Rong-Nan Chien

The effect of lamivudine therapy in hepatic decompensation during acute exacerbation of chronic hepatitis B

BACKGROUND/AIMS Severe acute exacerbation (AE) of chronic hepatitis B (CHB) can lead to hepatic decompensation and death. The aim of this study was to investigate the effect of lamivudine therapy in hepatic decompensation during such AEs. METHODS In a 10-month period, a total of 60 consecutive AE patients with jaundice and prolonged prothrombin time over 3s were treated with lamivudine 150 mg daily. As a historical control, another 31 CHB patients with AE resulting in hepatic decompensation hospitalized in an immediate past 6-month period were enrolled for comparison. RESULTS Patients in both groups were comparable in clinical and biochemical features. After a median treatment period of 6 weeks (range 1-48 weeks), all of the 25 patients with pretherapy bilirubin level < 20 mg/dl in the treatment group survived, while five (25%) of 20 patients in the control group died (P=0.013; odds ratios, 2.667; 95% confidence interval, 1.787-3.979). However, the mortality rate was similar in patients with pretherapy bilirubin level > or =20 mg/dl in both groups. CONCLUSIONS These results suggest that lamivudine may prevent fatality in CHB patients with hepatic decompensation if therapy starts early enough or before serum bilirubin level rise over 20 mg/dl, but helps little if serum level already risen over that level.

Comparison of long-term effects of lymphoblastoid interferon alpha and recombinant interferon alpha-2a therapy in patients with chronic hepatitis B.

Summary.  To compare the long‐term effect of natural lymphoblastoid interferon‐alpha (IFN‐αnl) and recombinant IFN‐α2a therapy in patients with chronic hepatitis B, 210 patients in two trials were followed‐up for 1.1–15.5 years following the end of therapy. They included 34 patients who received placebo (control), 67 treated with IFN‐αnl (36 after prednisolone priming) and 109 treated with IFN‐α2a (56 after prednisolone priming). The cumulative sustained response was higher in patients who had been treated with IFN‐αnl after prednisolone priming than was exhibited using IFN‐αnl alone, IFN‐α2a alone or the placebo (P < 0.05), or IFN‐α2a following prednisolone priming (P = 0.052) at the end of 11 years. Hepatocellular carcinoma (HCC) was detected in 1.5% of the IFN‐αnl group, 3.7% of the IFN‐α2a group and 14.7% of the control group (control vs IFN‐αnl or IFN‐α2a, P < 0.05). The cumulative HCC development was higher in the control group than in the IFN‐αnl group (P < 0.002) and the IFN‐α2a group (P = 0.06). The cumulative survival rate was lower in the control group than in the IFN‐αnl group (P < 0.01) and the IFN‐α2a group (P = 0.02). Multivariate analysis revealed that IFN‐αnl therapy and female gender are significant predictors of sustained response; preexisting cirrhosis, age at entry and IFN therapy are significant factors in both HCC development and survival. In conclusion, IFN‐αnl treatment may have a better long‐term effect on hepatitis B virus (HBV) clearance than IFN‐α2a and placebo, and IFN therapy may provide better long‐term beneficial effects than placebo in terms of HBV clearance, reduction of HCC and prolonged survival.

Entecavir vs. lamivudine in chronic hepatitis B patients with severe acute exacerbation and hepatic decompensation

BACKGROUND & AIMS We compared the mortality and treatment response between lamivudine (LAM) and entecavir (ETV) in chronic hepatitis B (CHB) patients with severe acute exacerbation and hepatic decompensation. METHODS From 2003 to 2010 (the LAM group) and 2008 to 2010 (the ETV group), 215 and 107 consecutive CHB naïve patients with severe acute exacerbation and hepatic decompensation treated with LAM and ETV respectively, were recruited. RESULTS At baseline, the LAM group had higher AST levels and end-stage liver disease (MELD) scores, and lower albumin levels than the ETV group. Univariate analysis showed that the LAM group had a higher rate of overall (p=0.02) and liver-related mortality (p=0.052) at week 24 than the ETV group, including in patients with acute-on-chronic liver failure. Multivariate analysis showed that MELD scores, ascites, and hepatic encephalopathy were independent factors for overall and liver-related mortality at week 24. ETV or LAM treatment was not an independent factor for mortality in all patients or patients with acute-on-chronic liver failure. The best cut-off value of MELD scores were 24 for 24-week liver-related mortality. The ETV group achieved better virological response (HBV DNA <300 copies/ml) than the LAM group at week 24 (p=0.043) and 48 (p=0.007). The T1753C/A mutation was also an independent predictor associated with overall and liver-related mortality at week 24. CONCLUSIONS The choice between ETV and LAM was not an independent factor for mortality in CHB patients with acute exacerbation and hepatic decompensation. Patients with ascites, hepatic encephalopathy, and MELD scores ⩾24 were associated with poor outcome and should be considered for liver transplantation.

Nucleos(t)ide analogues for hepatitis B virus : Strategies for long-term success

Studies in the past decades have shown that active hepatitis B virus (HBV) replication is the key driver of liver injury and disease progression, and thus sustained viral suppression is of paramount importance in the management of chronic HBV infection. The nucleos(t)ide analogues lamivudine, adefovir, entecavir, telbivudine and tenofovir are potent inhibitors of HBV polymerase/reverse transcriptase activity and are highly effective in the suppression of HBV replication, but rarely eliminate the virus. Long-term therapy is usually required to achieve sustained hepatitis B e antigen seroconversion, HBV DNA suppression, ALT normalization and fibrosis reversal. Maintained long-term therapy has been demonstrated to significantly lower the rate of hepatic decompensation and development of cirrhosis or hepatocellular carcinoma. However, drug resistance is a serious risk on prolonged nucleos(t)ide analogue therapy, and this poses a critical challenge. Prevention and proper management of drug resistance are crucial to ensure long-term success.

Therapeutic effects of pegylated interferon plus ribavirin in chronic hepatitis C patients with occult hepatitis B virus dual infection

Background and Aim:  Occult hepatitis B virus (HBV) infection is defined by the detectable serum HBV–DNA in HBV surface antigen‐negative patients. This retrospective study aims to evaluate the therapeutic effects of combined pegylated interferon (PEG–IFN) plus ribavirin (RBV) in patients with concurrent occult HBV/hepatitis C virus (HCV) dual infection.

Clinical outcomes after spontaneous and nucleos(t)ide analogue-treated HBsAg seroclearance in chronic HBV infection

Both spontaneous and nucleos(t)ide analogue (Nuc)‐treated hepatitis B surface antigen (HBsAg) seroclearance are associated with excellent clinical outcomes.

C ASE R EPORT: Dramatic response to lamivudine therapy following corticosteroid priming in chronic hepatitis B

A 21 year‐old male patient with chronic hepatitis B was treated with lamivudine 150 mg daily after withdrawal of a short course of oral prednisolone (30 mg daily for 3 weeks, 15 mg daily for 1 week). Serum hepatitis B virus (HBV)‐DNA increased during prednisolone pretherapy and serum alanine aminotransferase (ALT) was increasing after withdrawal of prednisolone. Clearance of HBV‐DNA with hepatitis B e antigen seroconversion and ALT normalization occurred within 2 months after starting lamivudine therapy. If this dramatic response to lamivudine therapy after corticosteroid priming is confirmed by further studies, the regimens used in this particular case might become a powerful therapeutic tool for chronic HBV infection.

Short-term lamivudine therapy in patients with chronic hepatitis B.

Lamivudine is a nucleoside analogue with potent inhibitory effects on hepatitis B virus (HBV) polymerase/reverse transcriptase activity. The rate of hepatitis B e antigen (HBeAg) seroconversion in a large series of Asian patients treated with lamivudine 100 mg daily for 1 year was only 16% and the incidence of YMDD mutants was 14%. Further analysis of this Asian trial has shown that patients with a pretreatment alanine aminotransferase (ALT) level higher than 5-fold the upper limit of normal (ULN) have a much higher HBeAg seroconversion rate as compared with patients with a pretreatment ALT level <2 × upper limit of normal (64 vs. 5%; p < 0.001). In order to avoid the development of YMDD mutants, we selected 186 patients with acute exacerbation for treatment with lamivudine during 9 months, if possible, and not more than 15 months. They were all seropositive for both hepatitis B surface antigen and HBeAg for more than 6 months and also had serum HBV DNA; 138 (74%) of them were male. HBV genotypes were A in 2 (1%), B in 115 (62%), C in 65 (35%), D in 2 (1%) and F in the remaining 2 (1%). Four patients (2%) had liver cirrhosis. They had mean pretreatment levels of ALT at 608 IU/l (range: 184–2,400 IU/l), total bilirubin at 1.5 mg/dl (0.3–14.8 mg/dl), and HBV DNA at 2,246 pg/ml (0.5–25,903 pg/ml). After a median of 8.2 months (3–15 months) on lamivudine, 96 patients (51%) achieved HBeAg seroconversion, while the other 90 (48%) patients did not. Genotype B was detected comparably frequently in seroconverters and nonconverters (63 vs. 61%). During 1-year follow-up after withdrawal of lamivudine, 56 (58%) of the 96 seroconverters experienced flare-ups with ALT levels elevated higher than 5 × ULN in 50 (89%). Of 90 patients who remained HBeAg-positive, in contrast, 80 (86%) experienced ALT flares (with ALT >5 × ULN in 84%) within 1 year. YMDD mutants did not develop in any of these 186 patients during the course of lamivudine therapy. In conclusion, short-term lamivudine therapy in patients with chronic active hepatitis B can reduce the incidence of YMDD mutants and achieve an acceptable HBeAg seroconversion rate. However, the relapse rate was high (60% during 1-year follow-up). Further study is needed to establish how to improve a sustained HBeAg response.

Identification of hepatitis B virus rtS117F substitution as a compensatory mutation for rtM204I during lamivudine therapy

OBJECTIVES The replication defect of hepatitis B virus (HBV) lamivudine-resistant mutants can be restored by the development of compensatory mutations. Such mutations have long been recognized for the rtM204V mutant, while little is known about any compensatory mutation specific to the rtM204I mutant. The aim of this study was to search for previously unrecognized compensatory mutations following development of lamivudine-resistant mutants. METHODS Of 83 lamivudine-resistant patients, 49 and 34 patients harboured the rtM204I and rtM204V mutations, respectively. Serial serum samples obtained during the therapeutic course were submitted to sequence analysis. Site-directed mutagenesis experiments were performed to examine the functions of the identified associated mutations. RESULTS Of the 49 patients carrying the rtM204I mutation, 5 subsequently developed an rtS117F substitution during the follow-up, whereas 4 harboured an rtN124D substitution prior to the development of the rtM204I mutation. Emergence of the rtS117F mutation was associated with an increase in hepatitis activity, whereas prior existence of the rtN124D mutation was associated with decompensated liver function upon development of the rtM204I mutation. Site-directed mutagenesis experiments showed that the rtS117F mutation by itself did not confer lamivudine resistance but it compensated for replication deficiency of the rtM204I mutant in HepG2 and Mahlavu cells. Additionally, virion and hepatitis B surface antigen secretion of the rtS117F mutant was significantly impaired. CONCLUSIONS The rtS117F substitution served as a compensatory mutation for rtM204I. Emergence of the rtS117F mutation in lamivudine-resistant patients carrying rtM204I was associated with increased hepatitis activities. Prior existence of the rtN124D substitution was associated with liver decompensation upon development of the rtM204I mutation.

CASE REPORT: Primary Calcified Gastrinoma of the Liver

The liver is a rare site for primary neuroendocrine tumors including gastrinomas. We are aware of only 12 cases of hepatic gastrinoma reported in the English literature (1–12), some of these reports focused on the liver as the primary site of gastrinoma (7–12). Calcification within a hepatic mass is most commonly seen in hepatocellular carcinoma (HCC) and metastases from colorectal cancer (13), but is rare in liver metastases of endocrine tumors (14). To the best of our knowledge, only two cases of calcified hepatic metastases have been documented in ZollingerEllison syndrome (ZES) (15, 16). We present a case of primary hepatic gastrinoma with calcification that had never been reported before.