Historical epidemiology of hepatitis C virus in select countries-volume 4.

Due to the introduction of newer, more efficacious treatment options, there is a pressing need for policy makers and public health officials to develop or adapt national hepatitis C virus (HCV) control strategies to the changing epidemiological landscape. To do so, detailed, country-specific data are needed to characterize the burden of chronic HCV infection. In this study of 17 countries, a literature review of published and unpublished data on HCV prevalence, viraemia, genotype, age and gender distribution, liver transplants and diagnosis and treatment rates was conducted, and inputs were validated by expert consensus in each country. Viraemic prevalence in this study ranged from 0.2% in Hong Kong to 2.4% in Taiwan, while the largest viraemic populations were in Nigeria (2 597 000 cases) and Taiwan (569 000 cases). Diagnosis, treatment and liver transplant rates varied widely across the countries included in this analysis, as did the availability of reliable data. Addressing data gaps will be critical for the development of future strategies to manage and minimize the disease burden of hepatitis C.

Strategies to manage hepatitis C virus infection disease burden-Volume 4.

The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 17 countries in Africa, Asia, Europe, Latin America and the Middle East, and interventions for achieving the Global Health Sector Strategy on viral hepatitis targets-"WHO Targets" (65% reduction in HCV-related deaths, 90% reduction in new infections and 90% of infections diagnosed by 2030) were considered. Scaling up treatment and diagnosis rates over time would be required to achieve these targets in all but one country, even with the introduction of high SVR therapies. The scenarios developed to achieve the WHO Targets in all countries studied assumed the implementation of national policies to prevent new infections and to diagnose current infections through screening.

The present and future disease burden of hepatitis C virus infections with today's treatment paradigm: Volume 4.

Factors influencing the morbidity and mortality associated with viremic hepatitis C virus (HCV) infection change over time and place, making it difficult to compare reported estimates. Models were developed for 17 countries (Bahrain, Bulgaria, Cameroon, Colombia, Croatia, Dominican Republic, Ethiopia, Ghana, Hong Kong, Jordan, Kazakhstan, Malaysia, Morocco, Nigeria, Qatar and Taiwan) to quantify and characterize the viremic population as well as forecast the changes in the infected population and the corresponding disease burden from 2015 to 2030. Model inputs were agreed upon through expert consensus, and a standardized methodology was followed to allow for comparison across countries. The viremic prevalence is expected to remain constant or decline in all but four countries (Ethiopia, Ghana, Jordan and Oman); however, HCV-related morbidity and mortality will increase in all countries except Qatar and Taiwan. In Qatar, the high-treatment rate will contribute to a reduction in total cases and HCV-related morbidity by 2030. In the remaining countries, however, the current treatment paradigm will be insufficient to achieve large reductions in HCV-related morbidity and mortality.

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

BACKGROUND: Both spontaneous and nucleos(t)ide analogue (Nuc)-treated hepatitis B surface antigen (HBsAg) seroclearance are associated with excellent clinical outcomes. AIM: To conduct a case-control study to explore whether there is difference of clinical outcomes between these two groups. METHODS: A total of 312 chronic hepatitis B patients with spontaneous HBsAg seroclearance and 110 patients with Nuc-treated HBsAg seroclearance were recruited retrospectively. Propensity score (PS) matching method produced 98 patients in each group for comparison. The development of hepatocellular carcinoma (HCC), hepatic complications and cumulative incidence of antibody to HBsAg (anti-HBs) was compared. RESULTS: During a mean follow-up period of 107 months after HBsAg seroclearance, five patients developed HCC after a mean period of 75.3 months (four and one patients with spontaneous and Nuc-treated HBsAg seroclearance, respectively) in overall population. One died of pneumonia with sepsis and one experienced variceal bleeding in Nuc-treated patients but none in spontaneous group. The incidence of anti-HBs seroconversion was comparable between spontaneous and Nuc-treated HBsAg seroclearance (69.6% vs. 66.4%, respectively, P = 0.617). There were no significant differences in HCC development (2% vs. 1.1%), overall mortality (0% vs. 1%), variceal bleeding (0% vs. 4.2%) and 6-year cumulative incidence of anti-HBs seroconversion (62.3% vs. 61.5%) among PS-matched patients with spontaneous and Nuc-treated HBsAg seroclearance. CONCLUSIONS: The clinical outcomes between patients with spontaneous and Nuc-treated HBsAg seroclearance are comparable. HCC can develop at a low rate during long-term follow-up and periodic surveillance after HBsAg seroclearance is still mandatory.

Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.

Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts' personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.

Clinical outcomes after interruption of entecavir therapy in HBeAg-negative chronic hepatitis B patients with compensated cirrhosis.

BACKGROUND: Long-term nucleos(t)ide analogues therapy may reduce hepatocellular carcinoma (HCC) in chronic hepatitis B patients with advanced fibrosis or cirrhosis. AIM: To investigate in a retrospective-prospective study whether this beneficial effect would be reduced in cirrhotic patients who discontinued a successful course of entecavir (ETV) therapy. METHODS: The study included 586 hepatitis B e antigen (HBeAg)-negative patients with compensated cirrhosis, mean age of 53.8 ± 10 years and 81% males, treated with ETV for at least 12 months. After ETV therapy for 46.5 ± 22.9 months, 205 patients who achieved hepatitis B virus (HBV) DNA suppression discontinued therapy. The clinical outcomes were assessed and HCC incidence was compared between propensity score (PS)-matched patients who continued and patients who discontinued ETV therapy by Asian Pacific Association for the Study of Liver stopping rule. RESULTS: During a mean duration of 59.3 ± 19 months after start of ETV therapy, nine and six HCC developed in an estimated annual incidence of 2.3% and 1.6% in 154 PS-matched patients who continued and who discontinued ETV therapy, respectively (P = 0.587). Multivariate Cox proportional hazards regression analyses showed that age (HR 1.065, P < 0.001) and HBV DNA (HR 1.216, P = 0.048) were the significant factors for HCC development. The rates of adverse clinical outcomes were comparable. CONCLUSIONS: The clinical outcomes, including HCC, after cessation of a successful course of entecavir therapy in patients with compensated cirrhosis were comparable to those who continued therapy. The results suggest that this strategy of finite therapy is safe and a feasible alternative to indefinite therapy, especially in a low resources setting.

Efficacy and safety of ribavirin plus pegylated interferon alfa in geriatric patients with chronic hepatitis C.

BACKGROUND: Limited data are available on the efficacy and safety of antiviral therapy in geriatric patients with chronic hepatitis C virus (HCV) infection. AIM: To evaluate the efficacy and safety of pegylated interferon (pegIFN) plus ribavirin (RBV) therapy in geriatric HCV-infected patients. METHODS: Ninety-one geriatric patients (age ≥65 years; the elderly group) with HCV infection and 91 gender- and HCV genotype-matched middle-aged patients (age 50-64 years; the younger group) were assigned to receive weekly pegIFN injection plus weight-based oral RBV for 24 weeks. The on- and off-treatment virological responses were evaluated for treatment efficacy. RESULTS: In intention-to-treat analysis, the sustained virological response (SVR) rate was substantially decreased in the elderly patients (elderly group vs. younger group, 40.7% vs. 61.5%, respectively; P = 0.005). The SVR rate was significantly lower in geriatric patients than in middle-aged patients with HCV genotype non-1 (54.3% vs. 82.9%; P = 0.01), but the difference was not significant with HCV genotype 1 (32.1% vs. 48.2%; P = 0.083). Furthermore, the older patients infected with HCV genotype non-1 who achieved a rapid virological response had a similar SVR rate to that of the younger patients. The withdrawal rate was 13.2% in the elderly group and 7.7% in the younger group. CONCLUSIONS: Compared with middle-aged patients, the therapeutic efficacy of pegylated interferon plus ribavirin therapy is lower in hepatitis C virus-infected geriatric patients with an acceptable withdrawal rate. Considering prolonged lifespan in geriatric patients, we recommend treating geriatric hepatitis C virus-infected patients who have significant hepatic fibrosis and no other health problems.

Comparison of the once-daily levofloxacin-containing triple therapy with the twice-daily standard triple therapy for first-line Helicobacter pylori eradication: a prospective randomised study.

BACKGROUND/AIMS: Simple compound of Helicobacter pylori eradication therapy may improve drug compliance of patients. The aims of this study were to compare the efficacy and tolerability of a simple combination containing levofloxacin 7-day once-daily with standard twice-daily triple therapy. PATIENTS AND METHODS: This was a prospective, randomised, open-label trial. A total of 189 consecutive patients diagnosed with peptic ulcer and H. pylori infection were enrolled. Patients were randomly divided into two groups: LEC group--levofloxacin 500 mg, esomeprazole 40 mg and clarithromycin 500 mg once daily for 7 days; AEC group--amoxicillin 1 g, esomeprazole 40 mg and clarithromycin 500 mg twice daily for 7 days. RESULTS: There were 90 patients in the LEC group and 99 patients in the AEC group. By intention-to-treat and per-protocol analysis, the H. pylori eradication rate was 78.9% [71/90; 95% confidence interval (CI), 70.3-87.5%] and 83.5% (71/85; 95% CI, 75.5-91.6%) respectively, in the LEC group; and 74.8% (74/99; 95% CI, 66.0-83.5%) and 86.0% (74/86; 95% CI, 78.6-93.5%) respectively, in the AEC group. The incidence and tolerability of side effects were similar between these two groups. CONCLUSION: The efficacy and tolerability of once-daily levofloxacin-containing triple therapy are equal to those of the standard twice-daily triple therapy in this study. However, none of the treatment regimens evaluated achieved enough eradication efficacies to be considered as a recommendable first-line treatment.

Elucidating therapeutic effects on patients with hepatocellular carcinoma and main portal vein thrombosis.

BACKGROUND/AIMS: The survival duration for patients diagnosed with hepatocellular carcinoma (HCC) with main portal vein thrombosis (MPVT) was usually less than 3 months. The aim of this study is to elucidate whether treatment can prolong the survival for such patients. METHODOLOGY: Retrospectively we analyzed the clinical features and outcomes of 63 patients with HCC and MPVT over a 7-year period. Three therapeutic modalities--transcatheter arterial chemotherapy (TAC) with or without radiotherapy (RT), and systemic chemotherapy--were applied. RESULTS: The patients were divided into two groups: 34 (54%) patients were treated, while the remaining 29 (46%) were not. Multivariate analysis revealed that Child-Pugh class, Okuda stage for HCC and the presence of treatment were the principal factors to predict survival. The survival was significantly longer in treated patients than those untreated both in the Child-Pugh class A or B patients. Significantly longer survival is evident in patients treated by TAC combing RT compared to those underwent TAC alone, systemic chemotherapy or no treatment. CONCLUSIONS: The survival of Child-Pugh class A or B patients can be extended by the use of an appropriate therapeutic modality. TAC combined with RT did the best benefit to prolong survival in such patients.

Liver injury is associated with enhanced regulatory T-cell activity in patients with chronic hepatitis B.

Chronic hepatitis B virus (HBV) infection is associated with impairment of HBV-specific immune responses. Recently, it has been shown that regulatory T (Treg) cells downregulate HBV-specific immune responses but their role in chronic hepatitis B is still controversial. We hypothesized that liver injury enhances the influence of Treg cells on HBV-specific immune responses. The frequency of Treg cell and the in vitro expansion of HBV-specific CD8+ T cell detected by the tetramer method were investigated in 79 patients with chronic hepatitis B. Thirty-three healthy volunteers were enrolled to measure the frequency of Treg cell as controls. The results showed that in chronic hepatitis B cases, the frequency of Treg cells in peripheral blood was significantly higher than that in normal volunteers. The higher level of serum transaminase was associated with higher frequency of Treg cells, which both had a linear correlation relationship. HBV-DNA level, HBe status, age and sex had no statistical association with Treg cell frequency. Furthermore, in patients with higher serum transaminase levels, the expansion of HBV-specific CD8+ T cells was higher after removal of Treg cells when compared with patients with lower serum transaminase levels. In conclusion, our data indicate a significant association between serum transaminase level and frequency/activity of Treg cells. Based on this observation, we propose that liver-injury enhances Treg cell frequency/activity in chronic hepatitis B patients.

Hepatitis B virus genotype B is associated with better response to thymosin alpha1 therapy than genotype C.

Hepatitis B virus (HBV) genotype has been reported to correlate with response to interferon treatment in several studies. The relationship between HBV genotype and thymosin alpha1 (T-alpha1) treatment is unknown. We retrospectively examine HBV genotypes, precore and core promoter mutations in patients treated with Talpha1 and analyse the correlation between complete response [alanine aminotransferase (ALT) normalization plus seroclearance of HBeAg and HBV-DNA] and HBV genotype. It consisted 98 patients with chronic hepatitis B randomly allocating to three groups: (i) T6 group (n = 32) received a 26-week course of Talpha1 1.6 mg two times a week; (ii) T12 group (n = 34) received the same regimen as T6 group, but Talpha1 therapy extended for 52 weeks; (iii) T0 group (n = 32) served as a control and was followed up for 18 months without specific treatment. Stepwise logistic regression analysis showed that genotype (OR, 3.747; 95% CI, 1.066-13.170; P = 0.039), precore mutation (OR, 6.285; 95% CI, 1.874-21.086; P = 0.003) and Talpha-1 treatment (OR, 12.045; 95% CI, 2.220-65.354; P = 0.004) as independent factors associated with complete response. The complete response of Talpha-1 therapy was higher in patients with genotype B compared to patients with genotype C (52%vs 24%; P = 0.036) and in patients with precore mutation (64%vs 19%; P = 0.002). In conclusion, genotype, presence of precore mutation and Talpha-1 therapy were independent predictors to complete response. Genotype B, compared to genotype C, is associated with a higher response rate to T-alpha1 therapy.

Switching to adefovir monotherapy after emergence of lamivudine-resistant mutations in patients with liver cirrhosis.

Switching to adefovir (ADV) monotherapy is effective in patients with lamivudine (LAM)-resistant hepatitis B virus (HBV) mutations (rtM204 I/V). However, it was recommended to continue LAM therapy for months after starting ADV therapy for safety concern. The safety and efficacy of switching to ADV monotherapy was examined in compensated and decompensated patients with liver cirrhosis. The clinical, biochemical and virological responses were compared between ADV monotherapy in 18 cirrhotic patients and ADV add-on LAM therapy in 10 comparable cirrhotic patients with LAM-resistant rtM204 I/V. After switching to ADV monotherapy, Child-Pugh's score, serum alanine aminotransferase (ALT), bilirubin, albumin and HBV DNA levels improved significantly (P < 0.01). Serum HBV DNA response, defined as HBV DNA decreased to below 10(5) copies/mL or > or =2 log(10) reduction form baseline, was achieved in all patients. A transient ALT flare without concurrent changes in serum bilirubin or prothrombin time was observed in only two patients (11%). The efficacy and safety profile was similar to those with ADV add-on LAM therapy. In conclusion, switching to ADV monotherapy after emergence of LAM-resistant rtM204 I/V is effective and safe in cirrhotic patients, even in those with hepatic decompensation. To stop LAM and switch to ADV in patients with breakthrough is a reasonably safe and cost-effective approach.

Solitary actinomycotic abscesses of liver: report of two cases.

Hepatic actinomycotic abscesses are rare and secondary to other intra-abdominal infections. History of intra-abdominal surgery is a principal contributing factor for the abscess formation. Patients with hepatic actinomycotic abscess may suffer from fever, malaise, abdominal pain and bodyweight loss. The clinical progress of actinomycotic abscess is more indolent than the usual course of other pyogenic abscess. It is sometimes diagnosed as malignancy. This report consists of two cases of hepatic actinomycotic abscess mimicking tumours. Laboratory data revealed elevated alkaline phosphatase and leucocytosis. The abdominal computed tomography scan showed multiloculated lesions with peripheral contrast enhancement appearance. Diagnosis confirmation was based on the typical histologic feature of sulfur granules with inflammatory process by echo-guided fine needle biopsy or surgical specimen. These two cases were resolved with extended courses of intravenous and oral penicillin treatment.

High frequency of functional anti-YMDD and -mutant cytotoxic T lymphocytes after in vitro expansion correlates with successful response to lamivudine therapy for chronic hepatitis B.

BACKGROUND: Many determinants for a sustained response to lamivudine therapy have been reported but the role of T cell responsiveness remains unclear. The finding that tyrosine-methionine-aspartate-aspartate (YMDD) motif of the reverse transcriptase domain of hepatitis B virus (HBV) DNA polymerase carries a HLA-A2 restricted cytotoxic T lymphocyte (CTL) epitope makes quantitative measurement of the numbers of peptide specific CTLs feasible using MHC tetramer-peptide complex staining. AIM: To investigate the correlation between anti-YMDD motif CTL activity and the efficacy of lamivudine therapy in HLA-A2 positive patients with chronic hepatitis B (CH-B). METHODS: The function and phenotype of peptide and interleukin 2 expanded peripheral blood mononuclear cells were quantified by cell lytic assay and immunocytochemical analysis by staining with HLA-A2-peptide tetramer complexes. RESULTS: After in vitro expansion, sustained responders had more potent CTL responses against YMDD, YVDD, and YIDD, as well as other epitopes on HBV antigens than non-responders. The frequency of YMDD/YVDD/YIDD motif specific CTLs increased significantly with an effective cell lytic function during and after therapy in sustained responders but not in non-responders. YMDD specific CTLs cross reacted with YIDD and YVDD mutant epitopes, and shared T cell receptor gene usages with YIDD and YVDD specific CTLs. CONCLUSIONS: Sustained responders, at least HLA-A2 patients, elicited a more potent CTL immunity against YMDD and its mutants. YMDD specific CTLs are cross reactive with YVDD and YIDD mutant epitopes, which may further contribute to immune clearance of the mutant viruses and a successful response to lamivudine therapy in CH-B patients.

Splenic tumour: a clinicopathological study.

Splenic tumours are occasionally found during routine physical check-ups or elective abdominal image studies. Histologically, most splenic tumours are of benign vascular origin. To avoid unnecessary surgery for asymptomatic patients with benign splenic tumours and clarify the clinicopathological features of spleen tumours, this study gathered 44 cases of primary or isolated metastatic spleen tumours confirmed by pathology from surgery specimens or biopsies. The differences in clinicopathological features and image presentations between benign and malignant spleen tumour were investigated. Thirty-two cases involved benign tumours while 12 cases were malignant. Among the benign tumours, vascular originating tumours were most common (with 14 cases of cavernous haemangiomas, 13 cases of lymphangioma, three cases of lymphangiohaemangioma and one case of Littoral cell angioma). Notably, one, case of inflammatory pseudotumour because of Schistosoma parasite infection was also noted. Among the malignant tumours, there were four cases of angiosarcomas with vascular endothelium origins, as well as lymphomas and six metastatic tumours. Image studies were non-specific. Image study alone is an inadequate basis for making differential diagnoses between benign and malignant tumours. Instead, pathological studies are required for a final diagnosis. Using previous studies and this investigation, fine needle aspiration biopsy of spleen tumours with the help of ultrasonic or computed tomography appears a safe and effective method for obtaining biopsy specimens. Splenectomy is recommended only for patients with malignancies or complications such as intractable abdominal pain, coagulopathy or tumour rupture with an unstable haemodynamic state.

Acute leukaemia in chronic hepatitis B patients with lamivudine therapy.

Extensive clinical data have shown that lamivudine is an effective and safe drug for patients with chronic hepatitis B virus infection. No significant serious side effect has been reported. Four hundred and forty-eight patients with chronic hepatitis B, treated with lamivudine for more than 6 months, were closely monitored. Two patients developed acute myeloid leukaemia during or after lamivudine therapy. The first case developed acute myeloid leukaemia, 1 year after stopping lamivudine therapy, when A529T mutant HBV-DNA was still detectable. The second case achieved complete virological response but suffered from acute myeloid leukaemia during the ninth month of lamivudine treatment. D553N mutant hepatitis B virus was detected in granulocytes of her peripheral blood. Based on our lamivudine therapy data, the calculated incidence of acute myeloid leukaemia in patients during or after lamivudine therapy was higher in males and females than that of the general population. Whether lamivudine-selected viral mutations have enhanced activity/production of transcriptional transactivator and thereby increased the chance of leukaemic transformation of haematopoietic progenitor cells deserves further investigation.

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

To compare the long-term effect of natural lymphoblastoid interferon-alpha (IFN-alpha nl) and recombinant IFN-alpha 2a 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-alpha nl (36 after prednisolone priming) and 109 treated with IFN-alpha 2a (56 after prednisolone priming). The cumulative sustained response was higher in patients who had been treated with IFN-alpha nl after prednisolone priming than was exhibited using IFN-alpha nl alone, IFN-alpha 2a alone or the placebo (P < 0.05), or IFN-alpha 2a following prednisolone priming (P = 0.052) at the end of 11 years. Hepatocellular carcinoma (HCC) was detected in 1.5% of the IFN-alpha nl group, 3.7% of the IFN-alpha 2a group and 14.7% of the control group (control vs IFN-alpha nl or IFN-alpha 2a, P < 0.05). The cumulative HCC development was higher in the control group than in the IFN-alpha nl group (P < 0.002) and the IFN-alpha 2a group (P = 0.06). The cumulative survival rate was lower in the control group than in the IFN-alpha nl group (P < 0.01) and the IFN-alpha 2a group (P = 0.02). Multivariate analysis revealed that IFN-alpha nl 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-alpha nl treatment may have a better long-term effect on hepatitis B virus (HBV) clearance than IFN-alpha 2a 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.

Unintentional rechallenge resulting in a causative relationship between ketoconazole and acute liver injury.

We present the case of a female patient in whom acute overt hepatitis developed after 60 days of ketoconazole administration (200 mg/day). A prompt renewed hepatic injury 48 hours after an unintentional rechallenge 30 months later provided definitive evidence for a causative relationship between ketoconazole and acute liver injury. Histological examination revealed acute hepatitis with bridging hepatic necrosis. Clinicians should be aware of this cause and effect relationship between ketoconazole and acute liver injury, which can result in prompt severe acute liver injury after rechallenge.

Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy.

A study in Chinese patients with chronic hepatitis B showed that treatment with lamivudine for 1 year significantly improves liver histology and enhances hepatitis B e antigen (HBeAg) seroconversion compared with placebo. Fifty-eight patients from this 1-year study have received long-term treatment with lamivudine 100 mg; the outcome of 3 years of lamivudine is reported here. Before treatment, all patients had detectable HBeAg. HBeAg seroconversion (HBeAg-negative, anti-HBe-positive), hepatitis B virus (HBV)-DNA suppression, alanine transaminase (ALT) normalization, emergence of YMDD variant HBV, liver histology, and long-term safety were assessed. After 3 years of continuous treatment with lamivudine 100 mg daily, 40% (23 of 58) of patients achieved HBeAg seroconversion. In patients with baseline serum ALT >2 x upper limit of normal (ULN), the rate of HBeAg seroconversion was 65% (17 of 26). Median serum HBV-DNA concentrations were below the level of detection, and median ALT concentrations were within the normal range throughout 3 years of treatment. YMDD variant HBV emerged in 33 of 58 (57%) patients during the 3 years, of whom 9 (27%) achieved HBeAg seroconversion (6 after emergence of YMDD variant HBV). ALT levels and histologic scores after emergence of YMDD variant HBV did not show major deterioration. Lamivudine was well tolerated during 3 years of therapy. In conclusion, these data in Chinese patients with chronic hepatitis B show enhanced seroconversion rates with extended lamivudine treatment. Up to two thirds of patients with moderately elevated pretreatment ALT achieved HBeAg seroconversion after 3 years of therapy.