To examine the long-term effect of interferon (IFN) therapy in patients with chronic hepatitis B virus (HBV) infection, particularly on survival and hepatocellular carcinoma (HCC) prevention, 101 male patients with chronic hepatitis B in a randomized controlled trial were followed up for 1.1 to 11.5 years after the end of therapy. Of the 101 patients, 34 patients received a placebo (control), and 67 patients were treated with IFN (31 patients were treated with IFN alone and 36 patients were treated with IFN after prednisolone priming). Follow-up studies included clinical, biochemical, and virological aspects and HCC screening every 3 to 6 months. Twenty-eight (42%) of the 67 IFNtreated patients and 8 (24%) of the 34 untreated patients seroconverted by the end of the trial. During follow-up, 22 (56%) of the 39 patients who did not seroconvert in the treated group and 5 (19%) of the 26 patients who did not seroconvert in the control group showed a delayed sustained response (P F .005). The cumulative incidence of sustained response was highest in the steroid priming group (P ‫؍‬ .049 vs. the IFN-alone group; P ‫؍‬ .028 vs. the control group). HCC was detected in 1 (1.5%) of the 67 treated patients and 4 (12%) of the 34 untreated patients (P ‫؍‬ .043). The interval between entry and HCC detection was 3.5 to 8.2 years. The cumulative incidence of HCC development was significantly higher in the control group than in the treated group (P ‫؍‬ .013). In contrast, the cumulative survival rate was higher in the treated group than the control group (P ‫؍‬ .018). Multivariate analysis showed that IFN therapy, preexisting cirrhosis, and the patient's age at entry are significant independent factors for both survival and HCC development. The results suggest that IFN has long-term beneficial effects in terms of HBV clearance, reduction of HCC, and prolonging survival. (HEPATOLOGY 1999;29:971-975.)Interferon (IFN) has antiviral, immunomodulatory, antitumoral, and antiproliferative effects. 1-3 The aims of IFN therapy for chronic hepatitis B virus (HBV) infection are to eradicate HBV, to halt hepatic necroinflammation, and to prevent or reduce the risk of cirrhosis and hepatocellular carcinoma (HCC) development. 4 It is generally agreed that IFN therapy is effective in 30% to 40% of the patients with chronic HBV infection in terms of virological and histological remission. 5,6 However, long-term follow-up data are limited. 7-10 Although several studies have suggested that IFN therapy may reduce the risk of HCC in patients with HBV or hepatitis C virus-related cirrhosis, 11-17 evidence derived from randomized controlled studies is still lacking. Therefore, the effect of IFN on the prevention of HCC in patients with chronic HBV infection still remains to be clarified or confirmed.A randomized controlled trial comparing the effect of IFN, prednisolone priming followed by IFN, and placebo in patients with chronic hepatitis B was conducted in our unit starting in December 1986. 18 The last patient was enrolled in the study in March 1...

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Ultrasonography of prospectively followed chronic hepatitis B patients who developed liver cirrhosis were reevaluated in order to identify the ultrasonographic changes of early cirrhosis. Ultrasonographic features of 29 patients before and after cirrhosis were as follows: portal vein diameter--1.20 cm/1.29 cm (NS); cirrhosis score--5.69/7.52 (p < 0.01); spleen size index--21.99 cm2/25.84 cm2 (NS). The result suggests that ultrasonographic diagnosis of early cirrhosis is not easy on a single occasion; however, the score system method is helpful in longitudinal follow-up chronic hepatitis patients. A careful comparison of hepatic parenchymal and surface changes are mandatory.

The baseline alanine aminotransferase (ALT) level was reported to have prognostic value in chronic hepatitis B virus (HBV) infection, during which ALT may change over time. Instead of baseline ALT, this study aimed to study the prognostic value of the height of ALT during the course of chronic HBV infection. A total of 4376 asymptomatic hepatitis B e antigen (HBeAg) negative, surface antigen (HBsAg) carriers with baseline ALT less than 2 times the upper limit of normal (ULN) were monitored with ALT measurement and ultrasonography every 3 to 12 month for over 3 years. Maximal ALT levels during follow-up were correlated with long-term outcomes using morbidity and mortality data from hospital records, cancer registration, and national mortality database. Baseline ALT level was normal in 3673 subjects and increased to abnormal level in 1720 (46.8%) during a mean follow-up period of 13.4 ؎ 5.2 (3.0-28.7) years. The incidence of liver cirrhosis, hepatocellular carcinoma (HCC), and mortality increased with increasing maximal ALT level during follow-up, especially in those with maximal ALT of at least 2 times ULN, as compared with those who maintained normal ALT. Cox regression analysis indicated that age at entry, sex, and maximal ALT level during follow-up were significant independent factors associated with the development of cirrhosis, HCC, and mortality whereas cirrhosis was also an independent factor for HCC development and mortality. Conclusion: Persistently normal ALT was associated with excellent long-term prognosis, whereas increasing ALT levels of at least 2 times ULN during follow-up was associated with increasing morbidity and mortality. ALT of at least 2 times ULN is therefore an appropriate threshold for anti-HBV therapy, whereas those with ALT 1 to 2 times ULN require liver biopsy for decision. (HEPATOLOGY 2009;49: 1859-1867.) C hronic hepatitis B virus (HBV) infection is one of the major causes of liver morbidity and mortality. 1,2 Recent community-based studies involving a large number of hepatitis B surface antigen (HBsAg) positive subjects, mainly (Ͼ85%) hepatitis B e antigen (HBeAg) negative, have shown that baseline age, sex, HBeAg serostatus, and serum HBV-DNA level are factors associated with hepatocellular carcinoma (HCC) development and liver-related mortality. 3,4 Abnormal alanine aminotransferase (ALT) at entry was also found to be associated with cirrhosis development and liver-related mortality. 5,6 All HBV treatment guidelines of major liver associations also recommend that patients with active HBV replication and an ALT level greater than 2 times Abbreviations: AFP, alpha-fetoprotein; ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HDV, hepatitis D virus; maxALT, maximal alanine aminotransferase; PNALT, persistently normal alanine aminotransferase; ULN, upper limit of normal; US, ultrasonography.

BACKGROUND Hepatocellular carcinoma (HCC) recurrence after ablation therapy for primary tumors is common. METHODS To evaluate the effectiveness of interferon‐alpha (IFN‐α) in preventing HCC recurrence, 30 eligible patients were randomized into three groups: 11 patients treated with three mega units (MU) of IFN‐α three times weekly for 24 months (IFN‐α‐continuous group), 9 patients treated with 3 MU of IFN‐α daily for 10 days every month for 6 months followed by 3 MU of IFN‐α daily for 10 days every 3 months for a further 18 months (IFN‐α‐intermittent group), and 10 patients who received no IFN‐α therapy (control group). The three groups were comparable in terms of etiology, demographics, and laboratory data at entry and HCC characteristics. RESULTS After a median follow‐up of 27 months (range 4–53 months), 9 patients (90%) in the control group and 9 patients (45%) in 2 treatment groups (6 patients in the IFN‐α‐continuous group and 3 patients in the IFN‐α‐intermittent group) developed an HCC recurrence (P = 0.021). Cumulative HCC recurrence rates in the IFN‐α‐intermittent, IFN‐α‐continuous, and control groups were 22.2%, 27.3%, and 40% at the end of 1 year and 33.3%, 54.6%, and 90% at the end of 4 years (P = 0.0375), respectively (control vs. IFN‐α‐intermittent group, P = 0.0123; vs. IFN‐α‐continuous group, P = 0.0822). If both IFN‐α groups were combined, the cumulative HCC recurrence rate of the patients treated with IFN‐α and the control group was 25% and 40% at the end of 1 year and 47% and 90% at the end of 4 years, respectively (P = 0.0135). CONCLUSIONS The data suggested that IFN‐α therapy may reduce HCC recurrence after medical ablation therapy for primary tumors. Cancer 2004;100:376–82. © 2003 American Cancer Society.

Pathways involving androgen signaling may affect the risk of HBV-related HCC among men.

Changes in hepatic fibrosis after interferon-based therapy may be important in determining the long-term outcome of chronic hepatitis C (CHC). The use of liver biopsy for posttreatment assessment is not a viable option as a routine follow-up procedure. This study evaluated the predictive value of a simple noninvasive index, the aspartate aminotransferase (AST)-to-platelet ratio index assessed 6 months after end of treatment (APRI-M6). We evaluated APRI-M6, platelet-M6, AST-M6, and ␣-fetoprotein-M6 of 776 CHC patients with interferon-based therapy as well as the parameters at baseline of 562 untreated patients who were evaluated to predict the risk of hepatocellular carcinoma (HCC) and mortality, during a mean follow-up period of 4.75 (1.0-12.2) and 5.15 (1.0-16) years, respectively. Based on analysis of receiver operating characteristics (ROC) and using optimized cutoff point, the APRI-M6 and platelet-M6 had superior prediction models for long-term outcome with area under the curve of 0.870-0.875 and 0.824-0.847, respectively, and accuracy of 78%-81% and 76%-78%, respectively, for interferonbased-treated patients. The predictive values of all 4 parameters were poor in untreated patients. In subgroup analysis, the APRI-M6 provided a more consistent prediction ratio than platelet-M6 for sustained responders and cirrhosis-free subgroups; both parameters had similar prediction power for nonresponders and were unsatisfactory in patients with cirrhosis. According to Cox proportional hazards analysis, cirrhosis and APRI-M6 were the 2 most important factors for predicting HCC. In conclusion, APRI-M6 can accurately predict the long-term outcome of patients subjected to interferon-based treatment. Nevertheless, the data needs further validation, particularly since the predictive accuracy for patients with cirrhosis is low. (HEPATOLOGY 2006;44:1086-1097

Hepatocellular carcinoma (HCC) is more prevalent in men than in women. Estrogen may play some role in the development of HCC. We conducted a multicenter case-control study to evaluate the effects of reproductive factors on HCC risk, and to assess whether the association between each factor and HCC differs between hepatitis B surface antigen (HBsAg)-positive and -negative women, in which hepatitis C virus (HCV) is the major cause of HCC. The study included 218 women with HCC and 729 control women selected from nonbiological and firstdegree female relatives of patients with HCC. The risk of HCC was inversely related to the number of full-term pregnancies (FTP) (P trend ‫؍‬ .0216) and age at natural menopause (P trend ‫؍‬ .0251 among women aged 45-55 without prior surgical menopause). Oophorectomy at age <50 during premenopausal years was also a risk factor (multivariate-adjusted OR, 2.57; 95% CI, H epatocellular carcinoma (HCC) is a highly malignant disease characterized by a striking male predominance; the male-to-female ratios in the incidence of HCC range from 2 to 4 in geographically diverse populations. 1,2 This gender difference may be, at least in part, attributable to differences in exposure to lifestyle risk factors for HCC, such as alcohol consumption and cigarette smoking. 3,4 However, sex hormone and X-linked genetic factors may also be important.Estrogen receptors exist in both mammalian and human livers. [5][6][7][8] In experimental rats and mice, there is also a greater preponderance of HCC in male subjects compared with female subjects. This sex difference has been observed in various animal models, including transgenic mice expressing hepatitis B or C viral proteins. [9][10][11][12][13][14][15] In addition, ovariectomy in mice increased susceptibility to chemically induced hepatocarcinogenesis. 11,16 Although these observations may suggest some role for endogenous estrogen in the etiology of HCC in humans, these aspects received relatively scant attention. [17][18][19] Exogenous estrogen use may also be associated with the risk of HCC. Several case reports have described the occurrence of liver adenomas or focal nodular hyperplasia in women taking oral contraceptives, 20 and the possible association between use of oral contraceptives and the risk of HCC has been assessed in several studies. 3,17,[21][22][23][24][25][26][27] However, most of these studies were based on a very limited number of case subjects, and the results have been incon-