Ther. 2012; 91:272–280.
    1. Chokephaibulkit K, Cressey TR, Capparelli E, et al. ; IMPAACT P1069 Team. Pharmacokinetics and safety of a new paediatric fixed-dose combination of zidovudine/lamivudine/nevirapine in HIV-infected children. Antivir Ther. 2011; 16:1287–1295.
    1. Fillekes Q, Kendall L, Kitaka S, et al. ; ARROW Trial Team. Pharmacokinetics of zidovudine dosed twice daily according to World Health Organization weight bands in Ugandan HIV-infected children. Pediatr Infect Dis J. 2014; 33:495–498.
    1. Charman WN, Porter CJ, Mithani S, et al. . Physiochemical and physiological mechanisms for the effects of food on drug absorption: the role of lipids and pH. J Pharm Sci. 1997; 86:269–282.
    1. Biressaw S, Abegaz WE, Abebe M, et al. . Adherence to antiretroviral therapy and associated factors among HIV infected children in Ethiopia: unannounced home-based pill count versus caregivers’ report. BMC Pediatr. 2013; 13:132.

Source: PubMed

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