Hepatitis viruses and chronic liver disease

We have investigated several groups of Thai patients diagnosed with chronic liver disease including chronic hepatitis, cirrhosis and hepatocellular carcinoma, as well as cholangiocarcinoma, for the prevalence of infection with either one of the hepatitis viruses B, C, G and the novel hepatitis virus TT (TTV). The 168 patients tested comprised 120 men and 48 women with their median age ranging from 42.3 to 62.3 years. Screening for antibodies to HBV and HCV was performed by a commercially available serological test kit, for the presence of HBV and TTV DNA by PCR, and of HCV and HGV RNA by RT-PCR, respectively. There was a clear two-fold higher prevalence of HBV (49%) over HCV (27%) infection and a four-fold higher frequency compared to HGV (13%) and TTV (11%) infection, respectively, in those individuals with chronic hepatitis, cirrhosis, and hepatocellular carcinoma, whereas all but one patient with cholangiocarcinoma the etiology of which has been ascribed to parasitic infestation, were free of all viral markers. In Thailand chronic HBV, and to a lesser extent, chronic HCV infection represent the two most common causes of hepatitis potentially proceeding to chronic liver disease, whereas the clinical significance pertinent to HGV and TTV remains to be elucidated.     

A case-control study on a novel DNA virus (TT virus) infection and hepatocellular carcinoma. The Brescia HCC Study.

We performed a case-control study to evaluate the association of a new human DNA virus named TT virus (TTV) with hepatocellular carcinoma (HCC). We recruited 174 subjects hospitalized for HCC (84% males; mean age: 64 years) and 118 patients hospitalized for non-liver diseases in Brescia, northern Italy, as controls (94% males; mean age: 66 years). TTV DNA was found in serum by polymerase chain reaction (PCR) in 26 cases (15%) and 11 controls (9.3%) (P >. 1). TTV group 2 infection was identified in 16 cases (61.5%) and 4 controls (36.4%) (P >.1) using a type-specific PCR method. Sequence analysis of 222 nt of TTV DNA demonstrated that the remaining 10 cases and 7 controls were all infected by group 1. The odds ratio (OR) for TTV-DNA positivity, adjusted for demographic variables, hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) RNA, and heavy alcohol intake was 1.8 (95% CI: 0.7-4.8; P >.1). The OR did not change when the analysis was restricted to 14 HCC cases and 56 controls who were negative for each known risk factor for HCC (OR = 1.7; 95% CI: 0.8-4.0). TTV-DNA positivity was not associated with transfusion history. The prevalence of TTV DNA was higher among HCC cases positive for HBsAg (10 of 38 [26.3%]) than among those positive for HCV RNA (8 of 62 [12.9%]) or negative for hepatitis B virus (HBV), HCV, and hepatitis G virus (HGV) infections (5 of 62 [8. 1%]) (P =.02). This study does not support the hypothesis of an association between TTV infection and HCC.     

TT virus infection among Egyptian patients with hepatocellular carcinoma

Hepatitis B and C viruses (HBV and HCV) have been associated with hepatocellular carcinoma (HCC). Recently, a novel DNA virus was isolated from a patient with posttransfusion hepatitis of unknown etiology and designated TT virus (TTV). To examine whether this virus is associated with HCC, we investigated sera from 82 Egyptian patients with histopathologically-diagnosed HCC. All subjects underwent serological investigations for detection of hepatitis B surface antigen (HbsAg), hepatitis B core antibody (HbcAb) and anti-HCV. Detection of TTV-DNA was performed by semi-nested polymerase chain reaction (PCR) using TTV-specific primers. TTV-DNA was detected in 28% of the patients. Age, gender, risk factors and biochemical liver functions did not significantly differ between TTV-DNA positive and negative patients. TTV was detected in 27.1% of patients with HCV-HCC, 25% of HBV-HCC, 66.7% of dual HCV and HBV infection and 40% of those with non-B, non-C-HCC (NBNC-HCC). It is concluded that, in this the cohort of Egyptian patients with HCC, TTV infection is common and is not associated with HCV, HBV, NBNC-HCC, history of schistosomiasis or blood transfusion.     

Virologic analysis of non-B, non-C hepatocellular carcinoma in Japan: frequent involvement of hepatitis B virus

Serum and liver tissues from hepatitis B surface antigen-negative/anti-hepatitis C virus (HCV)-negative (non-B, non-C) hepatocellular carcinoma (HCC) patients in Japan were examined for the presence of hepatitis B virus (HBV), HCV, and TT virus (TTV) by polymerase chain reaction. The studies evaluated the contribution of these viruses to pathogenesis of HCC. HBV DNA was detected in the sera of 20 (47.6%) of 42 non-B, non-C HCC patients, which was significantly higher than in age-matched controls without liver disease (P<.001). In 8 of 12 patients with liver tissues available, HBV DNA was detected in cancerous and adjacent noncancerous liver tissues. No HCV RNA was detected. The positivity for TTV DNA was not significantly different between HCC patients and controls. These results indicate that HBV is associated with a substantial proportion of non-B, non-C HCC cases in Japan. The role of HBV in hepatocarcinogenesis in such patients needs to be clarified.     

The epidemiology of TT virus (TTV) infection in a hepatitis C and B virus hyperendemic area of southern Taiwan

TT virus (TTV) is a newly isolated DNA virus from the serum of a patient with posttransfusion hepatitis of unknown etiology in 1997. To evaluate the clinical and molecular characteristics of TT virus (TTV) in a hepatitis C virus (HCV) and B (HBV) hyperendemic area (Masago), 200 residents were enrolled in the study. The sera were tested for alanine aminotransferase (ALT), HCV RNA and GB virus C/Hepatitis G virus (HGV) RNA, TTV DNA, HBsAg, anti-HCV and antibodies to HGV E2-protein (anti-E2). TTV DNA was positive in 99 of the 200 sera with a prevalence rate of 49.5%. The prevalence of HBsAg, anti-HCV, HCV RNA, HGV RNA, anti-E2 and HGV exposure (defined as positive for serum HGV RNA and/or anti-E2) was 38.9%, 69.5%, 64.5%, 17.0%, 25.5% and 39.5%, respectively. Neither clinical nor virological factors were associated with TTV viremia. The rate of ALT abnormality was significantly elevated in HCV RNA-positive (34.9%) than -negative (7.0%) residents (p < 0.001). HCV viremia was the only factor significantly associated with ALT elevation by multiple logistic regression (odds ratio: 6.96; 95% C.I.: 2.60-18.7). We concluded that in this HCV/HBV hyperendemic area, the prevalence of TTV DNA was high. No significant clinical factor was observed to be associated with TTV infection. TTV infection is not related to abnormal ALT levels and ALT abnormality was mainly attributable to HCV but not TTV, HBV or HGV infection.     

The prevalence of viral hepatitis among the Hmong people of northern Thailand

Sera from 269 Hmong people (102 males and 167 females, with mean age 35.4 years, range 16-63 years) were examined in order to determine the seroprevalence of hepatitis virus infection. The seroprevalence rates for HAV (hepatitis A virus), HBV (hepatitis B virus), HCV (hepatitis C virus), HDV (hepatitis D virus), HEV (hepatitis E virus), HGV (hepatitis G virus) and TTV (TT virus) infection were 87.8% (n=140), 76.0% (n=150), 2.0% (n=150), 0.7% (n=150), 6.5% (n=139), 5.3% (n=94) and 25.6% (n=121) respectively. The rate for carriers of HBV (HBsAg) was 13.8% (20.5% in males and 9.6% females) with a peak prevalence in the 21-40 year age group. A high rate of HAV seropositivity was found among the younger subjects. The rate of HEV seroprevalence was low. The prevalence of TTV-DNA was high with no difference between the sexes. HGV-RNA prevalence was low and seen primarily in males. This study indicates that the Hmong people are endemically infected with HAV and HBV infection and should be considered for targeted vaccination. The role of TTV and HGV in producing illness and hepatic disease has yet to be determined in this population.     

GB virus C/hepatitis G virus infection among patients with hepatocellular carcinoma in the inshore area of the Yangtze river, China

To investigate the association between GB virus C/hepatitis G virus (GBV-C/HGV) infection and the development of hepatocellular carcinoma (HCC) in H city, in the inshore area of the Yangtze River, where high prevalence of HCC has been reported, we determined hepatitis B virus (HBV) and hepatitis C virus (HCV) markers, GBV-C/HGV-RNA and GBV-C/HGV E₂ antibody (anti-HG E₂) among 114 HCC patients and the same number of age- and sex-matched controls. There were no significant differences in the clinical and demographic characteristics between them, except for serum alanine aminotransferase level and history of liver diseases. There was a significant difference of hepatitis B virus surface antigen (HBsAg) prevalence between the HCC patients (75.4%) and the controls (20.2%; P < 0.01). Hepatitis C virus antibody was detected in 4.4% of the HCC patients, compared with 1.7% of the controls. GB virus-C/HGV-RNA and anti-HG E₂ were detected in 14.9 and 1.7% of the HCC patients, respectively, compared with 7.0 and 1.7% of the controls, respectively. Nucleotide sequences and molecular evolutionary analysis showed the strains of GBV-C/HGV-RNA were classified into genotype 2 and 3 (HG and ASIA type). An effect analysis showed an odds ratio (OR) for developing HCC from GBV-C/HGV infection among HBsAg-positive subjects was 14.9, with a 95% CI of 4.9–45.4. HBsAg infection alone was 13.83 (95% CI 7.4–25.9) and GBV-C/HGV infection alone, 3.74 (95% CI 1.1–13.1), respectively. These data indicate that HBV infection is considered to be one of the major risk factors in patients with HCC and although GBV-C/HGV infection was observed in both the HCC and the control groups, it might not play an important role in the development of HCC in this area.     

Epidemiology of viral hepatitis and hepatocellular carcinoma

Most cases of hepatocellular carcinoma (HCC) are associated with cirrhosis related to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Changes in the time trends of HCC and most variations in its age-, sex-, and race-specific rates among different regions are likely to be related to differences in hepatitis viruses that are most prevalent in a population, the timing of their spread, and the ages of the individuals the viruses infect. Environmental, host genetic, and viral factors can affect the risk of HCC in individuals with HBV or HCV infection. This review summarizes the risk factors for HCC among HBV- or HCV-infected individuals, based on findings from epidemiologic studies and meta-analyses, as well as determinants of patient outcome and the HCC disease burden, globally and in the United States.     

Transfusion-transmissible virus and hepatocellular carcinoma: a case-control study

Although transfusion-transmissible virus (TTV) is often present in the serum of patients with acute and chronic non-A–C liver diseases, its hepatotropism, pathogenicity to the liver and hepatocarcinogenicity have not been proven. We used a case-control format to compare the prevalence of TTV infection among 148 southern African Blacks with hepatocellular carcinoma and 148 matched hospital-based controls, and to test for possible interactive effects between this virus and hepatitis B virus (HBV) and hepatitis C virus (HCV) in the development of the tumour. We also determined the prevalence of TTV in 988 blood donors in Gauteng province of South Africa. The presence of TTV DNA in serum samples was detected by using the polymerase chain reaction, Southern hybridization and nucleotide sequencing. Individuals infected with TTV did not have an increased risk of developing hepatocellular carcinoma (relative risk 1.1; 95% confidence limits 0.5–2.4). Moreover, co-infection with TTV did not further increase the risk of tumour development in patients chronically infected with HBV and/or HCV. TTV was present in the serum of 2.2% of blood donors: 4.0% in Black and 1.5% in White donors. We conclude that TTV is unrelated to the development of hepatocellular carcinoma in Black Africans.     

Clinical characteristics and distribution of genotypes of TT virus infection in a hepatitis C virus-hyperendemic township of a hepatitis B virus-endemic country (Taiwan)

BACKGROUND: The prevalence of TT virus (TTV) viremia, without definite clinical significance, has been reported to be higher among chronic hepatitis C patients. The status and clinical characteristics of TT virus (TTV) infection and distribution of TTV genotypes in a hepatitis C virus (HCV) hyperendemic township (Masago community) in a hepatitis B virus (HBV) endemic country (Taiwan) were investigated. METHODS: Sera from 100 Masago residents were tested for alanine aminotransferase (ALT) and markers of HBV, HCV and GB virus C/hepatitis G virus (GBV-C/HGV) and TTV-DNA. Sera of 250 blood donors as a control group were tested for TTV-DNA. Sera of Masago residents and blood donors with positive TTV-DNA were directly sequenced, and phylogenetic analyses were performed subsequently. RESULTS: The prevalences of TTV viremia in different age groups among individuals from Masago were significantly higher than that among blood donors. In regard to the subtypes of TTV, 23, seven, two, eight, one, six and one isolate were related to the genotypes 1a, 1b, 2a, 2b, 3, 4 and 5, respectively, from Masago and 21, 14, one, nine and three isolates were related to the genotypes 1a, 1b, 2a, 2b, and 4, respectively, from donors. No clinical or virological factor was associated with TTV viremia or TTV genotypes. CONCLUSIONS: TT Virus prevalence was higher among HCV hyperendemic township residents than blood donors with similar genotype distributions (genotype 1 was the most prevalent) in Taiwan. Neither TTV viremia nor a particular genotype was associated with HBV, HCV or GBV-C/HGV infection and abnormal ALT levels.     

High prevalance of TT virus infection in Japanese patients with liver diseases and in blood donors.

BACKGROUND/AIMS: Although a novel DNA virus, TT virus (TTV), has been isolated from a patient with cryptogenic post-transfusion hepatitis, its pathogenic role remains unclear. To elucidate its prevalence and clinical impact in patients with liver diseases, the presence of TTV DNA was assessed in patients with liver diseases and blood donors (BDs) in Japan using two primer sets, one conventional and the other new and highly sensitive. METHODS: We studied 261 samples, 72 with chronic hepatitis associated hepatitis C virus (HCV-CH), 57 with hepatocellular carcinoma associated HCV (HCV-HCC), 12 with HCC without either HCV or hepatitis B virus (NBNC-HCC), and 120 of BDs. RESULTS: Using two primer sets, TTV DNA was detected in 68 (94.4%), 53 (93.0%), 12 (100%), and 98 (81.7%) HCV-CH, HCV-HCC, NBNC-HCC, and BDs, respectively. The prevalence was not significantly different between HCV-CH and HCV-HCC, or between HCV-HCC and NBNC-HCC. Comparison between patients with and without TTV revealed no significant differences in backgrounds or biochemical findings. Histopathological findings in patients with HCV-CH, and number, maximum diameter, and histological differentiation of HCC also did not demonstrate any relation to TTV infection. TTV strains can be divided into five groups using phylogenetic analysis, but no disease-specific group appears to exist. CONCLUSIONS: Our data suggest that: 1) TTV is very prevalent among patients with liver diseases and even among BDs in Japan, 2) TTV infection does not impact on liver damage with HCV infection, and 3) TTV infection also does not affect the development or progression of HCC.     

GB virus-C/hepatitis G virus infection in a hepatitis C virus endemic village: prevalence in residents with low educational attainment and frequent recovery in females

AIMS/BACKGROUND: GB virus-C/hepatitis G virus (HGV) is a newly identified flavivirus, which may share the same mode of transmission as hepatitis C virus (HCV). The aim of this study was to investigate associated factors of HGV infection and clearance in a HCV endemic village in southern Taiwan. METHODS: Five hundred and ninety-four residents of a village in southern Taiwan were enrolled for hepatitis virus screening. Clinical features were recorded and a questionnaire addressing the possible routes of transmission was filled in by the participating residents. RESULTS: The prevalence of antibody to hepatitis C virus and hepatitis B surface antigen in the 594 residents was 70.7% and 19.5% respectively. Of the 399 residents tested for HGV RNA, GB virus-C/Hepatitis G virus envelop 2 protein (HGV-E2) antibody, and HCV RNA, the prevalence was 13.5%, 25.3%, 53.1% respectively. Multivariate logistic regression analysis showed that low educational attainment was associated with HGV infection, old age and low educational attainment were associated with HCV infection, and female gender was associated with HGV clearance. Alanine aminotransferase (ALT) values were significantly higher for residents with HCV infection alone, HBV infection alone, and co-infection of HCV and HBV than for those without HBV, HCV, and HGV infection. There were no differences in ALT values between subjects with HGV infection alone and those without HBV, HCV, and HGV infections. Residents with co-infection of HGV and HBV, or HGV and HCV had ALT values similar to those with HBV or HCV infection alone. CONCLUSION: HGV infection is common in the HCV endemic village. The transmission of HGV is closely related to low educational attainment. HGV clearance is frequently encountered in females. Co-infection of HGV does not compound hepatocellular inflammation.     

乙型及丙型肝炎患者发生肝细胞癌的风险预测：REVEAL-HBV/HCV研究的回顾

乙型肝炎病毒（HBV）及丙型肝炎病毒（HCV）的慢性感染是肝细胞癌（HCC）的主要致病原因。全球约有3亿5千万人为HBV的慢性感染者;HCV慢性感染者则有2亿人。全球每年约有50万人死于乙型肝炎引起的HCC,另有25万人死于丙型肝炎引起的HCC。乙型肝炎慢性感染者,其血中HBV DNA及ALT持续处于高水平是HCC最重要的预测因子。其他的危险因子还包括HBV C基因型、HBV基础核心促进子A1762T/G1764A双突变、男性、老年、肝癌家族史、酗酒习惯、以及与HCV或人类免疫不全病毒的合并感染等。根据REVEAL-HBV研究的资料,我们发展出简单易用的列线图,可利用非侵入性的临床特征准确地预测慢性乙型肝炎患者发生HCC的风险。丙型肝炎慢性感染患者发生HCC最重要的预测因子包括高血中HCV RNA水平、高ALT水平、HCV基因型以及老年等。REVEAL-HCV研究案例中,与HCV RNA水平低于检测范围且低ALT水平者相比,HCV RNA可测得、高ALT水平且感染第一型病毒的案例具有最高的HCC发生风险,其多变项调整后的风险比值（95%CI）为21.87（5.09～93.95）,这些发现对于慢性丙型肝炎的临床处置具有重要的意义。     

Effects of HAART on hepatitis C, hepatitis G, and TT virus in multiply coinfected HIV-positive patients with haemophilia

In multiply coinfected human immunodeficiency virus (HIV)-positive patients, we investigated the effects of high-activity antiretroviral therapy (HAART) using HIV protease inhibitors on three other viruses: hepatitis C virus (HCV), hepatitis G virus (HGV), and TT virus (TTV). Viral concentrations were measured serially by polymerase chain reaction methods in five patients with quadruple infection (HIV, HCV, HGV, and TTV) and in two patients with triple infection (HIV, HCV, and HGV) before and during HAART. In addition, CD4+ cell counts and serum alanine aminotransferase (ALT) levels were measured serially. Generally we observed no difference in serum HCV RNA, HGV RNA, or TTV DNA concentrations between samples obtained before and after initiation of HAART, whereas HIV RNA concentration decreased and CD4 counts increased in most patients. However, two patients had markedly decreased concentrations of HCV RNA and HGV RNA, respectively, more than 12 months after beginning HAART. Normalization of serum ALT levels was observed in a patient with decline of HCV RNA concentrations. No interactions were observed among these four viruses. HAART had no apparent direct effects on HCV, HGV, or TTV. Further studies will be required to elucidate whether the restoration of immune status through suppression of HIV replication by HAART may affect HCV or HGV RNA concentrations.     

De novo hepatitis B virus infection in hepatocellular carcinoma following eradication of hepatitis C virus by interferon therapy

Epidemiological studies have revealed that hepatocellular carcinoma (HCC) is still observed in hepatitis C virus (HCV)‐positive patients with a sustained response to interferon (IFN) treatment, although a substantial decrease in the incidence of hepatocellular carcinoma (HCC) has been achieved in those patients. Why HCC develops in patients who have a complete clearance of HCV remains unclear. Here, we provided evidence of latent hepatitis B virus (HBV) infection in an initially HCV‐positive chronic hepatitis patient who developed HCC after the complete eradication of HCV by IFN therapy. Although he was initially negative for anti‐hepatitis B surface antigen (HBsAg) or circulating HBV DNA but positive for anti‐hepatitis B core antigen (anti‐HBc) in his sera, he developed HBsAg and HBV DNA during the course of the management of a series of cancers. HBV DNA was detectable in the liver tissues before HBV reactivation and the viral sequences derived from his anti‐HBc‐positive liver showed 100% homology to that from the serum after HBsAg appearance. These findings indicates that HCV‐positive individuals who are positive for anti‐HBc in the absence of HBsAg could have latent HBV infection in their liver tissues and intrahepatic HBV infection may play a pivotal role in the development of HCC after the IFN‐mediated eradication of HCV.     

Prevalence of hepatitis C virus antibodies in chronic liver disease and hepatocellular carcinoma patients in India

The prevalence of antibodies to hepatitis C virus (HCV) was investigated in 129 patients with chronic liver disease (85 with chronic active hepatitis and 44 with cirrhosis) and 53 patients with hepatocellular carcinoma. The commercially available second generation anti-HCV enzyme immunoassay kit was used. Antibodies to hepatitis C virus were detected in 16.2% of the patients with chronic liver disease and in 15.1% with hepatocellular carcinoma. Of the HCV positive patients in all groups 51.7% were positive for hepatitis B virus (HBV) markers indicating present or past infection. Prevalence of HBV markers in all the three groups (CAH, cirrhosis and HCC) was higher as compared with anti-HCV prevalence. These results suggest that HCV infection may not be a major cause of chronic liver disease and hepatocellular carcinoma in India and indicate the presence of other aetiological agents.     

维持性血透患者六种肝炎病毒感染的调查研究

目的：了解维持性血液透析患者六种肝炎病毒感染情况,探讨其与输血、透析时间、肝功能的关系。方法：对１６７例维持性血液透析患者进行调查,采用第二代酶联免疫法（ＥＬＩＳＡ）检测ＨＡＶ、ＨＢＶ、ＨＥＶ、ＨＧ,用套式ＰＣＲ法检测经输血传播的肝炎病毒（ＴＴＶ）ＤＮＡ,并按血透时间、输血次数等分组进行对比分析。结果：ＨＡＶ、ＨＢＶ、ＨＣＶ、ＨＨＥＶ、ＨＧＶ、ＴＴＶ感染率分别为０％、２０．４％、５５．７％、０％、