By Carol A. Kemper, MD, FACP
Source: Izzedine H, et al. Kidney Int. 2001;60:821-830.
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One of the greatest challenges facing HIV practitioners is the management of HIV-positive patients with renal failure. About 6-10% of HIV-positive patients have renal impairment. The appropriate dosing of antiretroviral therapy in these patients is critical to the success of these therapies and the prevention of the development of HIV resistance mutations. In my own practice, 4 patients have renal failure (3 on hemodialysis), each one of whom requires a tailor-made HAART regimen. Both NRTIs and NNRTIs are renally excreted to some degree, and several require dose adjustment in the presence of renal impairment or renal failure. On the other hand, the protease inhibitors are metabolized by the CYP hepatic isoenzyme system, and dose adjustment is not necessary. This article goes a long way in providing a useful clinical guide for dosing of antiretroviral therapy in renal disease, with subsequent confirmation of trough levels of NNRTIs and protease inhibitors, as needed.
NRTIs
Most of the NRTIs are metabolized by intracellular kinases; protein binding is low. About 10-60% of these drugs are renally excreted unchanged in the urine. Thus, with the exception of abacavir, all of the drugs in this class and their metabolites accumulate in patients with renal failure (see Table). Drugs with higher molecular weight, such as AZT, have lower fractional excretion during dialysis (FHD) compared with those agents with lower molecular weight, such as 3TC and d4T. For example, about 15-20% of AZT is excreted unchanged by the kidney and much of the rest is excreted in the urine as a glucuronide metabolite. While AZT clearance during dialysis is minimal, the FHD for the glucuronide metabolite is high. Therefore, it is recommended that a reduced dose of AZT be administered after dialysis. The other drugs, such as D4T, 3TC, and ddI, which have lower molecular weights than AZT, are eliminated to a much greater degree during dialysis. Therefore, it is probably easiest to remember that, with the exception of abacavir, all of the NRTIs require dose reduction in renal failure, and the dose should be administered after dialysis.
| Table: NRTIs and Renal Failure | |||||
| Agent | %
Protein Bound |
%
excreted unchanged by kidney |
Dose adjustment in Renal Insufficiency |
FHD* | Dose Recommendations |
| NRTI | |||||
| AZT | 7-38% | 15-20%; glucuronide metabolite largely excreted | Yes | 5-8% | 100 mg q8h post-HD |
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| D4T | 10% | 35-50% | Yes | 68%** | BW <60 kg: 15 mg q24h post HD |
| BW >60 kg: 20 mg q24h post HD | |||||
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| 3TC | 36% | 70-100% | Yes | 25% | 150 mg once, and then 25-50 mg q24h post HD |
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| Abacavir | < 15% | < 20% | No | 10% | No change |
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| ddI | < 5% | 50-55% | Yes | 40% | BW <60 kg: 150 mg q24h post HD |
| BW >60 kg: 100 mg q24h post HD | |||||
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| ddC | 4% | 70-75% | Yes | unknown | 0.75 mg q24h |
| NNRTI | |||||
| Nevirapine | 60% | < 5%; glucuronide metabolite largely excreted | No | 88% | 200 mg q12h post HD |
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| Efavirenz | 99-100% | < 1%; Extensive hepatic metabolism | No | unknown | Usual dose anytime |
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| Delavirdine | 99-100% | < 5% | No | unknown | Usual dose anytime |
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| * FHD = fractional elimination during dialysis of absorbed dose; assumed to be clinically relevant if > 25% of the total absorbed dose. | |||||
| ** Represents an extraction ratio; the FHD has not been evaluated in patients receiving d4T. | |||||
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Abacavir—the exception to this rule—has a comparatively high molecular weight, the fraction bound to plasma protein is ~15%, and less than 20% is excreted unchanged in the urine. The fractional excretion during dialysis is only 10%. Thus, abacavir does not require dosage adjustment in renal failure, and the dose can be administered irrespective of the timing of dialysis.
NNRTIs
Except for nevirapine, protein binding of NNRTIs is higher than normal and the free fraction of drug is lower in renal insufficiency. Because efavirenz and delavirdine are primarily metabolized by the CYP3A4 (although the metabolites are excreted both renally and hepatically), no changes in the dosing of these 2 drugs are required in renal insufficiency or in patients on hemodialysis. Nevirapine is different—similar to the NRTIs, only a tiny amount (5%) is excreted unchanged by the kidney, but about 75-80% of the glucuronide metabolite is excreted renally. However, no significant changes in the PK of the drug were observed in 2 patients with renal insufficiency, although concentrations of the glucuronide metabolite were not specifically examined. In addition, 88% of the drug is fractionally excreted during dialysis. Therefore, the usual dose of nevirapine should be administered following dialysis on dialysis days. Just remember: no dose adjustment is required for the NNRTIs in renal failure, although nevirapine should be administered after dialysis.
Protease Inhibitors
The pharmacokinetics of the PIs, which are extensively metabolized by the CYP hepatic enzyme system, suggest that dosage adjustment in renal failure and in those on hemodialysis is not necessary, although the specific pharmacokinetics of several of these agents in renal failure have not been examined. With the exception of indinavir, which is 60% bound to plasma protein and ~10% of which is found unchanged in the urine, all of the other PIs are extensively protein bound (90-94%). Both nelfinavir and amprenavir are probably weakly dialyzable, but significant amounts of drug are not removed to warrant dose adjustment. Therefore, no changes in the dosing or the timing of administration of the PIs are necessary in patients with renal failure on hemodialysis.
Dr. Kemper, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center, is Associate Editor of Infectious Disease Alert.
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