Dose modification of antiretroviral agents in adults with renal or hepatic dysfunction
- Amy L Graziani, PharmD
Amy L Graziani, PharmD
- Associate Professor in Pharmacy, Adjunct Faculty
- University of Pennsylvania School of Medicine and University of the Sciences, Philadelphia, PA
The introduction of potent antiretroviral therapy has markedly altered the natural history of human immunodeficiency virus (HIV) infection (see "Selecting antiretroviral regimens for the treatment-naïve HIV-infected patient" and "The natural history and clinical features of HIV infection in adults and adolescents"). These regimens have greatly extended life expectancy and reduced the incidence of most acquired immunodeficiency syndrome (AIDS)-defining conditions. However, the drug regimens are complex, costly, and are accompanied by a number of significant side effects, many of which are dose-related. Because organ dysfunction can result in slowed elimination and accumulation of these agents, it is important to dose-reduce select antiretroviral medications to avert dose-related side effects.
GENERAL DOSING RECOMMENDATIONS
Despite the fact that many HIV-infected patients also have renal or hepatic dysfunction, most antiretroviral agents have not been well studied in HIV-infected patients with renal or hepatic insufficiency, including those receiving hemodialysis or peritoneal dialysis. Thus, dosing recommendations for such patients are often extrapolated from information about the structure, chemical characteristics, metabolism, and elimination of the drug in patients with normal organ function . The Department of Health and Human Services (DHHS) has provided guideline recommendations based upon these limited data.
Because of the limited data and empiric nature of many of the guideline recommendations, patients with organ dysfunction should be monitored closely for drug toxicity and efficacy. It is important to note that the available data are from patients with either renal or hepatic dysfunction, but not from those with impairment of both organ systems. If patients do have both significant hepatic and renal dysfunction, it is even more difficult to predict the effects on parent drug and metabolites, drug efficacy, and safety. Although not currently performed routinely in most centers, the increasing availability and evolving database of antiretroviral drug serum concentration monitoring may prove helpful to these patients in the future.
A summary of renal and hepatic considerations for these classes of drugs will be reviewed here.
NUCLEOSIDE/TIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs)
Most NRTIs, including didanosine (ddI), emtricitabine, stavudine (D4T), tenofovir, and lamivudine (3TC) are eliminated primarily unchanged in the urine. These drugs require dose reduction and/or extension of the dosing interval in patients with renal insufficiency [2,3]. Two exceptions are zidovudine and abacavir, which undergo substantial extra-renal (hepatic) biotransformation, and therefore may require less significant or no dose reductions .
- Izzedine H, Launay-Vacher V, Baumelou A, Deray G. An appraisal of antiretroviral drugs in hemodialysis. Kidney Int 2001; 60:821.
- Jayasekara D, Aweeka FT, Rodriguez R, et al. Antiviral therapy for HIV patients with renal insufficiency. J Acquir Immune Defic Syndr 1999; 21:384.
- Ostrop NJ, Burgess E, Gill MJ. The use of antiretroviral agents in patients with renal insufficiency. AIDS Patient Care STDS 1999; 13:517.
- Lucas GM, Ross MJ, Stock PG, et al. Clinical practice guideline for the management of chronic kidney disease in patients infected with HIV: 2014 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2014; 59:e96.
- Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf (Accessed on May 01, 2014).
- Stribild Product Labeling, Gilead Sciences, 2012.
- Gupta SK. Tenofovir-associated Fanconi syndrome: review of the FDA adverse event reporting system. AIDS Patient Care STDS 2008; 22:99.
- Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis 2005; 40:1194.
- Longenecker CT, Scherzer R, Bacchetti P, et al. HIV viremia and changes in kidney function. AIDS 2009; 23:1089.
- Vogel M, Bertram N, Wasmuth JC, et al. Nevirapine pharmacokinetics in HIV-infected and HIV/HCV-coinfected individuals. J Antimicrob Chemother 2009; 63:988.
- Viramune Product labeling, Boehringer Ingelheim Pharmaceuticals, Inc. November 2012.
- Schöller-Gyüre M, Kakuda TN, De Smedt G, et al. Effects of hepatic impairment on the steady-state pharmacokinetics of etravirine 200 mg BID: an open-label, multiple-dose, controlled Phase I study in adults. Clin Ther 2010; 32:328.
- Agarwala S, et al. Pharmacokinetics of atazanavir in severely renally impaired subjects including those on hemodialysis. 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention. In: Program and abstracts of the 8th International Workshop on Clinical Pharmacology of HIV Therapy. April 16-18, 2007; Budapest. Abstract 2.
- Islam FM, Wu J, Jansson J, Wilson DP. Relative risk of renal disease among people living with HIV: a systematic review and meta-analysis. BMC Public Health 2012; 12:234.
- Gupta SK, Rosenkranz SL, Cramer YS, et al. The pharmacokinetics and pharmacogenomics of efavirenz and lopinavir/ritonavir in HIV-infected persons requiring hemodialysis. AIDS 2008; 22:1919.
- Knox TA, Oleson L, von Moltke LL, et al. Ritonavir greatly impairs CYP3A activity in HIV infection with chronic viral hepatitis. J Acquir Immune Defic Syndr 2008; 49:358.
- Selzentry product label. http://www.viivhealthcare.com/~/media/Files/G/GlaxoSmithKline-Plc/pdfs/us_selzentry.pdf.
- 2000-2001 Medical Management of HIV Infection, Bartlett JG, Gallant JE (Eds), Johns Hopkins University, Baltimore 2000.
- GENERAL DOSING RECOMMENDATIONS
- NUCLEOSIDE/TIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs)
- Lactic acidosis/severe hepatomegaly with steatosis
- Tenofovir and nephrotoxicity
- NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)
- PROTEASE INHIBITORS (PIs)
- Renal excretion
- CCR5 INHIBITORS
- FUSION INHIBITORS
- INTEGRASE INHIBITORS
- TIMING OF DOSES FOR PATIENTS ON HEMODIALYSIS
- SUMMARY AND RECOMMENDATIONS