Modulation of tumor necrosis factor receptors 1 and 2 in chronic hepatitis B and C: The differences and implications in pathogenesis

Tumor necrosis factor (TNF) plays a role in the pathogenesis of chronic hepatitis B (CHB) and chronic hepatitis C (CHC). The difference in the cytokine responses between hepatitis B virus (HBV) and hepatitis C virus (HCV) infections may have implications in the pathogenesis of these diseases. We performed a comparative study to examine the possible differences in the TNF-TNF receptor (TNFR) response between CHB and CHC. We studied the cytokine levels of 38 patients with CHB, 40 patients with CHC and 9 patients with dual hepatitis B and C, and compared them with the baseline levels of 12 healthy controls. The plasma levels of TNF-, interferon-, interleukin (IL)-2, IL-4, IL-10 and soluble TNFR-1 and 2 (sTNFR-1 and 2) were quantified by enzyme-linked immunosorbent assays. The expression of TNFR-1 and 2 in liver tissues was examined in 30 cases of CHB and 15 cases of CHC by semiquantitative reverse transcription polymerase chain reaction. The results showed that sTNFR-1 levels correlated with liver inflammation in all patients, whereas this correlation was not found with sTNFR-2 or other cytokines. Liver inflammation indicators were higher in HCV RNA+ than in HCV RNA– CHC. Most significantly, sTNFR-1 levels correlated with liver inflammation in CHB, but not in CHC. However, the expression of TNFR-1 and 2 in liver was similar between CHB and CHC. These findings suggest that the TNFR signal transduction pathway is modulated differently in HBV and HCV infection.<br />

Adefovir dipivoxil and pegylated interferon alpha for the treatment of chronic hepatitis B: an updated systematic review and economic evaluation

To update and extend a 2006 report on the clinical effectiveness and cost-effectiveness of adefovir dipivoxil (ADV) and pegylated interferon alpha (PEG-alpha) for the treatment of chronic hepatitis B (CHB). Thirteen bibliographic databases were searched including MEDLINE, EMBASE and the Cochrane Library. Searches were run from the beginning of 2005 to September 2007. For the clinical effectiveness review, randomised controlled trials (RCTs) comparing ADV, PEG-alpha-2a and PEG-alpha-2b with currently licensed treatments for CHB, including non-pegylated interferon alpha (IFN-alpha) and lamivudine (LAM), were included. Outcomes included biochemical, histological and virological response to treatment, drug resistance and adverse effects. A systematic review of economic evaluations of antiviral treatments for CHB was conducted. The economic Markov model used in the 2006 report was updated in terms of utility values, discount rates and costs. `

Entecavir for the treatment of chronic hepatitis B infection

This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of entecavir for the treatment of chronic hepatitis B (CHB) in adults based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submission's evidence came from five randomised controlled trials (RCTs), of good methodological quality and measuring a range of clinically relevant outcomes, comparing entecavir with lamivudine. After 1 year of treatment entecavir was statistically superior to lamivudine in terms of the proportion of patients achieving hepatitis B virus (HBV) DNA suppression, alanine aminotransferase (ALT) normalisation and histological improvement, but not in terms of the proportion of patients achieving hepatitis B e antigen (HBeAg) seroconversion. The incidence of adverse or serious adverse events was similar for both treatments. The results of the manufacturer's mixed treatment comparison (MTC) model to compare entecavir with the comparator drugs in nucleoside-naive patients were considered to be uncertain because of concerns over its conduct and reporting. For the economic evaluation the manufacturer constructed two Markov state transition models, one in HBeAg-positive and one in HBeAg-negative patients. The modelling approach was considered reasonable subject to some uncertainties and concerns over some of the structural assumptions. In HBeAg-positive patients the base-case incremental cost-effectiveness ratios (ICER) for entecavir compared with lamivudine and pegylated interferon alpha-2a were 14,329 pounds and 8403 pounds per quality-adjusted life-year (QALY) respectively. Entecavir was dominated by telbivudine. In HBeAg-negative patients the base-case ICERs for entecavir compared with lamivudine, pegylated interferon alpha-2a and telbivudine were 13,208 pounds, 7511 pounds and 6907 pounds per QALY respectively. In HBeAg-positive lamivudine-refractory patients entecavir dominated adefovir added to lamivudine. In one-way deterministic sensitivity analysis on all key input parameters for entecavir compared with lamivudine in nucleoside-naive patients, ICERs generally remained under 30,000 pounds per QALY. In probabilistic sensitivity analysis in nucleoside-naive HBeAg-positive patients the probability of the ICER for entecavir being below 20,000 pounds per QALY was 57%, 82% and 45% compared with lamivudine, pegylated interferon alpha-2a and telbivudine respectively. In nucleoside-naive HBeAg-negative patients the probabilities were 90%, 100% and 96% respectively. The manufacturer's lifetime treatment scenario for HBeAg-negative patients and the ERG's 20-year treatment scenario for HBeAg-positive patients increased the ICERs, particularly in the latter case. Amending the HBeAg-negative model so that patients with compensated cirrhosis would also receive lifetime treatment gave probabilities of entecavir being cost-effective at a willingness to pay of 20,000 pounds and 30,000 pounds of 4% and 40% respectively. The NICE guidance issued in August 2008 as a result of the STA states that entecavir is recommended as an option for the treatment of people with chronic HBeAg-positive or HBeAg-negative hepatitis B in whom antiviral treatment is indicated.

Replication of hepatitis B in HBsAg-positive siblings

Persistent hepatitis B virus (HBV) replication is important for progression of chronic liver diseases. To understand whether there is a trend of HBV replication in siblings or not, 1850 relatives of patients with hepatocellular carcinoma (HCC) were examined prospectively for liver function test, viral markers and HBV DNA. The prevalence of HBsAg in the parents', siblings', children's and grandchildren's generations were 43.4%, 57.2%, 35.5% and 32.1%, respectively. The prevalence of hepatitis B e antigen (HBeAg) in sibling's generation (mean age 44.4 years) was 19%, which is higher than that of asymptomatic HBsAg carriers. For siblings in the children's generation, the prevalence of HBeAg in hepatitis B surface antigen (HBsAg) carriers declined from 40% in the eldest siblings to 19% in the youngest siblings. In 75 families clustered with three or more HBsAg carrier siblings, the mean age for seven families of which all siblings remained HBeAg + was younger, whereas the mean age for 35 families of which all siblings had cleared HBeAg was older. For the remaining 33 families, in only 10 families had the older siblings cleared the HBeAg earlier than the younger siblings. Twenty families showed that younger siblings cleared the HBeAg earlier than the older or middle siblings. We concluded that HBV replication in HCC relatives cannot be explained by familial tendency alone. A significant number of younger siblings appeared to have a shorter HBV replication phase than their older siblings. The possible role of this in maternal–fetal transmission is discussed.

Hepatitis B Virus transmission and hepatocarcinogenesis: a 9 year retropective cohort of 13676 relatives with hepatocellular carcinoma

<b>Background/Aims b><br />Familial clustering of hepatitis B virus (HBV) infection is related to perinatal transmission, and is the main cause of familial-type hepatocellular carcinoma (HCC). The route of HBV transmission differs between the children and siblings of patients with HCC. This study examined the differences in HBV carrier rates and HCC-related mortality between two generations in HCC families.<br /><b>Methods b><br />From 1992 to 1997, relatives of individuals with HCC were screened prospectively with ultrasonography, alpha-fetoprotein, liver biochemistry tests and viral markers. Total HCC-related deaths during a 9-year period were compared between the generations of index patients and their children.<br /><b>Results b><br />The study included a total of 13 676 relatives in two generations. More HCC-related deaths occurred in the index patient generation than in the child generation. Furthermore, children of female index patients had higher rates of liver cancer related mortality than children of male index patients. The same was true when the analysis was limited to male HBV carriers. The prevalence of HBsAg in the offspring of HBsAg positive mothers was 66% in the child generation and 72% in the index patient generation. These high prevalences indicated high maternal HBV replication status.<br /><b>Conclusions b><br />Perinatal transmission and maternal viral load are important risk factors in hepatocarcinogenesis.<br />

The current pattern of hepatitis B virus infectiion in Australia

Summary. There is little recent data of the seroprevalence of hepatitis B in Australia. We have surveyed a large cohort of endoscopy patients attending a teaching hospital in central Sydney, and related the presence of hepatitis B virus (HBV) markers with putative risk factors for exposure using the SAS statistical package. Of the 2115 patients tested: 2.1% (45/2115) were HBV surface antigen positive, 0.75% (14/2115) viraemic, 9.5% (200/2115) anti-HBs and anti-HBc positive, 20.1% (430/2115) vaccinated (anti-HBs only) and the remaining 70% were susceptible. The adjusted OR of HBV infection was significantly increased in patients who had been diagnosed with human immunodeficiency virus (36.3-fold), born in Asia or Pacific islands (12.4-fold), born in North Africa, Middle East & Mediterranean countries (6-fold) or born abroad elsewhere in the world (2.7-fold), had household contact with someone diagnosed with hepatitis between 1980 and 1990 (3.9-fold), injected drugs between 1980 and 1990 (4.4-fold), resided in a military establishment for 3 months (2.3-fold) or in a hospital for 3 months (2.2-fold), never been vaccinated for hepatitis B (2.8-fold), received blood transfusion due to an accident and/or a haemorrhage (1.92-fold) and finally been a male gender (1.59-fold). The prevalence of HBV in this hospital population was higher than predicted on the basis of notifications to the passive surveillance scheme. Most HBV patients had multiple risk factors for infection, but the hierarchy of odds ratios provides a rational basis for targeted programmes to identify asymptomatic HBV carriers who might benefit from treatment.

The significance of transfusion in the past as a risk for current hepatitis B and Hepatitis C infection: a study in endoscopy patients

<b>BACKGROUND:b> The objective was to determine the contribution of transfusion in the past to the risk of current infection with hepatitis B or C among patients attending a large hospital for endoscopic procedures.<br /><b>STUDY DESIGN AND METHODSb>: Blood samples had been tested for hepatitis markers by routine methods. Patients completed a comprehensive risk factor questionnaire and results were analyzed using computer software.<br /><b>RESULTSb>: Twenty-seven percent of the 2120 participants in the study received transfusions in the past. There was no increase in prevalence of hepatitis B among those transfused. Compared with nontransfused participants, recipients of blood before the implementation of hepatitis C virus (HCV) screening in 1990 had a 4.6-fold increased risk of HCV infection, whereas those transfused with screened blood had a 3-fold increased risk. The difference between the odds ratios for patients before and after screening was not significant.<br /><b>CONCLUSIONS:b> Because screening has almost completely eliminated HCV from the blood supply, our finding of a continuing association of HCV infection with transfusion was unexpected. It implies that there are significant other nosocomial risks for hepatitis C transmission associated with the clinical situations where patients received blood. These should be actively investigated.<br />

Natural history of hepatitis B in perinatally infected carriers

Objectives: To establish natural seroconversion rates and incidence of hepatic pathology in perinatally infected hepatitis B carriers.<br /><br />Methods: Seventy three perinatally infected hepatitis B carriers identified through maternal screening were evaluated. Fifty three were born to parents from the Indian subcontinent, nine were Oriental, six were Afro-Caribbean, and five were white. Median follow up was 10.24 (range 2.02–20.16) years.<br /><br />Results: Only three of the children followed up had cleared hepatitis B surface antigen during this period, and 30% of the children had seroconverted to anti-HBe. Seroconversions to anti-HBe were observed in Asian (18/50) and white (4/5) children, but not in Oriental or Afro-Caribbean children. More girls (40%) than boys (23%) had seroconverted, but the difference was not significant. All children were asymptomatic with normal physical examination, growth, and development. Almost half (48%) of the hepatitis B e antigen (HBeAg) positive children had normal hepatic transaminases and liver function. Thirty five liver biopsies were performed in children with active virus replication (HBeAg or hepatitis B virus DNA positive) who were being considered for antiviral treatment as part of a clinical trial and were scored using the Ishak method. Two thirds (62%) of the children had mild hepatitis, 60% had mild fibrosis, and 18% had moderate to severe fibrosis. There was a weak correlation between histological evidence of hepatitis and hepatic transaminase activity, implying that biochemical monitoring of hepatic disease activity may be ineffective.<br /><br />Conclusions: These asymptomatic hepatitis B virus carrier children remain infectious in the medium to long term with notable liver pathology. They should receive antiviral treatment to reduce infectivity and to prevent further progression of liver disease. Hepatic transaminases alone are not a reliable marker of liver pathology, and liver histology is essential before consideration for antiviral treatment. <br />

Targeting hepatitis B virus and human papillomavirus induced carcinogenesis : novel patented therapeutics

Viral infections leading to carcinogenesis tops the risk factors list for the development of human cancer. The decades of research has provided ample scientific evidence that directly links 10-15% of the worldwide incidence of human cancers to the infections with seven human viruses. Moreover, the insights gained into the molecular pathogenetic and immune mechanisms of hepatitis B virus (HBV) and human papillomavirus (HPV) viral transmission to tumour progression, and the identification of their viral surface antigens as well as oncoproteins have provided the scientific community with opportunities to target these virus infections through the development of prophylactic vaccines and antiviral therapeutics. The preventive vaccination programmes targeting HBV and high risk HPV infections, linked to hepatocellular carcinoma (HCC) and cervical cancer respectively have been recently reported to alter age-old cancer patterns on an international scale. In this review, with an emphasis on HBV and HPV mediated carcinogenesis because of the similarities and differences in their global incidence patterns, viral transmission, mortality, molecular pathogenesis and prevention, we focus on the development of recently identified HBV and HPV targeting innovative strategies resulting in several patents and patent applications.<br />

Nurse-led clinic: Effective and efficient delivery of assessment and review of patients with Hepatitis B and C

Hepatology and gastroenterology services are increasingly utilising the skills and experience of nurse practitioners and nurse specialists to help meet the increasing demand for health care. A new nurse-led assessment clinic has been established in the liver clinic at Geelong Hospital to utilise the expertise of nurses to assess and triage new patients and streamline their pathway through the health care system. The aim of this study is to quantitatively assess the first two years of operation of the nurse assessment clinic at Geelong Hospital, and to assess advantages and disadvantages of the nurse-led clinic. Data was extracted retrospectively from clinical records of new patients at the liver clinic. Quarterly one-month periods were recorded over two-years. Patients were categorised according to the path via which they saw a physician, including missed and rescheduled appointments. The number of appointments, the waiting time from referral to appointments and the number of ‘did-not-attend’ occasions were analysed before and after the institution of the nurse-led assessment clinic. The Mann-Whitney rank sum test of ordinal data was used to generate median wait times. There was shown to be a statistically significant longer waiting time for physician appointment if seen by the nurse first. The difference in waiting time was 10 days. However, there was also a reduction in the number of missed appointments at the subsequent physician clinic. Other advantages have also been identified including effective triage of patients, and organisation of appropriate investigations from the initial nurse assessment.

Effects of chronic treatment with arabose on glucose and lipid metabolism in obese diabetic wistar rats

<b>Aimsb>: The effect of chronic treatment with acarbose on fasting plasma glucose, insulin, triglyceride, cholesterol and free fatty acid (FFA) concentrations, as well as on the glucose and insulin excursions during oral glucose tolerance test (OGTT), in obese diabetic Wistar (WDF) rats was investigated. <b> Methodsb>: Forty-five mature male WDF rats were randomly distributed to one of the three treatment groups (no acarbose, 20 mg and 40 mg of acarbose/100 g of chow, respectively). After 3.5, 7.5 and 11.5 months, animals were tested for glucose tolerance by means of an OGTT, and their respective metabolic profiles were determined. Control determinations were done in obese and age-matched lean animals before the start of the trial. <b>Resultsb>: The WDF rats exhibit higher body weight and fasting blood glucose, insulin, triglyceride and cholesterol concentrations compared to lean animals. Moreover, they show marked glucose intolerance as indicated by the glucose and insulin excursions during OGTT. Interestingly, in both treated and untreated animals, a reversion of the hyperglycaemic state as well as an improvement of the glucose tolerance is observed. However, whereas in the group receiving no acarbose this is accounted for by dramatic increases in fasting plasma insulin concentrations and insulin secretion during OGTT (as indicated by the ΔInsulin area), in rats treated with acarbose the reversion of the diabetic state takes place without increments in hormone concentration. In addition, rats treated with acarbose for 3.5 and 7.5 months show lower plasma triglyceride and FFA concentrations, and the same was observed for cholesterol at the highest dosage of the drug. <b>Conclusionsb>: Chronic treatment with acarbose of WDF rats improves the glycaemic and lipidic control as well as the glucose tolerance, with a lower demand of pancreatic insulin than in untreated rats. This data suggests that the long-term modulation of glucose and insulin excursions after meals improves the insulin sensitivity in this rat strain.<br />

Survival of relatives of patients with hepatocellular carcinoma

<b>Backgroundb>:Families of patients with hepatocellular carcinoma (HCC) carry a high risk of developing HCC. We determine the number of fatalities in relatives of HCC patients during an 8-year period to understand the risk and cause of HCC in relatives of patients with HCC.<br /><b>Methodsb>:From 1992 to 1997, 15 410 relatives of HCC patients in three generations were screened prospectively for HCC by ultrasonography, α-fetoprotein, liver biochemistry and viral markers. By using national citizen identification numbers, we searched the total fatalities in relatives of HCC patients between 1992 and 1999 from the national mortality data bank. The results were compared among different viral infection groups.<br /><b>Resultsb>:Of the relatives studied, 37.8% were hepatitis B s antigen (HBsAg) positive (+), 4.3% were anti-hepatitis C virus (HCV) (+) and 1.7% were both HBsAg (+) and anti-HCV (+). A total of 399 fatalities, including 139 because of HCC (34.8%), 37 because of liver diseases (9.3%), 88 because of other cancers (22.1%) and 135 because of other diseases (33.8%), were found. Relatives who were HBsAg (+) or anti-HCV (+)showed a lower cumulative survival than did relatives who were negative for both HBsAg and anti-HCV. Relatives with dual infection of hepatitis B and C virus showed the highest mortality due to HCC or terminal liver diseases.<br /><b>Conclusionsb>:Chronic viral infection rather than a hereditary factor is the main cause of a familial tendency for HCC. Dual infection of hepatitis B and C virus increases the risk of HCC or decompensated liver diseases.<br />Background:Families of patients with hepatocellular carcinoma (HCC) carry a high risk of developing HCC. We determine the number of fatalities in relatives of HCC patients during an 8-year period to understand the risk and cause of HCC in relatives of patients with HCC.<br /><b>Methodsb>:From 1992 to 1997, 15 410 relatives of HCC patients in three generations were screened prospectively for HCC by ultrasonography, α-fetoprotein, liver biochemistry and viral markers. By using national citizen identification numbers, we searched the total fatalities in relatives of HCC patients between 1992 and 1999 from the national mortality data bank. The results were compared among different viral infection groups.<br /><b>Resultsb>:Of the relatives studied, 37.8% were hepatitis B s antigen (HBsAg) positive (+), 4.3% were anti-hepatitis C virus (HCV) (+) and 1.7% were both HBsAg (+) and anti-HCV (+). A total of 399 fatalities, including 139 because of HCC (34.8%), 37 because of liver diseases (9.3%), 88 because of other cancers (22.1%) and 135 because of other diseases (33.8%), were found. Relatives who were HBsAg (+) or anti-HCV (+)showed a lower cumulative survival than did relatives who were negative for both HBsAg and anti-HCV. Relatives with dual infection of hepatitis B and C virus showed the highest mortality due to HCC or terminal liver diseases.<br /><b>Conclusionsb>:Chronic viral infection rather than a hereditary factor is the main cause of a familial tendency for HCC. Dual infection of hepatitis B and C virus increases the risk of HCC or decompensated liver diseases.<br />

New regimen for eccentric calf-muscle training in patients with chronic insertional achilles tendinopathy : results of a pilot study

<b>Background: b>Chronic painful insertional Achilles tendinopathy is seen in both physically active and non-active individuals. Painful eccentric training, where the patients load the Achilles tendon into full dorsiflexion, has shown good results in patients with mid-portion Achilles tendinosis. However, only 32% of patients with insertional Achilles tendinopathy had good clinical results with that type of eccentric training regimen. <br /><br /><b>Aim:b> To investigate whether a new model of painful eccentric training had an effect on chronic painful insertional Achilles tendinopathy. <br /><br /><b>Patients and methods:b> 27 patients (12 men, 15 women, mean age 53 years) with a total of 34 painful Achilles tendons with a long duration of pain (mean 26 months), diagnosed as insertional Achilles tendinopathy, were included. The patients performed a new model of painful eccentric training regimen without loading into dorsiflexion. This was done as 3x15 reps, twice a day, 7 days/week, for 12 weeks. Pain during Achilles-tendon-loading activity (VAS) and patient’s satisfaction (back to previous activity) were evaluated. <br /><b><br />Results:b> At follow-up (mean 4 months) 18 patients (67%, 23/34 tendons) were satisfied and back to their previous tendon-loading activity. Their mean VAS had decreased from 69.9 (SD 18.9) to 21 (SD 20.6) (p<0.001). Nine patients (11 tendons) were not satisfied with the treatment, although their VAS was significantly reduced from 77.5 (8.6) to 58.1 (14.8) (p<0.01). <br /><b><br />Conclusion:b> In this short-term pilot study this new model of painful eccentric calf-muscle training showed promising clinical results in 67% of the patients.<br />