Boceprevir early-access for advanced-fibrosis/cirrhosis in Asia-Pacific hepatitis C virus genotype 1 non-responders/relapsers.

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Boceprevir can be used successfully in PR treatment failures with a SVR12 > 80% if they have good on-treatment responses; however, discontinuations occurred in 30% because of virological failure or adverse events.

Clinical outcomes of lamivudine-adefovir therapy in chronic hepatitis B cirrhosis.

GOALS: To determine the clinical outcome of chronic hepatitis B cirrhotics on antiviral therapy. BACKGROUND: The long-term outcome of hepatitis B cirrhotics on therapy remains to be characterized. METHODS: A large clinic cohort of chronic hepatitis B cirrhotic patients were enrolled in a treatment program of lamivudine ± adefovir therapy. Patients were analyzed for clinical outcomes, and predictors of these outcomes were evaluated by multivariate analysis. Clinical outcomes of ascites, encephalopathy, hepatocellular carcinoma (HCC), and progression in Child-Pugh score, Model for End-stage Liver Disease score, and mortality were assessed. Data were analyzed by Kaplan-Meier graphs, log-rank test, and Cox regression. RESULTS: Of 143 chronic hepatitis B cirrhotics, 19.6% had decompensated cirrhosis. At 5 years, the mean survival was 83.6%, development of ascites, HCC, encephalopathy, and deterioration in Child-Pugh score were 7.0%, 15.9%, 10.8%, and 16.9%, respectively. The overall progression of liver-related complications was 32.8% at 5 years. Multivariate analysis showed that ascites, albumin ≤28 g/L, Child-Pugh score ≥7.9, Model for End-stage Liver Disease score ≥10.9 were significantly associated with liver-related complications. Low albumin and low hepatitis B virus DNA were independent factors for liver-associated mortality. Lamivudine resistance did not affect mortality or liver disease progression. When stratified by Child-Pugh status, the mean survival of those with Child C cirrhosis was worse than Child A and B cirrhosis (P<0.001, log-rank test). Early deaths (≤12 mo) were due to liver failure or sepsis, whereas deaths ≥12 mo were mainly due to HCC. CONCLUSION: Decompensated chronic hepatitis B cirrhotics may suffer early mortality despite antiviral treatment, and therefore should be considered for early liver transplantation.

Alanine aminotransferase is an inadequate surrogate marker for detecting lamivudine resistance.

AIM: To investigate the accuracy of serum alanine aminotransferase (ALT) in diagnosing lamivudine resistance and factors that contributed to abnormal serum ALT. METHODS: This was a retrospective study of chronic hepatitis B patients on lamivudine therapy who were followed for 3-mo with liver function tests and hepatitis B virus (HBV) DNA measurement. Lamivudine resistance was defined as HBV DNA ≥ 1 log from nadir on at least 2 occasions, confirmed by genotyping. Serum ALT levels in patients with lamivudine resistance were compared to serum ALT levels in those without lamivudine resistance. RESULTS: There were 111 patients with and 117 without lamivudine resistance. The area under the receiver operating characteristic of serum ALT to diagnose lamivudine resistance was 0.645 ± 0.037. Serum ALT > 42.5 U/L gave the best diagnostic accuracy with sensitivity = 61%, specificity = 60%, positive predictive value = 60%, negative predictive value = 61%, positive likelihood ratio = 1.53 and negative likelihood ratio = 0.65 for predicting lamivudine resistance, missing 39% of resistant patients. Using other serum ALT cutoffs, diagnostic accuracy was lower. By multivariate analysis, baseline abnormal serum ALT was associated with abnormal ALT during resistance (OR = 5.98, P = 0.003), and males were associated with serum ALT flares during resistance (OR = 8.9, P = 0.016). CONCLUSION: Serum ALT is inadequate for diagnosing lamivudine resistance and has implications where viral resistance testing is suboptimal and for reimbursement of rescue therapy.

The response of Asian patients with functional dyspepsia to eradication of Helicobacter pylori infection.

OBJECTIVES/BACKGROUND: The role of Helicobacter pylori infection in functional dyspepsia (FD) remains controversial. Several randomized controlled trials involving populations in the West, observed no statistically significant advantage over placebo. However, none of these studies involved Asian populations which have high infection rates. METHODS: A double blind, randomized, placebo-controlled trial of H. pylori eradication for FD was conducted in our Singapore-based Asian population. Forty-one patients received active treatment consisting of a 1-week course of omeprazole 20 mg once daily, clarithromycin 250 mg twice daily and tinidazole 500 mg twice daily whereas another 41 patients received matching placebo tablets. A dyspepsia score was derived by grading 5 dyspeptic symptoms on a Likert scale. Symptom assessment and urea breath test were repeated at 6 weeks, 6 and 12 months from the start of treatment. The primary end point was symptom resolution, defined as a dyspepsia score of 0 or 1 at the end of 12 months follow-up. RESULTS: On intention-to-treat analyses, symptom resolution was observed in 24% of patients on active treatment and 7% on placebo; the difference in proportion of patients with symptom resolution was statistically significant (P=0.02, 95% confidence interval: 1.1-17.7). H. pylori eradication rates perprotocol and intention-to-treat were 80.0 and 68.3%, on active treatment and 5.6 and 4.9% on placebo (both P values<0.0001). Among patients with H. pylori eradicated on active treatment the symptom resolution rate was 39% (10 of 26), whereas it was 3% (one of 35) among patients in the placebo group who had persistent H. pylori infection. In multivariate analysis, posttreatment H. pylori status was the only predictor of symptom resolution. The majority of patients, 91.5%, had ulcer-like dyspepsia; heartburn and acid regurgitation were uncommon, and no increase was observed after treatment. CONCLUSION: In contrast to Western populations, our results suggest that patients with FD in Asia would benefit from treatment for H. pylori infection with as much as a 13-fold increased chance of symptom resolution following its eradication.

A randomized controlled pilot study of Pentoxifylline in patients with non-alcoholic steatohepatitis (NASH).

PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) is implicated in non-alcoholic steatohepatitis (NASH). Pentoxifylline inhibits TNF-alpha. We wanted to evaluate the efficacy of Pentoxifylline on NASH patients. METHODS: Patients with biopsy proven NASH and persistently elevated alanine aminotransferase (ALT) greater than 1.5 times the upper limit of normal were randomized to 3 months of treatment with a step 1 American Heart Association diet and daily exercise with Pentoxifylline or placebo. Liver function tests, serum lipids and TNF-alpha, Interleukin 6 (IL-6), and plasma hyaluronic acid were measured at baseline, at weeks 6 and 12. Categorical data were analyzed by Fisher's exact test while independent sample t-test and Mann-Whitney test were used for continuous data. RESULTS: Eleven patients were randomized into the Pentoxifylline and nine to the placebo group. After 3 months of treatment body mass index (BMI), ALT and aspartate aminotransferase (AST) decreased significantly in both groups. There was no difference between the two groups in reduction of BMI (P = 0.897). There was significantly greater reduction in AST in the Pentoxifylline group (P = 0.038). There was a trend toward lower ALT level (P = 0.065) in the Pentoxifylline group. TNF-alpha and IL-6 decreased significantly in both groups after treatment, but there was no significant difference between the two groups. CONCLUSION: Three months of Pentoxifylline treatment in combination with diet and exercise results in significantly greater reduction in AST levels in patients with NASH as compared with controls.

Drug-induced liver injury at an Asian center: a prospective study.

BACKGROUND/AIMS: The aetiology of drug-induced liver injuries (DILI) in Asia is different from that in the West, as anecdotal studies have shown that traditional complementary and alternative medicines (CAM) accounted for a major proportion of offending drugs in DILI in Asia. We aimed to study DILI in Asia prospectively, and to test whether DILI caused by traditional CAM was related to adulterants. METHODS: A collaborative group consisting of a tertiary-hospital hepatology department, a pharmaceutical laboratory, and a pharmacovigilance unit was formed to study patients with DILI at a tertiary hospital over a 26-month period prospectively. Traditional medicines that were implicated were tested for the presence of adulterants. RESULTS: Thirty-one patients with DILI were enrolled: age 51+/-3 (18-79) years, 17 (55%) male. Twenty-three (74%) had hepatocellular, six (19%) had cholestatic, and two (7%) had a mixed pattern of injury. Chinese traditional CAM was the most common medication type implicated, accounting for 17 (55%) patients, followed by Malay CAM in five (16%). Thirty-one traditional medicines from 17 patients were available for chemical analysis. Adulterants were found in nine (29%) of them. CONCLUSIONS: DILI in Asia has a different aetiology as compared with the West, and could be related to presence of adulterants in traditional CAM.

MARS: a futile tool in centres without active liver transplant support.

BACKGROUND AND AIM: Studies on Molecular Adsorbent Recycling Systems (MARS) showed inconclusive survival benefits. PATIENTS AND METHOD: We evaluated the efficacy of MARS for patients with either acute liver failure (ALF) or acute-on-chronic liver failure (AoCLF) at our centre, from February 2002 till April 2006 retrospectively. RESULTS: Fifty ALF patients underwent median (range) three (1-10) sessions of MARS. Acute exacerbations of chronic hepatitis B (n=26) and drug-induced liver injury (n=12) were the commonest causes. Living donors were available in 6, 2 paediatric patients underwent left lobe and four adults underwent right lobe living donor liver transplant. Among the 44 ALF patients without a suitable living donor, one underwent deceased donor liver transplant and survived, another 19-year-old male with acute exacerbations of chronic hepatitis B recovered without transplant, and the rest died. Twenty-six had AoCLF and underwent four (1-10) MARS sessions. Sepsis (n=16) and upper gastrointestinal bleeding (n=4) were the commonest precipitating factors. None had a suitable living or deceased donor, suitable for transplantation during their hospitalization. Only one of 26 AoCLF patients survived the hospitalization, but the survivor died of sepsis 1 month later. CONCLUSION: In this non-randomized study, survival after MARS was related to the availability of transplant, and in patients where living or deceased donor transplant was unavailable, MARS was of little benefit. Randomized-controlled trials on MARS((R)) are urgently needed to clarify its clinical utility.

Prevalence and clinical associations of posttransplant fatty liver disease.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) could recur after liver transplant in patients with preexisting NAFLD, and has recently been reported to occur after transplant in patients transplanted without preexisting NAFLD. The literature on posttransplant NAFLD is limited. We aimed to study the prevalence of posttransplant NAFLD in patients transplanted for non-NAFLD-related liver diseases. METHODS: Thirty liver transplant recipients: 18 with chronic hepatitis B (CHB), seven with chronic hepatitis C (CHC), five others, were recruited. Liver biopsies were performed in all CHB and CHC patients annually as per protocol, or when clinically indicated. All biopsies were reviewed by one hepato-histopathologist blindly to assess and stage for steatosis and steatohepatitis. RESULTS: After a mean follow-up of 44+/-4 months, 12 (40%) and four (13%) developed posttransplant steatosis and steatohepatitis, respectively. None developed steatosis-related fibrosis or cirrhosis. Posttransplant steatohepatitis was associated with higher pretransplant body mass index (BMI) (32.3+/-3.9 vs 23.1+/-0.8, P=0.02) and higher BMI at last biopsy (32.5+/-4.3 vs 22.9+/-0.7, P=0.01). CONCLUSION: Posttransplant steatosis is common after liver transplant even in patients transplanted for non-NAFLD-related liver diseases. However, it is mostly benign during our follow-up, with only 13% developing steatohepatitis and none with fibrosis or cirrhosis.

A randomized, placebo-controlled trial of thymosin-alpha1 and lymphoblastoid interferon for HBeAg-positive chronic hepatitis B.

Combination therapy between two immunomodulators used for treatment of chronic hepatitis B was explored based on reported therapeutic efficacy of interferon-alpha, and thymosin-alpha1 as monotherapeutic agents to determine if combination therapy was superior to interferon alone. This double-blinded, randomized, placebo-controlled trial compares the addition of thymosin-alpha1, 1.6 microg taken three times per week (combination therapy) or thymosin placebo (monotherapy) to lymphoblastoid interferon (Wellferon), 5 million international units (MIU) taken three times per week, for 24 weeks. Entry criteria included positive hepatitis B e antigen (HBeAg); alanine aminotransferease (ALT) > or = 1.5 x upper normal limit, but < or = 10 x upper normal limit; positive HBV DNA; absence of cirrhosis; treatment naivety and no co-morbid factors. A total of 98 HBeAg-positive patients were recruited, of which 48 were randomized to combination therapy and 50 to monotherapy. The primary endpoint was the loss of HBeAg at 72 weeks. The secondary endpoints were HBeAg seroconversion, normalization of ALT, loss of HBV DNA and improvement in histology. The HBeAg loss was 45.8% and 28.0% for combination therapy and monotherapy, respectively (difference, 17.8%; 95% CI -1.2%-35.3%, P = 0.067). There was a trend towards HBeAg loss when using combination therapy. There were also no statistically significant differences between the different therapies with respect to the secondary endpoints of HBeAg seroconversion, changes in histology, normalization of ALT or loss of HBV DNA. In conclusion, this trial showed a 17.8% improvement in HBeAg loss rates using combination therapy over interferon monotherapy. This could clinically indicate a potential important difference that would need confirmation in subsequent trials.

Outcome from molecular adsorbent recycling system (MARS) liver dialysis following drug-induced liver failure.

RATIONALE: Fulminant liver failure from drug ingestion is associated with a high mortality, and the introduction of liver transplantation has improved the mortality significantly if done in a timely fashion. Recently, molecular adsorbent recycling system (MARS) liver dialysis has been introduced as a support for liver failure with varying results. We review our experience with drug-induced liver failure and the impact of MARS liver dialysis on the outcome, in a setting where cadaveric liver transplantation is rarely available. RESULTS: A total of 13 patients were treated, and 40 sessions of MARS liver dialysis were conducted in the intensive care unit. The majority of cases were because of herbal medicine toxicity. Total bilirubin, conjugated bilirubin, and delta bilirubin were significantly reduced, with no change in unconjugated bilirubin. All patients satisfied the criteria for urgent liver transplantation with an average Model End Stage Liver Disease (MELD) score of 35. Only one patient received a liver transplantation from a live donor (right lobe). Overall mortality was 85%. Median time-to-death from the start of MARS was 8 days. CONCLUSIONS: MARS liver dialysis in a setting without timely liver transplantation is associated with a poor outcome. It does, however, provide a window of time for consideration of living donors in the setting of limited cadaveric donors.

Outcome of lamivudine-resistant hepatitis B virus is generally benign except in cirrhotics.

AIM: We set to determine factors that determine clinical severity after the development of resistance. METHODS: Thirty-five Asian patients with genotypic lamivudine resistance were analyzed in three groups: 13/35 (37%) were non-cirrhotics with normal pre-treatment ALT (Group IA), 12/35 (34%) were non-cirrhotics with elevated pre-treatment ALT (Group IB), and 10/35 (29%) were cirrhotics (Group II). Patients were followed for a median of 98 wk (range 26-220) after the emergence of genotypic resistance. RESULTS: Group IA patients tended to retain normal ALT. Group IB patients showed initial improvement of ALT with lamivudine but 9/12 patients (75%) developed abnormal ALT subsequently. On follow-up however, this persisted in only 33%. Group II patients also showed improvement while on treatment, but they deteriorated with the emergence of resistance with 30% death from decompensated liver disease. Pretreatment ALT levels and CPT score (in the cirrhotic group) were predictive of clinical resistance and correlated with peak ALT levels and CPT score. CONCLUSION: The phenotype of lamivudine-resistant HBV correlated with the pretreatment phenotype. The clinical course was generally benign in non-cirrhotics. However, cirrhotics had a high risk of progression and death (30%) with the development of lamivudine resistance.

Remember to crush the tablets after esophageal stent insertion.

The main mode of palliation for inoperable esophageal cancer is by insertion of expandable metallic stents. While major complications include occlusion by tumor ingrowth and migration, impaction by food has been reported in as many as 10% of cases. Although patients are routinely instructed to follow a soft and finely minced diet after insertion of esophageal stents, stent blockage can still occur if patients swallow large-sized tablets. We report a case of stent blockage by 2 large-sized tablets, about which the endoscopist did not forewarn the patient or his family. The tablets were eventually dislodged easily through a repeat endoscopy. We caution about the possibility of such complication after esophageal stenting. We recommend inspection of patients' medication before the stenting procedure as well as instructing patients, their family, and care providers to crush their large-sized tablets before consumption.