Add-on Combination Therapy with Adefovir Dipivoxil Induces Renal Impairment in Patients with Lamivudine-refractory Hepatitis B Virus

A. Tamori; M. Enomoto; S. Kobayashi; S. Iwai; H. Morikawa; H. Sakaguchi; D. Habu; S. Shiomi; Y. Imanishi; N. Kawada


J Viral Hepat. 2010;17(2):123-129. 

In This Article

Abstract and Introduction


Combination therapy with adefovir dipivoxil (ADV) and lamivudine (LAM) is recommended for patients infected with LAM-refractory hepatitis B virus (HBV). However, the effects of such therapy on renal function and serum phosphorus levels have not been fully evaluated. Combination therapy with ADV and LAM was given to 37 patients infected with LAM-refractory HBV, including 17 with hepatic cirrhosis. Serum HBV DNA levels decreased to below 2.6 log10 copies/mL in 23 (62%) of 37 patients at 12 months, 25 (78%) of 32 patients at 24 months, and 16 (84%) of 19 patients at 36 months. Except for one cirrhotic patient, serum alanine aminotransferase levels were below 50 IU/L in all patients during combination therapy. Serum creatinine levels increased in 14 (38%) of 37 patients, and serum phosphate levels decreased to below 2.5 mg/mL in 6 (16%) of 37 patients during combination therapy. Patients who received combination therapy for 36 months or longer had a significantly incidence of elevated serum creatinine levels. Fanconi syndrome occurred in a 57-year-old woman with cirrhosis after ADV was added to LAM. Combination therapy with ADV and LAM can maintain biochemical remission in patients with LAM-refractory HBV. However, the dosing interval of ADV should be adjusted according to renal function and serum phosphate levels in patients receiving long-term treatment.


Hepatitis B virus (HBV) is a widely prevalent pathogen that causes chronic hepatitis, hepatic cirrhosis, and hepatocellular carcinoma (HCC).[1] Interferon and nucleos(t)ide analogues are used for antiviral therapy in patients infected with chronic hepatitis B infection.[2,3] Lamivudine (LAM) is the first nucleoside analogue approved for the treatment of HBV-infected liver disease. LAM suppresses HBV replication in most patients and improves hepatic inflammation.[4] However, more than 60% of patients with HBV who receive long-term LAM therapy become resistant to the drug within 4 years after starting treatment.[5] For LAM-resistant HBV, a switching-to adefovir dipivoxil (ADV) or entecavir (ETV) treatment is a choice of treatment.[6,7] However, in ADV monotherapy for LAM-refractory chronic hepatitis B, virological breakthrough due to development of ADV resistant mutations occurred in three (21%) of 14 patients within 18 months.[8] In another study, ETV-resistant mutations developed in 12 (8%) of 151 patients with LAM-refractory chronic hepatitis B who received 1 mg ETV once daily for 2 years.[7] In contrast, combination therapy with ADV and LAM decreased HBV DNA levels in patients with LAM-resistant HBV and maintained the effect without virological and biochemical breakthroughs for 3 years.[8,9] In one study performed in Japan, ADV-resistant mutations occurred in only 2 of 129 patients with LAM-refractory chronic hepatitis B who received ADV plus LAM for 2 years.[10] These studies concluded that combination therapy with ADV and LAM was the treatment of choice for patients with LAM-resistant HBV.

An important limitation of previous studies of combination therapy with ADV and LAM is the lack of adequate safety data. Monotherapy with LAM is given to more than 30 000 patients with HBV-related chronic liver disease in Japan. LAM has not been reported to induce serious adverse effects, except for the emergence of LAM-resistant HBV. On the other hand, nephrotoxicity is the dose-limiting adverse effect in the use of ADV. In phase III, randomized, controlled studies, there were no increases from baseline of 0.5 mg/dL or greater in the serum creatinine level and no confirmed instances of serum phosphate levels below 2.0 mg/dL during 48 weeks of monotherapy with 10 mg ADV.[11] However, the renal safeness of combination therapy with ADV and LAM in long-term use is not enough to be evaluated. In particular, there are few reports about decrease of serum phosphate during the combination therapy. In our hospital, an open-label study of long-term add-on treatment with ADV in patients with LAM-refractory HBV has been in progress since 2003.

In the present study, we investigated the incidence of serum creatinine increase and hypophosphorus in patients with HBV-related chronic liver diseases during long-term ADV and LAM combination therapy. In addition, clinical characteristics of patients in whom mild renal impairment was observed were evaluated, since early detection of adverse event is important.