Comparison of a triple antigen and a single antigen recombinant vaccine for adult hepatitis B vaccination.

Hepatitis B and its sequelae are a major public health problem. Vaccines have been available for almost 20 years; however the disease still remains a global problem. Many factors contribute to the failure to control hepatitis B, including the limited nature of the vaccination programs implemented initially. Only relatively recently has mass childhood vaccination begun to be implemented and vaccination of high-risk groups, other than healthcare workers, is still not general policy. Additional factors contributing to continued persistence of hepatitis B in the developed world are that the present vaccines are not fully used by those recommended to be vaccinated and even when vaccination is carried out appropriately, there remain some who fail to achieve adequate protection. Clearly, the protection of at-risk groups who have inadequate response to current vaccines, and those who are unwilling or unable to comply with protracted multi-dose vaccine regimens, could be improved if there were a more potent vaccine and/or a shorter vaccination regimen available. Adults who had never been vaccinated against hepatitis B were randomised to receive a vaccination course of either a present single antigen (S) vaccine (Recombivax-HB) or a novel triple antigen (S, pre-S1, and pre-S2) recombinant vaccine (Hepacare Medeva Pharma plc). Doses were given at baseline and 1 month and 6 months later. Hepatitis B surface antibody (anti-HBs) levels were measured at 2, 4, 6, and 7 months after beginning vaccination. The primary efficacy parameter was the degree of protection, measured as the percentage of subjects with anti-HBs titres > or = 10 IU/L, 6 or 7 months (26 +/- 2 weeks) after beginning vaccination. A total of 303 adult subjects entered the study and were vaccinated. Of these, 11 failed to complete the study (4 on Hepacare and 7 on Recombivax-HB); however all but 2 (1 to receive the triple antigen vaccine and 1 to receive Recombivax-HB) were included in the intent-to-treat population for efficacy evaluation. Treatment randomisation was stratified at entry based on age (above and below 40 years old) and gender. The standard three-dose/6-month vaccination regimen of the single antigen vaccine protected 83% of subjects by 7 months after starting vaccination whereas the triple antigen vaccine as a two-dose/1-month regimen protected 88% within 6 months and as a three-dose/6-month regimen protected 97% by 7 months after starting vaccination. Thus the protection rate provided by the shortened (0, 1) regimen of the novel vaccine was "essentially equivalent" (i.e., not statistically inferior) to that provided by the full (0, 1, and 6) regimen of today's vaccine (88% vs. 81%, P < 0.001), and the protection rate provided by a three-dose/6-month (0, 1, and 6) regimen of the new vaccine was significantly superior to that provided by present vaccines (97% vs. 83% P < 0.001). The percentage of subjects protected increases with time after beginning vaccination and at all time points up to and including 6 months was significantly greater with the two-dose regimen of the triple antigen vaccine than with the single antigen vaccine regimen. In adults at risk for a reduced response to hepatitis B vaccination [i.e., older adults (>/=40), the obese, males, and smokers], the triple antigen vaccine produced a significantly greater percentage of protected subjects (P < 0.001) and higher geometric mean titre (P < 0.001). Indeed as a three-dose/6 month regimen, the triple antigen vaccine raised the level of protection in these vulnerable subgroups to that seen when a single antigen vaccine is used in the optimal younger adult group. Both vaccines were well tolerated and had similar safety profiles. The most frequently (> or = 10%) reported adverse events with the use of either vaccine were pain at the site of injection (38% vs. 41% vs. 20% for the two-dose Hepacare regimen, the three-dose Hepacare regimen, and the three-dose Recombivax-HB regimen, respectively), infections at the site of injection (1% vs. 14% vs. 9%), headache (9% vs. 13% vs. 11%), and nausea (7% vs. 11% vs. 3%). It is concluded that in healthy normal adults, a triple antigen hepatitis B vaccine that contained S and pre-S antigens produced an enhanced immunological response. This was exemplified by the novel vaccine's ability to overcome factors such as advancing age (> or = 40 years), obesity, and smoking, each of which is known to reduce the potential for protection with present recombinant S only vaccines. A two-dose/1-month (0 and 1) regimen of this triple antigen vaccine was as effective as the standard three-dose/6 month (0, 1, and 6) regimen of present single antigen vaccines. (c) 2001 Wiley-Liss, Inc.

Hepatitis B--an important public health issue.

Hepatitis B is one of the most common infectious diseases in the world. It has been estimated that 350 million people worldwide are chronic hepatitis B virus (HBV) carriers. The global prevalence of chronic HBV infection varies widely, from high ( > 8%, e.g., Africa, Asia and the Western Pacific) to intermediate (2-7% e.g., Southern and Eastern Europe) and low (< 2%, e.g., Western Europe, North America and Australia). The predominant routes of transmission vary according to the endemicity of the HBV infection. In areas of high endemicity, perinatal transmission is the main route of transmission, whereas in areas of low endemicity, sexual contact amongst high-risk adults is predominant. Between one-third and one-quarter of people infected chronically with HBV are expected to develop progressive liver disease (including cirrhosis and primary liver cancer). Although mass vaccination programs have begun to control the spread of HBV infection, therapeutic intervention is the only option for those with established chronic HBV-associated liver disease. Until recently, the only treatment for chronic hepatitis B was the immune modulator, interferon (IFN) alpha. However, IFN alpha treatment has several disadvantages; it is expensive, it must be administered by injection, there are side-effects, and IFN alpha is poorly tolerated. Lamivudine, a nucleoside analogue, is the first effective, and well tolerated, oral treatment for chronic hepatitis B. In conclusion, although we are still some way from eradicating or curing chronic hepatitis B, the advent of lamivudine allows new populations to benefit from therapy and helps to address the global public health problem of hepatitis B.

Hepatitis B: an important public health issue.

Hepatitis B is one of the most common infectious diseases in the world. It has been estimated that 350 million people world-wide are chronic hepatitis B virus (HBV) carriers. The global prevalence of chronic HBV infection varies widely, from high (>/=8%, e.g., Africa, Asia and the Western Pacific) to intermediate (2-7% e.g., Southern and Eastern Europe) and low (<2%, e.g., Western Europe, North America and Australia). The predominant routes of transmission vary according to the endemicity of the HBV infection. In areas of high endemicity, perinatal transmission is the main route of transmission, whereas in areas of low endemicity, sexual contact amongst high-risk adults is the predominant route. Between one-third and one-quarter of people infected chronically with HBV are expected to develop progressive liver disease (including cirrhosis and primary liver cancer). Although mass vaccination programmes have begun to control the spread of HBV infection, therapeutic intervention is the only option for those with established chronic HBV-associated liver disease. Until recently, the only treatment for chronic hepatitis B was the immune modulator, interferon (IFN) alpha. IFN alpha treatment has several disadvantages; it is expensive, it must be administered by injection, there are side effects, and IFN alpha is poorly tolerated. Lamivudine, a nucleoside analogue, is the first effective, and well tolerated, oral treatment for chronic hepatitis B. In conclusion, although we are still some way from eradicating or curing chronic hepatitis B, the advent of lamivudine allows new populations to benefit from therapy and helps to address the global public health problem of hepatitis B.

The hepatic safety and tolerability of the novel cyclooxygenase-2 inhibitor celecoxib.

Celecoxib is a cyclooxygenase- (COX)-1-sparing inhibitor of COX-2 that is indicated for the treatment of osteoarthritis and rheumatoid arthritis. Many agents used for treating these diseases, both symptom-modifying and disease-modifying, are associated with the potential for hepatotoxicity. This article presents an analysis of the hepatic effects of celecoxib in 14 controlled studies of patients with arthritis (2 to 24 weeks' duration), in a long-term, open-label safety study (as long as 2 years), in 11 studies of patients receiving treatment for pain after oral or orthopedic surgery (up to 5 days' duration), and in five pharmacology studies. The overall incidence of hepatic adverse events in arthritis patients receiving celecoxib was similar to that for placebo but significantly lower than in the combined group of patients receiving nonsteroidal anti-inflammatory drugs (NSAIDs). The most commonly reported hepatic adverse events were elevations in liver transaminase levels, most of which occurred in patients receiving diclofenac. Similarly, clinically significant elevations of transaminase levels occurred more frequently with NSAIDs than with celecoxib. A pharmacology study performed in patients with mild or moderate hepatic impairment showed that celecoxib did not produce any clinically relevant changes from baseline in creatinine clearance, alanine aminotransferase, or bilirubin values in these settings. In the four interaction studies performed with drugs metabolized in the liver, none of the adverse events was hepatic in nature, and no clinically relevant liver function test abnormalities occurred. In conclusion, this analysis suggests that celecoxib has a very low potential for hepatic toxicity, even after exposures of as long as 2 years at therapeutic doses.

The effect of ursodeoxycholic acid on the florid duct lesion of primary biliary cirrhosis.

The frequency with which florid duct lesions are seen in needle-biopsy specimens of the liver was assessed in patients with primary biliary cirrhosis (PBC) enrolled in a 2-year randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid (UDCA) versus placebo. Paired biopsy specimens obtained at entry and after 2 years on medication were reviewed blindly and mostly simultaneously by a panel of 5 hepatopathologists who, earlier, had characterized the florid duct lesion, which has been well described in the pathology literature. Florid duct lesions at entry were identified in approximately 36%. Patients with earlier disease showed florid duct lesions much more frequently than those with more advanced disease. The prevalence of florid duct lesions in 60 patients receiving placebo medication fell from 38.3% to 21.7%, P =. 025, over the period of 2 years. The prevalence of florid duct lesions also decreased in the 55 patients receiving UDCA, from 32.7% to 18.2%, P =.046. The prevalences of these lesions in the placebo and UDCA patients at entry and at 2 years were not significantly different from each other. The findings suggest that UDCA does not prevent ongoing bile duct destruction in patients with PBC. Instead, they support the impression that UDCA exerts its beneficial effects by protecting against the consequences of bile duct destruction.

Safety of combination interferon alfa-2b/ribavirin therapy in chronic hepatitis C-relapsed and treatment-naive patients.

The coadministration of ribavirin with recombinant interferon alfa-2b (rIFN-alpha 2b) compared with rIFN-alpha 2b alone markedly enhanced sustained virologic response rates in relapsed and treatment-naive chronic hepatitis C patients. The potential for ribavirin to likewise exacerbate the adverse events associated with the alpha interferons is reviewed. The overall safety and tolerability of combination rIFN-alpha 2b/ribavirin therapy was evaluated in 2,089 patients treated in phase III clinical studies conducted in the United States and internationally. Serious adverse events were also evaluated on an interim basis in > 25,000 patients--a majority of whom were treated with combination therapy (open label)--treated worldwide in investigator-initiated studies. Patients in the phase III studies received 3 million International Units rIFN-alpha 2b three times per week by subcutaneous injection plus either ribavirin or placebo orally in divided daily doses of 1,000 or 1,200 mg for patients weighing < or = 75 or > 75 kg, respectively. Adverse event frequency and severity and dose modifications were recorded throughout the 24-week (relapse) or 48-week (naive) treatment period and 24-week follow-up period. Clinically significant adverse events included anemia and depression. There was no evidence that the adverse effects of alpha interferon (e.g., fatigue, depression, neutropenia) were exacerbated by ribavirin. Severe adverse events were limited due to strict adherence to dose-modification criteria; approximately 6% to 9% of patients discontinued combination therapy because of an adverse event. Clinically serious adverse events, dose reductions and discontinuations, and potential mechanisms of toxicity associated with rIFN-alpha 2b and ribavirin are examined.

Containing hepatitis C.

Screening of donated blood has eliminated a major transmission route for hepatitis C, the accuracy of diagnostic tests has improved, and longer regimens of interferon have improved therapeutic response. Nevertheless, millions are infected, and other transmission routes remain open. Treatment is often unsuccessful, but it may offer the only check to slow destruction of the liver.

Chronic viral hepatitis: diagnosis and management.

Most patients with chronic hepatitis are infected with the B or C virus. Diagnosis has been simplified with the advent of increasingly accurate assays. Treatment, however, is still less than ideal; only about 50% of patients respond to alpha-interferon, and the rate of relapse is particularly high in hepatitis C. Refinements in patient selection criteria and treatment modalities are on the horizon.

Antitumor effect of deferoxamine on human hepatocellular carcinoma growing in athymic nude mice.

BACKGROUND: Iron is essential for the growth of all living cells. One of the important intracellular roles for iron is in the activation of ribonucleotide reductase, the enzyme that catalyzes the first step in DNA synthesis. Thus, the intracellular iron level may serve as a regulator of cell growth. The authors tested the hypothesis that lowering body iron concentration inhibits the growth of human-derived hepatocellular carcinoma (HCC) cells by depleting these cells of iron. Deferoxamine (DFO), an iron-chelating agent, was used to lower intracellular iron level. METHODS: HCC cells, PLC/PRF/5 (7 x 10(6) cells/mouse), were transplanted subcutaneously into athymic nude mice. When tumors reached 200-300 microliters in size, mice with comparable tumor sizes were paired; one was treated with DFO (300 mg/kg body weight/day, 5 days/week) intraperitoneally while the other received no treatment. RESULTS: Eight pairs of mice with HCC were observed for 5-18 weeks. Mean tumor growth rates (TGR) (mean +/- standard error) for the untreated and treated mice were 30.5 +/- 3.7 microliters/week and 11.9 +/- 1.5 microliters/week. The difference was significant (P < 0.02). In the second set of studies, DFO treatment was begun when the tumor size was smaller (100-200 microliters). Four pairs of mice were observed for 4-15 weeks; mean TGR for the four untreated mice was 18.1 +/- 5.1 microliters/week. In two mice treated with DFO, tumors regressed completely by the seventh week after initiation of treatment. The two remaining mice on DFO therapy had much slower growing tumors, with a mean TGR of 1.8 +/- 0.5 microliters/week. CONCLUSIONS: Thus, our results suggest that (1) reduction of intracellular iron concentration by DFO may be useful as antitumor therapy in HCC and (2) the favorable effects of DFO treatment are best seen when treatment is begun when the tumor is small.

Intrahepatic cholestasis and phospholipidosis associated with the use of trimethoprim-sulfamethoxazole.

Although liver injury after administration of the trimethoprim-sulfamethoxazole combination is rare, hepatocellular necrosis and cholestasis have developed in a few cases. We describe a patient who developed a severe, prolonged cholestatic reaction after trimethoprim-sulfamethoxazole administration. The findings from serial liver biopsy samples showed characteristic abnormalities of phospholipidosis that have not been previously described for trimethoprim-sulfamethoxazole-related hepatic injury. The most prominent finding on electron microscopic evaluation of the liver was the presence of prominent hepatocyte lysosomal inclusions characterized by concentric arrangements of membranous and lamellated structures. The patient improved after several courses of exchange plasmapheresis, which may have assisted in the removal of toxic drug-lipid complexes. The pathogenesis of this acquired secondary phospholipidosis is unknown. Possible mechanisms include generation of highly lipid-soluble metabolites and inhibition of the lysosomal enzyme phospholipase A1.

Chromosomal rearrangements in a primary hepatocellular carcinoma.

Chromosome analysis of cells obtained at biopsy from a 65-year-old man with primary hepatocellular carcinoma revealed characteristic abnormalities of chromosomes 1, 5, 6, 9, 13, 16, and 22 in each cell and maintenance of a pseudodiploid chromosome number (46,XY). Five of the chromosomal sites involved in these rearrangements are either in fragile site regions or in regions containing genes that encode cellular oncogenes. Some of the tumor cells manifest mitotic deviations in the form of asynchronies, spiralization, premature centromere division, and non-sister chromatid associations. The significance of these findings to hepatocellular carcinogenesis is discussed.

Ectopic soft tissue calcium deposition following liver transplantation.

We observed ectopic soft tissue calcification affecting seven patients following orthotopic liver transplantation. The cause of such calcification is unknown, but potential pathogenetic factors include hyperparathyroidism, calcium administered during and following surgery, renal failure, acid-base changes and citrate in fresh frozen plasma. To investigate some of the mechanisms underlying ectopic calcification following liver transplantation, we determined preoperative levels of ionized serum calcium, phosphate, magnesium, parathyroid hormone (midmolecule assay) and 1,25-(OH)2 vitamin D in 20 patients who underwent 24 liver transplants. In addition, these parameters were measured weekly in 15 patients during the first month after liver transplantation. Preoperatively, 5 of the 20 patients had elevated serum levels of parathyroid hormone, and 9 others had low levels of 1,25-(OH)2 vitamin D. After liver transplantation, ectopic calcification was found in seven patients (47%). The organs affected in order of frequency were lungs, liver graft, colon, vascular walls, kidneys, adrenal glands and gastric mucosa. One patient with ectopic calcification of both lungs had markedly restricted pulmonary function as well as radiologic evidence of osteopenia and pathologic fractures of three vertebrae. Postoperatively, increased parathyroid hormone levels were found in all patients who developed soft tissue calcification. Parathyroid hormone levels peaked during the second week after transplantation and were higher at all times compared to subjects without calcification. Five of the seven patients with ectopic calcification had associated renal failure. Individuals who developed calcification had received significantly more fresh frozen plasma, red blood cells and elemental calcium postoperatively, but showed no difference in serum levels of calcium, magnesium, vitamin D, total plasma CO2 or phosphate levels when compared to patients without calcification.(ABSTRACT TRUNCATED AT 250 WORDS)

Submassive hepatic necrosis associated with the use of progabide: a GABA receptor agonist.

Progabide, a recently introduced gamma-aminobutyric acid mimetic, is currently undergoing clinical evaluation for a variety of convulsive disorders. We describe a patient in whom severe hepatic failure developed after four weeks of Progabide therapy. The patient's course was marked by encephalopathy, jaundice, hypoglycemia, markedly elevated serum aminotransferase levels, and prolongation of the prothrombin time. Liver biopsy showed extensive hepatocellular necrosis. The patient recovered slowly after discontinuation of the drug. The finding of eosinophilia and increased serum IgE suggests an immunologically mediated mechanism for the Progabide-induced hepatic injury. Alternatively, the lipophilic moiety of Progabide may interact with hepatocyte cell membrane lipids leading to toxic injury. We conclude that Progabide may occasionally cause severe hepatic injury.

The periportal collar: a CT sign of liver transplant rejection.

A low-attenuation region around the peripheral portal tracts (periportal collar) was noted on 13 of 43 computed tomographic studies obtained in 17 patients who had undergone 20 orthotopic liver transplantations. This region was then correlated with acute liver transplant rejection. The periportal collar as a sign of rejection has a sensitivity of 1.0, a specificity of 0.86, a negative predictive value of 1.0, and a positive predictive value of 0.62. This sign corresponds histopathologically with the lymphocytic portal infiltration that occurs during acute liver transplant rejection. Though viral hepatitis and nonspecific portal triad edema can also result in a periportal collar, acute liver rejection is strongly suggested when this sign is seen after liver transplantation. Early diagnosis and confirmation of rejection permit faster and more appropriate clinical intervention.

Surgery in the patient with liver disease.

This article deals with the effects of anesthesia and surgery on the healthy and diseased liver and the preoperative assessment of patients with liver disease. Emphasis is placed on estimating surgical risk. Guidelines for optimal preoperative preparation are discussed.

Hepatic vein thrombosis (Budd Chiari syndrome): possible association with the use of oral contraceptives.

PIP: Although cases of hepatic vein thrombosis (Budd Chiari Syndrome) in oral contraceptive (OC) users have been reported in the literature, the association has not been definitively established. Hepatic vein thrombosis, an uncommon disorder, presents with right upper quadrant abdominal pain, hepatomegaly, and ascites. Diagnostic procedures include hepatic scintiscans, ultrasonography, computerized tomography and magnetic resonance imaging, determination of intrahepatic pressure, liver biopsy, and inferior vena cava and hepatic venography. Hepatic vein thrombosis may develop without an apparent underlying cause or as a complication of an illness known to be associated with vascular thromboses such as polycythemia rubra vera or paroxysmal nocturnal hemoglobinuria. In relation to the large numbers of women taking OCs, there have been very few cases of hepatic vein thrombosis. Evidence linking OC use to the development of hepatic adenomas is far more convincing. In a multicenter case-control study of 33 cases of hepatic vein thrombosis in women 15-45 years of age, each of whom was matched to 3-4 controls, the relative risk of hepatic vein thrombosis in OC users compared with nonusers was 2.37 (p 0.02). It was noted that the 1 patient with paroxysmal nocturnal hemoglobinuria, 5 of 12 patients with overt primary myeloproliferative disorder, and 7 of 8 patients with a forme fruste of a myeloproliferative disorder were OC users, suggesting that OCs--through their thrombogenic action--augmented the thrombotic tendency of the underlying condition. The objectives of therapy in hepatic vein thrombosis are to relieve the hepatic congestion and prevent further clot formation. The majority of patients die within 3 years of diagnosis.^ieng

Sclerosing cholangitis. Anatomical distribution of obstructive lesions.

The cholangiograms of 36 patients with sclerosing cholangitis were reviewed. The mean age of the patient group was 43 years, and the mean disease duration was 4.5 years. Seventeen of the patients had associated inflammatory bowel disease. The mean serum bilirubin was 6.8 mg/dl, the mean SGOT was 105 IU/L, the mean SGPT was 108 IU/L, and the mean serum alkaline phosphatase was 534 IU/L. The cholangiograms demonstrated involvement of the extrahepatic bile ducts in 33 patients, involvement of the hepatic duct bifurcation in 33 patients, and involvement of the intrahepatic bile ducts in 35 patients. The cholangiograms were graded as to the areas of the most severe obstructive involvement. In 24 patients the area of most severe involvement was the hepatic duct bifurcation. In eight additional patients the hepatic duct bifurcation, along with the extrahepatic ducts and/or the intrahepatic ducts, were felt to be the areas most severely affected. This predilection for severe obstructive disease at the hepatic duct bifurcation in sclerosing cholangitis held for both patients with and without inflammatory bowel disease. Thus, most patients with sclerosing cholangitis have cholangiographic evidence of diffuse extrahepatic and intrahepatic biliary tract disease, with the hepatic duct bifurcation being the area generally most severely affected.

Hepatic vein thrombosis (Budd-Chiari syndrome).

Hepatic vein thrombosis (Budd-Chiari Syndrome) is a rare disorder resulting from obstruction to the outflow of blood from the liver. The characteristic pathologic findings are intense congestion most pronounced around the terminal hepatic venules, cell necrosis, and a scant inflammatory reaction. Major clinical manifestations include hepatomegaly, right upper quadrant abdominal pain, and ascites. Disorders associated with hepatic vein thrombosis include those associated with a thrombotic tendency, such as polycythemia vera and paroxysmal nocturnal hemoglobinuria. Use of oral contraceptive agents probably increases tendency to develop hepatic vein thrombosis. Biochemical tests of the liver are of little value. The hepatic scan may be useful in suggesting the diagnosis with a marked decrease in uptake of isotope over affected areas of the liver. The diagnosis is confirmed by inferior vena caval and attempted hepatic venous catheterization. An associated thrombosis of the inferior vena cava is frequently found. Therapy in hepatic vein thrombosis is directed towards correction, in so far as possible, the underlying disorder, prevention of further extention of thrombosis, and management of ascites. Side-to-side portacaval or mesocaval shunt operation may convert the portal vein into an effective hepatic outflow vessel and reduce intrahepatic pressure and decrease injury. Mesoatrial shunts have proven useful in a few patients with hepatic vein thrombosis and either an inferior vena caval thrombosis or a marked pressure gradient from the abdomen to the thorax from ascites and an hypertrophied caudate lobe of the liver. For patients with extensive hepatocellular disease and portal hypertension, hepatic transplantation would seem to offer the best chance for survival.