Territory-wide population-based study of chronic hepatitis C infection and implications for hepatitis elimination in Hong Kong.

BACKGROUND: To study the epidemiology of chronic hepatitis C virus infection in Hong Kong and to estimate the service gap for achieving the WHO hepatitis elimination targets of attaining a diagnosis rate of 90%, treatment rate of 80% and 65% reduction in mortality rate by 2030. METHODS: From January 2005 to March 2017, patients who were tested positive for anti-HCV were retrospectively retrieved from all public hospitals in Hong Kong. The epidemiological data of 15 participating hospitals were analysed. RESULTS: A total of 11 309 anti-HCV+ patients were identified and the estimated diagnosis rate was 50.9%. Our HCV-infected patients were ageing (median age 59). The all-cause mortality rate increased from 26.2 to 54.8 per 1000 person-years over the last decade. Our estimated treatment rate was 12.4%. Among the treated patients, 93.6% had received pegylated interferon/ribavirin (Peg-IFN/RBV) but only 10.8% had received interferon-free direct-acting antivirals (DAAs). In a cohort of 1533 patients, 39% already had advanced liver fibrosis or cirrhosis. The sustained virological response rate for Peg-IFN/RBV and DAAs were 74.8% and 97.2% respectively. However, more than 70% of patients were not subjected to interferon treatment for various reasons. Patients who achieved SVR were associated with a significantly lower risk of HCC (4.7% vs 9.6%, P = 0.005) and death (1.7% vs 23.8%, P < 0.001). CONCLUSION: Our diagnosis rate, treatment rate and mortality rate reduction were still low, particularly the Peg-IFN outcomes, making it difficult to meet the WHO hepatitis elimination targets. A more generalized use of DAAs is urgently needed to improve the situation.

Early Viral Kinetics with Telbivudine, Tenofovir or Combination of Both in Immunotolerant Patients with Hepatitis B e Antigen-Positive Chronic Hepatitis B.

INTRODUCTION: Viral kinetics has proved useful in understanding antiviral potency, determining antiviral profiles and optimizing treatment strategy. METHODS: This was a randomized, open-label study comparing the viral kinetics in 46 hepatitis B e antigen-positive patients during 12-week treatment with telbivudine monotherapy, tenofovir monotherapy or the combination of telbivudine plus tenofovir. A standard biphasic mathematical model was used to compare hepatitis B virus (HBV) DNA decay parameters. RESULTS: Forty-six patients received telbivudine (n = 16), tenofovir (n = 14) or telbivudine plus tenofovir (n = 16). From baseline to Week 12, the mean (SD) reduction in HBV DNA levels was not significantly different between treatment groups: -3.9 (0.9) log10 copies/mL in telbivudine group, -4.2 (0.7) log10 copies/mL in tenofovir group, and -4.4 (1.0) log10 copies/mL in combination group. No significant difference was observed among the three groups for viral clearance rate per day (0.97, 1.02, and 0.88, respectively) or for infected cell loss rate per day (0.04, 0.05, and 0.05, respectively). Antiviral efficiency in blocking viral production was similar in the monotherapy groups (median; 99.7% in telbivudine group and 99.4% in tenofovir group), but was slightly better and more homogeneous in the combination treatment group than in the monotherapy groups: mean (SD), 99.1% (0.8%) and 98.8% (1.6%), respectively (Wald-Wolfowitz test; P = 0.038). All treatments were well tolerated and no serious adverse event was reported during the study. Of the 46 patients in the safety population, 23 experienced adverse events. Most of the adverse events were not suspected to be related to the study drug by the investigators. CONCLUSION: Monotherapy with telbivudine or tenofovir showed similar antiviral effectiveness in HBV DNA reduction and viral kinetics of HBV DNA decay. Efficiency in blocking viral production was slightly improved in the combination treatment group compared to the monotherapy groups.

Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab.

PURPOSE: Reactivation of hepatitis B virus (HBV) infection is a well-recognized complication in cancer patients with chronic HBV (hepatitis B surface antigen [HBsAg] positive) undergoing cytotoxic chemotherapy. In patients who have resolved HBV (HBsAg negative and antibody to hepatitis B core antigen [anti-HBc] +/- antibody to hepatitis B surface antigen [anti-HBs] positive), such incidence has been much less common until recent use of rituximab. In this study on HBsAg-negative/anti-HBc-positive lymphoma patients, the objectives were to determine the HBV reactivation rate in patients treated with rituximab-containing chemotherapy and to compare it with the rate in patients treated without rituximab. PATIENTS AND METHODS: Between January 2003 and December 2006, all patients diagnosed with CD20(+) diffuse large B-cell lymphoma (DLBCL) had HBsAg determined before anticancer therapy. They were treated with either cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) alone or rituximab plus CHOP (R-CHOP). HBsAg-negative patients had anti-HBc determined; serum was stored for anti-HBs and HBV DNA. All patients were observed for HBV reactivation, which was defined as detectable HBV DNA with ALT elevation during and for 6 months after anticancer therapy. RESULTS: Among 104 CD20(+) DLBCL patients, 80 were HBsAg negative. Of the latter, 46 patients (44.2%) were HBsAg negative/anti-HBc positive; 25 of these patients were treated with CHOP, and none had HBV reactivation. In contrast, among the 21 patients treated with R-CHOP, five developed HBV reactivation, including one patient who died of hepatic failure (P = .0148). Exploratory analysis identified male sex, absence of anti-HBs, and use of rituximab to be predictive of HBV reactivation. CONCLUSION: Among HBsAg-negative/anti-HBc-positive DLBCL patients treated with R-CHOP, 25% developed HBV reactivation. Close monitoring until at least 6 months after anticancer therapy is required, with an alternative approach of prophylactic antiviral therapy to prevent this potentially fatal condition.

How should we manage patients with non-alcoholic fatty liver disease in 2007?

Evidence-based management guidelines for non-alcoholic fatty liver disease (NAFLD) are lacking in the Asia-Pacific region or elsewhere. This review reports the results of a systematic literature search and expert opinions. The Asia-Pacific Working Party on NAFLD (APWP-NAFLD) has generated practical recommendations on management of NAFLD in this region. NAFLD should be suspected when there are metabolic risk factors and/or characteristic changes on hepatic ultrasonography. Diagnosis by ultrasonography, assessment of liver function and complications, exclusion of other liver diseases and screening for metabolic syndrome comprise initial assessment. Liver biopsy should be considered when there is diagnostic uncertainty, for patients at risk of advanced fibrosis, for those enrolled in clinical trials and at laparoscopy for another purpose. Lifestyle measures such as dietary restrictions and increased physical activity (aerobic exercise) should be encouraged, although the best management strategy to achieve this has yet to be defined. Complications of metabolic syndrome should be screened for regularly. Use of statins to treat hypercholesterolemia is safe and recommended; frequent alanine aminotransferase (ALT) monitoring is not required. Obese patients who do not respond to lifestyle measures should be referred to centers specializing in obesity management; consideration should be given to bariatric surgery or gastric ballooning. The role of pharmacotherapy remains investigational and is not recommended for routine clinical practice. Non-alcoholic fatty liver disease should be recognized as part of the metabolic syndrome and managed in a multidisciplinary approach that addresses liver disease in the context of risk factors for diabetes and premature cardiovascular disease. Lifestyle changes are the first line and mainstay of management.

Hepatitis B viral load predicts survival of HCC patients undergoing systemic chemotherapy.

UNLABELLED: HCC is a common cause of morbidity and mortality. For patients who are not candidates for curative surgery, systemic chemotherapy is one of the standard treatments. In parts of China and the Far East, over 80% of HCC patients have chronic HBV infection. In this study, we aimed to assess the relationship between pre-chemotherapy HBV viral load and the survival of HCC patients. HBV infection status was determined prior to chemotherapy in 188 patients, 170 of whom had evidence of HBV chronic infection/exposure (160 hepatitis B surface antigen [HBsAg]-positive, 10 HBsAg-negative/hepatitis B core antibody-positive). Of these, 125 had pretreatment HBV DNA levels determined via real-time PCR. Virological data were analyzed using conventional clinical variables to identify factors that influenced survival. Multivariate analysis revealed that high total bilirubin (P = 0.0016; hazard ratio = 1.040 per 1 muM increase; 95% CI 1.015-1.065), HCV infection (P = 0.0095; hazard ratio = 6.955; 95% CI 1.606-30.129), and high HBV DNA level (P = 0.0217; hazard ratio = 1.650; 95% CI 1.076-2.531) affected survival significantly. Exploratory analysis revealed that high levels of pretreatment HBV DNA had a significantly higher incidence of severe hepatitis during chemotherapy. CONCLUSION: For HCC patients with HBV chronic infection/exposure, a high viral load prior to treatment is an adverse factor for survival and may be associated with a higher incidence of severe hepatitis during chemotherapy. Future strategies to improve the prognosis of HCC patients undergoing chemotherapy should consider supportive therapy that incorporates antiviral therapies to reduce HBV viral load.

Intrahepatic hepatitis B virus covalently closed circular DNA can be a predictor of sustained response to therapy.

BACKGROUND & AIMS: This study aimed to determine whether intrahepatic hepatitis B virus (HBV) covalently closed circular (ccc) DNA and total HBV DNA levels at the end of therapy would predict sustained response to therapy. METHODS: Hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients receiving either lamivudine monotherapy or combination of peginterferon and lamivudine had liver biopsy at the end of 1 year therapy and were followed for 52 more weeks after cessation of therapy. Serum HBV DNA, intrahepatic HBV ccc DNA, and total HBV DNA levels were determined. RESULTS: Forty-seven patients, including 34 males and 13 females, were studied. Twenty-seven patients received combination therapy, and 20 patients received lamivudine monotherapy. Twenty-nine patients had end-of-treatment virologic response, and 15 patients had sustained response 52 weeks after therapy. At the end of treatment, log serum HBV DNA levels correlated well with log intrahepatic HBV cccDNA and log intrahepatic total HBV DNA levels. Log intrahepatic cccDNA and log intrahepatic total DNA levels were significantly lower among patients with sustained virologic response. The adjusted odds ratio for log cccDNA was 5.3 (95% CI: 1.5-18.2, P = .009) and, for log intrahepatic HBV DNA, was 4.4 (95% CI: 1.3-14.7, P = .015) to predict sustained virologic response. Using log cccDNA at -0.80 copies/genome equivalent as cutoff, the sensitivity, specificity, and positive and negative predictive values and accuracy of predicting sustained virologic response were 73%, 78%, 56%, 86%, and 77% respectively. CONCLUSIONS: Intrahepatic HBV cccDNA and intrahepatic total HBV DNA levels at the end of therapy are superior to serum HBV DNA as surrogates of sustained virologic response.

Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B.

YMDD variants of hepatitis B virus (HBV) emerge in some patients with chronic hepatitis B who receive lamivudine. YMDD variants were examined in 794 patients in 4 controlled studies of 1 year's duration. The long-term effects of YMDD variants were examined in a subset of patients treated up to 4 years. YMDD variants were detected by polymerase chain reaction (PCR) and restriction fragment-length polymorphism assays. After 1 year, YMDD variants were detected in 81 (24%) of 335 patients. In these patients, the median serum HBV DNA concentration at 1 year was <20% of the baseline level, and serum alanine transaminase (ALT) levels and liver histologic findings had significantly improved. In patients with YMDD variants who were treated for up to 4 years, median HBV DNA and ALT levels showed improvements. Sex, baseline body mass index, and HBV DNA level were associated with emergence of YMDD variants. Patients with YMDD variants losing clinical response with a significant increase in the HBV DNA and ALT levels may require additional therapy.

Management of viral hepatitis C.

The hepatitis C virus was first identified in 1989. It causes chronic hepatitis, cirrhosis and hepatocellular carcinoma. Global anti-HCV prevalence is 1-3%. Contaminated blood product, dirty needles and instruments, and injection drug use are the main parenteral routes of transmission. Cultural practices, such as acupuncture, tattoo, body piercing and scarring, also play a role. Universal precaution is the mainstay for prevention before vaccine is developed. Therapy for chronic hepatitis C (CHC) with interferon (IFN) is not satisfactory. Non-response and early relapse reduce sustained response (SR). In 1997, National Institute of Health consensus recommended IFN therapy only for selected patients with compensated CHC, raised ALT and moderate to severe histologic disease activity; 15-20% SR is expected. Major advances in CHC therapy is combination therapy. Ribavirin in combination with IFN significantly increases SR to 30-40%. Even patients with high viral load, genotype 1, significant fibrosis or cirrhosis respond better. EASL and APASL Consensus in 1999 recommended IFN-ribavirin combination as the first line therapy. Recent data on pegylated IFN showed very encouraging results. Combined with ribavirin, 60% SR was achieved. It benefits patients with severe bridging necrosis and also cirrhosis. However, 23-27% of patients receiving combination therapy with either IFN type, experienced adverse events and required therapy discontinuation. Many important issues remained unsolved. Therapy for children, the elderly, patients with comorbidity and extra-hepatic syndromes need to be addressed. Therapy is too expensive and not affordable to the majority of patients in developing countries.