Dosing of Antiretroviral Drugs in Adults with Renal Insufficiency and Hemodialysis

Authors: Rudolph A. Rodriguez, MD, University of California, San Francisco and Ian R. McNicholl, PharmD, University of California, San Francisco

Source: AETC National Resource Center and UCSF Center for HIV Information
Date: July 2010

Introduction

Several nucleoside and nucleotide analogue reverse transcriptase inhibitors are excreted primarily through the kidney and must be dose adjusted for patients with chronic kidney disease, and for those who are on hemodialysis. Although there are few data on the pharmacokinetic properties of the nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, fusion inhibitors, chemokine coreceptor antagonists, or integrase inhibitors in patients with chronic kidney disease, the pharmacokinetic profiles of these drugs suggest that renal function has minimal effect on drug elimination. Despite this, protease inhibitors and the NNRTI nevirapine may require modified dosing strategies in patients on hemodialysis, and the chemokine coreceptor antagonist maraviroc should not be used in certain patients with chronic kidney disease (see below). These tables summarize antiretroviral drug dose recommendations for patients with impaired renal function.

For further information, see the Renal Manifestations of HIV Knowledge Base Chapter .

Tables

Nucleoside/Nucleotide Analogues

Drug	Standard Dosage	Dosing in Chronic Kidney Disease and Hemodialysis			References
Abacavir	300 mg PO BID	Dosage adjustment for chronic kidney disease does not appear necessary			Ziagen package insert ( 1 )
Didanosine (enteric-coated capsules)	250 mg to 400 mg PO QD, depending on wt	ClCr (mL/min)	Wt ≥60 kg	Wt <60 kg	Videx EC package insert ( 2 , 3 )
		≥60	400 mg QD	250 mg QD
		30-59	200 mg QD	125 mg QD
		10-29	125 mg QD	125 mg QD
		<10	125 mg QD	formulation not suitable
		HD	125 mg QD	formulation not suitable
Emtricitabine	200 mg PO QD	ClCr (mL/min)			Emtriva package insert
		≥50	200 mg QD
		30-49	200 mg Q 48 H
		15-29	200 mg Q 72 H
		<15	200 mg Q 96 H
		HD	200 mg Q 96 H, give dosage after dialysis
Lamivudine	150 mg PO BID or 300 mg PO QD	ClCr (mL/min)			Epivir package insert ( 4 , 5 , 6 )
		≥50	150 mg BID or 300 mg QD
		30-49	150 mg QD
		15-29	150 mg first dose, then 100 mg QD
		5-14	150 mg first dose, then 50 mg QD
		<5	50 mg first dose, then 25 mg QD
Stavudine	20 mg to 40 mg PO BID, depending on wt	ClCr (mL/min)	Wt ≥60 kg	Wt <60 kg	Zerit package insert ( 7 )
		>50	40 mg BID	30 mg BID
		26-50	20 mg BID	15 mg BID
		10-25	20 mg QD	15 mg QD
		HD	20 mg QD	15 mg QD
Tenofovir	300 mg PO QD	Experience in patients with ClCr <60 mL/min is limited. Preliminary data suggest:			Viread package insert ( 8 )
		ClCr (mL/min)
		≥50	300 mg QD
		30-49	300 mg Q 48 H
		10-29	300 mg twice weekly (ie, Q 3-4 days)
		HD	300 mg QW
Zidovudine	300 mg PO BID	ClCr (mL/min)			Retrovir package insert ( 9 , 10 , 11 )
		<15	100 mg Q 6-8 H
		HD	100 mg TID

Fixed-Dose Combinations

Drug	Standard Dosage	Dosing in Chronic Kidney Disease and Hemodialysis		References
Abbreviations: BID = 2 times daily; ClCr = creatinine clearance; H = hours; HD = hemodialysis; PO = by mouth; Q = every; QD = 1 time daily; QHS = at bedtime; QW = once a week; TID = 3 times daily; Wt = weight
Atripla (efavirenz/emtricitabine/ tenofovir)	1 tab PO QHS	Substitute component drugs, adjusting dosage of each drug for ClCr		Atripla package insert
Combivir (zidovudine/lamivudine)	1 tab PO BID	Substitute component drugs, adjusting dosage of each drug for ClCr		Combivir package insert
Epzicom or Kivexa (abacavir/lamivudine)	1 tab PO QD	Substitute component drugs, adjusting dosage of each drug for ClCr		Epzicom package insert
Trizivir (zidovudine/lamivudine/abacavir)	1 tab PO BID	Substitute component drugs, adjusting dosage of each drug for ClCr		Trizivir package insert
Truvada (emtricitabine/tenofovir)	1 tab PO QD	ClCr (mL/min)		Truvada package insert
		≥50	1 tab QD
		30-49	1 tab Q 48 H
		<30	Substitute component drugs, adjusting dosage of each drug for ClCr

Nonnucleoside Reverse Transcriptase Inhibitors

Delavirdine, efavirenz
Dosage adjustment for chronic kidney disease does not appear necessary.

Nevirapine
For patients with chronic kidney disease (not on hemodialysis): Dosage adjustment does not appear necessary.
For patients on hemodialysis: An additional 200 mg dose of nevirapine following each dialysis treatment is recommended ( 15 )

Protease Inhibitors

Amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir
For patients with chronic kidney disease (not on hemodialysis): Dosage adjustment does not appear necessary.
For patients on hemodialysis: Hemodialysis normally would not be expected to change serum levels of drugs that are hepatically cleared, such as protease inhibitors. However, pharmacokinetic studies suggest that levels of atazanavir, lopinavir, and ritonavir are reduced significantly in patients on hemodialysis; the mechanism for this is not clear. Pharmacokinetic evaluations of most other protease inhibitors in hemodialysis patients have not been conducted. Further studies are needed to describe protease inhibitor levels in patients on hemodialysis and to define dosing recommendations.

Atazanavir
Although atazanavir is not cleared by hemodialysis, patients on hemodialysis have substantially lower plasma atazanavir concentrations compared with controls.( 12 , 13 )

Unboosted atazanavir should not be used.
For treatment-naive patients receiving hemodialysis, atazanavir must be boosted by ritonavir.
For treatment-experienced patients receiving hemodialysis, atazanavir (boosted or unboosted) is not recommended.

Lopinavir/ritonavir
Lopinavir and ritonavir also are not cleared by hemodialysis, but a recent study found that levels of both agents were lower than those of historical controls (C _min was 44% lower).( 14 )

For patients receiving hemodialysis, once-daily dosing should not be used (consider twice-daily dosing; dosage adjustments have not been studied).
Exercise caution in patients with resistance to protease inhibitors; lopinavir and ritonavir levels may not be adequate for viral suppression.

Other PIs
The pharmacokinetics of other protease inhibitors in the setting of hemodialysis have not been studied, and it is not known whether the finding of lower-than-expected drug levels in dialysis patients is a drug-class effect.

Fusion Inhibitors

Enfuvirtide
Dosage adjustment for chronic kidney disease does not appear necessary.

Chemokine Coreceptor Antagonists

Maraviroc
Dosage adjustment for patients with mild or moderate chronic kidney disease does not appear necessary. Maraviroc should not be used in patients with severe renal impairment or end-stage renal disease (CrCl <30 mL/min) who are taking a potent CYP3A inhibitor or inducer.( 16 )

Integrase Inhibitors

Raltegravir
Dosage adjustment for chronic kidney disease does not appear necessary.

References

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4.		Bohjanen PR, Johnson MD, Szczech LA, Wray DW, Petros WP, Miller CR, Hicks CB. Steady-state pharmacokinetics of lamivudine in human immunodeficiency virus-infected patients with end-stage renal disease receiving chronic dialysis. Antimicrob Agents Chemother 2002; 46:2387-92.

5.		Izzedine H, Launay-Vacher V, Deray G. Dosage of lamivudine in a haemodialysis patient. Nephron 2000; 86:553.

6.		Johnson MA, Verpooten GA, Daniel MJ, Plumb R, Moss J, Van Caesbroeck D, De Broe ME. Single dose pharmacokinetics of lamivudine in subjects with impaired renal function and the effect of haemodialysis. Br J Clin Pharmacol 1998; 46:21-7.

7.		Grasela DM, Stoltz RR, Barry M, Bone M, Mangold B, O'Grady P, Raymond R, Haworth SJ. Pharmacokinetics of single-dose oral stavudine in subjects with renal impairment and in subjects requiring hemodialysis. Antimicrob Agents Chemother 2000; 44:2149-53.

8.		Personal communication with J. Flaherty. 2002.

9.		Kimmel PL, Lew SQ, Umana WO, Li PP, Gordon AM, Straw J. Pharmacokinetics of zidovudine in HIV-infected patients with end-stage renal disease. Blood Purif 1995; 13:340-6.

10.		Pachon J, Cisneros JM, Castillo JR, Garcia-Pesquera F, Canas E, Viciana P. Pharmacokinetics of zidovudine in end-stage renal disease: influence of haemodialysis. Aids 1992; 6:827-30.

11.		Tartaglione TA, Holeman E, Opheim K, Smith T, Collier AC. Zidovudine disposition during hemodialysis in a patient with acquired immunodeficiency syndrome. J Acquir Immune Defic Syndr 1990; 3:32-4.

12.		Reyataz [patient information]. Princeton, NJ: Bristol-Myers Squibb; April 2009. Available at http://packageinserts.bms.com/pi/pi_reyataz.pdf. Accessed June 22, 2009.

13.		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.

14.		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 Oct 1;22(15):1919-27.

15.		Viramune [prescribing information]. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT. June 2010. Accessed July 27, 2010.

16.		Selzentry [prescribing information]. Pfizer, Inc. New York, NY: Pfizer, Inc. May 2010. Accessed July 20, 2010.