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％、     

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.     

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.     

A prospective study of transfusion-transmitted virus transmission by blood transfusion

Recently, a new single-stranded DNA virus (TT virus, TTV) has been isolated and related to post-transfusion hepatitis. The aim of this study was to investigate the prevalence of TTV in blood donors and blood recipients, and the incidence of TTV transmission by blood transfusion. TTV DNA and serum markers of hepatitis B virus (HBV) and hepatitis C virus (HCV), were examined in 130 blood recipients, and the presence of TTV was studied in their 340 corresponding blood donors. The prevalence of TTV infection was 10.6% (36/340) in donors and 8.5% (11/130) in blood recipients, before transfusion. Eighteen subjects (15.1%) were found to be TTV positive, after transfusion, in the 119 blood recipients without TTV before transfusion; at least one of the corresponding donors was TTV positive. There were 46 subjects with post-transfusion hepatitis virus infection, 45 with HCV infection (including seven co-infected with TTV) and two with HBV infection (including one co-infected with HCV and one co-infected with TTV). The recipient with TTV and HBV co-infection and three of the seven patients with TTV and HCV infection had alanine aminotransferase (ALT) levels higher than 90Ul^–1, but only two of the 10 isolated TTV infections had a mild ALT elevation. These results show that prevalence of TTV was high in blood donors and hospitalized patients, and isolated TTV infection is not related to significant ALT elevation.     

Lower Hepatitis G Virus Infection Prevalence Compared to Hepatitis B and C Virus Infection Prevalences

To more accurately determine the seroprevalence of hepatitis G virus (HGV) infection, we surveyed antibody to HGV (anti-E2) by enzyme-linked immunosorbent assay (ELISA) and HGV RNA by nested polymerase chain reaction (PCR) in 298 residents of a hepatitis C virus (HCV)-endemic area of Japan and in 225 hemodialysis patients. We then compared these findings with known HCV and hepatitis B virus (HBV) infection prevalences. Anti-E2 and HGV RNA prevalences were 32 (10.7%) and 5 (1.7%) in the residents and 24 (10.7%) and 10 (4.4%) in the hemodialysis patients, respectively. Anti-E2 and HGV RNA concurrence was found in two of the hemodialysis patients. Total HGV marker (anti-E2 and/or HGV RNA) prevalences [37 (12.4%) in residents and 32 (14.2%) in hemodialysis patients], were significantly lower than the prevalences of antibody to HCV (anti-HCV) by ELISA [59 (19.8%) and 96 (42.7%)], and antibody to hepatitis B core antigen (anti-HBc) by radioimmunoassay (RIA) [87 (29.2%) and 101 (44.9%)] (P < 0.05). The anti-HCV prevalence in subjects with total HGV marker was significantly higher than in those without total HGV marker. There was no significant difference in anti-HBc prevalence between those with and without total HGV marker. The viremic rate was highest in HCV infection (HCV RNA by PCR/anti-HCV) (83.2%), with HGV infection (HGV RNA/total HGV marker) (21.7%) intermediate, and HBV infection (hepatitis B surface antigen by RIA/anti-HBc) (5.3%) lowest (P < 0.05). These findings indicate that HGV infection was less endemic than HCV and HBV. HGV was eliminated naturally more frequently than HCV infection and less frequently than HBV infection.     

High rate of TTV infection in multitransfused patients with pediatric malignancy and hematological disorders

The prevalence of transfusion-transmitted virus (TTV) infection has not been known in patients suffering from pediatric malignancies and hematological disorders who receive blood transfusion and/or blood products during treatment. Blood samples were taken from 75 patients. TTV infection was identified when TTV DNA was detected in serum by a polymerase chain reaction (PCR) assay. Hepatitis C virus (HCV) and hepatitis G virus (HGV) RNA were also assayed by PCR. TTV DNA was detected in 38 of 75 patients (51%). In 4 of 38 patients, the amount of blood transfused was less than 3 units. By time since last transfusion, TTV DNA was detected in 12 of 35 patients after more than 4 years, 12 of 21 between 1 and 4 years, and 14 of 19 within 1 year. Six patients had mixed infection of TTV and HCV, and 12 patients had mixed infection of TTV and HGV. Three different kinds of virus were found simultaneously in serum from 3 patients. Eight out of 75 patients showed abnormal levels of alanine aminotransferase (ALT) (>40 IU/liter), and 3 of them had TTV DNA. All patients who had TTV DNA and elevated ALT levels also were positive for HCV RNA and HGV RNA. The prevalence of TTV infection is high in patients with pediatric malignancies and hematological disorders after episodes of blood transfusion. Transfusion is one of the most important risk factors for TTV infection regardless of the amount of blood transfused.     

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.     

Clinical significance of hepatitis G virus infection in patients on long-term haemodialysis

Infection with the newly discovered hepatitis G virus (HGV) was analysed in 163 patients on long-term haemodialysis to clarify its prevalence and clinical significance. Hepatitis G virus RNA in serum was measured by polymerase chain reaction with primers corresponding to the putative non-structural 5’ region. Of the 163 patients, three (1.8%) were positive for hepatitis B surface antigen, 40 (24.5%) were positive for hepatitis C virus (HCV)-RNA and 16 (9.8%) were positive for HGV-RNA. Five of the 16 patients with HGV-RNA were also positive for HCV-RNA. Patients with HCV and HGV coinfection had undergone a longer duration of haemodialysis (P=0.001) and had higher units of transfusion (P=0.031) compared with those without hepatitis virus infection. Transfusion history was significantly higher (P=0.039) in patients with only HGV infection than in those without hepatitis virus infection. Hepatitis C virus RNA concentration was higher (P=0.032) in patients with HCV and HGV coinfection than in those with HCV infection only, but alanine aminotransferase (ALT) levels were similar between these two groups. In conclusion, about 10% of patients on haemodialysis were infected with HGV and the infection was closely associated with transfusion history.     

Superinfection of TT virus and hepatitis C virus among chronic haemodialysis patients

BACKGROUND: The TT virus (TTV), a new DNA virus found in Japan from a patient with post-transfusion hepatitis non-A-non-G, is frequently positive in the sera of patients with liver disease. It is not established whether this virus causes liver damage. We studied the frequency of superinfection of this virus and hepatitis C virus (HCV) known to be endemic among haemodialysis patients, and the possible deleterious effect of TTV on HCV-induced chronic liver disease. METHODS: We used primers from a conservative region in the TTV genome (Okamoto, 1998) to detect TTV. Sera from 163 dialysis patients positive for anti-HCV and 77 dialysis patients negative for anti-HCV (control) were tested. RESULTS: TT Virus positivity was 35% among HCV antibody (anti-HCV)-positive patients and 45.4% among anti-HCV-negative patients. TT Virus positivity was unrelated to the length of haemodialysis or amounts of blood the patients had received in the past. More anti-HCV-positive patients had a history of transfusion, but TTV positivity was not as closely associated with transfusion as anti-HCV positivity. The severity of chronic liver disease was estimated from peak serum alanine aminotransferase levels in the preceding 6 months. Among anti-HCV positives, TTV-positive patients tended to have less active disease; at least there was no indication that TTV superinfection aggravated chronic hepatitic C in long-term dialysis patients. Four of 35 anti-HCV-negative, TTV-positive patients had chronic active liver disease, while none of the anti-HCV-negative and TTV-negative patients did. CONCLUSIONS: TT Virus infection is prevalent among haemodialysis patients. Its transmission occurs not only by blood transfusion, but also by non-parenteral infection. Superinfection of TTV does not exert deleterious effects on the liver disease induced by HCV. However, it may cause chronic hepatitis in a limited number of patients, but remains dormant most of the time. Triple infection, HCV and TTV plus HBV or HGV (one case each), did not cause severe liver disease.     

Clinical impact of genotype 1 TT virus infection in patients with chronic hepatitis C and response of TT virus to alpha-interferon

BACKGROUND: The relationship between genotype 1 TT virus (TTV) infection and the status of chronic hepatitis C was studied. METHODS: A total of 52 patients with chronic hepatitis C who were treated with interferon (IFN)-alpha were enrolled in the present study. Of those, 12 were infected with genotype 1 TTV and 40 were uninfected. RESULTS: Clinical backgrounds, including mean age, sex, blood transfusion history, serum alanine aminotransferase (ALT) level, and the results of liver biopsy did not differ between patients with and without genotype 1 TTV infection. The distribution of hepatitis C virus (HCV) genotypes did not differ between the two groups of patients, but TTV-infected patients tended to have a lower serum HCV-RNA level than uninfected patients (median (range) 26.0 (< 1-460) vs 135 (1.2-740) kilo copies/mL, respectively; P = 0.065). Patients with a sustained response of HCV to IFN-alpha were significantly more common in TTV-infected than -uninfected patients (58 vs 23%, respectively; P = 0.018). Multivariate logistic regression analysis revealed that patients with a sustained response of HCV correlated significantly with the serum HCV-RNA level (P = 0.006), but not with the presence or absence of genotype 1 TTV infection (P = 0.161). Serum TTV-DNA decreased with IFN-alpha therapy in all 12 patients and remained negative in six patients even after treatment. There was no correlation between patients with a sustained response of HCV and the same of TTV. Serum ALT levels correlated with changes in the status of HCV viremia, but not with changes in the status of TTV viremia. CONCLUSIONS: An opposing relationship between HCV and TTV proliferation was suggested, but coinfection with genotype 1 TTV did not affect the status of chronic hepatitis C.     

Infection with TT virus, a novel transfusion-transmissible DNA virus, in haemophiliacs and in blood products

We evaluated the characteristics and rate of infection with TT virus (TTV), a novel DNA virus, in Japanese haemophiliacs. TTV DNA was measured in 60 haemophiliacs by semi-nested polymerase chain reaction. Co-infection with hepatitis C virus (HCV), hepatitis G virus (HGV) and human immunodeficiency virus (HIV) was also evaluated. In addition, the rate of detection of TTV DNA in blood products was evaluated. TTV DNA was detected in 35/60 haemophiliacs (58.3%). There were no differences in the backgrounds or characteristics between haemophiliacs with and without TTV infection, except for higher levels of IgG and IgM in patients with TTV infection. In patients infected with TTV of types other than type 1, which are rarely detected in Japan, the rate of co-infection with HCV of imported types was high; TTV of types other than type 1 in Japanese haemophiliacs were probably transmitted by imported blood products. TTV DNA was detected in over half of the blood products tested, but TTV DNA concentrations in these products were lower than in the serum of haemophiliacs.     

上海地区血液透析患者与供血者中输血传播病毒DNA检测及部分核苷酸序列分析

目的　了解上海地区暴露于血及血制品的血透患者中输血传播病毒（ＴＴＶ）感染率。方法　采用套式ＰＣＲ技术,检测了 ６例血透患者和 ４９例供血员血清中 ＴＴＶ ＤＮＡ,并对其中各 １例 ＰＣＲ产物（２７２ｂｐ）测］３。结果血透患者ＴＴＶ ＤＮＡ的检出率为 ３２．８％（２０／６１）,供血员的检出率为 ２４． ５％（１２／４９）。 ２０例 ＴＴＶＤＮＡ阳性血透患者中,６例为单纯ＴＴＶ感染,６例为ＴＴＶ、ＨＣＶ及ＨＧＶ重叠感染,４例为ＴＴＶ、ＨＣＶ和４例为ＴＴＶ、ＨＧＶ重叠感染。在所有ＴＴＶ感染者中,仅发现１例血清ＡＬＴ升高,该病例为ＴＴＶ、ＨＣＶ及ＨＧＶ重叠感染。对ＰＣＲ阳性扩增产物２７２ｂｐ测序结果显示,上海株（ＳＨＰ、ＳＨＤ）核苷酸的同源性为９９．６％,与深圳株、２株日本株核着酸的同源性分别为９７．４％、９８．７％和９８．７％,表明ＴＴＶ上海株与深圳株及日本株（Ｎ２２、Ｇ１ａ）属同一亚型,首次证实了上海地区的ＴＴＶ感染。结论ＴＴＶ感染可经血传播。其致病性较弱,对ＴＴＶ的研究尚属开始,ＴＴＶ的病原学、流行病学及临床意义等问题还有待进一步探索和阐明。     

Interferon treatment of two patients with quadruple infection with hepatitis C virus (HCV), human immunodeficiency virus (HIV), hepatitis G virus (HGV), and TT virus (TTV)

Abstract: We administered interferon (IFN) to two patients who had quadruple infection with hepatitis C virus (HCV), human immunodeficiency virus (HIV), hepatitis G virus (HGV), and TT virus (TTV), a recently isolated novel DNA virus. Nine mega-units of natural alpha-IFN were administered daily during the first two weeks and thrice weekly during the following 22 weeks (total dose, 720 mega-units). In both cases, serum alanine aminotransferase (ALT) levels decreased during IFN administration but increased thereafter. The concentrations of HCV, HIV, HGV, and TTV declined with the administration of IFN. However, the concentrations of these 4 viruses increased after the cessation of IFN with the except of TTV in patient 2 which disappeared during treatment and did not subsequently reappear. IFN reduced the concentrations of 4 viruses, in an apparently independent manner.     

TTV阳性肝病患者的临床与病理学特征初步观察

目的 观察ＴＴＶ阳性肝病患者的临床和病理特征。方法 用巢式ＰＣＲ法检测ＴＴＶ－ＤＮＡ,同时观察血清生化指标,肝组织活检观察其病理变化。结果 ＴＴＶ感染者的血清学模式以重叠ＨＢＶ、ＨＣＶ、ＨＡＶ、ＨＥＶ、ＨＧＶ二重感染为主占５７．９％（２２／３８）,以乏力、纳差、腹胀为临床特征,ＴＢｉＬ、ＡＬＴ变化不明显,ＴＴＶ单独感染者为４２．１％（１６／３８）,急性发病者临床特征多与“急性黄疸性肝炎”相似,病理改变与各型病毒性肝炎的病理变化基本相似,但主要以肝门脉区炎症,小叶间胆管损伤,灶状坏死为多见。结论 ＴＴＶ可与各型已知肝炎病毒重叠感染也可单独感染。     

TT virus and hepatitis G virus infections in Korean blood donors and patients with chronic liver disease

AIM: To determine the prevalences of TTV and HGV infections among blood donors and patients with chronic liver disease in Korea, to investigate the association of TTV and HGV infections with blood transfusion, and to assess the correlation between TTV and HGV viremia and hepatic damage. METHODS: A total of 391 serum samples were examined in this study. Samples were obtained from healthy blood donors (n=110), hepatitis B surface antigen (HBsAg)-positive donors (n=112), anti-hepatitis C virus (anti-HCV)-positive donors (n=69), patients with type B chronic liver disease (n=81), and patients with type C chronic liver disease (n=19). TTV DNA was detected using the hemi-nested PCR. HGV RNA was tested using RT-PCR. A history of blood transfusion and serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were also determined. RESULTS: TTV DNA was detected in 8.2 % of healthy blood donors, 16.1 % of HBsAg-positive donors, 20.3 % of anti-HCV-positive donors, 21.0 % of patients with type B chronic liver disease, and 21.1 % of patients with type C chronic liver disease. HGV RNA was detected in 1.8 % of healthy blood donors, 1.8 % of HBsAg-positive donors, 17.4 % of anti-HCV-positive donors, 13.6 % of patients with type B chronic liver disease, and 10.5 % of patients with type C chronic liver disease. The prevalence of TTV and HGV infections in HBV- or HCV-positive donors and patients was significantly higher than in healthy blood donors (P<0.05), except for the detection rate of HGV in HBsAg-positive donors which was the same as for healthy donors. There was a history of transfusion in 66.7 % of TTV DNA-positive patients and 76.9 % of HGV RNA-positive patients (P<0.05). No significant increase in serum ALT and AST was detected in the TTV- or HGV-positive donors and patients. CONCLUSION: TTV and HGV infections are more frequently found in donors and patients infected with HBV or HCV than in healthy blood donors. However, there is no significant association between TTV or HGV infections and liver injury.     

TT viral infection through blood transfusion: retrospective investigation on patients in a prospective study of post-transfusion hepatitis

AIM To investigate the role of blood transfusion in TT viral infection (TTV).METHODS We retrospectively studied serum samples from 192 transfusion recipients who underwent cardiovascular surgery and blood transfusion between July 1991 and June 1992. All patients had a follow-up every other week for at least 6 months after transfusion. Eighty recipients recipents blood before screening donors for hepatitis C antibody (anti-HCV), and 112 recipients reveiver screened blood.Recipients with alanine aminotransferase level ＞ 2.5 times the upper normal limit were tested for serological markers for viral hepatitis A, B,C, G, Epstein-Barr virus and cytomegalovirus.TTV infection was defined by the positivity for serum TTV DNA using the polymerase chain reaction method. RESULTS Eleven and three patients, who reveiver anti-HCV unscreened and screened blood, respectively, had serum ALT levels ＞90 IU/L. Five patients (HCV and TTV: 1; HCV,HGV, and TTV: 1; TTV: 2; and CMV and TTV: 1 )were positive for TTV DNA, and four of them had sero-conversion of TTV DNA. CONCLUSION TTV can be transmitted via blood transfusion. Two recipients infected by TTV alone may be associated with the hepatitis.However, whether TTV was the causal agent remains unsettled, and further studies are necessary to define the role of TTV infection in chronic hepatitis.     

TT-virus infection in Japanese general population and in hemodialysis patients

To determine TT virus (TTV) prevalence and the persistence of viremia, we prospectively did cross-sectional and longitudinal studies using by the polymerase chain reaction to test the successive sera of 150 Japanese hemodialysis patients and compared these with those of 166 residents of a rural Japanese area endemic for hepatitis C virus (HCV). TTV DNA positivity was significantly higher in 50 (30.1%) of the residents than in 25 (16.7%) of the patients in 1997 (P < 0.05). TTV DNA positively in the patients was not associated with HCV RNA positivity and also increased with the number of blood transfusions and decreased with the duration of hemodialysis, but not significantly. Longitudinal study from 1997 to 1999 showed that persistent TTV DNA positivity was found significantly more often in 35 (21.1%) of the residents than in 13 (8.6%) of the patients (P < 0.05), and that persistent TTV DNA negativity was found significantly more often in 103 (68.7%) of the patients than in 91 (54.8%) of the residents (P < 0.05). Of the 25 patients and 50 residents TTV DNA positive in 1997, TTV DNA was eliminated more often in 12 (48.0%) patients than in 15 (30.0%) residents over the three years, but the difference was not significant. The route of TTV transmission might differ from HCV in that it could be nonparenteral. TTV was less prevalent in hemodialysis patients than residents, and the virus was more often eliminated by hemodialysis patients than by residents during the three-year observation period, possibly because of the effect of the hemodialysis procedure.