Predictors of response to tenofovir disoproxil fumarate plus peginterferon alfa-2a combination therapy for chronic hepatitis B.

BACKGROUND: In patients with chronic hepatitis B, tenofovir disoproxil fumarate (TDF) plus pegylated interferon (PEG-IFN) for 48-weeks results in higher rates of hepatitis B surface antigen (HBsAg) loss than either monotherapy. AIM: To identify baseline and on-treatment factors associated with HBsAg loss at Week 72 and provide a model for predicting HBsAg loss in patients receiving combination therapy for 48 weeks. METHODS: A secondary analysis of data from an open-label study where patients were randomised to TDF (300 mg/day, oral) plus PEG-IFN (PI, 180 µg/week, subcutaneous) for 48 weeks (TDF/PI-48w); TDF plus PEG-IFN for 16 weeks, TDF for 32 weeks (TDF/PI-16w+TDF-32w); TDF for 120 weeks (TDF-120w) or PEG-IFN for 48 weeks (PI-48w). Logistic regression methods were used to identify models that best predicted HBsAg loss at Week 72. RESULTS: Rates of HBsAg loss at Week 72 were significantly higher in the TDF/PI-48w group (6.5%) than in the TDF/PI-16w+TDF-32w (0.5%), TDF-120w (0%) and PI-48w (2.2%) groups (P = 0.09). The only baseline factor associated with response was genotype A. HBsAg decline at Week 12 or 24 of treatment was associated with HBsAg loss at Week 72 (P < 0.001). HBsAg decline >3.5 log10 IU/mL at Week 24 in the TDF/PI-48w group resulted in a positive predictive value of 85% and a negative predictive value of 99% for HBsAg loss at Week 72. CONCLUSIONS: HBsAg decline at Week 24 of TDF plus PEG-IFN combination therapy may identify patients who, after completing 48 weeks of treatment, have a better chance of achieving HBsAg loss at Week 72.

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.

Resolution of adefovir-related nephrotoxicity by adefovir dose-reduction in patients with chronic hepatitis B.

BACKGROUND: Chronic hepatitis B patients (CHB) treated with adefovir were followed up to evaluate nephrotoxicity and its outcome. AIM: To assess the incidence of renal dysfunction during adefovir therapy in Asian patients and factors associated with it, and evaluate strategies to improve adefovir-related renal dysfunction and their impact on viral suppression. METHODS: Chronic hepatitis B clinic patients from a tertiary hospital on adefovir treatment, with their clinical and laboratory parameters were extracted from the hospital electronic clinical database in an observational study design. Patients were excluded if they had liver/renal transplant, baseline renal impairment or were on dialysis. Adefovir-related renal dysfunction was defined as adefovir-related abnormal serum creatinine (ARASC) > 125 µmol/L (males), >90 µmol/L (females); adefovir-related abnormal GFR <60 mL/min; and adefovir-related increased serum creatinine >0.5 mg/dL, without other known causes of nephrotoxicity. RESULTS: A total of 271/383 adefovir-treated patients were suitable for analysis and 33(12%) patients developed abnormal serum creatinine. Cumulative increase in proportion of patients with ARASC was 33.8% and GFR ≤60 mL/min was 38.3% by 6 years, while serum creatinine increase ≥0.5 mg/dL was 21.48% by 5 years. Using multivariate analysis, the only independent baseline predictor of ARASC was GFR ≤76.1 mL/min. Patients who had ARASC had similar levels of viral suppression to those who did not have ARASC. Those who had ARASC either continued adefovir (24%), switched therapy (24%) or had adefovir dose reduction (52%). ARASC resolved and GFR normalised in almost all patients after either switching therapy or reducing adefovir dose, with no difference between the two strategies (P = 0.737). Those with adefovir dose reduction had no significant increase in HBV DNA (P = 0.170). CONCLUSIONS: Adefovir-related renal dysfunction occurred in a significant number of adefovir-treated patients, but reduction of the dose led to renal improvement without compromising treatment efficacy.

Cultural adaptation and validation of a questionnaire for use in hepatitis B patients.

Health-related quality of life (HRQoL) is an important aspect of the overall management of hepatitis B virus (HBV) infection. The major challenge is to find a valid and reliable disease-specific HRQoL instrument designed specifically for measuring health status in hepatitis B patient. Consequently, this study was undertaken to adapt culturally the Hepatitis Quality of Life Questionnaire (HQLQ) and assess its suitability for use in English-speaking hepatitis B virus-infected (HBV) patients in Singapore. Two patient focus groups were conducted to facilitate the cultural adaptation of the HQLQ. Reliability was assessed using Cronbach's alpha coefficients and intraclass correlation coefficients. Item-to-scale correlation was assessed using Spearman's rank correlations (rho) between scale scores and their constituent items. Convergent and divergent construct validities were tested in three and two a priori hypotheses, respectively, and the correlations were assessed using Spearman's rank correlation coefficients (rho). The culturally adapted questionnaire was tested in 298 HBV patients. The test-retest reliability was supported with 10 of the 12 scales showing acceptable correlation coefficients (i.e. alpha>0.7). Item-to-scale correlations were good with most items highly correlated with their hypothesized scales. Convergent and divergent construct validities were supported by the presence of hypothesized correlations between the HQLQ and the EQ-5D domains (eight of 10 sub-hypotheses for convergent construct validity and all hypotheses for divergent construct validity were fulfilled). In conclusion, our results showed that the culturally adapted HQLQ has good validity and reliability, making it a potentially useful outcome measure in the evaluation of HBV patients in Singapore.

How big is the financial burden of hepatitis B to society? A cost-of-illness study of hepatitis B infection in Singapore.

Hepatitis B virus (HBV) infection is the most common cause of chronic viral liver disease in Singapore. Nevertheless, very little data exist on the financial burden of HBV infection to the society as a whole. The aim of this study was therefore to assess the direct and indirect cost of HBV infection in a cost-of-illness analysis. The combined data from the direct and indirect cost with the estimated prevalence for different disease stages of HBV infection would represent the annual financial burden of HBV infection to the Singaporean society as a whole. The estimated total annual cost of chronic HBV infection and its associated complications in Singapore was US$279 million (range US$34-941 million when allowing various assumptions as tested by the sensitivity analyses), with 58% or US$161 million attributable to direct cost. Based on the base-case estimation, total direct cost alone is equivalent to 12% of the national healthcare expenditure for 2003. The total cost incurred by chronic hepatitis B patients represents the biggest cost component, followed by decompensated cirrhosis (DC) patients. The ratio of direct to indirect costs based on the base-case estimation increased with disease severity, with the highest ratio obtained for the post-liver transplants (40.2:1), followed by hepatocellular carcinoma (7.4:1) and DC patients (2.7:1). The results of this study suggest that the management of HBV infection poses more than a medical challenge as it is a sizeable economic burden from both the payer and societal perspectives.

Clinical trial: a phase II, randomized study evaluating the safety, pharmacokinetics and anti-viral activity of clevudine for 12 weeks in patients with chronic hepatitis B.

BACKGROUND: Clevudine is a polymerase inhibitor that has the unusual feature of delayed viral rebound after therapy in some patients which may be related to its pharmacokinetics. AIM: To characterize pharmacokinetic and pharmacodynamic profile of clevudine, a potent hepatitis B polymerase inhibitor. METHODS: A multicenter, randomized study comparing 10, 30 and 50 mg clevudine once daily for 12 weeks with 24 weeks off-treatment follow-up. Patients had chronic HBV infection, were nucleoside-naïve without co-infection. HBV viral load (VL) was assayed using Digene Hybrid Capture II with a lower limit of detection of 4700 copies/mL (940 IU/mL). Clevudine levels were measured using a liquid chromatography/mass spectrometery method. RESULTS: A total of 31 patients were enrolled into the 10 mg (n = 10), 30 mg (n = 11) and 50 mg (n = 10) groups, respectively. At week 12, the median VL change was -3.2, -3.7 and -4.2 log(10) copies/mL (-0.64, -0.74 and -0.84 log(10) IU/mL) in the 10, 30 and 50 mg groups, respectively (P = 0.012). At week 12, one of 10, five of 11 and two of 10 patients had VL below the assay lower limit of detection. Clevudine was well tolerated with no severe/serious adverse events. The mean plasma half-life of clevudine was 70 h and consequently is not the cause of the delayed viral rebound seen in some patients. Through modelling, 97% of the maximal treatment effect was reached with a 30 mg daily dose. Six patients had genomic changes without viral rebound. CONCLUSION: Clevudine appears to be a potent and tolerable (over 12 weeks) anti-viral and the optimal dosage appears to be 30 mg once daily.

Clinical trial: effects of adefovir dipivoxil therapy in Asian and Caucasian patients with chronic hepatitis B.

BACKGROUND: Two-thirds of the 350 million people infected with chronic hepatitis B virus live in the Asia-Pacific region. AIM To compare the effects of adefovir dipivoxil therapy between Asian and Caucasian patients with chronic hepatitis B. METHODS: The safety and efficacy of 10 mg of adefovir dipivoxil was compared to placebo in 501 Asian (n = 259) or Caucasian (n = 242) HBeAg+ and HBeAg- chronic hepatitis B virus patients treated for 48 weeks in two randomized, double-blind, placebo-controlled studies. RESULTS: At week 48, histological improvement was observed in 60% and 56% of Caucasian and Asian patients, respectively. Change in serum hepatitis B virus DNA from baseline to week 48 for the adefovir dipivoxil-treated patients was -3.89 and -3.70 log(10) copies/mL in Caucasian and Asian patients, respectively, while 34 per cent of Caucasian patients and 39 per cent of Asian patients had undetectable serum hepatitis B virus DNA (<400 copies/mL) at week 48. The percentage of patients achieving alanine aminotransferase (ALT) normalization at week 48 was similar in both groups (Caucasian 64 per cent, Asian 63 per cent). No patients developed resistance through week 48. No differences in adverse events or grade 3 or 4 laboratory abnormalities were observed between groups. CONCLUSIONS: There were no significant differences in treatment response between Asians and Caucasians. Adefovir dipivoxil was well tolerated and no resistance developed up to week 48 in both racial groups.

Structural and expression analyses of two vitellogenin genes in the carp, Cyprinus carpio.

We cloned and sequenced two vitellogenin (vg) cDNAs of the carp, Cyprinus carpio, using a cDNA library constructed from estradiol-17 beta (E2)-treated livers. One was a novel, longer 5000 bp-long cDNA termed vg-B2 encoding 1624 amino acids in a single open reading frame. The other was a shorter cDNA (vg-B1), identical to that registered previously as carp vg cDNA in the international nucleotide sequence database. The deduced amino acid sequences of these two molecules were well-aligned with known vertebrate Vgs sharing common characteristics such as N-terminal lipovitellin I (LVI), phosvitin (PV) and C-terminal lipovitellin II (LVII). The novel Vg-B2 bore a highly conserved GL/ICG motif within the LVII region, in contrast to the shorter Vg-B1 that has a truncated C-terminal and lacks the beta-component within the LVII region including the GL/ICG motif. Both vg-B2 and vg-B1 genes were expressed in the livers of females and E2-injected males. Western blot analysis using anti-Vg and anti-vitellin (Vn) antisera demonstrated that both Vg-B2 and Vg-B1 were detected as polypeptides with an estimated molecular mass of 180 kDa and 160 kDa, respectively, in the blood of females and E2-injected males. The results suggest the potential utilization of these genes as sensitive xenoestrogenic markers.

Liver transplantation in Singapore 1990-2004.

INTRODUCTION: Liver transplantation is the accepted standard of care for patients with hepatocellular carcinoma, decompensated liver cirrhosis, and acute liver failure. Since the first liver transplant done in Singapore in 1990, results have been improving. We review the overall results of liver transplantation over the last 15 years. METHODS: All transplant cases from 1990 to 2004 were reviewed retrospectively. RESULTS: 100 liver transplants were performed over the last 15 years; four in the first five years and 96 in the subsequent ten years. Overall one- and five-year survival rates were 80 percent and 78 percent, respectively. 44 were paediatric transplants, of which biliary atresia was the commonest indication for paediatric transplant. 56 were adult transplants of which hepatocellular carcinoma and decompensated hepatitis B cirrhosis were the commonest indications for adult transplant. Infection remained the commonest cause of mortality. CONCLUSION: The number of transplants carried out per year was small due to the low cadaveric donation rate, but the survival of liver transplant patients was comparable to well-established liver transplant centres.

Liver transplantation for hepatocellular carcinoma in Singapore.

INTRODUCTION: The prognosis of patients with hepatocellular carcinoma (HCC) is poor. Surgical resection offers the benefit of removal of the tumour but is associated with liver decompensation and tumour recurrence, even after successful surgery. Liver transplantation offers the benefits of complete tumour removal with prevention of both decompensation and recurrence post-operation. This paper aims to review results of liver transplantation for patients with HCC in Singapore. METHODS: All adult patients with HCC accepted on the waiting list for liver transplantation (based on the Milan criteria) from 1996 to 2004 in Singapore were reviewed. Patients' HCC were managed with either transarterial chemoembolisation or percutaneous radiofrequency ablation while they were on the waiting list. Post-transplant survival and factors associated with mortality were analysed by Cox regression analysis. RESULTS: 41 patients with HCC were accepted onto the waiting list over the nine-year period. 22 underwent transplantation and 19 did not, with a one-year survival of 91 percent versus 24 percent, respectively. (p-value is less than 0.001). Mean waiting time for transplant was 39 weeks. Post-transplant HCC recurrence was 2/22 (nine percent). Among all patients, mortality was significantly related to baseline white cell counts, prothrombin time, age, alpha-foetoprotein level, Child-Pugh score, and whether patients underwent transplant. CONCLUSION: Despite the relatively long waiting time of a mean of 39 weeks, post-transplant recurrence of HCC was relatively low at nine percent. Liver transplant is an effective treatment for patients with a HCC, with a reasonable long-term survival.

Long-term results of liver transplant in patients with chronic viral hepatitis-related liver disease in Singapore.

INTRODUCTION: Liver disease from chronic hepatitis B (CHB) and C (CHC) constitutes 57 percent of adult liver transplant in Singapore. Their long-term results post-transplant may be affected by recurrence of the viral illness. This study aims to evaluate the long-term results and survival in patients transplanted for CHB- and CHC-related liver disease. METHODS: Patients transplanted for CHB- and CHC-related disease from 1990 until March 2004, which included decompensated cirrhosis and hepatocellular carcinoma (HCC), were reviewed and analysed. RESULTS: 25 patients were transplanted for CHB-related liver disease, with mean follow-up of 153 +/- 25 weeks. Two- and four-year survival rates were 75 percent and 69 percent, respectively. Hepatitis B recurrence from YMDD mutants occurred in five patients, and four were treated successfully with adefovir dipivoxil, with resolution in transaminases and/or improvement in histology. One patient became non-compliant with follow-up and medications, and died 173 weeks post-transplant from reactivation of the wild-type hepatitis B virus. Nine patients were transplanted for CHC-related liver disease, with mean follow-up of 188 +/- 40 weeks, and two- and four-year survival rates of 89 percent and 76 percent, respectively. Two patients developed hepatitis C recurrence and were treated with interferon and ribavarin. One responded with sustained response but the other remained viraemic and died of HCC recurrence two years post-transplant. CONCLUSION: Long-term results from CHB- and CHC-related liver diseases were satisfactory and comparable to major transplant centres in the USA and Europe. Recurrence of viral hepatitis post-transplant is controllable with current antiviral therapy.

MELD may not be the better system for organ allocation in liver transplantation patients in Singapore.

INTRODUCTION: The Model for End-Stage Liver Disease (MELD) score is a good predictor of mortality on the liver transplant waiting list and is the current system of organ allocation in the USA. However, a higher MELD may be associated with poorer outcome post-liver transplantation. The aim of this study was to determine if MELD should be implemented as the system for organ allocation for liver transplantation in Singapore. METHODS: There were 46 adult patients who underwent primary liver transplantation at the National University Hospital, Singapore from January 1996 to December 2002. We applied the MELD score to patients who were transplanted and looked for a correlation with survival post-transplant. Patients were followed-up until the most recent visit or death. Survival analysis was performed using Cox regression and Kaplan-Meier method. RESULTS: The mean age at transplant was 52.7 (SD 2.34) years. The majority of the patients transplanted had Hepatitis B (43 percent). The median MELD score at transplantation was 17 (7-42) and the median Child's score was 11 (6-15). There was a significant correlation between pre-transplant MELD and survival at six months (p-value is 0.037, 95 percent confidence interval [CI] is 1.004-1.13) but not at one year (p-value is 0.065, 95 percent CI is 0.99-1.12). There were no differences in the pre-transplant MELD (odds-ratio [OR] 1, 95 percent CI 0.9-1) as well as survival for patients with and without Hepatitis B (OR 0.72, 95 percent CI 0.22-2.35). CONCLUSION: MELD allows livers to be allocated to the patients with the greatest medical urgency but its influence on post-transplant survival should be further clarified so that post-transplant survival is not compromised.

Referral patterns and waiting times for liver transplantation in Singapore.

INTRODUCTION: Referral patterns, waiting times, waiting list, and mortality provide information on how effectively a transplant programme deals with referred patients. This paper aims to review these parameters in the Singapore National Liver Transplant Programme. METHODS: Data of all patients referred to the Singapore National Liver Transplant Programme since its inception were captured and outcomes were retrieved and described. RESULTS: 562 patients were referred for liver transplant evaluation from 1990-2004, consisting of 457 adults and 105 children. The main indications for referral were hepatitis B liver disease and hepatocellular carcinoma in adults, and biliary atresia in children. Most patients were of United Network of Organ Sharing (UNOS) status 3 or 4 at the time of referral. 114 (20.28 percent) patients had transplants, consisting of 66 adults (14.44 percent) and 48 (45.71 percent) children. 138 adults and ten children were rejected for transplant, mainly for the reason of being "too early". The median waiting time for adults who had transplants was 3.3 months while adults still on the waiting list had been waiting for 16.2 months. The overall waiting list mortality was 44.3 percent, being 52.5 percent in adults and 23.2 percent in children. CONCLUSION: The overall transplantation rate is low and the waiting list mortality is high as a result of low availability of organs, particularly in adults. Paediatric liver transplant appears to have been better at dealing with referred patients but this is probably due to availability of living-related liver transplant. Improvement in these may result from the Human Organ Transplant Act.

Long-term post-liver transplant complications of renal impairment and diabetes mellitus: data from Singapore.

INTRODUCTION: Patients who survive the initial post-liver transplantation period face the development of chronic diseases in the long run. We studied two important complications of liver transplantation, namely: renal impairment and diabetes mellitus. METHODS: We analysed adult patients followed-up for more than one year using data from our liver transplant clinical records. Long-term post-transplant renal impairment (RI) was defined as glomerular filtration rate (GFR) less than 60 ml/min/1.73 square metres and long-term post-transplant diabetes mellitus (DM) was defined as fasting blood glucose more than 7.8 mmol/L, that existed at least one year after liver transplantation. Pre- and post-transplant factors that could be associated with these conditions were examined. RESULTS: Altogether, 35 patients were evaluated. Mean age at transplant was 50 years. Mean duration of follow-up was 58.4 months. There was 11.4 percent of pre-transplant RI and 17.0 percent of pre-transplant DM. Prevalence of post-transplant RI was 43.5 percent at one year and 45.0 percent at four years. Long-term post-transplant RI was associated with renal impairment at six months post-transplant (p-value is 0.033). Prevalence of severe post-transplant RI (GFR is less than 30 ml/min/1.73 square metres) at four years was 5.7 percent. Prevalence of post-transplant DM was 45.5 percent at two years but declined to 5.3 percent at four years. CONCLUSION: Post-transplant renal impairment appears to be a potential long-term problem while post-transplant diabetes mellitus appears to improve with time.

Treatment of steroid-resistant acute liver transplant rejection with basiliximab.

Current rescue therapies for acute steroid-resistant rejection, such as OKT3 and high-dose tacrolimus, are not uncommonly associated with side effects that contribute to significant morbidity of the patient. Basiliximab is a chimeric monoclonal antibody that acts as an interleukin-2 receptor antagonist on the surface of activated T lymphocytes. It has until now only been used as immunoprophylaxis in adult liver transplant patients. In this report, we describe the use of Basiliximab as rescue therapy in a case of acute steroid-resistant rejection in an adult living related liver transplant recipient.