干扰素治疗慢性乙型病毒性肝炎疗效观察

目的观察重组基因干扰素α—1b治疗慢性乙型病毒性肝炎（CHB）的临床疗效、影响因素及其安全性。方法选择简阳市人民医院2001—01／2006—01门诊及住院的慢性乙型病毒性肝炎患者140例，其中干扰素治疗组84例；保肝治疗组56例。观察2组患者的肝功能、乙肝病毒标志物的变化和影响干扰素疗效的因素及干扰素α—1b的不良反应。结果①干扰素治疗组的ALT复常率和HBsAg的阴转率均较保肝治疗组高，但差异均无统计学意义（P均〉0．05）；HBeAg阴转率和HBeAg血清转换率及HBV-DNA阴转率均明显高于保肝治疗组，差异均有统计学意义（P均〈0．01）；②干扰素治疗组中，女性、治疗前高ALT水平、HBV-DNA≤10^6copies／ml的患者疗效更好；③干扰素α-1b的不良反应，主要为发热72例（占85．7％）、流感样症状50例（占59．5％）、白细胞减少40例（占47．6％）。不良反应一般不需作特殊处理，并能很快恢复正常，仅有2例白细胞减少者在加用升白细胞药物后恢复正常。结论干扰素α-1b是目前治疗慢性乙型病毒性肝炎较为有效且安全的可选择的药物，尤其对女性、高ALT水平、HBV-DNA低拷贝数（≤10^6copies／ml）的慢性乙肝患者更为有效。     

Clinical significance of liver biopsy in chronic hepatitis B patients with persistently normal transaminase

OBJECTIVE: The aim of this study was to study the clinical significance of liver biopsy for individuals who had chronic hepatitis B virus infection and persistently normal serum transaminases for more than 6 months. METHODS: A total of 452 patients with positive hepatitis B surface antigen for over 6 months underwent percutaneous liver biopsy. All liver biopsy specimens were assessed by experienced liver pathologists blinded to the liver biochemistry, and were scored according to the modified criteria of grade and stage of chronic hepatitis. Patients were divided into four groups: group A and group C patients had normal transaminases, and were hepatitis B e antigen (HBeAg) positive and HBeAg negative, respectively; group B and group D patients had elevated transaminases, and were HBeAg positive and HBeAg negative, respectively. RESULTS: All patients had necrosis and inflammation in the liver. Patients with increased serum transaminases had a significantly higher grade (G) of hepatic necrosis and inflammation and more severe (S) fibrosis compared with patients with normal transaminases (P < 0.05). However, in the latter patients, G3 was seen in 10 (5.5%) and 13 cases (9.1%), S3 in seven (3.8%) and 16 cases (11.1%), and S4 in three (1.6%) and seven cases (4.9%) in Group A and Group C, respectively. Moreover, in patients with normal transaminases, the HBeAg‐negative group had more severe fibrosis than the HBeAg‐positive group (P < 0.05). CONCLUSION: Although more severe pathological changes were more frequent in patients with elevated transaminases, significant hepatic pathology could still be found in cases with persistently normal transaminases. Liver biopsy in cases of chronic hepatitis B virus infection is helpful to accurately assess both the activity of the disease and the degree of fibrosis, and to estimate if antiviral therapy is justifiable. Patients with normal transaminases and serious hepatic necrosis, inflammation and fibrosis need proper management.     

Significance of Prior Hepatitis B Virus Infection in the Development of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C

To clarify the clinical significance of prior hepatitis B virus (HBV) infection in the development of C-viral hepatocellular carcinoma (HCC), we conducted two studies: (1) Two hundred thirty-four patients with C-viral HCC and 320 patients with C-viral chronic liver disease without HCC admitted to our hospital between 1990 and 1994 were analyzed for the association of hepatitis B core antibody (HBcAb) positivity with HCC by multivariate logistic regression analysis, and this revealed HBcAb positivity as an independent risk factor for development of HCC adjusted for age and sex. (2) Four hundred fifty-nine patients with biopsy-proven hepatitis C virus-related chronic liver disease between 1986 and 1998 were enrolled in the cohort study and followed for the development of HCC. During an average follow-up of 6.6 ± 3.3 years, HCC developed in 63 patients, 37 of 160 patients positive for HBcAb and 26 of 299 patients negative for HBcAb. Multivariate Cox proportional regression analysis showed that the incidence of HCC increased by age, advanced stage of liver fibrosis, mean alanine aminotransferase value of more than 80 IU/liter, and positivity of HBcAb. Sustained virological responders after interferon therapy revealed a reduced risk for HCC development. In conclusion, prior HBV infection was shown to be one of the independent risk factors for development of HCC in C-viral chronic liver disease.     

前列腺素E1治疗慢性乙型肝炎108例疗效观察

目的：探讨治疗乙型肝炎（乙肝）及抗肝纤维化的有效方法。方法：采用前列腺素E1（PGE1）静脉滴注治疗慢性乙肝患者108例（治疗组），并与行综合治疗90例（对照组）疗效比较，观察两组治疗前后，后血清Ⅲ型前胶原（PCⅢ），层粘蛋白（LN）、透明质酸（HA）、Ⅳ型胶原（Ⅳ－C）、肝功能等指标变化。结果：治疗组血清肝纤维化指标（PCⅢ、LN、HA、Ⅳ－C），丙氨酸转氨酶，天冬氨酸转氨酶，总清总胆红素均明显降低，与治疗前及对照组比较差异均有非常显著性意义（均P＜0．01），结论：PGE1具有较好的保肝和抗肝组织纤维化作用。     

Hepatitis C Virus Infection among Patients with Chronic Liver Disease in an Area Hyperendemic for Hepatitis B

Tsai J-F, Jeng J-E, Chang W-Y, Lin Z-Y, Tsai J-H. Hepatitis C virus infection among patients with chronic liver disease in an area hyperendemic for hepatitis B. Scand J Gastroenterol 1994;29:550-552.

Background: The prevalence of hepatitis C virus (HCV) infection was assessed in patients with nonalcoholic chronic liver disease (CLD).

Methods: Antibody levels to HCV (anti-HCV) were assessed in 100 pairs of CLD patients and healthy controls.

Results: The prevalence of anti-HCV was higher in patients (26.0%) than in controls (2.0% p = 0.0001). The patient group with anti-HCV was older (p equals; 0.0001) and had more smokers (p equals; 0.034), fewer hepatitis B surface antigen carriers (p equals; 0.0001), and more patients with active liver disease (p equals; 0.023) and a history of blood transfusion (p equals; 0.026). Multivariate analysis showed that anti-HCV (odds ratio, 8.1; 95% confidence intervals, 3.7-17.6) was strongly associated with CLD.

Conclusions: HCV infection is a risk factor of non-alcoholic CLD, and HCV causes more severe hepatocellular damage than HBV.     

慢性HBV感染重叠HEV感染的临床研究

目的进一步了解慢性乙型肝炎病毒(HBV)感染重叠戊型肝炎病毒(HEV)感染的临床特点及转归。方法对慢性HBV感染重叠HEV感染与单纯戊型肝炎进行临床对照研究。结果167例戊型肝炎均为散发型,发病无明显季节性,以40岁以上成人发病为主,平均年龄为42.12±14.06岁,男女比例为2.71∶1。其中,慢性HBV感染重叠HEV感染(简称乙戊肝)79例(47.31%),单纯戊型肝炎88例(52.69%)。乙戊肝组重度黄疸(TB>280μmol/L)、严重凝血功能异常(PTA<40%)和低蛋白血症的发生率明显高于单纯戊型肝炎组(P<0.01)。结论重叠戊型肝炎病毒感染是导致慢性HBV感染者病情急性加重和重症化,甚至发展成致死性重型肝炎的重要原因之一。     

Clinical Implications of HBsAg Quantification in Patients with Chronic Hepatitis B

Quantification of serum hepatitis B surface antigen (HBsAg) helps the management of patients with chronic hepatitis B virus (HBV) infection. Median HBsAg levels differ significantly during the natural history of HBV infection, progressively declining from immune tolerance to inactive phase. The combination of an HBsAg <1000 IU/mL and HBV DNA <2000 IU/mL at a single time point accurately identifies true inactive carriers. During antiviral treatment, HBsAg levels decline more rapidly in patients under peg-interferon (Peg-IFN) than in those under nucleos(t)ide analogues (NUC), and in responders to peg-IFN compared to non responders suggesting that a response-guided therapy in both HBeAg-positive and -negative patients treated with Peg-IFN could improve to cost-effectiveness of this therapeutic approach. Given the low rates of HBsAg clearance on NUC therapy, new studies to test whether Peg-IFN and NUC combination fosters HBsAg decline in long-term responders to NUC, are being explored.     

Management of Chronic Hepatitis B in HIV-Coinfected Patients

Hepatitis B virus infection occurs in approximately 7% of people living with HIV (PLWH), with substantial regional variation and higher prevalence among intravenous drug users. Early studies on the natural history of HIV/HBV coinfection demonstrated that in coinfected patients, chronic hepatitis B (CHB) has a more rapid progression than in HBV-monoinfected patients, leading to end-stage liver disease complications, including hepatocellular carcinoma. Therefore, the adequate management of CHB is considered a priority in HIV-coinfected patients. Several guidelines have highlighted this issue and have provided recommendations for preventing and treating HBV infection. This article discusses the management of liver disease in patients with HIV/HBV coinfection and summarizes the current and future therapeutic options for treating chronic hepatitis B in this setting.     

Differentiating Acute Hepatitis B from the First Episode of Symptomatic Exacerbation of Chronic Hepatitis B

In countries with intermediate or high endemicity for chronic hepatitis B virus (HBV) infection, exacerbations of chronic hepatitis B (CHB) are common. We studied the clinical, biochemical, and virologic characteristics of patients first presenting clinically with features of acute icteric hepatitis B, to identify features that might differentiate between acute viral hepatitis B (AVHB) from first episode of exacerbation of chronic hepatitis (ECHB). We retrospectively analyzed 79 patients (mean age 35.4 ± 14 years; M:F = 60:19) who first presented clinically as AVHB, within 4 weeks of onset of symptoms. Patients who on follow-up cleared HBsAg and/or did not develop any clinical, radiologic, or histologic evidence of chronic liver disease (CLD) were categorized as AVHB (group 1). Patients who had persistence of HBsAg and developed clinical, biochemical, radiologic, or histologic evidence of chronic liver disease were categorized as ECHB (group 2). Forty-nine patients were in group 1 and 30 in group 2. The 2 groups were comparable with respect to prodrome, onset of jaundice, serum bilirubin, ALT, prothrombin time prolongation, serum albumin, and A/G ratio. Among group 1 patients, 78% had IgM anti-HBc positive in titers > 1:1000; in group 2, there were negative or positive in titers < 1:1000 in 70% patients (P < .001). Forty-seven of 49 (95.9%) patients in group 1 had HBV-DNA levels < 0.5 pg/mL, whereas 26 of 30 (86.73%) patients in group 2 had levels > 0.5 pg/mL (P ≤ .001). Quantitative HBV DNA and IgM anti-HBc titers at initial presentation can differentiate patients with a true episode of acute hepatitis B from patients with first episode of symptomatic exacerbation of chronic hepatitis B. Clinical and biochemical features do not help in differentiating the two.     

Previous or Occult Hepatitis B Virus Infection in Hepatitis C Virus-Associated Hepatocellular Carcinoma Without Hepatic Fibrosis

We investigated the role of hepatitis B virus infection in development of hepatocellular carcinoma in hepatitis C virus-infected patients without hepatic fibrosis. Of 253 patients, 8 lacked hepatic fibrosis (group 1); group 2 included the remaining 245 patients. Clinicopathologic findings were compared between the groups. Hepatitis B x gene was sought in cancers and adjoining noncancerous liver. Group 1 showed better liver function parameters and milder active hepatitis than group 2. The proportion of patients with anti-hepatitis B virus antibody tended to be higher in group 1 than in group 2. The proportion of patients with hepatitis B x RNA in cancers was significantly higher in group 1 than in group 2. All group 1 patients had previous or occult hepatitis B virus infection. Previous or occult hepatitis B virus infection may be critical in development of hepatocellular carcinomas in hepatitis C virus-infected patients without hepatic fibrosis.     

拉米夫定治疗慢性乙肝病毒感染病人的疗效分析

目的：观察拉米夫定（Lamivudine）治疗慢性乙肝病毒（HBV）感染病人的疗效及影响因素。方法：60例慢性HBV感染病人予拉米夫定（100mg qd）治疗12个月。疗效评估包括血清HBV病毒学、血清HBV免疫学、血清生化学应答率。结果：治疗12个月后，HBV DNA PCR荧光定量检测总的血清HBV DNA转阴率为57.89％，HBeAg/抗-HBe血清转换率为6.25％，ALT复常率为68.89％。其中，（1）血清ALT异常、HBeAg阳性组病人的荧光定量检测HBV DNA转阴率为55.56％，HBeAg/抗-HBe血清转换率为8.33％，ALT恢复正常率为63.89％；完全应答率为8.33％，部分应答率为75.00％，无应答率为16.67％。（2）ALT正常、HBeAg阳性组的12例病人中，仅有4例病人的血清HBV DNA转阴，无1例发生HBeAg/抗-HBe血清转换。（3）ALT异常、HBeAb阳性组的9例病人中，8例病人的HBV DNA转阴同时伴ALT复常。结论：本组病例分析结果表明，拉米夫定可以有效地抑制血清HBV的复制，改善肝功能。机体免疫状况对拉米夫定抗病毒治疗有较大影响，治疗前ALT水平是预测疗效的重要指标。对ALT异常的慢性HBV感染病人，HBeAg阴性者似乎比HBeAg阳性者有更好的治疗反应，可能更适合用拉米夫定治疗。病人对拉米夫定普遍耐受性良好。     

Novel Pegylated Interferon for the Treatment of Chronic Viral Hepatitis

Ropeginterferon alfa-2b is a novel mono-pegylated and extra-long-acting interferon, being developed for the treatment of myeloproliferative neoplasm (MPN) and chronic viral hepatitis. It has a favorable pharmacokinetic profile and less frequent dosing schedule, i.e., once every two to four weeks, compared to conventional pegylated interferon products, which have multiple isomers and are administered weekly. It was approved for the long-term treatment of polycythemia vera, an MPN, and has been included in the NCCN clinical practice guidelines for this indication. Ropeginterferon alfa-2b has demonstrated efficacy and showed a favorable safety profile for the treatment of chronic viral hepatitis in several clinical studies. In this article, we review its pharmacokinetics and available clinical data and suggest that ropeginterferon alfa-2b administered once every two weeks can serve as a new treatment option for patients with chronic viral hepatitis, including chronic hepatitis B, C, and D.     

Hepatitis B Core Antigen-Specific Interferon Gamma Production of Peripheral Blood Mononuclear Cells during Acute Exacerbation of Chronic Hepatitis B

To examine the relationship between hepatitis B core antigen-specific interferon gamma production and the liver injury, we measured the sequential change in this production by peripheral blood mononuclear cells of seven patients with chronic hepatitis B. Four patients who experienced acute exacerbation showed increased interferon gamma production when the serum alanine aminotransferase level peaked or during the recovery phase. In the three patients who did not experience acute exacerbation, interferon gamma production gradually decreased in one who had a low peak of alanine aminotransferase but did not show significant change in the other two. Increased production of hepatitis B core antigen-specific interferon gamma at the time of acute exacerbation suggests that interferon gamma induced by hepatitis B core antigen plays a role in hepatocellular injury of patients with chronic hepatitis B.     

HBcrAg Predicts Hepatocellular Carcinoma Development in Chronic B Hepatitis Related Liver Cirrhosis Patients Undergoing Long-Term Effective Anti-Viral

Hepatitis B core-related antigen (HBcrAg) is a predictor of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. Studies on anti-viral therapy have shown that the use of NUC therapy in HBV patients could reduce the incidence of HCC. However, the incidence of HCC continues to increase after long-term anti-viral therapy. The relationship between HBcrAg and HCC development in CHB-related liver cirrhosis (LC) patients undergoing long-term anti-viral therapy is still unclear. This study enrolled 1108 treatment-naïve CHB patients diagnosed with HBV-related LC receiving NUC therapy from April 1999 to February 2015. The baseline biomarkers, disease history, and following results were collected by the hospital. Among the 1108 patients, 219 developed HCC within a median follow-up period of 6.85 years. A multivariable Cox regression model was used, with adjustment for age, gender, FIB-4, DM, and HBsAg-HQ. The adjusted hazard ratios for the HBcrAg tertile levels were 1.70 (95%CI: 1.21, 2.39) and 2.14 (95%CI: 1.50, 3.05) for levels 3.4–4.9 and >4.9 logU/mL, respectively, compared with levels ≤3.4. The effect of the HBcrAg level on HCC incidence was found to be significantly modified by HBsAg-HQ, where lower HBsAg-HQ (≤ 3) values were associated with a significantly higher risk, but HBsAg-HQ levels >3 were not. Our results highlight that, after adjustment for potential confounding factors, patients with CHB-related LC and higher HBcrAg levels are at significant risk for HCC development, even while undergoing long-term effective anti-viral therapy. The HBcrAg level is therefore an independent risk factor for HCC development, especially for patients with HBsAg-HQ levels <3.     

Idiopathic Chronic Active Hepatitis and Hepatic Cell Carcinoma

ABSTRACT. Only two patients with co-existing idiopathic (autoimmune) chronic active hepatitis and hepatic cell carcinoma have been reported hitherto. Two further cases are described. This complication may be more common than previously thought.     

The Delta Agent in Acute and Chronic Hepatitis B Infection in Sweden

The occurrence of the delta (δ) agent was analyzed in 89 patients with acute hepatitis B infection during 1976-1979 in Gothenburg, Sweden, and in 46 patients (16 drug addicts) with chronic HBsAg-positive liver disease. Four of the patients with acute hepatitis B had transiently detectable anti-δ antibodies in serum. At least three of these four cases were associated with intravenous drug abuse. Eleven of the HBsAg carriers (24%) were anti-δ-positive, and all of them were drug addicts. One of the drug addicts transmitted hepatitis B infection without detectable anti-δ in serum to two other non-addicts via parenteral routes. Apparently, in Sweden today δ-infection is mostly restricted to drug addicts and seldom found in other groups of hepatitis B patients.     

Hepatitis B Virus Gene in Liver Tissue Promotes Hepatocellular Carcinoma Development in Chronic Hepatitis C Patients

The hepatitis B virus (HBV) gene has been detected in hepatocellular carcinoma (HCC) tissue negative for the hepatitis B surface antigen and positive for the hepatitis C virus (HCV) antibody, but the precise role of the HBV gene in hepatocarcinogenesis has yet to be clarified. We studied the HBV gene in liver tissue several years before the emergence of HCC. Eleven patients diagnosed with HCV-positive chronic liver disease and who developed HCC were assigned to group A. HBV DNA was detected in 8 of the 11 patients (73%). Twenty-five patients, who did not develop HCC, were selected as group B. Six of the group B patients were classified as DNA-positive (24%). The HBV DNA in liver tissue was found to be significantly related to HCC development (P < 0.01). Thus, the presence of the HBV gene in patients with chronic HCV associated-liver injury appears to promote hepatocarcinogenesis, although prospective studies are needed to confirm this result.     

Hepatitis B Virus Genomes of Chronic Hepatitis Patients Do Not Contain Specific Mutations Related to Acute Exacerbation

To determine the specific viral variants associated with acute exacerbation of chronic hepatitis from hepatitis B virus (HBV) infection, we analyzed the complete nucleotide sequences of the HBV genome in serial serum samples from two chronic active hepatitis patients who seroconverted from HBeAg to anti-HBe. HBV DNA was amplified by polymerase chain reaction (PCR) and sequenced. A 1896 precore stop codon mutant (G to A at nt 1896) coexisting with the wild sequence was found in both patients prior to seroconversion from HBeAg to anti-HBe. Core promoter mutations at nucleotide positions 1762 (A to T) and 1764 (G to A) were found in both patients throughout the observation period. Mutations were observed in the HBV genome of the two patients at different time points, and there was no correlation between the mutations and liver disease or DNA polymerase levels. The nucleotide divergence rate and the composition of quasispecies in the HBV sequence at the time of acute exacerbation were almost the same as were found at other time points. These results suggest that acute exacerbation does not appear to be caused by a characteristic HBV species. The multiple factors that cause generalized HBV replication activation may contribute to acute exacerbation.     

Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2005 update.

BACKGROUND/AIMS: A large amount of new data on the treatment of chronic hepatitis B has become available such that the 2003 consensus statement requires revision and update. METHODS: New data were presented, discussed and debated in an expert pre-meeting to draft a revision. The revised contents were finalized after discussion in a general meeting of APASL. RESULTS: Conceptual background, including the efficacy and safety profile of currently available and emerging drugs, was reviewed. Nineteen recommendations were formed and unresolved issues and areas for further study were suggested. CONCLUSION: The current therapy of chronic hepatitis B is modestly effective but not satisfactory. The development of new drugs and new strategies is required to further improve the outcomes of treatment.     

Prevalence and Predictors of Liver Fibrosis in People Living with Hepatitis B in Senegal

Hepatitis B virus (HBV) infection is the first cause of liver cirrhosis and cancer in West Africa. Although the exposure to additional environmental and infectious risk factors may lead to the faster progression of liver disease, few large-scale studies have evaluated the determinants of HBV-related liver fibrosis in the region. We used transient elastography to evaluate the prevalence of liver fibrosis and assessed the association between HBV markers and significant liver fibrosis in a cohort of people living with HBV in Dakar, Senegal. The prevalence of significant liver fibrosis was 12.5% (95% confidence interval [CI] 9.6%–15.9%) among 471 people with HBV mono-infection (pwHBV) and 6.4% (95% CI 2.6%–12.7%) in 110 people with HIV/HBV co-infection (pwHIV/HBV) on tenofovir-containing antiretroviral therapy (p = 0.07). An HBV viral load > 2000 IU/mL was found in 133 (28.3%) pwHBV and 5 (4.7%) pwHIV/HBV, and was associated with significant liver fibrosis (adjusted odds ratio (aOR) 1.95, 95% CI 1.04–3.66). Male participants (aOR 4.32, 95% CI 2.01–8.96) and those with elevated ALT (aOR 4.32, 95% CI 2.01–8.96) were especially at risk of having significant liver fibrosis. Our study shows that people with an HBV viral load above 2000 IU/mL have a two-fold increase in the risk of liver fibrosis and may have to be considered for antiviral therapy, independent of other disease parameters.