Peginterferon plus adefovir versus either drug alone for hepatitis delta.

BACKGROUND: Chronic infection with hepatitis B virus and hepatitis delta virus (HDV) results in the most severe form of viral hepatitis. There is no currently approved treatment. We investigated the safety and efficacy of 48 weeks of treatment with peginterferon alfa-2a plus adefovir dipivoxil, peginterferon alfa-2a alone, and adefovir dipivoxil alone. METHODS: We conducted a randomized trial in which 31 patients with HDV infection received treatment with 180 µg of peginterferon alfa-2a weekly plus 10 mg of adefovir daily, 29 received 180 µg of peginterferon alfa-2a weekly plus placebo, and 30 received 10 mg of adefovir alone weekly for 48 weeks. Follow-up was conducted for an additional 24 weeks. Efficacy end points included clearance of HDV RNA, normalization of alanine aminotransferase levels, and a decline in levels of hepatitis B surface antigen (HBsAg). RESULTS: The primary end point--normalization of alanine aminotransferase levels and clearance of HDV RNA at week 48--was achieved in two patients in the group receiving peginterferon alfa-2a plus adefovir and two patients in the group receiving peginterferon alfa-2a plus placebo but in none of the patients in the group receiving adefovir alone. At week 48, the test for HDV RNA was negative in 23% of patients in the first group, 24% of patients in the second, and none of those in the third (P = 0.006 for the comparison of the first and third groups; P = 0.004 for the comparison of the second and third). The efficacy of peginterferon alfa-2a was sustained for 24 weeks after treatment, with 28% of the patients receiving peginterferon alfa-2a plus adefovir or peginterferon alfa-2a alone having negative results on HDV-RNA tests; none of the patients receiving adefovir alone had negative results. A decline in HBsAg levels of more than 1 log(10) IU per milliliter from baseline to week 48 was observed in 10 patients in the first group, 2 in the second, and none in the third (P<0.001 for the comparison of the first and third groups and P = 0.01 for the comparison of the first and second). CONCLUSIONS: Treatment with peginterferon alfa-2a for 48 weeks, with or without adefovir, resulted in sustained HDV RNA clearance in about one quarter of patients with HDV infection. (Current Controlled Trials number, ISRCTN83587695.).

A New Risk-Scoring System for Colorectal Cancer and Polyp Screening by Turkish Colorectal Cancer and Polyp Study Group.

BACKGROUND: Colorectal cancer is one of the most commonly diagnosed types of cancer worldwide. An early diagnosis and detection of colon cancer and polyp can reduce mortality and morbidity from colorectal cancer. Even though there are a variety of options in screen- ing tests, the question remains on which test is the most effective for the early detection of colorectal cancer. In this prospective study, we aimed to develop a simple, useful, effective, and reliable scoring system to detect colon polyp and colorectal cancer. METHODS: We enrolled 6508 subjects over the age of 18 from 16 centers, with colonoscopy screening. The age, smoking status, alcohol consumption, body mass index, polyp incidence, polyp size, number and localization, and pathologic findings were recorded. RESULTS: The age, male gender, obesity, smoking, and family history were found as independent risk factors for adenomatous polyp. We have developed a new scoring system which can be used for these factors. With a score of 4 or above, we found the following: sensitivity 81%, specificity 40%, positive predictive value 25.68%, and negative predictive value 89.84%, for adenomatous polyp detection; and sensitivity 96%, specificity 39%, positive predictive value 3.35%, negative predictive value 99.29%, for colorectal cancer detection. CONCLUSION: Even though the first colorectal cancer screening worldwide is generally performed for individuals over 50 years of age, we recommend that screening for colorectal cancer might begin for those under 50 years of age as well. Individuals with a score ≥ 4 must be included in the screening tests for colorectal cancer.

Quantitative HBsAg and HDV-RNA levels in chronic delta hepatitis.

UNLABELLED: Abstract Background: Hepatitis delta virus (HDV) causes severe liver disease. AIMS: To investigate the quantitative HDV-RNA, HBsAg and hepatitis B virus (HBV)DNA levels in correlation to histological, biochemical and demographical parameters in patients with chronic HDV infection as similar data in a large series of HDV patients are missing. METHODS: Eighty HDV patients were recruited in Germany, Turkey and Greece; quantitative determination of HDV-RNA, HBsAg and HBV-DNA was performed by real-time polymerase chain reaction, the Architect HBsAg assay and Cobas TaqMan HBV test respectively. RESULTS: All patients were infected with HDV-genotype 1. Thirty-five patients (48%) had significant fibrosis (Ishak 3-4) and 15 (20.5%) had cirrhosis. HDV viraemia ranged from 1.1 x 10(3) to 8.4 x 10(7) copies/ml with 60% of patients showing HDV-RNA levels above 10(5) copies/ml accompanied by low HBV viraemia (<10(5) copies/ml). However, HDV-RNA and HBV-DNA levels showed no direct inverse correlation. HDV-RNA correlated positively with HBsAg and negatively with age. HBsAg correlated negatively with age and positively with histological grading. Only gamma-glutamyltranspeptidase was independently associated with cirrhosis (P=0.032), while no biochemical parameter was associated with grading. CONCLUSIONS: (i) HBsAg levels correlated with HDV viraemia in chronic HDV. (ii) Biochemical parameters did not accurately indicate the stage and grade of liver disease in chronic HDV and thus liver biopsy seems to remain the major tool for the evaluation of delta hepatitis patients.

Seropositivity for delta hepatitis in patients with chronic hepatitis B and liver cirrhosis in Turkey: a meta-analysis.

BACKGROUND: Recent reports suggest a decline of delta hepatitis (DH) in the West as well as in the Far East. AIM: To study the DH seroepidemiology in Turkey. METHODS: Statistical power analysis was utilized based on data available in a recent article using prevalence figure estimates. Binominal distribution was applied in order to assess the number of samples required to estimate the prevalence with a given precision. RESULTS: Out of 62 studies in the original study, 32 were eliminated because of insufficient power. A total of 6734 patients (5231 with chronic hepatitis and 1503 with cirrhosis) were analysed. Anti-HDV seropositivity among patients with chronic hepatitis B (CHB) and hepatitis B-induced cirrhosis was lowest in the west of the country and highest in the southeast (5 vs. 27%, P<0.0001 and 20 vs. 46%, P<0.0001) respectively. Compared with data obtained before 1995, after 1995, DH prevalence in patients with CHB and cirrhosis decreased from 29 to 12% (P<0.0001) and from 38 to 27% (P=0.03) in central and southeast Turkey and from 38 to 20% (P<0.0001) and from 66 to 46% (P<0.002) in west and southeast Turkey respectively. CONCLUSION: Despite the decrease of its prevalence in Turkey, DH remains a significant health problem in parts of the country with low socio-economic level.

The prevalence of hepatitis delta virus infection in acute and chronic liver diseases in Turkey: an analysis of clinical studies.

BACKGROUND/AIMS: The objective of this study was to review the studies on hepatitis D virus-related liver diseases and to evaluate the national and regional outcomes in order to identify the hepatitis D virus infection in Turkey. METHODS: This retrospective study included 2182 acute viral hepatitis, 6613 inactive HBsAg carriers, 5961 chronic hepatitis B, 1264 liver cirrhosis and 748 hepatocellular carcinoma cases, who were evaluated for anti-hepatitis D virus positivity at several centers in Turkey since 1980's. ELISA method was used and the results were statistically evaluated. RESULTS: The anti-hepatitis D virus positivity was 3.0% in 1416 acute viral hepatitis and 8.1% in 766 acute hepatitis B cases. This ratio was significantly higher in Diyarbakir than in Istanbul and Ankara for acute viral hepatitis (p<0.001). The mean anti-hepatitis D virus was 4.9% in inactive HBsAg carriers and significantly decreased from 1980 to 2005 (4.1% and 2.9%, respectively p<0.001). The anti- hepatitis D virus was 20% in chronic hepatitis B and 32.5% in liver cirrhosis cases. The positivity were significantly lower in Istanbul and Izmir compared to Diyarbakr and Van (p<0.001). Antihepatitis D virus positivity was decreased in all regions for the last two decades (p<0.001). The rates decreased from 31% to 11% for chronic hepatitis B and from 43.3% to 24% for liver cirrhosis (p<0.001). The mean anti-hepatitis D virus was 23% in hepatocellular carcinoma cases, which was significantly lower in Istanbul and Izmir compared to Diyarbakr and Elaz currency (p<0.0001). CONCLUSIONS: The hepatitis D virus infection is a critical problem in our country, particularly in the Eastern and Southeastern Anatolia. In recent years, the hepatitis D virus infection is decreasing countrywise, however the rate still remains to be critical.

Comparison of 12-month courses of interferon-alpha-2b-lamivudine combination therapy and interferon-alpha-2b monotherapy among patients with untreated chronic hepatitis B.

We compared the use of prolonged synchronous combination therapy with interferon (IFN)-alpha-2b and lamivudine with the use of IFN-alpha-2b monotherapy in patients with untreated hepatitis B e antigen (HBeAg)-positive chronic hepatitis B virus (HBV) infection. Thirty-three patients received therapy with lamivudine (100 mg daily) and IFN-alpha-2b (10 million U 3 times per week) for 12 months; 16 patients received IFN-alpha-2b alone (10 million U 3 times per week for 12 months). The primary end point was sustained suppression of HBV DNA and HBeAg seroconversion, which was observed in 15 (45%) of 33 patients treated with combination therapy and in 3 (19%) of 16 patients treated with monotherapy (P=.133). Both therapeutic regimens were well tolerated. Combination therapy increased the rate of sustained suppression of HBeAg and resulted in significant improvement in Knodell histologic activity index scores, compared with monotherapy. However, there was no significant difference in rates of sustained suppression between the 2 groups at the end of follow-up.

A severe hepatitis flare in an HBV-HCV coinfected patient during combination therapy with alpha-interferon and ribavirin.

We report a reactivation of hepatitis B virus infection and a severe hepatitis flare in a patient with chronic hepatitis due to dual infection with hepatitis B and C viruses during combination therapy with alpha-interferon and ribavirin. Pretreatment, HCV was the dominant virus, with detectable serum HCV-RNA but undetectable HBV-DNA. The patient responded to therapy, with the disappearance of HCV-RNA and normalization of serum alanine aminotransferase (ALT) at months 1 and 6. In the seventh month of therapy, an ALT flare was observed, and serum HBV-DNA became detectable. The patient had a severe hepatitis flare leading to impending hepatic failure. Treatment was discontinued and the patient had marked clinical and biochemical improvement and recovered with normalization of liver function test results within 1 month. Two months later, serum HBV-DNA was again undetectable, both by hybridization and polymerase chain reaction (PCR) assays. The patient had a rapid progression to cirrhosis in a year. At month 24, 17 months after the end of therapy, serum HCV-RNA reappeared, with a level of 2.4 x 10(5) copies/ml. In conclusion, severe HBV reactivation may occur during interferon plus ribavirin therapy in patients with chronic hepatitis C who are also hepatitis B surface antigen (HBsAg)-positive, and thus more careful monitoring than usual should be considered. Longterm follow-up is recommended, because very late HCV relapses may occur in coinfected patients. These data exemplify the complexity of viral dominance in patients infected with multiple hepatitis viruses, and this has significant importance for treatment decisions. Lamivudine may be administered early in HCV-RNA/HBsAg-positive patients who are at high risk of liver failure once reactivation of HBV occurs during interferon therapy.

The role of HBeAg seroconversion in acute exacerbation of liver disease with termination of hepatitis B and D virus infection in a chronic hepatitis D patient during alpha-interferon therapy.

We report a severe flare-up in a chronic hepatitis patient due to dual infection with hepatitis B and D viruses during alpha-interferon therapy. Pre-treatment, the patient had detectable levels of both viruses. After 9 months of therapy, an alanine aminotransferase flare with acute hepatic decompensation was detected. Alpha-interferon was discontinued and lamivudine (100 mg once daily) was started, after which the patient reversed slowly. Hepatitis B early antigen (HBeAg) seroconversion with hepatitis B virus-DNA clearance was observed 1 month after the flare; 15 months later, the patient had persistently normal alanine aminotransferase levels with negative results for both serum hepatitis B virus-DNA and hepatitis D virus-RNA. In conclusion, liver disease may be exacerbated during interferon therapy in patients with chronic hepatitis D who are also positive for hepatitis B surface antigen (HBsAg) and HBeAg. Therefore, extra care in monitoring should be considered and strict follow-up is recommended, since clearance of hepatitis D may occur after HBeAg seroconversion in coinfected patients. Lamivudine may be administered early in hepatitis D-RNA/HBsAg-positive patients at high risk of liver failure once a severe flare-up occurs during interferon therapy.

Clear cell carcinoma of the liver: a case report.

Hepatocellular carcinoma represents the 8th most frequent malignancy worldwide. The World Health Organization recognizes five histologic patterns and four cytologic variants of hepatocellular carcinoma. Clear cell carcinoma of the liver is a well-defined variant of hepatocellular carcinoma in which a large number of cells show clear cytoplasm that does not stain with hematoxylin and eosin. It can be confused with other clear-cell malignancies. A 52-year-old man presented with mild dyspeptic symptoms, right-sided upper abdominal pain, weakness, weight loss, abdominal mass and jaundice symptoms for nearly six weeks. After diagnostic procedures, an ultrasonography-guided liver biopsy was performed. In microscopic examination, malignant cells with vacuolated foamy to clear cytoplasm and central and eccentric nuclei, tumor composed of solid mass and cords, and clear cells were observed, and hepatocellular carcinoma, clear cell variant, is diagnosed. We report this rare case of primary clear cell carcinoma in the cirrhotic liver. The case was discussed in detail regarding histological presentation, with particular attention to histopathologic differential diagnosis.

A three-month course of lamivudine therapy in HBeAg-positive hepatitis B patients with normal aminotransferase levels.

BACKGROUND/AIMS: HBeAg-positive patients with normal ALT levels are unlikely to respond to current therapy. In addition, there is a high risk of hepatocellular carcinoma in HBeAg-positive patients in the natural course of HBV infection. For this purpose, we aimed to investigate the clinical efficacy and safety of a three-month course of lamivudine therapy in HBeAg-positive hepatitis B patients with normal aminotransferase levels for assessing a more practical and economical approach to these patients. METHODS: Forty-six patients were prospectively randomized into two groups. Group A consisted of 13 patients treated with lamivudine 100 mg/day, for 12 weeks [7 males, mean age 23.30+/-5.82 years, median ALT of 27 IU/L (21-40), median HBV DNA of 4116 pg/ml (2885-6628)]. Group B consisted of 33 patients without treatment [18 males, mean age 24.75+/-6.92 years, median ALT of 30 IU/L (19-39), median HBV DNA of 4094 pg/ml (782-7387)]. Main outcome measure was sustained virologic response, which was defined as loss of HBV DNA in serum with HBeAg seroconversion at least 12 months thereafter. Follow-up lasted 12 months after the first dose. RESULTS: No significant effects were observed in the treated population in the reduction of HBV DNA to undetectable levels, in HBeAg/anti-HBe seroconversion, or in transaminase levels. At the end of follow-up, sustained virologic response was almost similar in the study as well as control group (7.6% vs. 3.0%, p=0.502). None of the 13 patients who received lamivudine therapy had HBeAg seroconversion during the study period. In addition, the suppression of serum HBV DNA was temporary; prolonged suppression could be achieved in only one patient in the follow-up period. The median levels of HBV DNA and ALT values between baseline and month 12 did not differ significantly between groups. All patients remained HBsAg positive and none developed anti-HBs. The therapy was well tolerated and post-therapy flare was not observed in any patient after stopping lamivudine therapy. CONCLUSIONS: A short course of lamivudine therapy resulted mostly in only temporarily depressed serum HBV DNA levels without significant change in viral clearance. Whether permanent suppression of HBV DNA can be achieved in this special population of HBsAg carriers by long-term treatment with lamivudine awaits further controlled trials. New and safe modalities of therapy are needed for the satisfactory treatment of these asymptomatic but viremic patients.

Determination of serum hepatitis B virus DNA in chronic HBsAg carriers: clinical significance and correlation with serological markers.

BACKGROUND/AIMS: Hepatitis B virus infection is among the most devastating health problems in the world, including Turkey. In this cross-sectional study, we aimed to investigate the correlations between hepatitis B virus genomic load and various measures of the progression of chronic hepatitis B virus infection. METHODS: A total of 354 chronic HBsAg carriers [126 inactive HBsAg carriers, 50 asymptomatic replicative carriers (immune tolerant patients), 90 chronic hepatitis B patients and 88 patients with liver cirrhosis] were enrolled into the study. Eligible patients included males and females, 14-62 years of age, with detectable serum HBsAg, HBeAg or anti-HBe in serum at the time of screening and for at least six months before study entry. Serum hepatitis B virus DNA was detected by liquid hybridization, and results under the level of 1 pg/ml were additionally confirmed by polymerase chain reaction. RESULTS: Of 354 patients, 118 (33%) were HBeAg-positive and 236 (67%) HBeAg-negative. Of HBeAg-negative patients, 126 (53%) had normal alanine aminotransferase, 31 (13%) had elevated alanine aminotransferase (chronic hepatitis B) and 79 (33%) had evidence of cirrhosis; corresponding figures in the HBeAg-positive patients were 50 (42%), 59 (50%) and 9 (8%). There is a significant correlation between transaminase values and histological liver damage, whereas no correlation was found between viral replication and liver damage. CONCLUSIONS: Hepatitis B virus DNA is an important and specific marker for ongoing hepatitis B virus related liver disease, but alanine aninotransferase was shown to be the best marker for liver inflammation and not hepatitis B virus viral load. Although these findings are not new, they are of some utility since they prevent unnecessary and cost-intensive viral load determinations in chronic HBsAg carriers.

The relationship between insulin resistance, metabolic syndrome and nonalcoholic fatty liver disease in non-obese non-diabetic Turkish individuals: A pilot study.

BACKGROUND/AIMS: Nonalcoholic fatty liver disease is related to obesity, metabolic syndrome, and insulin resistance. Nonalcoholic fatty liver disease and metabolic syndrome may also be encountered in non-obese, non-diabetic individuals, and there are no published data about the prevalence of these conditions in non-obese, non-diabetic Turkish subjects. We aimed to determine the difference between non-obese, non-diabetic nonalcoholic fatty liver disease patients and healthy controls in terms of insulin resistance and metabolic syndrome in Turkish subjects. MATERIALS AND METHODS: Non-obese, non-diabetic individuals (n=219) were enrolled. The cohort was divided into two groups according to presence of steatosis in ultrasonography: nonalcoholic fatty liver disease group (n=143) and healthy control group (n=76). Insulin resistance and metabolic syndrome were analyzed and compared between the two groups. RESULTS: The prevalences of metabolic syndrome (32.2% vs. 5.3%, respectively; p<0.001) and insulin resistance (46.2% vs. 9.2%, respectively; p<0.001) were significantly higher in the nonalcoholic fatty liver disease group. According to multiple logistic regression analysis, age (odds ratio 1.534; p=0.0032), insulin resistance (odds ratio 1.074; p<0.001), and serum ALT levels (odds ratio 1.102; p<0.001) were independently associated with nonalcoholic fatty liver disease. CONCLUSION: Insulin resistance and metabolic syndrome are not rare in non-obese, non-diabetic Turkish subjects with nonalcoholic fatty liver disease. Ultrasonographically detected fatty liver was independently associated with insulin resistance, irrespective of the presence of metabolic syndrome.

Late failure of combined recombinant hepatitis B vaccine and lamivudine in treatment of a patient with chronic hepatitis B.

We report the first case of a woman having chronic hepatitis B treated with a combination therapy of recombinant hepatitis B vaccine and lamivudine for 18 months. The main aims of such a combined therapy were to assess whether the concomitant anti-hepatitis B virus (HBV) vaccination might prevent the emergence of a mutant HBV and lead to sustained hepatitis B e antigen seroconversion with undetectable serum HBV DNA. The data from the present case demonstrated that combination of anti-HBV vaccine and lamivudine did not eliminate viral DNA despite prolonged treatment and did not have any effect on preventing resistant-type HBV. Although the combined therapy failed to reach the therapeutic endpoints, it concerned a single and unique patient. Hepatitis B vaccine and lamivudine for HBV treatment should be further investigated in randomized controlled trials.

Markers of disease activity in chronic hepatitis B virus infection.

BACKGROUND: Assessment of disease activity is important in the management of chronic hepatitis B virus (HBV) infection. Our objective was to study the correlation between serum HBV DNA levels and HBV e antigen (HBeAg) status, alanine aminotransferase (ALT) levels, histologic activity, age and sex in patients who had chronic HBV, with emphasis on those who were HBeAg negative with high replication but had normal or below-normal liver enzyme levels and mild liver disease. METHOD: At our university-affiliated tertiary care medical centre in Turkey, we studied prospectively 179 consecutive patients who were long-term hepatitis B surface antigen carriers. These patients were first separated into 2 groups according to HBeAg positivity and then subdivided into 4 groups according to the presence of HBV DNA, HBeAg status and ALT levels. The clinical, virologic and histologic differences in these patients were evaluated with respect to the HBeAg status. RESULTS: Of the 179 patients, 120 (67%) were HBeAg positive and 59 (33%) were HBeAg negative. The mean (and standard deviation) age in the former group was 24.8 (7.60) and in the latter group was 32.2 (11.2) years (p < 0.001). HBeAg-negative patients had significantly more severe liver disease, more male predominance and lower serum HBV DNA levels than HBeAg-positive patients (p < 0.05). HBeAg status had a close correlation with age. There was a significant correlation between age and serum HBV DNA levels but not between HBV DNA levels and disease activity in study groups. We found that some of anti-HBe-positive patients had below-normal ALT levels with minimal or absent histologic changes despite high viral replication. CONCLUSIONS: Monitoring of ALT is of value in assessing hepatocellular damage in patients with chronic hepatitis B virus infection. HBeAg-negative patients with elevated ALT levels and some with normal ALT levels should be considered highly infectious in the course of chronic HBV infection.

The lack of effect of therapeutic vaccination with a pre-S2/S HBV vaccine in the immune tolerant phase of chronic HBV infection.

BACKGROUND/AIMS: Even if the results are controversial and preliminary, several reports suggest that the HBV vaccine might be effective in treating HBV infection. In this study, we aimed to evaluate the efficacy and safety of specific anti-HBV vaccination for the immune tolerance phase of chronic HBV infection in a randomized, controlled study. PATIENTS AND METHODS: The 47 subjects included patients that were treatment-naive with hepatitis B e antigen positivity, active hepatitis B virus replication as measured by hepatitis B virus DNA levels, persistently normal alanine transaminase levels, and with minimal or absent disease activity by liver biopsy. Thirty patients were given three intramuscular injections of 20 micro g of a pre-S2/S vaccine (GenHevac-B) on days 0, 30, and 60, and the remaining 17 patients were included in the control group. The efficacy of vaccination was evaluated by testing for loss of serum HBV DNA or decrease in its level and for HBeAg seroconversion. A significant decrease in HBV DNA levels was accepted as a decrease of >50% of initial values. The complete response was defined as loss of HBV DNA in serum with HBeAg seroconversion. Postvaccination follow-up lasted 12 months after the first dose. RESULTS: No significant effects were observed in the vaccination population in the reduction of HBV DNA to undetectable levels, or to <50% of prevaccination levels, in HBeAg/anti-HBe seroconversion, or in transaminase levels. There was an early clearance/decrease in HBV DNA levels in five vaccinated patients by 3 months, and none in controls (P = 0.143), and two of them had sustained responses later. At the end of follow-up, complete response is almost similar in study as well as control group (13% vs. 12%, P > 0.05). Disappearance of serum HBV DNA was more frequently observed in those patients who had pretreatment viremia of <100 pg/mL in both groups. The median levels of HBV DNA and alanine transaminase activity between baseline and 12 months did not differ significantly in both groups. All patients remained HBsAg positive and none developed anti-HBs. No serious adverse event was encountered in vaccinated patients, and the therapy was well tolerated. Follow-up lasted a median of 16 months (range 12-30 months) for the study group and 18 months (range 12-31months) for the control group. CONCLUSIONS: Immunotherapy with specific anti-HBV vaccine in the immune tolerance phase of chronic HBV infection did not offer additional benefit. New immunotherapeutic strategies to control HBV infection by specific HBV vaccines in chronically infected subjects are needed.