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We herein present the case of a 66-year-old Japanese man with Fanconi's syndrome. He had been receiving adefovir dipivoxil (ADV) for the treatment of entecavir (ETV)-resistant chronic hepatitis B (CHB) for four years in his 8-year treatment of hepatocellular carcinoma (HCC), but was referred to our hospital after increased levels of bone pain in his ribs, knees, and ankles. Renal dysfunction, hypophosphatemia, and increased levels of bone alkaline phosphatase were found by a hematology test after admission for treatment of HCC. Radiography and 99m Tc-labeled hydroxymethylene diphosphonate (HMDP) scintigraphy revealed multiple insufficiency fractures in the ribs, knees, ankles, and heels. After switching from ADV to tenofovir disoproxil fumarate (TDF) and treatment with calcitriol and sodium dihydrogenphosphate, the patient's serum phosphate levels slightly increased and renal dysfunction did not improve, but after six months his clinical symptoms disappeared. To detect and prevent adverse effects from ADV, physicians and pharmacists should carefully monitor renal function and serum phosphate levels in patients with hepatitis B virus (HBV) treated for a long time with ADV.

Chronic hepatitis B (CHB) leads to cirrhosis and hepatocellular carcinoma (HCC). With a cohort of 1,206 CHB patients who visited Okayama University Hospital and related hospitals in 2011 and 2012, we compared the incidence rates of HCC among the patients grouped by age, hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg), and treatment. HCCs were observed in 115 patients with the median observation period of 1,687 days. Among the HCC patients aged > 35 years, HBV DNA > 4 log copies/mL and positive HBeAg at diagnosis (n＝184), the HCC incidence rate was 8.4% at 5 years in the entecavir (ETV)-treated patients, 21.8% in the lamivudine (LVD)-treated patients, and 26.4% among the patients not treated with drugs. The cumulative HCC incidence was significantly reduced in the ETV-treated patients compared to those treated with LVD or not treated (p＝0.013). Among the patients aged >35 years with HBV DNA > 4 log copies/mL and negative HBeAg (n＝237), the cumulative HCC incidence was 14.6% in 5 years in ETV group and 13.9% among those not treated with a drug (p＞0.05). Only small numbers of HCCs occurred in other patients. In CHB patients aged > 35 years with HBV DNA > 4 log copies/mL and positive HBeAg, ETV treatment is recommended for the suppression of HCC development.

Hepatitis B often progresses to decompensated liver cirrhosis requiring orthotopic liver transplantation (OLT). Although newer nucleos(t)ide analogues result in >90% viral and hepatitis activity control, severely decompensated patients still need OLT because of drug-resistant virus, acute exacerbation, or hepatocellular carcinoma. Acute hepatitis B is also an indication for OLT, because it can progress to fatal acute liver failure. After OLT, the hepatitis B recurrence rate is >80% without prevention, while >90% of transplant recipients are clinically controlled with combined hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogue treatment. However, long-term HBIG administration is associated with several unresolved issues, including limited availability and extremely high cost; therefore, several treatment protocols with low-dose HBIG, combined with nucleos(t)ide analogues, have been investigated. Another approach is to induce self-producing anti-hepatitis B virus (HBV) antibodies using an HBV envelope (HBs) antigen vaccine. Patients who are not HBV carriers, such as those with acutely infected liver failure, are good candidates for vaccination. For chronic HBV carrier liver cirrhosis patients, a successful vaccine response can only be achieved in selected patients, such as those treated with experimentally reduced immunosuppression protocols. The present protocol for post-OLT HBV control and the future prospects of newer treatment strategies are reviewed.

To clarify the factors associated with delayed reduction of HBV DNA during combination treatment with adefovir dipivoxil (ADV) and lamivudine (LAM) for patients with LAM-resistant hepatitis B virus (HBV), factors including patient characteristics, viral mutations, and drug metabolism were investigated during a 5-year observation period. Delayed reduction of HBV DNA was defined as delayed viral response of detectable HBV DNA after 3 years of combination therapy. Of 67 consecutive patients, 47 attained undetectable HBV DNA after 3 years of combination therapy, and the mean therapeutic duration was 5 years (range: 3.0-8.4 years). The patients with delayed viral response had high levels of HBV DNA and HBe antigen, while those with negative or low levels of HBe antigen were also negative for HBV DNA, even if they had high levels of HBV DNA. In the multivariate analysis with the proportional hazards model, a high baseline level of HBe antigen was negatively associated with viral decline to an undetectable level (P = 0.013). A higher baseline of HBe antigen corresponded to a lower annual decline in HBV DNA (R = -0.38, P = 0.004). No patients showed ADV-resistant mutations in the HBV reverse transcriptase region. Trough concentrations of LAM and ADV showed no clear associations with viral response. HBe antigen levels at the initiation of therapy, and reductions in these levels during therapy are predictive of the therapeutic response to combination therapy with ADV and LAM for patients with LAM-resistant HBV., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: For patients with chronic hepatitis due to hepatitis B virus (HBV), factors predicting hepatocellular carcinoma (HCC) other than high levels of HBV-DNA and alanine aminotransferase (ALT) are needed to prevent HCC development, as many patients with chronic HBV infection fulfill these conditions. The purpose of this study was to clarify factors predictive of HCC development for those patients., Methods: The study was a systematic cohort analysis of 303 consecutive patients with hepatitis B e-antigen, receiving laparoscopic examination for assessment of liver disease. Laparoscopic, histological, and clinical characteristics were investigated as related to HCC development., Results: HCC occurred in 27 patients during a mean follow-up of 8.0 ± 5.0 years, at the age of 37-72 years. Significant associations with HCC development were shown for liver cirrhosis, histological activity grade, reddish markings, and older age. Multivariate analysis revealed that HCC development was strongly associated with older age and male gender (P = 0.002 and P = 0.043, respectively). HCC occurred more frequently in patients of age ≥30 years even with early stage than in patients of age <30 years (P = 0.031). Severe reddish markings, a laparoscopic finding of widespread parenchymal destruction, were highly associated with HCC development in patients of age ≥30 years at diagnosis (odds ratio = 1.67, P = 0.034), while histological activity grade and ALT level were not (P = 0.075 and P = 0.69, respectively)., Conclusions: HCC development is associated with older age, male gender, and liver cirrhosis. Reddish markings, rather than histological activity or ALT level, can be useful to predict HCC for HBV patients of age ≥30 years.