title: Impaired maraviroc and raltegravir clearance in a human immunodeficiency virus-infected patient with end-stage liver disease and renal impairment: a management dilemma.
abstract: Current product labels for maraviroc and raltegravir provide no dosing guidance for patients with end-stage liver disease and worsening renal function. We describe a 41-year-old man with human immunodeficiency virus (HIV) infection and rapidly progressive liver failure and vanishing bile duct syndrome at presentation. Despite discontinuation of all potential offending drugs, the patient's liver function continued to deteriorate. To achieve and maintain HIV suppression while awaiting liver transplantation, a regimen consisting of maraviroc, raltegravir, and enfuvirtide was started. These agents were chosen because the patient was not exposed to them before the onset of liver failure. While receiving product label-recommended twice-daily dosing of these drugs, he achieved and maintained HIV suppression. During a complicated and prolonged hospitalization, the patient also developed renal dysfunction. As hepatic metabolism is the primary route of clearance of maraviroc and raltegravir, we predicted that using approved doses of these drugs could result in significant drug accumulation. Since the safety profiles of supratherapeutic concentrations of these agents are not well defined, we chose to use therapeutic drug monitoring to guide further dosing. The reported concentrations showed severely impaired metabolic clearance of both drugs, with markedly prolonged elimination half-lives of 189 hours for maraviroc and 61 hours for raltegravir. Previously reported half-lives for maraviroc and raltegravir in HIV-infected patients with normal hepatic and renal function are 14-18 hours and 9-12 hours, respectively. Based on these results, the dosing intervals were extended from twice/day to twice/week for maraviroc and every 48 hours for raltegravir. Unfortunately, the patient's clinical condition continued to deteriorate, and he eventually died of complications related to end-stage liver disease. This case illustrates the difficulties in managing antiretroviral therapy in an HIV-infected patient with combined severe liver and renal failure. Prolonged excessively high exposure to maraviroc and raltegravir is likely to result in some level of concentration-dependent toxicity. Until more data are available, therapeutic drug monitoring remains the only evidence-based approach to optimize dosage selection of these drugs in this patient population.
authors.affiliation: Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. apau@niaid.nih.gov
authors.forename: Alice K
authors.initials: AK
authors.lastname: Pau
authors.forename: Scott R
authors.initials: SR
authors.lastname: Penzak
authors.forename: Sarita D
authors.initials: SD
authors.lastname: Boyd
authors.forename: Mary
authors.initials: M
authors.lastname: McLaughlin
authors.forename: Caryn G
authors.initials: CG
authors.lastname: Morse
mesh_terms: D000328:Adult; D003510:Cyclohexanes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019468:Disease Management; D058625:End Stage Liver Disease / Q000150:complications* / Q000188:drug therapy; D017809:Fatal Outcome; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy; D006801:Humans; D008297:Male; D000077592:Maraviroc; D008657:Metabolic Clearance Rate; D011760:Pyrrolidinones / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000068898:Raltegravir Potassium; D051437:Renal Insufficiency / Q000150:complications* / Q000188:drug therapy; D014230:Triazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D003510:Cyclohexanes; D011760:Pyrrolidinones; D014230:Triazoles; D000068898:Raltegravir Potassium; D000077592:Maraviroc