Adding Adefovir (Hepsera) to Lamivudine (Epivir-HBV) Extends Biochemical Response, but May Cause Kidney Problems

		SUMMARY: Combination therapy with adefovir (Hepsera) and lamivudine (3TC; Epivir-HBV) can prolong biochemical response or liver enzyme normalization in chronic hepatitis B patients who experience treatment failure on lamivudine alone, but the addition of adefovir increases the risk of kidney impairment over the long term, according to a study reported in the February 1, 2010 Journal of Viral Hepatitis.

By Liz Highleyman

Epivir-HBV Tablet Hepsera Tablet

Several nucleoside/nucleotide analogs are effective against chronic hepatitis B virus (HBV) infection, but when they are used alone, the virus can develop resistance relatively easily, thereby compromising long-term treatment success. Combining these agents, however, slows the emergence of resistance.

A. Tamori and colleagues from Japan evaluated the safety and efficacy of combination therapy using lamivudine plus adefovir in 37 hepatitis B patients (including 17 with liver cirrhosis) who were no longer responding to lamivudine alone.

Combination therapy with adefovir and lamivudine is recommended for patients infected with lamivudine-refractory HBV, but the effects of such therapy on renal (kidney) function and serum phosphorus levels have not been fully evaluated, the authors noted as background.

Like its cousins tenofovir (Viread, approved for treatment of both HBV and HIV) and cidofovir (Vistide, used to treat cytomegalovirus), adefovir can cause kidney impairment, especially with long-term use in susceptible individuals; adefovir, in fact, was abandoned as an HIV drug candidate due to kidney toxicity, but it is used at lower doses for treatment of hepatitis B.

The investigators assessed virological response, or HBV DNA level, as well as biochemical response, or normalization of elevated serum liver enzymes including alanine aminotransferase (ALT).

Results

	Serum HBV DNA levels decreased to below 2.6 log10 copies/mL in a majority of study participants:
	23 of 37 patients (62%) at 12 months; 25 of 32 patients (78%) at 24 months; 16 of 19 patients (84%) at 36 months.
	Except for 1 individual with cirrhosis, all other patients achieved serum ALT levels below 50 IU/L during combination therapy.
	Serum creatinine levels (an indicator of kidney impairment) increased in 14 of 37 patients (38%) during combination therapy.
	Serum phosphate levels (another kidney function marker) decreased to below 2.5 mg/mL in 6 of 37 patients (16%).
	Individuals who received combination therapy for 36 months or longer had a significantly increased incidence of elevated serum creatinine.
	Fanconi syndrome (a type of kidney failure) occurred in a 57-year-old woman with cirrhosis after adefovir was added to lamivudine.

Based on these findings, the study authors concluded, "Combination therapy with adefovir and lamivudine can maintain biochemical remission in patients with lamivudine-refractory HBV."

However, they added, the dosing interval of adefovir should be adjusted according to renal function and serum phosphate levels in patients receiving long-term treatment."

Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan; Department of Medical Nutrition, Osaka City University Graduate School of Life Science, Osaka, Japan; Department of Nuclear Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan; Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.

3/19/10

Reference
A Tamori, M Enomoto, S Kobayashi, and others. Add-on combination therapy with adefovir dipivoxil induces renal impairment in patients with lamivudine-refractory hepatitis B virus. Journal of Viral Hepatitis 17(2): 123-129 (Abstract). February 1, 2010.