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.

Lactic acidosis in oat cell carcinoma with extensive hepatic metastases.

Lactic acidosis has been described in patients with leukemia and lymphoma, but its occurrence in other malignant diseases is not documented. We treated two patients with oat cell carcinoma of the lung and extensive liver metastases in whom lactic acidosis developed. Tumor-induced hepatic dysfunction appeared to be a major factor in the pathogenesis of the lactic acidosis observed in these patients.

Nonsteroidal anti-inflammatory drug use in relation to major upper gastrointestinal bleeding.

In a study in the United States, Sweden, and Hungary, 335 cases of gastric bleeding without predisposing factors were compared with 670 control subjects, and 239 cases of duodenal bleeding were compared with 489 control subjects. For aspirin taken at least every other day during the week before the onset of bleeding (regular use), the relative risk of gastric bleeding was 4.4 (95% confidence interval [CI], 2.9 to 6.7); for occasional use, it was 3.3 (95% CI, 2.1 to 5.0). For ibuprofen, the corresponding estimates were 1.0 (95% CI, 0.4 to 2.6) and 1.1 (95% CI, 0.5 to 2.4). For naproxen, the estimate for regular use was 4.0 (95% CI, 1.5 to 11). The estimates for any use of piroxicam (crude estimate), indomethacin, and diclofenac during the week before onset were 18 (95% CI, 4.1 to 83), 1.6 (95% CI, 0.4 to 5.9), and 0.9 (95% CI, 0.2 to 4.2), respectively. The corresponding relative risks of duodenal bleeding were 7.1 (95% CI, 4.2 to 12) and 2.2 (95% CI, 1.3 to 3.7) for the regular and occasional use of aspirin, 2.4 (95% CI, 0.5 to 11) and 0.8 (95% CI, 0.3 to 2.0) for ibuprofen, 12 (95% CI, 2.8 to 54) and 9.9 (95% CI, 2.3 to 44) for naproxen, 17 (95% CI, 3.6 to 79) for any use of piroxicam (crude estimate), and 1.7 (95% CI, 0.2 to 14) for any use of indomethacin. There was a significant trend in the risk of gastric bleeding with increasing dose of regular aspirin use (p = 0.002). The relative risk estimates for the regular use of 325 mg or less were significantly elevated for both gastric and duodenal bleeding at 3.1 and 6.4, respectively.

Problem hepatitis viruses: the mutants.

Genetic variations in the known human hepatitis viruses are probably the result (a) of high viral replication rates and poor or absent proofreading ability intrinsic to RNA viruses (HAV, HCV, HDV, HEV) and (b) to a DNA virus (HBV) that uses a reverse-transcription mechanism for genomic replication. Nucleotide substitutions, deletions, duplications, insertions, and rearrangements resulting in amino acid changes may have no consequences, may impair replication, change host susceptibility, or may lead to escape from immune attack. Genetic diversity has been identified in each of the known hepatitis viruses. The importance of mutant viruses in pathogenicity, immunity, natural history, clinical outcomes, vaccine production, and responsiveness to treatment has emerged as an area for intensive study.

Prevention of hepatitis C virus infection.

Despite the promising progress made in the development of experimental HCV hyperimmune globulin preparations and recombinant vaccines, prevention of HCV infection will continue to be an important research front for many years. Until effective and safe immunoprophylaxis is available, preventive efforts will require further understanding of risk factors associated with infection and implementation of strategies to reduce such exposures.

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.

Alpha-fetoprotein glycosylation is abnormal in some hepatocellular carcinoma, including white patients with a normal alpha-fetoprotein concentration.

Lectin-affinity analyses with Lens culinaris agglutinin (LCA) and other lectins have demonstrated that the glycosylation of alpha-fetoprotein (AFP) secreted by hepatocellular carcinomas (HCC) is frequently altered when the serum AFP concentration is increased. To determine if AFP LCA-binding properties are altered in patients with HCC whose serum AFP concentration is normal, the percentage of LCA-binding AFP in serum from white newborns, white normal adults, white patients with chronic hepatitis and hereditary tyrosinemia and white and black patients with HCC were determined. The serum LCA-binding AFP fraction was low in newborns (1-4%) and normal adults (1-8%). There was a significant increase in LCA-binding AFP in patients with chronic hepatitis (10-24%) and hereditary tyrosinemia (5-35%). The AFP LCA-binding fraction was clearly abnormal (greater than 40%) in three of the white patients with an HCC and a normal serum AFP concentration, and the range of values (10-63%) in these HCC patients was similar to that seen in both white and black patients with HCC accompanied by increased AFP concentrations.

Hepatitis B today: clinical and diagnostic overview.

The hepatitis B virus is a member of an unusual family of noncytopathogenic, hepatotropic DNA viruses--the hepadnaviruses. The complete virus comprises a lipoprotein coat, the hepatitis B surface antigen, enveloping a nucleocapsid core that contains a small, circular DNA molecule. Four open reading frames have been identified on the hepatitis B virus DNA genome. They encode seven proteins, including a hepatitis B virus DNA polymerase molecule with reverse transcriptase activity. The replication of the virus resembles that of retroviruses and occurs predominantly but not exclusively in hepatocytes. Virus variants involving genomic mutations have been identified. Testing for hepatitis B surface antigen permits detection of many but not all acutely infected patients. Diagnosis of acute infection rests on the identification of IgM antibodies to the hepatitis B core antigen. Antibody to hepatitis B surface antigen appears in serum during the convalescent phase of hepatitis B virus infection. It is the neutralizing, protective antibody largely responsible for immunity to reinfection. In persistent infection hepatitis B surface antigen is present, antibody to hepatitis B core antigen is predominantly an IgG antibody, antibody to hepatitis B surface antigen is not detectable or is present in very low titers and viral replication may be active. Persistent infection leads to an asymptomatic carrier state, chronic hepatitis, cirrhosis and hepatocellular carcinoma. No specific treatment exists for acute hepatitis B virus infection. Current data indicate that approximately 50% of adults who have chronic infection achieve virologic, biochemical and histologic remission from treatment with alpha-2b-interferon.

Polycythemia vera with myelofibrosis and myeloid metaplasia. Acute hepatic failure following splenectomy.

Myelofibrosis with myeloid metaplasia developed during the course of polycythemia vera in a middle-aged man. Severe megakaryocytopenia and thrombocytopenia were early features of this illness and were unresponsive to splenectomy. After splenectomy, hepatic enlargement and acute hepatic failure developed. Extensive extramedullary hematopoiesis dilating hepatic sinusoids and compressing liver cells was the major pathologic finding in the liver. The mechanism of hepatic failure in this disorder is uncertain.

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.

Preventing hepatitis A infections in travelers to endemic areas.

In 1995, 24 million travelers from the United States are anticipated to visit developing countries where hepatitis A is endemic. Passive immunization with immune globulin, before exposure or within two weeks following exposure to the hepatitis A virus, protects against clinical disease in < 70-90% of immunized individuals. The duration of protection, measured in months, is relatively short. Active immunization with a single dose of inactivated hepatitis A virus vaccine appears to provide greater protective efficacy and, based on the persistence of vaccine-induced protective antibodies, should provide protection for years. Booster doses given between six and 12 months are likely to provide immunity that may persist for at least a decade. The inactivated hepatitis A vaccine approved for use in the United States has been clinically well-tolerated; mild transient soreness at the injection site is the most frequently reported adverse reaction. Immunization with inactivated hepatitis A vaccine is a safe and effective method for travelers to endemic areas to protect themselves against this infection.

The effects of a single, intravenous dose of bumetanide versus furosemide in patients with ascites and edema due to alcoholic liver disease.

Ascites with or without edema, secondary to alcoholic liver disease, which had failed to respond to conventional in-hospital medical treatment with thiazides, spironolactone, and salt restriction was treated with a single intravenous dose of 0.5 mg bumetanide or 20 mg furosemide. In this single-blind, randomized, parallel study in 20 men over 18 years of age, significant diuresis and increased excretion of sodium, potassium, and chloride occurred with both drugs. Weight loss was slight but significant within groups but not between drug treatments. Osmolality was significantly decreased after both treatments due to the magnitude of urine volume. Sodium/potassium ratio was significantly increased up to 120 minutes after both treatments. Creatinine excretion and clearance were increased after treatment with bumetanide but not significantly. In the furosemide group, the increase was first significant but after 90 minutes remained decreased. Supine and standing blood pressure and pulse rate changes were negligible. EKG monitoring revealed no abnormalities. No consistent alterations of laboratory tests were identified after treatment, nor were any important clinical adverse responses recognized. A 15-decibel unilateral high-frequency hearing loss was observed following bumetanide treatment in one patient with prior evidence of ear disease.

A comparison of bumetanide and furosemide in the treatment of ascites. Cooperative study.

In a cooperative study by clinicians in three medical facilities, bumetanide was compared with furosemide in patients presenting with ascites, a complication of chronic liver disease. In an open, parallel, randomized trial, 43 patients received bumetanide and 16 patients received furosemide. They were treated for from one to 28 weeks. Weight loss and decrease in abdominal girth following diuretic action occurred in both groups but was statistically significant only in the bumetanide treated patients. Because of the small number of patients on furosemide, valid statistical analysis could not be obtained. No evidence of hepatic encephalopathy developed during this study, and only one patient on furosemide was discontinued as a result of severe electrolyte imbalance. Differences in changes of electrolytes and uric acid ere not statistically significant in the two groups. The majority of drug-related abnormalities were the result of the pharmacologic activity of the diuretic.

Prognostic indicators in chemotherapy for head and neck carcinoma: alkaline phosphatase levels.

Serum alkaline phosphatase (AP), total bilirubin, total protein, serum albumin, and serum glutamic oxaloacetic transaminase (SGOT) were determined in 55 patients with biopsy proven carcinoma of the head and neck prior to their induction chemotherapy with cis-platinum and bleomycin. Of the 55 patients, 40 (73%) exhibited either a complete or partial response (tumor mass decreased by over 50%) to the chemotherapy. Responses were noted more frequently in patients with elevated AP levels. Nine of the 10 patients (90%) with AP levels greater than 100 mU/ml experienced a major response; whereas, only 8 of 16 patients (50%) with AP levels less than 60 mU/ml demonstrated a favorable response to the chemotherapeutic agents. The source of the elevated AP levels has not yet been established. Possible sources include liver, bone, kidney, intestinal mucosa, or the tumor itself. Total bilirubin, total protein, serum albumin, and SGOT levels did not differentiate the responders from the non-responders as accurately as did the AP levels.

Feedback EEG in the detection of subclinical hepatic encephalopathy: a preliminary report.

The detection, monitoring, and quantification of subclinical hepatic encephalopathy present difficult problems for the clinician caring for patients with liver disease. Traditionally, pencil and paper tests such as signature-writing have been used at the bed-side to measure early encephalopathy. More recently, the Trail-making test has been employed to detect and quantify encephalopathic changes. While the electroencephalogram has provided information about the extent of clinically-obvious encephalopathy, it has only recently proved useful in the detection of subclinical disease. In these cases, evoked potentials and spectral analysis methods have discriminated between 35 and 62% of patients with subclinical hepatic encephalopathy. The present study used the method of feedback electroencephalography to detect and quantify differences in cortical arousal in 5 cirrhotic patients and 5 normal age-matched controls. Subject were also compared with respect to baseline measures of cortical arousal. Finally, arousal during feedback EEG stimulation was correlated with Trail-making test performance. The data revealed that cirrhotic patients can be discriminated from normal controls by baseline (80% detection) and feedback stimulation conditions (100% detection). In addition, feedback EEG reactivity (cortical arousal) was inversely correlated with Trail-making test performance (-0.86, P less than 0.01). The results indicate that simple features of the conventional EEG can reliably discriminate cirrhotic patients from normals. Clinical application of the feedback method in other metabolic encephalopathies, as well as in hypoaroused states secondary to, for example, narcolepsy, is discussed.

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.