Review article: the efficacy and safety of sofosbuvir, a novel, oral nucleotide NS5B polymerase inhibitor, in the treatment of chronic hepatitis C virus infection.

BACKGROUND: The treatment of chronic hepatitis C is changing rapidly. AIM: To review clinical studies of the efficacy and safety of sofosbuvir-containing regimens in the treatment of chronic hepatitis C. METHODS: Using PubMed and search terms 'sofosbuvir,' 'emerging HCV treatment,' and 'HCV polymerase inhibitor,' literature on the clinical development of sofosbuvir, as well as abstracts presented at the November 2013 annual meeting of the American Association for the Study of Liver Diseases (AASLD), was reviewed. The last search was undertaken on 15 November 2013 [corrected]. RESULTS: In a dose of 400 mg once daily, the drug has been safe and generally well tolerated with most adverse reactions attributable to the concurrent use of ribavirin or peginterferon plus ribavirin. A high barrier to resistance has been demonstrated. In genotype 1 (G1) patients, the addition of sofosbuvir to peginterferon plus ribavirin yielded sustained virological response rates at week 12 after discontinuation of treatment (SVR12) of about 90% with slightly lower levels in G1b and in patients with cirrhosis, but with no major impact of IL28B genotype, high viral load, body mass index (BMI), alanine aminotransferase (ALT) or race/ethnicity. In genotype 2 (G2), sofosbuvir and ribavirin for 12 weeks also resulted in SVR12 of 90% or better with little effect from cirrhosis. In contrast, genotype 3 (G3) was less responsive to 12 weeks of sofosbuvir plus ribavirin, especially in the presence of cirrhosis. CONCLUSION: The efficacy and safety of sofosbuvir-containing regimens with ribavirin alone or with peginterferon plus ribavirin signal a new era in treatment.

Review article: vaccination and viral hepatitis - current status and future prospects.

BACKGROUND: Viral hepatitis is the most common cause of liver disease in the world. In the past 25 years, vaccines have become available for two of the five hepatitis viruses, and, where implemented, vaccination has become a key component of hepatitis prevention. AIMS: To provide an update on recent advances in the use of current hepatitis vaccines and to examine progress in the development of vaccines for the remaining hepatitis viruses. METHODS: A Medline search was undertaken to identify the recent relevant literature. Search terms included hepatitis vaccines, hepatitis vaccination and hepatitis A-E vaccines. RESULTS: Dramatic vaccine-induced declines in the incidence of both hepatitis A and B have occurred in the USA. Strategies to integrate hepatitis A vaccine into universal childhood immunization are being adopted. Similarly, strategies with the goal of eliminating transmission of hepatitis B have been promulgated. A vaccine for hepatitis E has been reported to be effective and safe, but progress in the development of vaccines for hepatitis C and D has been limited. CONCLUSION: During the next few decades, the goals of eliminating hepatitis A and B virus transmission may be reached in the USA and elsewhere.

Risks associated with hepatitis A and hepatitis B in patients with hepatitis C.

Individuals with hepatitis C virus (HCV) are at risk for acquiring hepatitis A virus (HAV) or hepatitis B virus (HBV) because of shared risk factors. A number of organizations recommend vaccination against HAV and HBV for patients with HCV. The rationale for vaccinating these patients is to prevent hepatic superinfections. Acute HAV superinfection causes more severe disease, acute hepatic failure, and higher fatality rates in patients with underlying chronic liver disease, specifically chronic HBV infection and chronic HCV infection. Available data, although limited, suggest that HBV coinfection with HAV and HCV causes more severe hepatic injury than infection with HAV or HCV alone. At standard doses, hepatitis A and hepatitis B vaccines are safe and immunogenic in patients with mild-to-moderate hepatitis C or chronic liver disease. Regardless of disease severity, vaccination should be routinely administered to patients upon diagnosis of HCV infection. Early vaccination is important because response to vaccination is reduced as liver disease progresses. Prevaccination and postvaccination serology testing is recommended in specific populations. A new combination hepatitis A and hepatitis B vaccine has been shown to be as safe and effective as monovalent hepatitis A and B vaccines and is currently under review by the United States Food and Drug Administration. A combination vaccine would offer ease of administration and convenience and could increase compliance in patients with hepatitis C or other chronic liver disease: two groups that should be more aggressively targeted by healthcare professionals.

Hepatitis vaccines.

The development of highly effective and safe inactivated HAV vaccines and highly effective and safe recombinant HBsAg subunit HBV vaccines represents major advances in the control of viral hepatitis, but many challenges remain. Because current HAV immunization recommendations target high-risk groups only, infection rates are unlikely to fall dramatically until universal childhood immunization programs are implemented. Routine HBV vaccination of infants, children, adolescents, and individuals at high risk will reduce the incidence of infection, but vaccine nonresponsiveness and escape mutants are important potential challenges. Whether either HAV or HBV vaccine provide lifelong protection remains to be determined. Vaccines for HDV, HEV, and HCV are not yet available.

Diagnosis and monitoring of hepatic injury. I. Performance characteristics of laboratory tests.

PURPOSE: To review information on performance characteristics for tests that are commonly used to identify acute and chronic hepatic injury. DATA SOURCES AND STUDY SELECTION: A MEDLINE search was performed for key words related to hepatic tests, including quality specifications, aminotransferases, alkaline phosphatase, gamma-glutamyltransferase, bilirubin, albumin, ammonia, and viral markers. Abstracts were reviewed, and articles discussing performance of laboratory tests were selected for review. Additional articles were selected from the references. Guideline Preparation and Review: Drafts of the guidelines were posted on the Internet, presented at the AACC Annual Meeting in 1999, and reviewed by experts. Areas requiring further amplification or literature review were identified for further analysis. Specific recommendations were made based on analysis of published data and evaluated for strength of evidence and clinical impact. The drafts were also reviewed by the Practice Guidelines Committee of the American Association for the Study of Liver Diseases and approved by the committee and the Association's Council. RECOMMENDATIONS: Although many specific recommendations are made in the guidelines, some summary recommendations are discussed here. Alanine aminotransferase is the most important test for recognition of acute and chronic hepatic injury. Performance goals should aim for total error of <10% at the upper reference limit to meet clinical needs in monitoring patients with chronic hepatic injury. Laboratories should have age-adjusted reference limits for enzymes in children, and gender-adjusted reference limits for aminotransferases, gamma-glutamyltransferase, and total bilirubin in adults. The international normalized ratio should not be the sole method for reporting results of prothrombin time in liver disease; additional research is needed to determine the reporting mechanism that best correlates with functional impairment. Harmonization is needed for alanine aminotransferase activity, and improved standardization for hepatitis C viral RNA measurements.

Diagnosis and monitoring of hepatic injury. II. Recommendations for use of laboratory tests in screening, diagnosis, and monitoring.

PURPOSE: To review information on the use of laboratory tests in screening, diagnosis, and monitoring of acute and chronic hepatic injury. DATA SOURCES AND STUDY SELECTION: A MEDLINE search was performed for key words related to hepatic diseases, including acute hepatitis, chronic hepatitis, alcoholic hepatitis, cirrhosis, hepatocellular carcinoma, and etiologic causes. Abstracts were reviewed, and articles discussing use of laboratory tests selected for review. Additional articles were selected from the references. Guideline Preparation and Review: Drafts of the guidelines were posted on the Internet, presented at the AACC Annual Meeting in 1999, and reviewed by experts. Areas requiring further amplification or literature review were identified for further analysis. Specific recommendations were made based on analysis of published data and evaluated for strength of evidence and clinical impact. RECOMMENDATIONS: Although many specific recommendations are made in the guidelines, only some summary recommendations are listed here. In acute hepatic injury, prothrombin time and, to a lesser extent, total bilirubin are the best indicators of severity of disease. Although ALT is useful for detecting acute and chronic hepatic injury, it is not related to severity of acute hepatic injury and only weakly related to severity of chronic hepatic injury. Specific tests of viral markers should be the initial differential tests in both acute and chronic hepatic injury; when positive, they are also useful for monitoring recovery from hepatitis B and C.

Watchful waiting with periodic liver biopsy versus immediate empirical therapy for histologically mild chronic hepatitis C. A cost-effectiveness analysis.

BACKGROUND: Not all patients with histologically mild chronic hepatitis C progress to cirrhosis. OBJECTIVE: To compare no antiviral treatment, periodic liver biopsy with subsequent antiviral treatment for moderate hepatitis or cirrhosis, and immediate antiviral therapy. DESIGN: Cost-effectiveness analysis. DATA SOURCES: Clinical trial data and published studies. TARGET POPULATION: Hepatitis C virus-infected patients with histologically mild hepatitis. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: Immediate combination antiviral treatment or biopsy every 3 years plus combination antiviral therapy for moderate hepatitis or cirrhosis. OUTCOME MEASURES: Life expectancy, quality-adjusted life expectancy, and costs. RESULTS OF BASE-CASE ANALYSIS: Over 20 years, biopsy every 3 years with treatment of moderate hepatitis would avoid treatment in 50% of the cohort and would result in an 18% likelihood of cirrhosis compared with 16% for immediate treatment and 27% for no antiviral therapy. Immediate antiviral treatment should increase life expectancy by 1.0 quality-adjusted life-year compared with biopsy management. Over an average lifetime, biopsy management would lead to six liver biopsies costing $6200; immediate antiviral treatment would cost $5100 less than biopsy management because of savings related to biopsy and prevention of future hepatitis C-related morbidity. Immediate therapy was cost-effective compared with biopsy management and had a cost-effectiveness ratio of $7000 compared with no antiviral therapy. RESULTS OF SENSITIVITY ANALYSIS: When age, sex, genotype, and estimates of histologic progression or compliance with follow-up are varied, immediate therapy should result in an increase of at least 0. 8 quality-adjusted life-year compared with biopsy management. CONCLUSION: For histologically mild chronic hepatitis C, initial combination treatment compared with periodic liver biopsy should reduce the future risk for cirrhosis, prolong life, and be cost-effective.

Isolated elevation of serum alkaline phosphatase level in an uncomplicated pregnancy: a case report.

Serum level of alkaline phosphatase of placental origin was increased >10-fold in a 28-year-old pregnant woman. Repeated abdominal ultrasonographic scans yielded negative results for hepatobiliary disease. After delivery of a healthy baby, the placenta showed no major pathologic characteristics, and the alkaline phosphatase level returned to the reference range.

Hepatitis B school-based vaccination programmes in the USA: a model for hepatitis A and B.

Following the recommendation for routine vaccination against hepatitis B virus for newborns, many states have started school-based catch-up vaccination of 11- to 12-year-olds. Implementation of these programmes requires educational and promotional initiatives to increase awareness among parents, children, teachers, school nurses, school boards and administration. Experience in Framingham, Massachusetts, suggests that over 90% of targeted hepatitis B vaccine coverage can be achieved. Because hepatitis B vaccination targeted at high-risk groups in the USA was largely unsuccessful, this suggests that the initial similar targeted approach with hepatitis A vaccination will also fail. Only about 50% of hepatitis A cases have a known risk factor, and multiple high-risk areas exist throughout the USA. However, the geographical clustering of these high-risk areas and the occurrence of periodic outbreaks, suggest that school-based hepatitis A vaccination programmes may be effective in reducing the risk of infection. A voluntary programme in San Antonio achieved 43% of the targeted coverage in its first year, and a compulsory programme is due to start in Oklahoma. The effectiveness of this programme is not yet known, but future recommendations are likely to include hepatitis A vaccination as a school entry requirement in areas with high incidence of hepatitis A.

The risk of acute major upper gastrointestinal bleeding among users of aspirin and ibuprofen at various levels of alcohol consumption.

OBJECTIVE: Major upper gastrointestinal bleeding (UGIB) is the most important adverse effect of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Alcoholic beverages also precipitate UGIB. This analysis was conducted to evaluate whether the deleterious effects of NSAIDs are further increased among drinkers. METHODS: An interview-based, case-control study was conducted in the U.S. and Sweden; 1224 patients hospitalized with acute major UGIB due to newly occurring peptic ulcer or gastritis were compared to 2945 neighbor controls. RESULTS: Compared with those who drank less than one drink/wk, the relative risk of acute UGIB increased with increasing alcohol consumption, rising to 2.8 among those who drank > or = 21 drinks/wk. Among current drinkers, the relative risk of acute UGIB due to the use of aspirin was raised at all levels of alcohol consumption; the estimate for aspirin taken at least every other day (regular use) at doses of > 325 mg among all current drinkers combined was 7.0; for regular use at lower doses, the corresponding estimate was 2.8, and for any occasional use, it was 2.4. All estimates were statistically significant. Data for ibuprofen were more limited, but the relative risk estimates did not appear to vary consistently with level of alcohol consumption. For regular use (all doses combined), the estimate among all drinkers combined was significantly elevated, at 2.7; occasional ibuprofen use was not associated with UGIB (1.2). There were insufficient data to evaluate other NSAIDs according to alcohol consumption. CONCLUSIONS: The findings suggest that acute UGIB is similarly associated with the use of the two most common nonprescription NSAIDs, aspirin and ibuprofen, at all levels of alcohol consumption. As heavy alcohol intake independently increases the risk, the incidence of UGIB is highest among persons who are both heavy drinkers and users of aspirin or ibuprofen.

A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis C.

Interleukin-12 (IL-12) plays a central role in mounting an effective cellular immune response directed towards elimination of intracellular pathogens. The present open-label, multicenter, dose-escalation phase I/II study was designed to assess tolerability, pharmacokinetics, pharmacodynamics, and efficacy of subcutaneously administered recombinant human interleukin-12 (rHuIL-12) in the treatment of chronic hepatitis C. Sixty patients (42 men, 18 women, aged 24-60) were treated with 0.03 microgram/kg (n = 16), 0.1 microgram/kg (n = 14), 0.25 microgram/kg (n = 15), or 0.5 microgram/kg rHuIL-12 (n = 15) for 10 consecutive weeks. rHuIL-12 was generally well tolerated, with 2 patients (3.3%) being withdrawn from treatment for adverse events. Treatment was associated with temporary decreases in neutrophils and lymphocyte counts and with elevations in serum transaminases and bilirubin. Serum IL-12 levels observed were higher at 0.5 microgram/kg compared with 0.25 microgram/kg doses, suggesting a dose-related increase in systemic exposure of IL-12. Measurable levels of interferon gamma (IFN-gamma) were also observed at the highest dose of 0.5 microgram/kg. At the end of treatment hepatitis C virus (HCV) RNA was detectable in all patients. A more than 50% decrease in pretreatment HCV RNA levels was observed in 3 of 16 patients of the 0.03-microgram/kg dose group, in 3 of 14 of the 0.10-microgram/kg dose group, in 6 of 15 of the 0.25-microgram/kg dose group, and in 8 of 15 patients of the 0.5-microgram/kg dose group. Although in several cases serum alanine transaminase (ALT) levels decreased either during or after treatment, ALT normalization was observed in only 4 patients at the end of treatment and in 5 patients at the end of follow-up. Significant anti-rHuIL-12 antibody titers were not detectable in any patient. In conclusion, antiviral activity of rHuIL-12 in patients with chronic hepatitis C does not appear advantageous in comparison with other currently available treatments.

Cost-effectiveness of treatment for chronic hepatitis C.

Concerns about the variable natural history of untreated chronic hepatitis C and the costs and benefits of current therapy for this disease have been addressed by the techniques of cost-effectiveness analysis. The methodologies of decision analysis and Markov computer simulation, and available data on natural history, costs of care, and response to treatment, have been utilized to project the long-term costs and benefits of treatment. These models indicate that interferon monotherapy and combination therapy (interferon plus ribavirin) for previously untreated patients, for retreatment of patients who relapse after interferon treatment, and for retreatment of those who are non-responders to interferon monotherapy have calculated cost-effectiveness ratios that fall within the bounds of other widely accepted therapies or are cost-saving. Even empirical treatment, without liver biopsy, HCV RNA quantitation, or HCV genotyping, has an acceptable cost-effectiveness.

Cost-effectiveness of combined interferon and ribavirin versus interferon alone.

Several decision analysis, computer-generated models developed to study the cost effectiveness of current treatment for chronic hepatitis C appear to have produced similar results. They indicate that IFN monotherapy and the combination of IFN plus ribavirin treatment have calculated cost-effectiveness ratios that either fall within the bounds of other widely accepted current therapies in medicine or are cost-saving. This cost effectiveness has been shown for the treatment of previously untreated patients, for the re-treatment of patients who experience relapse after an initial course of IFN monotherapy, and for the re-treatment of those patients who did not respond to IFN monotherapy. Although targeting treatment to patients most likely to respond will improve cost effectiveness, the benefits of treatment are such that even empiric IFN monotherapy, without liver biopsy, HCV RNA quantitation, or HCV genotyping, has an acceptable cost effectiveness. Although not studied, empiric combination therapy might result in even further cost efficiencies.