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BackgroundIn mainland China, peginterferon (PEG-IFN) alfa-2b 1.0μg/kg/wk for 24 weeks is the approved treatment for HBeAg-positive chronic hepatitis B.ObjectiveThis multicenter, randomized trial evaluated the safety and efficacy of regimens utilizing increased dose or treatment duration in treatment-naive Chinese patients with chronic hepatitis B.Study design670 HBeAg-positive patients from China, Malaysia, Taiwan area, Singapore, and Thailand were enrolled. Patients received PEG-IFN alfa-2b 1.0μg/kg/wk (arm A) or 1.5μg/kg/wk (arm B) for 24 weeks, or 1.5μg/kg/wk for 48 weeks (arm C). The primary end point was loss of HBeAg 24 weeks after end of treatment.ResultsAt the end of follow-up, HBeAg loss was significantly greater in arm C compared with arm A (31.3% vs. 17.3%; P=0.001) and arm B (31.3% vs. 18.1%; P=0.001). No significant difference in the rate of HBeAg loss was observed between arms A and B. The proportions of patients with HBe seroconversion, HBV DNA levels

Summary The Asia-Pacific region has disparate hepatitis C virus (HCV) epidemiology, with prevalence ranging from 0·1% to 4·7%, and a unique genotype distribution. Genotype 1b dominates in east Asia, whereas in south Asia and southeast Asia genotype 3 dominates, and in Indochina (Vietnam, Cambodia, and Laos), genotype 6 is most common. Often, availability of all-oral direct-acting antivirals (DAAs) is delayed because of differing regulatory requirements. Ideally, for genotype 1 infections, sofosbuvir plus ledipasvir, sofosbuvir plus daclatasvir, or ombitasvir, paritaprevir, and ritonavir plus dasabuvir are suitable. Asunaprevir plus daclatasvir is appropriate for compensated genotype 1b HCV if baseline NS5A mutations are absent. For genotype 3 infections, sofosbuvir plus daclatasvir for 24 weeks or sofosbuvir, daclatasvir, and ribavirin for 12 weeks are the optimal oral therapies, particularly for patients with cirrhosis and those who are treatment experienced, whereas sofosbuvir, pegylated interferon, and ribavirin for 12 weeks is an alternative regimen. For genotype 6, sofosbuvir plus pegylated interferon and ribavirin, sofosbuvir plus ledipasvir, or sofosbuvir plus ribavirin for 12 weeks are all suitable. Pegylated interferon plus ribavirin has been replaced by sofosbuvir plus pegylated interferon and ribavirin, and all-oral therapies where available, but cost and affordability remain a major issue because of the absence of universal health coverage. Few patients have been treated because of multiple barriers to accessing care. HCV in the Asia-Pacific region is challenging because of the disparate epidemiology, poor access to all-oral therapy because of availability, cost, or regulatory licensing. Until these problems are addressed, the burden of disease is likely to remain high.

Background: The hepatitis C pandemic has been systematically studied and characterized in North America and Europe, but this important public health problem has not received equivalent attention in other regions. Aim: The objective of this systematic review was to characterize hepatitis C virus (HCV) epidemiology in selected countries of Asia, Australia and Egypt, i.e. in a geographical area inhabited by over 40% of the global population. Methodology: Data references were identified through indexed journals and non-indexed sources. In this work, 7770 articles were reviewed and 690 were selected based on their relevance. Results: We estimated that 49.3‐64.0 million adults in Asia, Australia and Egypt are anti-HCV positive. China alone has more HCV infections than all of Europe or the Americas. While most countries had prevalence rates from 1 to 2% we documented several with relatively high prevalence rates, including Egypt (15%), Pakistan (4.7%) and Taiwan (4.4%). Nosocomial infection, blood transfusion (before screening) and injection drug use were identified as common risk factors in the region. Genotype 1 was common in Australia, China, Taiwan and other countries in North Asia, while genotype 6 was found in Vietnam and other Southeast Asian countries. In India and Pakistan genotype 3 was predominant, while genotype 4w as found in Middle Eastern countries such as Egypt, Saudi Arabia and Syria. Conclusion: We recommend implementation of surveillance systems to guide effective public health policy that may lead to the eventual curtailment of the spread of this pandemic infection.

SUMMARY Background: Alpha-interferon has been found to inhibit hepatitis B virus (HBV) replication in Chinese patients with chronic HBV infection although a sustained effect was rarely achieved in those with normal pre-treatment serum alanine amino transferase (ALT) levels. Prednisolone priming has been found to be beneficial over treatment with interferon alone in these subjects. We studied the effect of steroid pre-treatment followed by recombinant interferon alpha-2a in the treatment of asymptomatic HBV carriers with positive hepatitis Be antigen (HBeAg), hepatitis B viral DNA (HBV-DNA) and minimal changes in liver histology. Methods: The treatment regimen included a 6-week prednisolone priming, a 2 week rest followed by 14 weeks of three times weekly 9 mega units of interferon alpha-2a injection and 52 weeks of follow-up. There were seven patients in the treatment group and seven controls. Results: The mean age, pre-treatment ALT (normal in all except for one in each of the treatment and control groups), HBV-DNA levels and histological scores were similar in the two groups. Serum HBV-DNA levels fell in six patients during treatment and became undetectable in two of them by the end. During follow-up, serum HBV-DNA returned to pre-treatment levels in all patients. None of the treated patients had HBeAg sero-conversion and none of the controls had spontaneous clearance of HBV-DNA or sero-conversion of HBeAg. No improvement of liver histology was observed in any of the treated patients. There were only mild flu-like side-effects noted and interferon alpha-2a was well tolerated at the doses given among treated patients. Conclusion: Prednisolone priming followed by interferon alpha-2a treatment has no beneficial effect on HBV carriers in the early stages of chronic hepatitis B infection.

Clinicians face many challenges in striving to reduce the morbidity and mortality associated with chronic hepatitis B virus (HBV) infection. Some of the most urgent issues relate to preventing or reducing the development of antiviral resistance that may arise during oral antiviral therapy. In addition, the management of special populations, including patients with normal alanine aminotransferase levels, children and adolescents, women planning pregnancy or already pregnant, patients undergoing chemotherapy or other forms of immunosuppression, patients with HBV and human immunodeficiency virus coinfection, and those undergoing liver transplantation, present further challenges. This concise review examines recent findings on the efficacy of antiviral therapy in these special patient groups.

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.

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.

Of the estimated 50 million new cases of hepatitis B virus (HBV) infection diagnosed annually, 5-10% of adults and up to 90% of infants will become chronically infected, 75% of these in Asia where hepatitis B is the leading cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). In Indonesia, 4.6% of the population was positive for HBsAg in 1994 and of these, 21% were positive for HBeAg and 73% for anti-HBe; 44% and 45% of Indonesian patients with cirrhosis and HCC, respectively, were HBsAg positive. In the Philippines, there appear to be two types of age-specific HBsAg prevalence, suggesting different modes of transmission. In Thailand, 8-10% of males and 6-8% of females are HBsAg positive, with HBsAg also found in 30% of patients with cirrhosis and 50-75% of those with HCC. In Taiwan, 75-80% of patients with chronic liver disease are HBsAg positive, and HBsAg is found in 34% and 72% of patients with cirrhosis and HCC, respectively. In China, 73% of patients with chronic hepatitis and 78% and 71% of those with cirrhosis and HCC, respectively, are HBsAg positive. In Singapore, the prevalence of HBsAg has dropped since the introduction of HBV vaccination and the HBsAg seroprevalence of unvaccinated individuals over 5 years of age is 4.5%. In Malaysia, 5.24% of healthy volunteers, with a mean age of 34 years, were positive for HBsAg in 1997. In the highly endemic countries in Asia, the majority of infections are contracted postnatally or perinatally. Three phases of chronic HBV infection are recognized: phase 1 patients are HBeAg positive with high levels of virus in the serum and minimal hepatic inflammation; phase 2 patients have intermittent or continuous hepatitis of varying degrees of severity; phase 3 is the inactive phase during which viral concentrations are low and there is minimal inflammatory activity in the liver. In general, patients who clear HBeAg have a better prognosis than patients who remain HBeAg-positive for prolonged periods of time. The outcome after anti-HBe seroconversion depends on the degree of pre-existing liver damage and any subsequent HBV reactivation. Without pre-existing cirrhosis, there may be only slight fibrosis or mild chronic hepatitis, but with pre-existing cirrhosis, further complications may ensue. HBsAg-negative chronic hepatitis B is a phase of chronic HBV infection during which a mutation arises resulting in the inability of the virus to produce HBeAg. Such patients tend to have more severe liver disease and run a more rapidly progressive course. The annual probability of developing cirrhosis varies from 0.1 to 1.0% depending on the duration of HBV replication, the severity of disease and the presence of concomitant infections or drugs. The annual incidence of hepatic decompensation in HBV-related cirrhosis varies from 2 to 10% and in these patients the 5-year survival rate drops dramatically to 14-35%. The annual risk of developing HCC in patients with cirrhosis varies between 1 and 6%; the overall reported annual detection rate of HCC in surveillance studies, which included individuals with chronic hepatitis B and cirrhosis, is 0.8-4.1%. Chronic hepatitis B is not a static disease and the natural history of the disease is affected by both viral and host factors. The prognosis is poor with decompensated cirrhosis and effective treatment options are limited. Prevention of HBV infection thorough vaccination is still, therefore, the best strategy for decreasing the incidence of hepatitis B-associated cirrhosis and HCC.

Background & Aims: One-year lamivudine therapy significantly suppressed hepatitis B virus (HBV) replication, improved hepatic necroinflammatory activity, and prevented progression of fibrosis. However, the effects of prolonged therapy are unknown. Methods: A total of 334 Asian patients with chronic hepatitis B from a previously reported 1-year study were randomized to receive either lamivudine (100 or 25 mg) or placebo for another year. The effects of treatment on serum HBV-DNA suppression, alanine transaminase (ALT) normalization, and hepatitis B e antigen (HBeAg) seroconversion were measured. The presence of YMDD variant HBV and its effect were also determined. Results: A significantly greater proportion of patients achieved sustained HBV-DNA suppression and ALT normalization with 100 mg lamivudine daily for 2 years compared with lamivudine for 1 year followed by placebo for the second year ( P P Conclusions: Treatment with lamivudine for 2 years is both well tolerated and efficacious in patients with chronic hepatitis B. GASTROENTEROLOGY 2000;119:172-180

The aim of this study was to determine, first, whether racial differences exist in the seroprevalence of Helicobacter pylori infection in Singapore, and second, whether these differences correlate with racial differences in peptic ulcer frequency. A commercial serological test for immunoglobulin (Ig)G antibody to H. pylori which was 90% sensitive and 83% specific in our population was used to screen 403 adult blood donors of Chinese, Malay and Indian origin, aged between 15-60 years. Serum specimens from 84 paediatric patients admitted to the Paediatrics Department, National University of Singapore, with non-gastroenterological illnesses were also tested. In all three races, seroprevalence of H. pylori increased with age. Indians have the highest prevalence of infection followed by Chinese and Malays. Peptic ulcer prevalences are known to be highest in Chinese, followed by Indians and Malays. The Malays have the lowest prevalence of H. pylori and peptic ulcer among the three races in Singapore. Indians have a higher prevalence of H. pylori antibodies but a lower frequency of peptic ulcer than the Chinese. Racial differences in peptic ulcer frequency between Chinese and Indians are not explained by the prevalence of H. pylori infection; other environmental or genetic factors may be involved.

Summary Forty-one consecutive cases of liver abscesses seen at the National University Hospital, Singapore from 1988 to 1994 were reviewed. Twenty-seven cases (65%) were pyogenic, six (15%) amoebic, two (5%) tuberculous and six (15%) indeterminate. The predominance of pyogenic abscesses is in marked contrast to previous studies from the region a decade ago in which amoebic abscesses were the commonest type. The commonest pathogen causing pyogenic abscess was Klebsiella pneumoniae. Two cases were due to Mycobacterium tuberculosis, and this organism needs to be actively looked for in smears and cultures of aspirated material. As the majority of organisms isolated were resistant to ampicillin, empirical antibiotic treatment for suspected pyogenic abscess should include gentamicin or a cephalosporin. Percutaneous needle aspiration of the abscess was performed for 85% of pyogenic abscesses and surgery was necessary in only two cases because of complications. We found that percutaneous aspiration of liver abscess is helpful to confirm the diagnosis, provides a better bacteriological culture yield, gives a good outcome, and may uncover clinically unsuspected conditions like malignancy and tuberculoma which may mimic the presentation of liver abscesses. We recommend routine cytological examination of aspirated abscess material as well as stains and cultures for acid-fast bacilli.

5' untranslated and partial core (C) region sequence of hepatitis C virus (HCV) in 21 Singaporean and 15 Indonesian isolates were amplified by reverse-transcription polymerase chain reaction and sequenced with the use of conserved primer sequences deduced from HCV genomes identified in other geographical regions. The HCV genotypes are predominantly that of Simmonds type 1 and less of type 2 and 3 with the latter genotype currently not detected in Indonesia. The 5' untranslated sequences are related to HCV-1. DK-7 (Denmark), US-11 (United States of America), HCV-J4, SA-10 (South Africa), T-3 (Taiwan), HCV-J6, HCV-J8, Eb-1 and Eb-8. When compared with the prototype HCV-1, insertions are found within the 5' untranslated region of Singaporean isolates and not in the Indonesians. There are Singaporean and Indonesian isolates that have sequences within the 5' untranslated region that differ slightly from each other. Microheterogeneity is observed in the core region of two Singaporeans and one Indonesian isolate. Finally, not all HCV isolates can be amplified with the conserved core sequence primers when compared with the ease with which these isolates can be amplified with 5' untranslated region conserved primers.

A novel recombinant hepatitis B vaccine, trademarked Sci-B-Vac, was evaluated for safety, tolerability and immunogenicity in an open label trial performed in Singapore. The experimental vaccine, derived from Chinese hamster ovary (CHO) cells, consists of hepatitis B surface antigen (HBsAg) particles harbouring all three viral envelope polypeptides, the major S protein and the minor Pre-S2 and Pre-S1, in their glycosylated and non-glycosylated forms. The vaccine was administered intramuscularly at 0, 1 and 6 months. No unexpected adverse effects were observed. A high level anti-HBs response to Sci-B-Vac was indicative of its immunogenicity. Subsequent to the third injection, 100% and 92% of the 10 micrograms and 5 micrograms dose recipients, respectively, were seroprotected (anti-HBs titres greater than or equal to 10 mIU ml-1). Moreover, the geometric mean titres (GMT) of the anti-HBs response were very high: 2687 and 1473 mIU ml-1, respectively. An immunogenic advantage of Sci-B-Vac was also suggested by the rapid onset of antibody response: 96% of the 10 micrograms dose recipients were seroprotected with a GMT of 159 mIU ml-1, prior to the third injection.

The hepatocyte hepatitis B surface antigen (HBsAg) expression in 149 liver biopsies from 124 chronic hepatitis B virus (HBV) carriers was correlated with serum HBV DNA status and histologic activity. Hepatocyte HBsAg was stained by the peroxidase-antiperoxidase method and serum HBV DNA was determined by dot blot hybridization. Sixty-five biopsies (44%) showed minimal changes (MC), 82 biopsies (55%) showed chronic liver disease (CLD) and 2 biopsies (1%) showed hepatocellular carcinoma. Hepatocyte HBsAg was found in 144 biopsies (97%). It was present in the cytoplasm of 141 specimens (95%) and/or plasma membrane of 48 specimens (32%). Approximately half (45%) of the cytoplasmic HBsAg-positive biopsies showed discrete distribution, while the other half (55%) were grouped. Fifty-five per cent (77 of 141) of cytoplasmic HbsAg-positive biopsies had CLD, while 44% (62 of 141) showed MC. There was no relationship between the presence of cytoplasmic HBsAg or its topographic distribution with disease activity. Membrane HBsAg distribution was similar for both groups of patients (MC vs CLD: 25 of 65 (38%) vs 23 of 82 (28%); P = NS). Serum HBV DNA was detected in 98 patients (66%) and was seen mostly in association with CLD (CLD vs MC: 61% vs 39%, P less than 0.001). It was also detected more often in the sera of patients with membrane HBsAg than in those with cytoplasmic HBsAg staining (41 of 48 (85%) vs 97 of 141 (67%); P less than 0.02). However, discrete distribution of cytoplasmic HBsAg was associated with positive serum HBV DNA when compared with grouped distribution (52 of 63 (83%) vs 43 of 78 vs (55%); P less than 0.005).

Hepatitis B serology was performed on 270 family members of 78 hepatitis B carriers and hepatitis B e antigen status determined in those found to be HBsAg positive. The mean age of index patients was 38 years (range 3–74) and that of family members was 28 years (range 1–71). 67 family members (25%) were HBsAg positive. The proportions of family members positive for HBsAg and those negative for HBsAg but positive for anti-HBs and/or anti-HBc were 25% and 20% for children, 10% and 68% for spouses, 36% and 26% for siblings and 29% and 55% for parents. For children of index parents the proportions positive for HBsAg and those negative for HBsAg but positive for anti-HBs and/or anti-HBc were similar whether the index patient was the mother (24% and 24%) or the father (26% and 18%). Our results suggest that horizontal transmission is a significant mode of spread of hepatitis B within the family in Singapore.

Large amounts of new data on the natural history and treatment of chronic hepatitis B virus (HBV) infection have become available since 2005. These include long-term follow-up studies in large community-based cohorts or asymptomatic subjects with chronic HBV infection, further studies on the role of HBV genotype/naturally occurring HBV mutations, treatment of drug resistance and new therapies. In addition, Pegylated interferon alpha2a, entecavir and telbivudine have been approved globally. To update HBV management guidelines, relevant new data were reviewed and assessed by experts from the region, and the significance of the reported findings were discussed and debated. The earlier "Asian-Pacific consensus statement on the management of chronic hepatitis B" was revised accordingly. The key terms used in the statement were also defined. The new guidelines include general management, special indications for liver biopsy in patients with persistently normal alanine aminotransferase, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patients receiving immune-suppressive medications or chemotherapy and patients in the setting of liver transplantation, are also included.

A 0.5 g daily dose of cimetidine was as effective as a 1 g dose in the acute treatment of duodenal ulcer patients in Hong Kong. The aims of the present study were, first, to determine whether low-dose cimetidine treatment was as effective as standard doses in acute duodenal ulcer treatment of patients in Singapore, and second, to compare a single nocturnal dosage regimen with a twice daily regimen. In this single centre, double-blind, controlled trial, 282 patients with endoscopically proven duodenal ulcer were randomized to receive four weeks' treatment with cimetidine using one of three dosage regimens: (A) 800 mg at night; (B) 400 mg at night; or (C) 400 mg twice daily. Two hundred and forty-seven patients were evaluated. The incidences of healing at four weeks were: (A) 40/80 (50%), (B) 39/88 (44%); and (C) 48/79 (61%); (B vs C: P less than 0.05; A vs C: NS; 95% confidence limits: -5% to 27%; A vs B: NS, 95% confidence limits: -6% to 21%). Of 183 patients who had antral biopsies taken, 176 (96%) had histological gastritis, while 167 (91%) were positive for Helicobacter-like organisms. The occurrence of gastritis or Helicobacter-like organisms had no influence on ulcer healing. A 400 mg dose of cimetidine is therefore suboptimal for the treatment of duodenal ulcer in patients in Singapore. A single nocturnal dosage regimen may be less effective than a twice daily regimen.

Emtricitabine is a nucleoside analogue approved for treatment of human immunodeficiency virus 1 with clinical activity against hepatitis B virus (HBV).To compare the safety and efficacy of emtricitabine with placebo in patients with HBV, we conducted a randomized (2:1), double-blind study at 34 sites in North America, Asia, and Europe that enrolled adults between November 2000 and July 2002 who had chronic HBV infection but had never been exposed to nucleoside or nucleotide treatment. Each patient received either 200 mg of emtricitabine (n=167) or placebo (n=81) once daily for 48 weeks and underwent a pretreatment and end-of-treatment liver biopsy. Histologic improvement was defined as a 2-point reduction in Knodell necroinflammatory score with no worsening in fibrosis.At the end of treatment, 103 (62%) of 167 patients receiving active treatment had improved liver histologic findings vs 20 (25%) of 81 receiving placebo (P.001), with significance demonstrated in subgroups positive (P.001) and negative (P=.002) for hepatitis Be (HBe) antigen. Serum HBV DNA readings showed less than 400 copies/mL in 91 (54%) of 167 patients in the emtricitabine group vs 2 (2%) of 81 in the placebo group (P.001); alanine aminotransferase levels were normal in 65% (109/167) vs 25% (20/81), respectively (P.001). At week 48, 20 (13%) of 159 patients in the emtricitabine group with HBV DNA measured at the end of treatment had detectable virus with resistance mutations (95% confidence interval, 8%-18%). The rate of seroconversion to anti-HBe (12%) and HBe antigen loss were not different between arms. The safety profile of emtricitabine during treatment was similar to that of placebo. Posttreatment exacerbation of HBV infection developed in 23% of emtricitabine-treated patients.In patients with chronic HBV, both positive and negative for HBe antigen, 48 weeks of emtricitabine treatment resulted in significant histologic, virologic, and biochemical improvement.

In the Asia Pacific region Human Immunodeficiency virus (HIV) is often acquired in individuals already infected with hepatitis B virus (HBV). The immune suppression caused by HIV infection reduces cellular immune response against HBV and liver inflammation may improve, but the risk of developing cirrhosis is not. HBV infection does not affect the progression of HIV disease. Anti-retroviral agents may be directly hepatotoxic and cause ALT elevations in patients with chronic hepatitis. Highly active anti-retroviral therapy (HAART) improves immunity and as cytotoxic lymphocyte responses improve, hepatitis flares can occur, usually r within 3 months of initiation of HAART. These hepatitis flares may be followed by normalization of ALT and clearance of HBVDNA. If lamivudine is included in the HAART regime, hepatitis flares may not occur till late and these late flares signal the development of lamivudine resistant HBV strains (90% of HBV/HIV co-infection). Treatment options for chronic HBV infection include interferon (IFN), and nucleoside analogues. Lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (DF) are nucleoside analogues with activity against both HBVDNA polymerase and HIV reverse transcriptase. The latter two compounds have added activity against lamivudine resistant HBVDNA. Lamivudine should be avoided in the initial treatment of both hepatitis B as well as HIV because of the high incidence of resistance. Interferon should be considered first for treatment of HBV in HIV co-infected individuals and is usually unsuccessful in the later stages of HIV infection when immune suppression is extreme. As new and improved agents in HAART continue to prolong survival, the use of liver transplantation for cirrhotic patients co-infected with HIV and HBV may increase.

Four to 6 months of conventional interferon alpha (IFN-alpha) (5MU daily or 10MU three times weekly) resulted in HBeAg loss in approximately 33% of HBeAg positive patients (controls: 12%). Longer treatment duration improved HBeAg seroconversion. Children with chronic HBV infection and high ALT respond to IFN-a at similar rates. Good end-of-treatment (ET) biochemical and virological response were also achieved with IFN-alpha in HBeAg negative, HBV-DNA positive hepatitis patients. Sustained response (SR) however, was disappointing, but improved with longer duration of treatment: (10-15% SR with 4/6 months treatment: 30% SR with 24 months treatment). Weekly pegylated IFN-alpha2a (PegIFN-alpha2a) for 24 weeks gave a significantly higher HBeAg conversion rate (33%) than conventional IFN-alpha2a (25%). Fifty-two weeks of PegIFN-alpha2b gave a sustained HBeAg loss in 35% patients and HBeAg seroconversion in 29% patients. Similar results were obtained with 48 weeks of weekly PegIFN-alpha2a. PegIFN-alpha2a monotherapy was found to be superior to lamivudine monotherapy in affecting a 6-month SR (normal ALTs and HBV DNA20,000 copies/mL) in HBeAg negative/anti-HBe positive chronic hepatitis B patients. There is a tendency for IFN-a and lamivudine combination to result in better sustained response than lamivudine monotherapy. This tendency is also observed with PegIFN-a and lamivudine combination although the combination did not appear to be better than PegIFN-alpha monotherapy. IFN induced HBeAg seroconversion is durable, could increase over time and resulted in better overall survival and survival free of hepatic decompensation or hepatocellular cancer. The main advantage of IFN-a therapy is that a course of finite duration may achieve sustained off-therapy response in a proportion of both HBeAg positive and HBeAg negative chronic hepatitis B patients. However, IFN treatment is usually associated with side-effects, especially flu-like symptoms, fatigue, neutropenia, thrombocytopenia and depression. These are usually tolerable but may require dose modification and premature cessation of treatment (5%). Interferon therapy induced hepatitis flares may lead to decompensation in patients with cirrhosis and can be dangerous in patients with decompensated liver function despite dose reduction.

The Asia-Pacific Expert Committee on Hepatitis B Management recently reviewed the impact of hepatitis B in the region and assessed the differences and similarities observed in the practical management of the disease in individual Asia-Pacific countries. Hepatitis B is a major health concern in the Asia-Pacific region, and of all chronically infected carriers worldwide, approximately 75% are found in Asia. The disease poses a considerable burden on healthcare systems, and is likely to remain a cause of substantial morbidity and mortality for several decades. Disease prevention activities, including screening and vaccination programs, have been implemented successfully in some Asia-Pacific countries and similar measures are being established in other parts of the region. The management of hepatitis B in the Asia-Pacific varies throughout the region, with each country confronting different issues related to treatment options, disease monitoring and duration of therapy. The influence of cost, availability of diagnostic equipment, and patient awareness and compliance are of additional concern. Although guidelines such as those developed by the Asian Pacific Association for the Study of the Liver have been created to address problems encountered in the management of hepatitis B, many physicians in the region still find it difficult to make satisfactory management decisions because of the treatment choices available. This article examines the different approaches to hepatitis B management in a number of Asia-Pacific countries, and highlights the difficulties that can arise when adhering to treatment guidelines and disease prevention solutions that have proved to be successful in the region.

To examined the efficacy and safety of treatment with boceprevir, PEGylated-interferon and ribavirin (PR) in hepatitis C virus genotype 1 (HCVGT1) PR treatment-failures in Asia.The Boceprevir Named-Patient Program provided boceprevir to HCVGT1 PR treatment-failures. Participating physicians were invited to contribute data from their patients: baseline characteristics, on-treatment responses, sustained virological response at week 12 (SVR12), and safety were collected and analysed. Multivariate analysis was performed to determine predictors of response.150 patients were enrolled from Australia, Malaysia, Singapore and Thailand (Asians = 86, Caucasians = 63). Overall SVR12 was 61% (Asians = 59.3%, Caucasians = 63.5%). SVR12 was higher in relapsers (78%) compared with non-responders (34%). On-treatment responses predicted SVR, with undetectable HCVRNA at week 4, 8 and 12 leading to SVR12s of 100%, 87%, and 82% respectively, and detectable HCVRNA at week 4, 8 and 12, leading to SVR12s of 58%, 22% and 6% respectively. Asian patients were similar to Caucasian patients with regards to on-treatment responses. Patients with cirrhosis (n = 69) also behaved in the same manner with regards to on-treatment responses. Those with the IL28B CC genotype (80%) had higher SVRs than those with the CT/TT (56%) genotype (P = 0.010). Multivariate analysis showed that TW8 and TW12 responses were independent predictors of SVR. Serious adverse events occurred in 18.6%: sepsis (2%), decompensation (2.7%) and blood transfusion (14%). Discontinuations occurred in 30.7%, with 18.6% fulfilling stopping rules.Boceprevir can be used successfully in PR treatment failures with a SVR1280% if they have good on-treatment responses; however, discontinuations occurred in 30% because of virological failure or adverse events.

Background: Nucleoside analogues such as lamivudine for chronic hepatitis B have an excellent safety profile while patients are on therapy but reactivation flares occur in 19–50% of patients after stopping therapy, some of whom develop liver decompensation. Aims: To describe and report three cases who developed fatal hepatitis B reactivation after stopping nucleoside analogue therapy. Subjects and results: Three patients are described who developed hepatitis B reactivation and liver decompensation after stopping therapy. One of the three patients was participating in a famciclovir trial and the other two were receiving lamivudine therapy for active hepatitis B infection. All three patients had documented hepatitis B flares, and all had hepatitis B virus DNA detected at that time. All patients developed decompensated liver disease despite one patient having had a prior liver biopsy showing absence of cirrhosis. Reintroduction of lamivudine therapy failed to halt progression of liver decompensation even after hepatitis B virus DNA had been demonstrated to be absent. Sequencing for lamivudine resistant mutants in two cases where serum was available failed to show evidence of mutations associated with lamivudine resistance. Conclusion: Hepatitis B virus reactivation, leading to decompensation and death, are possible complications of treatment withdrawal and patients should be monitored closely if therapy is ceased.

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.

Fifty patients with inflammatory bowel disease (ulcerative colitis, 40; Crohn's disease, seven; indeterminate colitis, three) treated in one gastroenterology unit in Singapore over a 10 year period were reviewed. Clinical features were similar to those described in Western patients. Of the three main races of Singapore it was found that Indians are more susceptible to these diseases than Chinese or Malays. A survey of all gastroenterologists in Singapore indicated a possible prevalence of 8.6 per 100,000 people for ulcerative colitis and 1.3 per 100,000 people for Crohn's disease. These prevalence rates are much lower than those reported for Western populations.

Interferon-alpha (IFN-alpha) has been the only approved agent for the treatment of chronic hepatitis B in most countries, but this is rapidly changing. It is expensive, associated with frequent and unpleasant side effects, has limited efficacy and is ineffective in subjects with no/mild liver necro-inflammation. Loss of HBsAg and viral replication markers occur 6% and 20%, more often in IFN-treated subjects than controls. The most important factors that will predict favourable response to IFN-alpha therapy are elevated ALT and low serum HBV DNA levels. Chinese patients and children with active liver have similar response rates as Caucasian adults with equivalent ALT levels. Patients with HBeAg negative disease fare less well. Long-term follow up has shown that most IFN responders maintained their response although very few people have complete eradication of HBV.

Sixty-seven healthy adult volunteers aged 20-40 years with no previous exposure to hepatitis B virus were randomized to receive either a 10 micrograms or 5 micrograms dose of recombinant DNA hepatitis B (HB) vaccine (B-Hepavac II) intramuscularly at 0, 1 and 6 months. Two months after the third injection 100% of subjects had seroconverted: 97% of the 10 micrograms group and 91% of the 5 micrograms group had antibody to HB surface antigen (anti-HBs) levels greater than 10 iu/L. The geometric mean titres (GMT) of anti-HBs levels at this time were 891 iu/L in the 10 micrograms dose group and 923 iu/L in the 5 micrograms dose group. These differences were not significant. Adverse effects included fever and mild pain at the injection site. The reduced dose of 5 micrograms was as effective as the standard 10 micrograms dose.

Aims: To determine: (i) the prevalence of histological gastritis and peptic ulcer; and (ii) the clinical features of peptic ulcer, in patients with end-stage renal failure. Methods: Upper endoscopy was performed by a single observer in 268 patients with end-stage renal failure over a 6-year period. Gastric histology and Helicobacter pylori status were studied in 40 consecutive subjects in whom there were no contraindications for gastric biopsy and who had not used antibacterial drugs in the preceding 4 weeks. As there are only limited data for healthy volunteers in Singapore, 33 age-, sex- and race-matched patients with functional dyspepsia from an earlier drug trial and 18 healthy volunteers who were not age-matched were used as controls. The clinical features of 43 consecutive uraemic patients with peptic ulcer were compared with those of 118 consecutive non-uraemic peptic ulcer patients seen by the same author. Results: Among uraemic patients, histological gastritis was less common, compared with healthy volunteers and functional dyspepsia patients. Helicobacter pylori infection as assessed by histology was also less common among uraemic patients compared with functional dyspepsia patients, but the difference was not statistically significant on serological assessment. Uraemic patients with ulcer had an equal sex ratio, in contrast to a male preponderance among peptic ulcer patients with normal renal function. Uraemic patients with ulcer were more likely to be pain-free, to present with haemorrhage, to have multiple ulcers and postbulbar duodenal ulcers, but were less likely to have H. pylori infection. Among uraemic subjects, the prevalence of H. pylori infection was similar whether or not peptic ulcer was present. Conclusions: The prevalence of histological gastritis was lower in uraemic patients when compared with patients with functional dyspepsia and healthy volunteers. Peptic ulcers in uraemic subjects have different clinical characteristics from peptic ulcer in non-uraemic subjects.

A nucleic acid photo-cross-linking technology was used to develop a direct assay for the quantification of hepatitis B virus (HBV) DNA levels in serum. Cross-linker-modified DNA probes complementary to the viral genomes of the major HBV subtypes were synthesized and used in an assay that could be completed in less than 6 h. The quantification range of the assay, as determined by testing serial dilutions of Eurohep HBV reference standards and cloned HBV DNA, was 5 x 105 to 3 x 109 molecules of HBV DNA/ml of serum. Within-run and between-run coefficients of variation (CVs) for the assay were 4.3 and 4.0%, respectively. The assay was used to determine HBV DNA levels in 302 serum samples, and the results were compared to those obtained after testing the same samples with the Chiron branched-DNA (bDNA) assay for HBV DNA. Of the samples tested, 218 were positive for HBV DNA by both assays and 72 gave results below the cutoff for both assays. Of the remaining 12 samples, 10 were positive for HBV DNA by the cross-linking assay only; the 2 other samples were positive by the bDNA assay only. Twenty-eight samples had to be retested by the bDNA assay (CV, >20% between the results obtained from the testing of each sample in duplicate), whereas only three samples required retesting by the cross-linking assay. The correlation between the HBV DNA levels, as measured by the two tests, was very high (r = 0.902; P = 0.01). We conclude that the cross-linking assay is a sensitive and reproducible method for the detection and quantification of HBV DNA levels in serum., published_or_final_version

BACKGROUND Treatment of chronic replicative hepatitis B virus (HBV) infection is aimed at stopping viral replication and preventing the development of chronic liver disease. beta-Interferon treatment has been less well studied than alpha-interferon. METHODS The efficacy and tolerability of a 6-month course of subcutaneously administered human recombinant beta-interferon (rINF-beta ser) was studied and the results of a low-dose regime compared with a high-dose regime. Twenty patients (17 men and three women), aged 24-54 years, with chronic hepatitis B virus infection (all hepatitis B surface antigen-positive with detectable HBV-DNA in their sera for at least 3 months prior to therapy) were randomized into two treatment groups of 10 patients each. The low-dose group received 6 x 10(6) U/dose and the high-dose group received 30 x 10(6) U/dose, both groups receiving their respective doses three times a week initially for 1 month and continuing for a total of 6 months. RESULTS The treatment was well tolerated in both groups. None of the patients required dosage reduction or cessation of treatment because of side-effects. HBV-DNA decreased in all patients during treatment, demonstrating the anti-viral efficacy of rINF-beta ser, and was undetectable in 20 and 40% of patients receiving low-dose and high-dose regimes, respectively, at the end of 6 months treatment (P = N.S.). One year after completion of treatment, HBV-DNA was undetectable in 50 and 30% of patients in the low-dose and high-dose groups, respectively (P = N.S.). However, only one patient achieved seroconversion with loss of the hepatitis B surface antigen and appearance of an antihepatitis B 'e' antigen at the end of 18 months. CONCLUSION This study shows that subcutaneously administered rINF-beta ser is well tolerated, but the optimal dose and duration of treatment still needs to be defined by further studies.

SUMMARY Background: Polyunsaturated phosphatidyl choline is a preparation often advocated for diseases of the liver. Methods: In a randomized open controlled trial, a preparation of polyunsaturated phosphatidyl choline, at a dose of 900 mg orally daily, was given to 22 patients with acute viral hepatitis. A control group of 25 patients was not treated. Results: Serial serum bilirubin and alanine amino transferase levels were measured up to 12 weeks. The falls in their levels after 2 and 5 weeks, and the lengths of time to their normalization, were not significantly different in the treated group compared to the control group. Conclusion: The results indicated that polyunsaturated phosphatidyl choline had no beneficial effect on the course of acute viral hepatitis.

A new recombinant hepatitis B vaccine (SCI-B-VAC), derived from Chinese hamster ovary (CHO) cells and consisting of both the major S protein and the minor pre-S1 and pre-S2 proteins of the viral coat were compared with two yeast-derived vaccines containing only S proteins (B-Hepavac II and Engerix-B) for immunogenicity in human volunteers in a randomized controlled study. Two hundred and ninety-five healthy subjects completed the 12 month follow up. There was no difference in the mean age and sex distribution among the three study groups. Seroconversion rates for all the three groups were similar at months 6, 9 and 12. However, hepatitis B surface antibody (anti-HBs) geometric mean titres (GMT) were significantly higher with 10 micrograms SCI-B-VAC and 20 micrograms Engerix-B than with 10 micrograms B-Hepavac-II at months 6, 9 and 12. SCI-B-VAC at month 6 also showed a significantly higher anti-HBs GMT than Engerix-B (295 vs 143 miu/mL, P < 0.02).

In Singapore, peptic ulcer is more common amongst Chinese than amongst Malays or Indians. Earlier work has suggested that, amongst female Chinese, Cantonese women are more susceptable to ulcer disease when compared to females of other dialect groups. The aim of the present study was to confirm or refute this possibility. The dialect group distribution of 897 Chinese patients with peptic ulcer (duodenal ulcer 601, gastric ulcer 296) was compared with that of non-ulcer dyspepsia patients and 1602 general medical patients attending the same medical units. The proportion of various dialect groups (including Cantonese) was similar in all patient groups. The proportion of ulcer patients presenting with haemorrhage was also similar in the different dialect groups. We conclude that no major dialect differences exist in peptic ulcer frequency amongst the Chinese in Singapore.

The aims of this study were to determine whether the development of acid induced duodenal ulcer pain was influenced by the symptomatic status of the patient and whether the administration of an antispasmodic could abolish pain. One hundred millilitres of 0.1 N hydrochloric acid was infused onto the ulcer craters or scars of 143 duodenal ulcer patients on 168 occasions. Symptomatic patients were randomised to receive 40 mg of hyoscine intravenously before acid infusion, or to a control group. Typical ulcer pain developed in seven of 55 (13%) instances for non-symptomatic patients, 24/57 (42%) of control symptomatic patients, and 20/56 (36%) of symptomatic patients given hyoscine. (Asymptomatic group v control symptomatic group, p less than 0.005; control symptomatic group v hyoscine group, NS - 95% confidence limits 12% in favour of the control and 24% in favour of the hyoscine group). The results suggest that acid infusion seldom reproduces ulcer pain in non-symptomatic duodenal ulcer patients and that the pathogenesis of acid induced duodenal ulcer pain probably involves a mechanism other than spasm, as pain was not prevented by an anticholinergic.

Patients with recently healed duodenal ulcers diagnosed by endoscopy were randomly allocated to receive 10 g apple pectin USP powder twice daily, 150 mg ranitidine at night, or one tablet matching ranitidine placebo at night for 6 months. Repeat endoscopy was performed at 6 months or if symptoms recurred. Eighty-three patients completed the study. Recurrences occurred in 23 of 27 (85%) patients taking pectin, 6 of 28 (21%) patients taking ranitidine, and 20 of 28 (71%) patients taking placebo. (Pectin versus placebo, NS; ranitidine versus pectin, p less than 0.00001; ranitidine versus placebo, p less than 0.0005). The average amount of pectin taken was 12.7 g/day in patients who relapsed and 12.4 g/day in those who did not. At the doses taken, therefore, dietary supplementation with pectin did not reduce the incidence of duodenal ulcer relapse.

Although early studies attributed an important role to acid in the pathogenesis of duodenal ulcer pain, recent reports are conflicting. The aim of the present study is to determine whether direct acidification of the duodenal ulcer crater in symptomatic patients reproduces ucler pain. Patients with endoscopically diagnosed duodenal ulcers were studied. No premedication or sedation was given. A washing tube was passed via the endoscope and 0.1 N hydrochloric acid as well as normal saline were sequentially administered on to the ulcer crater, the sequence of infusion being randomised and double blind. Forty patients were studied. Sixteen developed typical ulcer pain during acid infusion compared with four with saline (p less than 0.005). Ten patients who developed pain on acid were rechallenged with acid after their pains disappeared. Typical pain recurred in all. Twenty patients without duodenal ulcer did not develop pain when 200 ml of 0.1 N hydrochloric acid was infused into the duodenum. Acid therefore appears to have a definite role in the pathogenesis of duodenal ulcer pain although other factors may also be important.

Several hospital series of peptic ulcer patients have suggested that ulcer prevalence may be different in the different races in Singapore. However, such studies may be biased because different races use hospital services differently and also because hospital catchment populations are difficult to define. In the present study the racial composition of a consecutive series of 1248 peptic ulcer patients seen in two medical units of a general hospital was compared to that of 2023 general medical patients attending the same units. For both sexes, the racial structure of the gastric ulcer as well as the duodenal ulcer patients was significantly different from that of the general medical group. There was an excess of Chinese patients of both sexes with gastric ulcer and duodenal ulcer. In contrast, the numbers of male Malay gastric ulcer, male Malay duodenal ulcer, female Malay duodenal ulcer as well as Indian gastric ulcer patients of both sexes were fewer than expected. These results cannot be accounted for by racial differences in either health-seeking behaviour or analgesic and tobacco usage. These observations confirm the probable occurrence of racial differences in peptic ulcer frequency in Singapore.

Summary A 27 year old woman with hepato-lenticular degeneration (Wilson's disease) was found to have primary hepatocellular carcinoma (PHC) three and a half years after she was started on treatment with D-penicillamine. The tumour was resected since when she has remained well. Her liver function tests were normal throughout the course of her disease. The available literature is reviewed and possible mechanisms for this association proposed.

The aims of this study were to define the localization of duodenal ulcer and to determine whether the site influenced the initial presentation. Eight hundred eighty-four duodenal ulcer patients diagnosed by endoscopy in Singapore and Sydney were studied. The ulcer was situated on the anterior wall of the bulb in 49% and the posterior wall of the bulb in 23%. The distribution was not influenced by sex, age, or the center of diagnosis. Those situated posteriorly in the bulb were more likely to present with hemorrhage than those situated elsewhere.

Summary A case of thyrotoxicosis presenting with periodic paralysis and later complicated by acropachy, pretibial myxoedema and transient atrial fibrillation is described. This association has not been reported previously. Possible aetiological links are discussed.