Ching-Lung Lai - Academia.edu (original) (raw)

Papers by Ching-Lung Lai

Hepatology, 2011

This free journal suppl. contain abstracts of the 62nd Annual Meeting of the American Association... more This free journal suppl. contain abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2011

The treatment of chronic hepatitis B is in constant evolution. Interferon, the first agent licens... more The treatment of chronic hepatitis B is in constant evolution. Interferon, the first agent licensed for chronic hepatitis B treatment, has been superseded by the growing popularity of nucleoside/nucleotide analogues (NA). However, resistance to these agents is a major challenge. Newer NAs, such as entecavir and tenofovir dipivoxil fumarate, have very low resistance rates and favorable safety profiles. Long-term use of these agents can effectively suppress hepatitis B virus DNA, leading to decrease in incidence of hepatitic flares, as well as in the development of cirrhosis and hepatocellular carcinoma. The efficacy and safety of various antiviral agents is discussed in this review.

Alimentary Pharmacology & Therapeutics, 2017

SummaryBackgroundChronic hepatitis B (CHB) cannot be completely eradicated due to the presence of... more SummaryBackgroundChronic hepatitis B (CHB) cannot be completely eradicated due to the presence of covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes. While quantification of intrahepatic cccDNA requires liver biopsies, serological markers can be non‐invasive alternatives to reflect intrahepatic viral replicative activity. Recently, hepatitis B core‐related antigen (HBcrAg) has been advocated as a novel serum marker for disease monitoring and prognostication of CHB.AimTo examine the virological aspect and clinical application of HBcrAg with respect to the natural history and treatment of CHB.MethodsWe reviewed all papers published in the PubMed journal list and abstracts from major international meetings that included the keyword “HBcrAg” or “hepatitis B core‐related antigen” until March 2017. Selected studies were compared and summarised on the basis of existing theories, as well as the authors’ experience.ResultsHBcrAg exhibited good correlation with intr...

Journal of Hepatology, 2017

Background and aims: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), a minichrom... more Background and aims: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), a minichromosome essential for HBV replication, is supposed to be resistant to nucleos(t)ide analogue treatment. We investigated the effect of long-term nucleos(t)ide analogue treatment on cccDNA. Methods: Among 129 patients who had been enrolled in previous international nucleos(t)ide analogue clinical trials and had liver biopsies at baseline and one year after treatment, we recruited 43 patients on long-term continuous treatment for 72 to 145 months for a third liver biopsy. Serum HBV DNA, hepatitis B surface antigen (HBsAg) levels, total intrahepatic HBV DNA (ihHBV DNA), cccDNA, HBV pregenomic RNA (pgRNA) as well as histologic changes were examined. Results: At the time of the third biopsy, serum HBV DNA levels were undetectable in all but one patient. The median levels of HBsAg, ihHBV DNA, and cccDNA were 2.88 logIU/mL, 0.03 copies/cell, and 0.01 copies/cell, respectively. Compared to baseline levels, there was reduction of HBsAg levels by 0.54 log (71.46%), ihHBV DNA levels by 2.81 log (99.84%), and cccDNA levels by 2.94 log (99.89%), with 49% having cccDNA levels below the detection limit. One patient had undetectable HBsAg. The median pgRNA level, measured only in the third biopsy, was 0.021 copies/cell, with 40% of patients having undetectable pgRNA. Conclusions: Long-term nucleos(t)ide analogue treatment induced marked depletion of cccDNA in the majority of patients while serum HBsAg levels, though reduced, were detectable in all but one patient. Whether cccDNA depletion is sustained and associated with better patient outcome requires further study.

Cold Spring Harbor perspectives in medicine, 2015

Here we review the management of chronic hepatitis B (CHB) in four special categories of patients... more Here we review the management of chronic hepatitis B (CHB) in four special categories of patients: CHB in pregnancy, in patients on immunosuppressive treatments, in patients undergoing liver transplantation, and in patients coinfected with human immunodeficiency virus (HIV) or hepatitis C virus (HCV).

Hepatology International, 2009

New England Journal of Medicine, 2008

tive effects of ACE inhibitors and calcium antagonists: theoretical basis for a combination thera... more tive effects of ACE inhibitors and calcium antagonists: theoretical basis for a combination therapy in hypertension and other cardiovascular diseases. Cardiovasc Drugs Ther 1995;Suppl 3: 509-23. Chobanian AV, Bakris GL, Black HR, et al. The Seventh 14.

Gut, 2013

Background Besifovir (LB80380) is an acyclic nucleotide phosphonate effective in hepatitis B viru... more Background Besifovir (LB80380) is an acyclic nucleotide phosphonate effective in hepatitis B virus (HBV) DNA suppression for both treatment-naive and lamivudine-resistant chronic hepatitis B (CHB) patients in preliminary studies. Design We aimed to compare the safety and antiviral activity of two doses of besifovir (90 mg and 150 mg daily) with entecavir 0.5 mg daily in CHB patients. 114 patients were randomised to receive besifovir 90 mg daily (n=36), besifovir 150 mg daily (n=39) or entecavir 0.5 mg daily (n=39). HBV DNA and liver biochemistry, including serum L-carnitine levels, were monitored. Results At week 48, in the intention-to-treat population, the proportion of patients achieving undetectable HBV DNA (<20 IU/mL) were 63.6%, 62.9% and 58.3%, respectively (p>0.05). The serum mean log 10 HBV DNA changes from baseline for the HBeAg-positive patients were −5.84, −5.91 and −6.18, respectively; and for the HBeAg-negative patients were −4.65, −4.55 and −4.67, respectively (p>0.05). There were no differences in the proportions of patients achieving normalisation of alanine aminotransferase (91.7%, 76.9%, 89.7%, respectively) and HBeAg seroconversion (11.11%, 15%, 9.52%, respectively) among all three groups. None of the patients had resistant mutations or increase in serum creatinine of >0.5 mg/dL from baseline. 64 (94.1%) patients on besifovir had lowering of serum L-carnitine (not tested in entecavir patients). L-carnitine levels returned to normal with carnitine supplement. Conclusions At 48 weeks, 90 mg and 150 mg daily of besifovir were non-inferior to entecavir 0.5 mg daily in treatment-naive CHB patients. The only significant side effect of besifovir was L-carnitine depletion, requiring carnitine supplementation.

Chronic hepatitis B virus (HBV) infection affects over 350 million individuals worldwide. Chronic... more Chronic hepatitis B virus (HBV) infection affects over 350 million individuals worldwide. Chronic hepatitis B is associated with complications of end-stage liver disease, including cirrhosis and hepatocellular carcinoma. Six drugs have been approved for the treatment of chronic hepatitis B: interferon-alpha, pegylated interferonalpha, lamivudine, adefovir dipivoxil, entecavir and recently telbivudine. Most agents designed to target hepatitis B are hindered by the development of resistance, poor tolerability or limited efficacy; therefore, the search for new agents and treatment strategies continues. Telbivudine is the latest approved anti-HBV agent; it is an orally administered nucleoside analog that selectively inhibits HBV early adulthood. The intermediate immune clearance phase is associated with fluctuating or elevated alanine aminotransferase (ALT) levels, active inflammation on liver histology and finally HBeAg seroconversion with antibody against HBeAg (anti-HBe). In the residual phase, the ALT usually becomes normal with low HBV DNA level. 1 Although HBeAg seroconversion has been commonly regarded as a sign of disease remission and therefore as a treatment endpoint, more recent evidence suggests that in fact the majority of patients who acquire HBV early in life and subsequently develop complications of cirrhosis and HCC are HBeAg negative. 2-4 These complications develop during the residual phase of CHB. Current treatment for CHB The two main classes of treatment for CHB currently available replication. It has demonstrated potent activity against HBV in clinical studies, with good tolerance, lack of mitochondrial toxicity and no dose-limiting side effects. This review focuses on telbivudine, the latest oral antiviral agent for the treatment of chronic hepatitis B.

Journal of Antimicrobial Chemotherapy, 2011

The current available agents for the treatment of chronic hepatitis B (CHB) include immunomodulat... more The current available agents for the treatment of chronic hepatitis B (CHB) include immunomodulatory agents, such as interferon-α and pegylated interferon-α, and oral nucleoside/nucleotide analogues (NAs), including lamivudine, adefovir, telbivudine, entecavir and tenofovir. The NAs work mainly by inhibiting hepatitis B virus (HBV) DNA polymerase activity and thus suppress HBV replication. Oral NAs have become the mainstay of CHB treatment, mainly due to their profound viral suppressive effects and also due in part to the ease of single daily dosing and lack of significant side effects. One major drawback of NA therapy is the development of drug resistance mutations with long-term treatment. Lamivudine, the first oral NA approved for CHB patients, is associated with high rates of drug resistance, with resultant virological relapse and biochemical flare. Fortunately, newer and more potent NAs, such as entecavir and tenofovir, have very low resistance rates, with potent and durable viral suppression. This review is aimed at the current developments in NAs for CHB treatment, detailing the mechanisms of antiviral activity of the different agents, the efficacy of viral suppression, the achievement of treatment endpoints, the development of drug resistance and the optimal strategies for using these drugs.

Hepatology, 2013

Chronic hepatitis B (CHB) infection is the major cause of hepatocellular carcinoma (HCC). Primary... more Chronic hepatitis B (CHB) infection is the major cause of hepatocellular carcinoma (HCC). Primary prevention of hepatitis B infection by vaccination is effective in reducing the incidence of HCC. In persons with CHB infection, the two accepted treatment modalities are interferon alpha (IFN-a) given subcutaneously for a limited period and nucleoside/nucleotide analogs given orally on a long-term basis. These treatments are effective in suppressing viral activity and improving disease markers in short-term studies. The longterm effect on the development of liver cancers with these two forms of treatment appears to be different. However, there are no studies directly comparing IFN-a and nucleoside/nucleotide analogs. Comparisons across studies are inevitably limited by differences in the baseline characteristics of the study cohorts. Long-term follow-up studies of IFN-a therapy show inconsistent results. The beneficial effect in reducing the development of liver cancer is observed mainly in treatment responders who have preexisting cirrhosis of the liver. The long-term studies of lamivudine (and adefovir) show a consistent reduction in the development of liver cancers in patients with, and without, cirrhosis. This beneficial effect is blunted by the development of resistance. The effects of the newer nucleoside/nucleotide analogs, with higher potency and minimal risk of resistance development, are, as yet, unknown.

Hepatology, 1999

A total of 318 children were prospectively randomized in group 1 with two 5-g doses of recombinan... more A total of 318 children were prospectively randomized in group 1 with two 5-g doses of recombinant vaccine given at 0 and 1 month; in group 2 with three 5-g doses of recombinant vaccine given at 0, 1, and 6 months; or in group 3 with three doses of plasma-derived vaccine given at 0, 1, and 6 months. Eleven subjects with a hepatitis B surface antigen antibody (anti-HBs) titer of less than 10 mIU/mL at 12 months were given an extra dose of vaccine and were excluded from analysis. No booster doses were given to any other subjects. All children were followed up yearly for the level of anti-HBs titers and for the detection of hepatitis B infection. At the 12th year of follow-up, there were significantly fewer subjects with anti-HBs of 10 mIU/mL or above in group 1 (60.4%) when compared with group 2 (81.4%; P ‫؍‬ .0287) and group 3 (79.0%; P ‫؍‬ .0381). The geometric mean titers (GMTs) of subjects of group 1 were significantly lower than those of group 2 and group 3 throughout the 12 years of follow-up. A total of 65 subjects had one or more episodes of anamnestic response. No subject became positive for hepatitis B surface antigen (HBsAg); 2 became positive for hepatitis B core antigen antibody (anti-HBc). In conclusion, the long-term protective immunity was better with three doses of hepatitis B vaccine (either the recombinant or plasma-derived) than with two doses. However, protection from hepatitis B infection could be equally achieved by either two doses or three doses of the vaccine. Booster doses were not necessary, probably because of effective anamnestic response. (HEPATOLOGY 1999;29:924-927.