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The Effect of Malnutrition on the Pharmacokinetics and Virologic Outcomes of Lopinavir, Efavirenz and Nevirapine in Food Insecure HIV-infected Children in Tororo, Uganda

Bartelink, Imke H. PharmD, PhD*†; Savic, Rada M. PhD; Dorsey, Grant PhD; Ruel, Theodore MD§; Gingrich, David*; Scherpbier, Henriette J. MD, PhD; Capparelli, Edmund PhD**; Jullien, Vincent PhD††; Young, Sera L. PhD‡‡; Achan, Jane MMed§§; Plenty, Albert PhD; Charlebois, Edwin MPH, PhD; Kamya, Moses MMed, PhD¶¶; Havlir, Diane MD; Aweeka, Francesca PharmD*

Pediatric Infectious Disease Journal: March 2015 - Volume 34 - Issue 3 - p e63–e70
doi: 10.1097/INF.0000000000000603
HIV Reports

Background: Malnutrition may impact the pharmacokinetics (PKs) of antiretroviral medications and virologic responses in HIV-infected children. The authors therefore evaluated the PK of nevirapine (NVP), efavirenz (EFV) and lopinavir (LPV) in associations with nutritional status in a cohort of HIV-infected Ugandan children.

Methods: Sparse dried blood spot samples from Ugandan children were used to estimate plasma concentrations. Historical PK data from children from 3 resource-rich countries (RRC) were utilized to develop the PK models.

Results: Concentrations in 330 dried blood spot from 163 Ugandan children aged 0.7–7 years were analyzed in reference to plasma PK data (1189 samples) from 204 children from RRC aged 0.5–12 years. Among Ugandan children, 48% was malnourished (underweight, thin or stunted). Compared to RRC, Ugandan children exhibited reduced bioavailability of EFV and LPV; 11% (P = 0.045) and 18% (P = 0.008), respectively. In contrast, NVP bioavailability was 46% higher in Ugandan children (P < 0.001) with a trend toward greater bioavailability when malnourished. Children receiving LPV, EFV or NVP had comparable risk of virologic failure. Among children on NVP, low height and weight for age Z scores were associated with reduced risk of virologic failure (P = 0.034, P = 0.068, respectively).

Conclusions: Ugandan children demonstrated lower EFV and LPV and higher NVP exposure compared to children in RRC, perhaps reflecting the consequence of malnutrition on bioavailability. In children receiving NVP, the relation between exposure, malnutrition and outcome turned out to be marginally significant. Further investigations are warranted using more intensive PK measurements and adequate adherence assessments, to further assess causes of virologic failure in Ugandan children.

From the Department of *Clinical Pharmacy, Bioengineering & Therapeutic Sciences, Medicine, and §Pediatrics, and Center for AIDS Prevention Studies of the University of California, San Francisco, CA; Department of Pediatric Immunology and Infectious Diseases, Emma Children’s Hospital AMC, The Netherlands; **University of California San Diego, La Jolla, CA; ††Department of Pharmacology, Hôpital Européen Georges Pompidou, Paris Descartes, France; ‡‡Division of Nutritional Sciences, Cornell University, Ithaca, NY; and Departments of §§Pediatrics and Child Health, and ¶¶Medicine, Makerere University, Kampala, Uganda.

Accepted for publication October 14, 2014.

The primary sponsor of the PROMOTE-Pregnant Women and Infants trial is the National Institute for Child Health and Human Development P01 HD059454 (Havlir). Dr. Young is supported by K01 MH098902-01 from the National Institute of Mental Health. Abbvie provided Lopinavir/ritonavir for the parent trial. Dr. Ruel received support from the NIH (K236045901A2). The authors have no conflicts of interest to disclose.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Address for correspondence: Francesca Aweeka, PharmD, Department of Clinical Pharmacy, University of California, San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0622. E-mail: faweeka@sfghsom.ucsf.edu.

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