Hepatitis: Liaw YF

Liaw YF, Leung N, Guan R, Lau GK, Merican I, Anonymous00265. · Liver Research Unit, Chang Gung University, Taipei, Taiwan. · J Gastroenterol Hepatol. · Pubmed #12603522 No free full text.

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Liaw YF. · No affiliation provided · Hepatology. · Pubmed #17256763 No free full text.

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Lin DY, Liaw YF. · No affiliation provided · J Gastroenterol Hepatol. · Pubmed #11446876 No free full text.

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Liaw YF. · No affiliation provided · J Gastroenterol Hepatol. · Pubmed #11422609 No free full text.

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Farrell G, Liaw YF, McCaughan G. · No affiliation provided · J Gastroenterol Hepatol. · Pubmed #11022819 No free full text.

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Farrell GC, Liaw YF. · Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, New South Wales, Australia. · J Gastroenterol Hepatol. · Pubmed #10921372 No free full text.

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Liaw YF. · No affiliation provided · J Gastroenterol Hepatol. · Pubmed #10029270 No free full text.

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Liaw YF. · Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan. · Antivir Ther. · Pubmed #19320233 No free full text.

Abstract: Studies published to date regarding on-treatment outcome prediction during chronic hepatitis B therapy were reviewed. Studies have shown that initial virological responses in terms of week 24 serum hepatitis B virus (HBV) DNA levels are associated with therapeutic outcomes of 1-year pegylated interferon-alpha and entecavir therapy, and weeks 52 or 104 of lamivudine and telbuvudine therapy. HBV DNA levels at week 48 are also associated with long-term adefovir therapy outcomes. Conceptual on-treatment adjustment and strategies have been proposed; however, this approach seems only necessary during therapy with nucleos(t)ide analogues with substantial risk of drug resistance. In addition, studies are needed to decide whether switching to or adding on a second drug, and with which drug, is the most cost-effective strategy.

Liaw YF. · Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan. · Liver Int. · Pubmed #19207972 No free full text.

Abstract: Chronic hepatitis B virus (HBV) infection is a dynamic state of interactions among HBV, the hepatocytes and the immune system of the patient. Perinatally or early childhood-acquired chronic HBV infection has a long 'immune tolerant phase', when patients are young, and HBeAg seropositive with a high viral load but with no significant liver disease. Persistent or episodic liver injuries during the 'immune clearance phase' may lead to decompensation, fibrosis progression or cirrhosis development in some patients, but may eventually lead to HBV-DNA seroclearance with HBeAg seroconversion and entry into the 'inactive phase' with remission. Hepatitis may relapse, because of reactivation of HBV with precore or basal core promptor mutations, and develop 'HBeAg-negative chronic hepatitis', in some patients. In contrast, HBsAg seroclearance may occur in those with sustained remission. During the course, HBV replication is the key driver of disease progression including development of cirrhosis and hepatocellular carcinoma (HCC). Among the currently available anti-HBV drugs, the most extensive and longest experience has been gained with conventional interferon (IFN)-alpha and lamivudine. A finite course of IFN therapy has long-term benefit in achieving a cumulative response, increasing HBsAg seroclearance and reducing cirrhosis and/or HCC. Maintained virological response to lamivudine therapy has a similar long-term benefit in reducing disease progression. Pegylated IFN and newer nucleos(t)ide analogues may have even better long-term outcomes because of better therapeutic efficacy and/or a low risk of drug resistances. The treatment outcomes are still far from satisfactory. The development of safe and affordable anti-HBV agents/strategies is needed to further improve outcomes.

Chien RN, Liaw YF. · Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan. · Best Pract Res Clin Gastroenterol. · Pubmed #19187868 No free full text.

Abstract: 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.

Lok AS, Zoulim F, Locarnini S, Bartholomeusz A, Ghany MG, Pawlotsky JM, Liaw YF, Mizokami M, Kuiken C, Anonymous00198. · Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109-0362, USA. · Hepatology. · Pubmed #17596850 No free full text.

Abstract: Substantial advances have been made in the treatment of chronic hepatitis B in the past decade. Approved treatments for chronic hepatitis B include 2 formulations of interferon and 4 nucleos(t)ide analogues (NAs). Sustained viral suppression is rarely achieved after withdrawal of a 48-week course of NA therapy, necessitating long, and in many cases, indefinite treatment with increasing risk of development of drug resistance. Antiviral resistance and poor adherence are the most important factors in treatment failure of hepatitis B. Thus, there is a need to standardize nomenclature relating to hepatitis B antiviral resistance, and to define genotypic, phenotypic, and clinical resistance to NA therapy.

Liaw YF. · Liver Research Unit, Chang Gung University, Taipei, Taiwan. · Antivir Ther. · Pubmed #17310811 No free full text.

Abstract: Chronic hepatitis B virus (HBV) infection is a serious health issue worldwide. The presence of HBV replication markers--hepatitis B e antigen (HBeAg) or HBV DNA--is associated with continuing hepatitis activity or intermittent hepatitis flares and subsequent disease progression, including hepatic decompensation and development of liver cirrhosis or hepatocellular carcinoma (HCC). Long-term (>10 years) prospective studies in patients >30 years of age have shown that HBeAg seropositivity is associated with increased risk of disease progression, and the risk of cirrhosis and HCC begins to increase at an HBV DNA level of 10(4) copies/ml. Therefore, elimination of HBV, or at least sustained or maintained suppression of HBV, is the key to reducing hepatitis and thereby halting or preventing disease progression. Therapy with interferon-alpha or a direct antiviral agent has been shown to reduce the risk of cirrhosis and prevent further disease worsening. In both the woodchuck hepatitis model and in HBV patients, maintained suppression of HBV replication by a direct antiviral agent may reduce the progression to HCC. However, the efficacy of current antiviral therapy is still far from satisfactory. The ability to achieve a high rate of sustained or maintained HBV suppression with a low risk of drug resistance would be the ultimate goal in the treatment of chronic HBV infection.

Chu CM, Liaw YF. · Liver Research Unit, Chang Gung Memorial Hospital and University, Taipei, Taiwan. · J Viral Hepat. · Pubmed #17305879 No free full text.

Abstract: In high endemic areas of hepatitis B virus (HBV) infection, the vast majority of infection is acquired perinatally or during early childhood. The age of the patient is, therefore, almost equivalent to the duration of HBV infection. The natural history of chronic HBV infection consists of three chronological phases: immune tolerance, immune clearance and low replicative phases. The prevalence of hepatitis B e antigen (HBeAg) in asymptomatic HBV carriers is around 90% before 15 years of age, and decreases remarkably to less than 10% after 40 years of age. The immune clearance phase is characterized by a series of hepatitis flares and remissions. These will be followed eventually by HBeAg seroconversion, which is usually accompanied by remission of liver disease and confers favourable outcome. However, patients with persistent HBeAg seropositivity over 40 years of age are associated with a significantly higher risk for progression to cirrhosis than those with HBeAg seroconversion before 40 years of age, and thus should be considered as patients with 'delayed' HBeAg seroconversion. Antiviral or immunomodulatory therapy should be considered seriously for these patients.

Chu CM, Liaw YF. · Liver Research Unit, Chang Gung Memorial Hospital and Chang Gung University, Taipei, Taiwan. · Semin Liver Dis. · Pubmed #16673292 No free full text.

Abstract: In patients with compensated hepatitis B virus (HBV) cirrhosis, active viral replication correlates significantly with the risk of hepatic flare, decompensation, and the development of hepatocellular carcinoma (HCC). The 5-year survival of patients with compensated cirrhosis was reported to be 80 to 85%, and is significantly lower in patients with replicative HBV. Both interferon and maintenance lamivudine therapy have been shown to reduce the risk of decompensation or HCC and prolong survival in responders. A finite course of interferon is recommended as the first-line agent. For patients who had a contraindication for or who have failed interferon therapy, direct antiviral(s) can be considered for long-term treatment. Once decompensation occurs, mortality increases remarkably. Early treatment with nucleoside analogues should be instituted. Lamivudine therapy is associated with rapid viral suppression, improvement in Child-Pugh scores, and improved survival, but drug resistance is a major problem and is associated directly with a poor clinical outcome. Adefovir or entecavir is preferred in patients with decompensated cirrhosis who require long duration of treatment, due to the lower rate of development of resistance.

Liaw YF. · Liner Research Unit, Chang Gung Memorial Hospital and University, Taipei, Taiwan. · J Clin Virol. · Pubmed #16461216 No free full text.

Abstract: Lamivudine and adefovir have potent inhibitory effects on hepatitis B virus (HBV) replication. Although short-term therapy is feasible in a selected subgroup of patients, prolonged therapy is required for sustained suppression in the majority of patients. However, HBV species with mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV RNA-dependent DNA polymerase (rtM204 I/V) conferring resistance to lamivudine may emerge after 9-10 months therapy. The incidence increases with duration of therapy up to 70% after 5 years lamivudine therapy. Serum alanine aminotransferase (ALT) elevation and HBV DNA rebound ( I log) occur in >90% of the patients with rtM204 I/V during continued lamivudine therapy. Marked flare of serum ALT may occur, sometimes severe, and may be complicated with decompensation or even fatality. The initial clinical and histologic improvement may also reverse after emergence of rtM204 IN Studies do suggest that stopping seems better than continuing lamivudine therapy. Limited data show that interferon therapy seems ineffective. Add-on adefovir therapy is effective in suppressing rtM204 I/V in both compensated and decompensated patients. Switching to adefovir monotherapy is effective and safe even in cirrhotic patients with decompensation. The overall incidence of adefovirresistant rtN236T and A181V is low, being 0 after one year and 5.9% after 3 years' therapy. The impact of adefovir resistance is less clear but is responsive to lamivudine therapy. In conclusion, monitoring of viral breakthrough to start effective intervention is mandatory during direct antiviral therapy.

Liaw YF. · Liver Research Unit, Chang Gung Memorial Hospital and Chang Gung University, Taipei, Taiwan. · Semin Liver Dis. · Pubmed #16103980 No free full text.

Abstract: Hepatocellular carcinoma (HCC) is associated with hepatitis B virus (HBV) infection in approximately 50% of cases, although the oncogenic mechanisms of HBV are not well understood. Vaccination for HBV has successfully lowered the rates of both HBV infection and HCC. Once chronic HBV infection is established, the objective of antiviral treatment is to prevent disease progression to liver cirrhosis or HCC, or both. Studies have found HBV DNA level to be a strong predictor for the development of cirrhosis and HCC, irrespective of the status of viral and biochemical factors. This article reviews recent clinical trials evaluating sustained viral suppression with interferon alfa and lamivudine. The results support the need to reduce viral load as an important therapeutic goal. For HCC not prevented by these measures, surveillance using ultrasonography and serum alpha-fetoprotein assay every 3 to 6 months is able to detect HCC at an earlier stage and allows curative therapy with survival benefit.

Liaw YF, Leung N, Guan R, Lau GK, Merican I, McCaughan G, Gane E, Kao JH, Omata M, Anonymous00046. · Liver Research Unit, Chang Gung Memorial Hospital, Taipei, Taiwan. · Liver Int. · Pubmed #15910483 No free full text.

Abstract: BACKGROUND/AIMS: A large amount of new data on the treatment of chronic hepatitis B has become available such that the 2003 consensus statement requires revision and update. METHODS: New data were presented, discussed and debated in an expert pre-meeting to draft a revision. The revised contents were finalized after discussion in a general meeting of APASL. RESULTS: Conceptual background, including the efficacy and safety profile of currently available and emerging drugs, was reviewed. Nineteen recommendations were formed and unresolved issues and areas for further study were suggested. CONCLUSION: The current therapy of chronic hepatitis B is modestly effective but not satisfactory. The development of new drugs and new strategies is required to further improve the outcomes of treatment.

Liaw YF. · Liver Research Unit, Chang Gung University and Memorial Hospital, Taipei, Taiwan. · J Gastroenterol Hepatol. · Pubmed #15641208 No free full text.

Abstract: Chronic hepatitis B virus (HBV) infection is a serious clinical problem because of its world-wide distribution and potential adverse sequelae. Globally, there are approximately 350 million people infected with chronic HBV, 75% of whom live in the Asia-Pacific region. Interferon-alfa and direct anti-viral agents such as lamivudine and adefovir are effective in the therapy of chronic HBV infection but the efficacy is far from satisfactory, particularly in perinatally infected patients, patients with lower ALT levels and those with HBeAg-negative chronic hepatitis B. Thymalfasin (thymosin-alphal) is an immunoregulatory agent able to enhance Thl response. It has been shown to trigger maturational events in lymphocytes, to augment T-cell function, and to promote reconstitution of immune defects. Studies are underway in both monotherapy and combination therapy with thymalfasin and interferon and results are promising.

Liaw YF. · Liver Research Unit, Chang Gung University and Memorial Hospital, 199, Tung Hwa North Road, Taipei, Taiwan. · J Gastroenterol Hepatol. · Pubmed #15546254 No free full text.

Abstract: Chronic hepatitis B virus (HBV) infection is a serious clinical problem because of its worldwide distribution and potential adverse sequelae. Globally, there are approximately 350 million people infected with chronic HBV, 75% of whom live in the Asia-Pacific region. Interferon-alfa and direct antiviral agents such as lamivudine and adefovir are effective in the therapy of chronic HBV infection but the efficacy is far from satisfactory, particularly in perinatally infected patients, patients with lower ALT levels and those with HBeAg-negative chronic hepatitis B. Thymalfasin (thymosin-alpha1) is an immunoregulatory agent able to enhance Th1 response. It has been shown to trigger maturational events in lymphocytes, to augment T-cell function, and to promote reconstitution of immune defects. Studies are underway in both monotherapy and combination therapy with thymalfasin and interferon and results are promising.

Liaw YF. · Liver Research Unit, Chang Gung Memorial Hospital and Chiang Gung University, 199 Tung Hwa North Road, Taipei, Taiwan. · J Hepatol. · Pubmed #14708688 No free full text.

Abstract: In summary, 100 mg daily lamivudine therapy is safe and effective in Asian patients in terms of HBV suppression, ALT normalization and improvement in histology. The complete response rate after 1 year of lamivudine therapy is only around 15% but increases with increasing duration of treatment and increasing pretherapy ALT levels. Similar results were observed in patients with HBeAg-negative chronic hepatitis but published data are limited. YMDD mutations may emerge after 6-9 months of lamivudine therapy and its incidence also increases with increasing duration of therapy. The emergence of YMDD mutations is associated with viral and biochemical breakthrough. Hepatitis flares, sometimes associated with hepatic decompensation, may develop after stopping lamivudine therapy and in patients with YMDD mutations during continuing lamivudine therapy. The benefit of long-term lamivudine therapy therefore must be weighed carefully against the concern about YMDD mutations and the durability of therapeutic response. The development of new strategies, including selection of patient and timing of therapy, and new drugs are needed to further improve the therapeutic efficacy.

Liaw YF. · Liver Research Unit, Medical College, Chang Gung University, Taipei, Taiwan. · J Gastroenterol Hepatol. · Pubmed #12603523 No free full text.

Abstract: Hepatitis flares or acute exacerbations, defined as an abrupt elevation of serum alanine aminotransferase (ALT) over fivefold the upper limit of normal (ULN), of chronic hepatitis B virus (HBV) infection are the results of HLA-I restricted, cytotoxic T lymphocyte (CTL)-mediated immune response against HBV and its downstream mechanisms. Higher ALT levels reflect a more vigorous immune response and a more extensive hepatolysis that, in the extreme situation, may lead to decompensation and failure. In contrast, higher ALT also reflects a more robust immune clearance of HBV and, therefore, a higher chance of HBV-DNA loss and hepatitis B e antigen (HBeAg) seroconversion, both in the setting of natural course and drug therapy. Alanine aminotransferase of fivefold the ULN appears to be a significant cut-off level to categorize the patients in terms of endogenous immune response against HBV. Patients with ALT levels less than fivefold the ULN or those with a less vigorous immune response require immunomodulation to induce robust immune response to enhance HBV clearance. In contrast, those with a more vigorous immune response or those with ALT flare over fivefold the ULN should be monitored closely for spontaneous HBV clearance/HBeAg seroconversion or to start direct antiviral therapy in time to prevent the occurrence or deterioration of hepatic decompensation. In conclusion, a better understanding of the pathogenetic mechanisms and natural course of hepatitis flares, wiser selection of patients and the timing of drug therapy are crucial to achieve better treatment results.

Liaw YF. · Liver Research Unit, Chang Gung Memorial Hospital and University, Taipei, Taiwan. · J Gastroenterol Hepatol. · Pubmed #12472959 No free full text.

Abstract: Lamivudine is a nuleoside analog with potent inhibitory effects on hepatitis B virus (HBV) replication. Prolonged therapy is required for sustained suppression. However, HBV species with mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV-RNA-dependent DNA polymerase confering resistance to lamivudine may emerge after 6-9 months therapy with an incidence of 38% and 67% after 2 and 4 years of lamivudine therapy, respectively. During continued lamivudine therapy, patients with YMDD mutant HBV usually show serum alanine aminotransferase (ALT) and HBV-DNA elevations at lower median levels than their baseline. Marked flare of serum ALT or acute exacerbation may occurred as the results of cytotoxic T lymphocyte mediated immune response directed against YMDD mutant. Although viral clearance with or without emergence of distinct lamivudine resistant mutants may occur after such exacerbations, 20% of the exacerbations are complicated with decompensation or even fatality. The exacerbations appear to be more severe than those occur during the natural course of wild type HBV chronic infection. The current practice of continuing lamivudine therapy, therefore, requires careful evaluation. Alternatives include interferon therapy but this seems ineffective. Adefovir dipivoxil and entecavir may effectively suppress the YMDD mutant but these treatments have not yet been available for use. Recent studies have shown no benefit to continuing lamivudine therapy in patients with YMDD mutantions. Before a rescue drug becomes available, the most cost-effective strategy is to select patients with stronger endogenous anti-HBV immunity to increase efficacy and to shorten the duration of lamivudine therapy to avoid the emergence of YMDD mutations.

Liaw YF. · Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan. · J Viral Hepat. · Pubmed #12431200 No free full text.

Abstract: Better understanding of hepatitis B virus (HBV) replication, natural history and the immunopathogenesis of chronic hepatitis B, together with the introduction of effective agents with different mechanisms of action are the basis for better therapeutic strategies against chronic hepatitis B. Among currently available drugs, interferon-alpha and thymosin-alpha1 have only modest efficacy (approximately 40% vs 9-20% in controls). In the past decade, lamivudine has dominated in the treatment of chronic HBV infection because it is easy to use, safe, and is effective in terms of hepatitis B e antigen and/or HBV-DNA loss, ALT normalization, and improvement in histology. The response rate increases with increasing pretherapy alanine aminotransferase (ALT) levels, suggesting that patients with stronger endogenous immune response against HBV have a better response to direct antiviral agents. Lamivudine is also beneficial in decompensated cirrhotics with HBV replication. Hepatitic flares may occur after stopping lamivudine therapy in nonresponders and also in responders. Therefore, prolonged therapy is usually required. However, tyrosine-methionine-aspartate-aspartate (YMDD) mutations conferring resistance to lamivudine start to emerge after 6-9 months of therapy, and hepatitis flare, even decompensation, may develop after viral breakthrough. Thus the benefits of long-term lamivudine therapy must be balanced against the concern about YMDD mutations and the durability of treatment response. Adefovir dipivoxil, entecavir, emtricitabine, clevudine and other nucleoside/ nucleotide analogues have shown encouraging results and some agents appear effective in patients with YMDD mutants. Further development of new drugs and new strategies may help to improve treatment in the new century.

Liaw YF. · Liver Research Unit, Chang Gung Memorial Hospital, Taipei, Taiwan. · J Gastroenterol. · Pubmed #12109669 No free full text.

Abstract: Because hepatitis B virus (HBV) and hepatitis C virus (HCV) have the same transmission routes, dual infection may occur and even persist in the same patient. The reported series on seroprevalence of HCV indicate that HCV is found in more than 10% of HBV-infected patients worldwide. HCV superinfection in patients with chronic HBV infection tends to cause severe and progressive liver disease that is resistant to interferon therapy. Paradoxically, HCV exerts a suppressive effect on HBV and may enhance seroclearance of HBV antigens, or even usurp the role of HBV as the agent for continuing hepatitis. In view of the complex dynamism of viral interaction, the importance of HCV assay and the necessity of monitoring patients with chronic HBV infection in clinical studies cannot be overemphasized. The basic mechanisms that regulate the viral interactions largely remain to be investigated.

Liaw YF. · Liver Research Unit, Chang Gung University Memorial Hospital, 199 Tung Hwa North Road, Taipei, Taiwan. · J Gastroenterol Hepatol. · Pubmed #11982720 No free full text.

Abstract: Better understanding of hepatitis B virus (HBV) replication and the natural history and immunopathogenesis of chronic hepatitis B, together with the introduction of effective agents with different mechanisms of action, is the basis for better therapeutic strategies against chronic hepatitis B. Substantial experience has now been accumulated in the use of some of these drugs, and an Asia-Pacific Consensus has been reached on indications for their use. The goals of therapy and aspects of general management will be reviewed here. Among currently available drugs, alpha-interferon therapy gives a response rate (hepatitis B e antigen (HBeAg) seroconversion) of 30-40% compared with 10-20% in matched controls, but patients with lower alanine aminotransferase (ALT), higher HBV-DNA, and immunosuppressed patients have a poorer response, and alpha-interferon can be dangerous in cirrhosis. Meta-analysis of four controlled trials also suggests that thymosin-alpha1 is effective, but more studies are needed. Lamivudine has been most extensively studied. It is effective in terms of HBV-DNA loss, ALT normalization, HBeAg seroconversion, and improvement in histology, as well as being well tolerated. After 1 year of treatment, HBeAg seroconversion rate increased with higher pretherapy ALT levels, suggesting that patients with stronger endogenous antiviral defenses to kill hepatocytes harboring covalently closed circular DNA have a better response to direct antiviral effects. Lamivudine is also beneficial in HBeAg negative chronic hepatitis B, and patients with decompensated cirrhosis and HBV replication. However, genotypic-resistant tyrosine-methionine-aspartate-aspartate (YMDD) mutations start to emerge after 9-10 months of lamivudine therapy, and their incidence increases more quickly than the HBeAg seroconversion rate durating prolonged therapy. Thus the benefits of long-term lamivudine must be balanced against concern about YMDD mutations, and the durability of treatment response. There are encouraging preliminary results for adefovir dipivoxil, entecavir, emtricitabine, clevudine and other nucleoside/nucleotide analogs in the early stages of appraisal; entecavir and adefovir dipivoxil appear effective in patients with YMDD mutants. Further development of new drugs and new strategies, such as combination or sequential therapy, may help to better achieve the goals of treatment for chronic hepatitis B in the new century.