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 .
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- 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
- SOCIETY GUIDELINE LINKS
- SUMMARY AND RECOMMENDATIONS