Editorial: Direct Antiviral Agents Eliminate the Age Barrier to Treatment of Chronic Hepatitis C.

Interferon-based therapy for chronic hepatitis C in elderly patients, who are at greatest risk for advanced disease, resulted in low sustained virologic response rates, poor tolerability, a significant frequency of adverse events leading to treatment discontinuation, and the occasional precipitation of hepatic decompensation. In contrast, in the era of direct-acting antiviral therapy, age is no longer a predictor of response rates in those with or without cirrhosis and adverse events are much less frequent. The benefits of treatment of the elderly appear to outweigh potential risks but long-term follow-up is necessary, particularly in those with advanced disease.

Toxicity from repeated doses of acetaminophen in children: assessment of causality and dose in reported cases.

Liver injury has been reported in children treated with repeated doses of acetaminophen. The objective of this study was to identify and validate reports of liver injury or death in children younger than 6 years who were administered repeated therapeutic doses of acetaminophen. We reviewed US Poison Center data, peer-reviewed literature, US Food and Drug Administration Adverse Event Reports, and US Manufacturer Safety Reports describing adverse effects after acetaminophen administration. Reports that described hepatic abnormalities (description of liver injury or abnormal laboratory testing) or death after acetaminophen administration to children younger than 6 years were included. The identified reports were double abstracted and then reviewed by an expert panel to determine if the hepatic injury was related to acetaminophen and whether the dose of acetaminophen was therapeutic (≤75 mg/kg) or supratherapeutic. Our search yielded 2531 reports of adverse events associated with acetaminophen use. From these cases, we identified 76 cases of hepatic injury and 26 deaths associated with repeated acetaminophen administration. There were 6 cases of hepatic abnormalities and no deaths associated with what our panel determined to be therapeutic doses. A large proportion of cases could not be fully evaluated due to incomplete case reporting. Although we identified numerous examples of liver injury and death after repeated doses of acetaminophen, all the deaths and all but 6 cases of hepatic abnormalities involved doses more than 75 mg/kg per day. This study suggests that the doses of less than 75 mg/kg per day of acetaminophen are safe for children younger than 6 years.

Report of an international workshop: Roadmap for management of patients receiving oral therapy for chronic hepatitis B.

An international group of experienced hepatologists and virologists conducted a single-day workshop to review the management of patients with chronic hepatitis B receiving treatment with oral nucleosides or nucleotides. Guidelines regarding on-treatment management and available published data on the importance of serum hepatitis B virus (HBV) DNA as a marker of outcomes were reviewed. On-treatment monitoring strategies to define early virologic responses that might be predictive of better outcomes and a reduced risk of viral resistance were proposed for further study. This treatment plan, labeled the roadmap concept, recommends monitoring of serum HBV DNA levels to identify outcomes of therapy. Primary treatment failure was defined as a reduction of serum HBV DNA levels by less than 1 log10 IU/mL from baseline at week 12. Measurement of the HBV DNA level at week 24 was considered essential to characterize virologic responses as complete, partial, or inadequate. Complete virologic response was defined as negative HBV DNA by a sensitive assay (<60 IU/mL or <300 copies/mL); partial virologic response was defined as HBV DNA levels less than 2000 IU/mL (4 log10 copies/mL), and inadequate virologic response was defined as HBV DNA levels of 2000 IU/mL or greater (4 log10 copies/mL). Strategies are proposed for managing patients in each of these categories, depending in part on the rapidity with which HBV DNA suppression is achieved and the emergence of genotypic mutations that reduce the effectiveness of a specific drug. Future studies of the use of the roadmap concept in improving outcomes of chronic hepatitis B are warranted.

The therapeutic use of acetaminophen in patients with liver disease.

Acetaminophen has been used safely and effectively for many years to manage pain and/or fever in patients of all ages. It is commonly recommended as first-line therapy for a variety of patients and conditions, including the elderly, children with viral illnesses, and patients with osteoarthritis, gastrointestinal conditions, bleeding disorders, cardiovascular disease, or renal disease. However, its use is often avoided in patients with chronic liver disease. The perception that acetaminophen should be avoided in such patients arose from awareness of the association between massive acetaminophen overdose and hepatotoxicity, combined with a lack of understanding of the metabolism of acetaminophen in patients with liver disease. There are various theoretical mechanisms of acetaminophen hepatotoxicity in chronic liver disease including: altered metabolism and depleted glutathione stores that would be expected to increase accumulation of the hepatotoxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI). Available studies in patients with chronic liver disease, however, have shown that although the half-life of acetaminophen may be prolonged, cytochrome P-450 activity is not increased and glutathione stores are not depleted to critical levels in those taking recommended doses. Furthermore, acetaminophen has been studied in a variety of liver diseases without evidence of increased risk of hepatotoxicity at currently recommended doses. Therefore, acetaminophen can be used safely in patients with liver disease and is a preferred analgesic/antipyretic because of the absence of the platelet impairment, gastrointestinal toxicity, and nephrotoxicity associated with nonsteroidal antiinflammatory drugs.

Regional variation in the cost effectiveness of childhood hepatitis A immunization.

BACKGROUND: Routine childhood hepatitis A immunization is recommended in regions with incidence rates twice the national average, but it may be cost-effective in a wider geographic area. OBJECTIVE: To evaluate the costs and benefits of potential hepatitis A immunization of healthy US children in regions with varying hepatitis A incidences. METHODS: We considered vaccination of the 2000 US birth cohort in states defined by historic hepatitis A incidence rates. Infections among potential vaccinees and their personal contacts were predicted from age 2 through 85 years. Net vaccination costs were estimated from health system and societal perspectives and were compared with life-years saved and quality-adjusted life years (QALYs) gained using a 3% discount rate. RESULTS Nationally vaccination would prevent >75 000 cases of overt hepatitis A disease. Approximately two-thirds of health benefits would accrue to personal contacts rather than to vaccinees themselves. In states with incidence rates of > or =200%, 100 to 199%, 50 to 99% and <50% the national average, societal costs per QALY gained would be <0, <0, 13,800 and 63,000 US dollars, respectively. Nationally vaccination would cost 9100 US dollars per QALY gained from the perspective of the health system and 1400 US dollars per QALY gained from society's perspective. Results are most sensitive to vaccination costs and rates of disease transmission through personal contact. CONCLUSION: Childhood hepatitis A vaccination is most cost-effective in areas with the highest incidence rates but would also meet accepted standards of economic efficiency in most of the US. A national immunization policy would prevent substantial morbidity and mortality, with cost effectiveness similar to that of other childhood immunizations.

An economic assessment of pre-vaccination screening for hepatitis A and B.

OBJECTIVE: The availability of a single vaccine active against hepatitis A and B may facilitate prevention of both infections, but complicates the question of whether to conduct pre-vaccination screening. The authors examined the cost-effectiveness of pre-vaccination screening for several populations: first-year college students, military recruits, travelers to hepatitis A-endemic areas, patients at sexually transmitted disease clinics, and prison inmates. METHODS: Three prevention protocols were examined: (1) screen and defer vaccination until serology results are known; (2) screen and begin vaccination immediately to avoid a missed vaccination opportunity; and (3) vaccinate without screening. Data describing pre-vaccination immunity, vaccine effectiveness, and prevention costs borne by the health system (i.e., serology, vaccine acquisition, and administration) were derived from published literature and U.S. government websites. Using spreadsheet models, the authors calculated the ratio of prevention costs to the number of vaccine protections conferred. RESULTS: The vaccinate without screening protocol was most cost-effective in nine of 10 analyses conducted under baseline assumptions, and in 69 of 80 sensitivity analyses. In each population considered, vaccinate without screening was less costly than and at least equally as effective as screen and begin vaccination. The screen and defer vaccination protocol would reduce costs in seven populations, but effectiveness would also be lower. CONCLUSIONS: Unless directed at vaccination candidates with the highest probability of immunity, pre-vaccination screening for hepatitis A and B immunity is not cost-effective. Balancing cost reduction with reduced effectiveness, screen and defer may be preferred for older travelers and prison inmates.

Hepatitis vaccines: recent advances.

Despite the availability of hepatitis A vaccines that might provide protection for decades, hepatitis B vaccines that provides protection for at least 15 years and the recent introduction of a combined hepatitis A and B vaccine, these infections continue to spread in both the developed and developing world. Hepatitis A vaccine coverage has been limited to high-risk groups: such a selective immunisation policy is unlikely to have a major impact. If adequate immunogenicity in infants is confirmed, dosing schedules can be improved and the costs of vaccination reduced, universal paediatric immunisation with combined hepatitis A and B products is likely to result in the eventual eradication of these infections. In the interim, novel hepatitis A vaccines are being investigated and additional studies on hepatitis A vaccine immunogenicity in infants are in progress. Worldwide use of hepatitis B vaccines for the newborn, young children and high-risk groups should control this infection and obviate the need for a vaccine against hepatitis D. Newer hepatitis B vaccines that may reduce the likelihood of non-responsiveness and have immunotherapeutic value are under study. A recombinant hepatitis E vaccine for use in endemic regions is currently in clinical trials. The development of an effective hepatitis C vaccine has been agonisingly slow and many impediments have been recognised. These include the lack of a susceptible small animal, a high degree of hepatitis C virus (HCV) genomic diversity and failure to produce high quantities of HCV in tissue culture. The development of a novel HCV replicon system may be a major breakthrough. Nonetheless, it may still be exceedingly difficult to produce a vaccine that uniformly provides sterilising immunity; the possibility of developing a hepatitis C vaccine that can prevent chronic infection is an exciting concept that requires further investigation. Advances in recombinant technology, the use of novel genetic (DNA-based) vaccines, expression of hepatitis antigens in plants and improved adjuvants also hold considerable promise.

Cholestatic hepatitis induced by Epstein-Barr virus infection in an adult.

Liver involvement is nearly universal in healthy persons with Epstein-Barr Virus (EBV) infection-induced infectious mononucleosis. It is usually mild, undetected clinically and resolves spontaneously. Jaundice is distinctly uncommon and may reflect either more severe hepatitis or an associated hemolytic anemia. Cholestatic hepatitis due to EBV infection is infrequently reported and may pose a diagnostic quandary. We describe a patient who presented with jaundice and a markedly elevated serum alkaline phosphatase level due to serologically confirmed acute infection with EBV. Imaging studies excluded biliary obstruction. Symptoms and laboratory abnormalities resolved spontaneously. EBV infection should be included in the differential diagnosis of cholestatic hepatitis in adults.

Prevention of Viral Hepatitis.

Despite the availability of vaccines against hepatitis A and B, acute viral hepatitis due to these agents continues to be among the most commonly reported notifiable infectious diseases in the United States. Currently available hepatitis A and B vaccines are highly immunogenic and well tolerated, but vaccine coverage needs to be expanded. Use of the hepatitis A vaccine in children age 2 years and older should be more widespread than is currently the case. Hepatitis A vaccine has been shown to be cost effective when given to children in regions with high attack rates and to patients with chronic hepatitis C. Routine newborn immunization against hepatitis B has been a successful approach to disease control and is among the most cost-effective interventions. Use of the hepatitis B vaccine for all sexually active individuals with more than one sex partner should be recommended for this sexually transmitted disease. The availability of a combined hepatitis A and B vaccine should facilitate vaccine coverage in those individuals at risk for both infections. For those hepatitis infections for which no vaccine is currently available, namely hepatitis C, D, and E, reducing exposure risk by modifying lifestyle behaviors is the only control measure available. Early education and counseling about high-risk behaviors for the acquisition of blood-borne hepatitis viruses needs to be expanded to young children and adolescents. The eventual eradication of hepatitis virus infections through universal immunization is plausible for those agents for whom human beings are the only host and effective vaccines have been developed. If hepatitis E is shown to be a zoonosis with an extensive reservoir in pigs, eradication of this agent may be very difficult.

Iron and HFE or TfR1 mutations as comorbid factors for development and progression of chronic hepatitis C.

BACKGROUND/AIMS: Recent evidence implicates iron as a comorbid factor for development of non-hemochromatotic liver diseases. Mutations or polymorphisms in the HFE gene or the TfR1 gene may influence the accumulation of iron in the liver or other tissues or may influence chronic viral hepatitis apart from effects on iron homeostasis. The aim of this study was to assess the role of hepatic iron, HFE and TfR1 variations on development and progression of chronic hepatitis C infection. METHODS: We studied 119 consecutive patients with chronic hepatitis C, correlating clinical, laboratory, histopathological, and genetic data. Frequencies of genetic variations were compared with local and national controls. RESULTS: HFE mutations were more common in patients than controls (48% vs. 38%, P=0.04), and advanced degrees of fibrosis developed at younger ages in subjects with the C282Y mutation (38.6 vs. 46.5 years, P=0.03). Patients carrying C282Y had higher mean hepatic iron concentrations (P=0.02), hepatic iron indices (P<=0.0001), and hepatic fibrosis scores (P=0.01). Hepatic fibrosis was correlated with hepatic iron concentration (P=0.03). TfR1 polymorphisms bore no detectable relation to disease severity or response to therapy. CONCLUSIONS: Hepatic iron and HFE mutations are comorbid factors that increase development and progression of chronic hepatitis C.

Immunogenicity of hepatitis B vaccines: implications of immune memory.

The subunit recombinant hepatitis B virus (HBV) vaccines available in the US differ in hepatitis B surface antigen content. Clinical studies have linked higher antigen formulations with enhanced peak protective antibody levels. This is important for the elderly, smokers, the obese, and the immunocompromised. Immune memory, which is responsible for prolonged protection when HBV vaccine-induced antibody levels become undetectable, may be related to antigen persistence on immunologically active cells. Antigen persistence may be related to antigen content of the vaccine and thereby influences the duration of immunity. Proof of this concept will require additional studies of immune memory in HBV.

Hepatitis A, hepatitis B, and combination hepatitis vaccines for immunoprophylaxis: an update.

Since the publication of the last extensive review of hepatitis vaccines, use of inactivated hepatitis A vaccines has been extended to high-risk regions of the United States and specific patient groups, such as those with chronic liver disease, and use of the recombinant hepatitis B vaccines has been recommended for older adolescents. A combination hepatitis A and B vaccine, recently approved for licensure by the US Food and Drug Administration, should increase convenience and compliance, reduce the costs of vaccination, and provide prolonged and dual protection for those at risk for hepatitis. Although commercially available vaccines for hepatitis C, D, and E remain a distant goal, advances in vaccine and adjuvant technology, including immunization with DNA-based vaccines, hold promise for the future.