Early acquisition of TT virus (TTV) in an area endemic for TTV infection

TT virus (TTV) is widely distributed, with high frequencies of viremia in South America, Central Africa, and Papua New Guinea. The incidence and timing of infection in children born in a rural area of the Democratic Republic of Congo was investigated. TTV viremia was detected in 61 (58%) of 105 women attending an antenatal clinic and in 36 (54%) of 68 infants. Most infants acquired the infection at >/=3 months postpartum. Surprisingly, TTV infection was detected in a large proportion of children with TTV-negative mothers (13 [43%] of 30). Nucleotide sequences of TTV-infected children were frequently epidemiologically unlinked to variants detected in the mother. These three aspects contrast with the maternal transmission of hepatitis G virus/GB virus C in this cohort and suggest an environmental source of TTV infection comparable to hepatitis A virus and other enterically transmitted infections.     

Molecular epidemiology and clinical implications of TT virus (TTV) infection in Indian subjects

GOALS: This study was aimed at obtaining data on the epidemiology and clinical course of TT virus (TTV) infections among Indian subjects. BACKGROUND: The TTV is a nonenveloped DNA virus, first identified in the peripheral blood of individuals with posttransfusion hepatitis of unknown etiology. There has been much conjecture regarding the disease association of this virus. STUDY: A total of 494 serum specimens from various groups of high-risk and control subjects were screened for TTV DNA by a semi-nested PCR, using the ORF1-derived N22 primers. The sera were also screened for the HBsAg surface antigen by an ELISA, HCV RNA by a 5' NCR-based RT-PCR and GBV-C/HGV RNA by a 5' UTR-based RT-PCR. The clinical and hepatic profiles of the various subjects were also studied. Seventy-one randomly picked TTV isolates were directly sequenced and their phylogeny was studied. RESULTS: TTV showed an overall positivity rate of 45.34% with a significant higher prevalence of 52.9% among the high-risk subjects as against a prevalence of 28% among healthy control subjects (P < 0.001). Abnormal liver function profiles were frequent among TTV viremic individuals and among the acute hepatitis cases studied a higher mortality rate correlated with a superimposed TTV infection. The 71 TTV isolates sequenced were found to belong to genotype 1a being closely homologous to TTV prototype TA278. CONCLUSION: The TT virus shows a significant prevalence in the Indian population, particularly among subjects at risk for acquiring parenterally transmitted infections. Our study corroborates a putative role of the virus in the etiology of liver disease, particularly in coinfection with other agents.     

Hepatitis C virus infection in an area hyperendemic for hepatitis B and chronic liver disease: the Taiwan experience

To assess the contribution of hepatitis C virus (HCV) in liver disease in Taiwan, antibody to HCV (anti-HCV) was studied by radioimmunoassay in 392 patients with chronic liver disease and in 440 healthy adults and 444 subjects at risk. The anti-HCV prevalence was 0.95% in 420 volunteer blood donors, 90% in 100 hemophiliacs, and 81% in 58 parenteral drug abusers. Anti-HCV was present in 6 (7.7%) of 78 hepatitis B surface antigen (HBsAg)-positive and 28 (65%) of 43 HBsAg-negative patients with chronic hepatitis, 3 (10%) of 31 HBsAg-positive and 13 (43%) of 30 HBsAg-negative cirrhotics, and 7 (17%) of 42 HBsAg-positive and 15 (63%) of 24 HBsAg-negative patients with hepatocellular carcinoma (HCC). An outbreak of non-A, non-B hepatitis revealed 18% of 57 patients to be positive for anti-HCV, and in 29 patients with posttransfusion hepatitis prospectively followed, 7 (24%) developed anti-HCV. Thus, HCV infection appears to play a relatively minor role in HBsAg-positive liver disease in Taiwan but is strongly associated with HBsAg-negative chronic liver disease and HCC. The infection is extremely common in hemophiliacs and parenteral drug abusers.     

TT virus infection in patients with chronic hepatitis B and response of l－TTV to lamivudine

AIM: To investigate the responses of TT virus (TTV) and hepatitis B virus (HBV) to a long-term lamivudine therapy. METHODS: Sixteen patients infected with both TTV and HBV were treated with lamivudine 100 mg daily for 30 months. Blood samples were drawn at the beginning of the therapy and subsequently at month 3, 6, 9, 12 and 30. Serum TTV was quantified by real time PCR and serum HBV was detected by hybridization assay and nested polymerase chain reaction. RESULTS: TTV infection was detected in 100 % of HBV-infected patients. Loss of serum TTV DNA after one year of treatment occurred in 1/16 (6 %) patients. At the end of therapy, TTV DNA was positive in 94 % of them. The decline of HBV viremia was evident at 3 months after therapy and the response rate was 31 %, 44 %, 63 %, 50 % and 50 % at month 3, 6, 9, 12 and 30, respectively. CONCLUSION: TTV replication is not sensitive to lamivudine and is highly prevalent in HBV-infected patients.     

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.     

IgM-class antibodies to TT virus (TTV) in patients with acute TTV infection

TT virus (TTV) is a human circovirus with a single-stranded, circular DNA genome of 3.8 kb. A method was developed to detect IgM antibodies to TTV as a serological marker for the diagnosis of acute TTV infection. IgM antibodies in test sera were captured by a monoclonal antibody against IgM/μ on a solid support followed by binding of IgM with TTV derived from fecal extract of a TTV carrier. The presence of IgM-specific TTV particles was determined by polymerase chain reaction (PCR) using nucleic acids extracted from the solid support. Anti-TTV IgM was detected in sera from two patients with non-A to G post-transfusion hepatitis, who were positive for TTV DNA during weeks 10–21 and 12–17, respectively, following transfusion. The anti-TTV IgM was detectable after alanine transaminase levels were elevated and TTV DNA was detectable in the patients. The duration of the anti-TTV IgM was short-lived compared with anti-TTV IgG. Anti-TTV IgM was not detected in sera from any of 36 healthy individuals, with no detectable anti-TTV IgG or TTV DNA in their serum. These results indicate that anti-TTV IgM antibodies would be a useful marker to detect acute TTV infection.     

TT virus (TTV) is not associated with acute sporadic hepatitis

Summary A novel virus, TT virus (TTV), recently discovered byOkamoto et al. in the serum of a patient with posttransfusion hepatitis, is thought to be one of the causative agents of blood-borne acute hepatitis. The association of this virus with acute sporadic hepatitis was evaluated. TTV DNA was detected in 4 (4.9%) of 81 cases of acute hepatitis A, in 5 (16.7%) of 30 cases of acute hepatitis B, in 1 (25.0%) of 4 cases of acute hepatitis C, in 1 (9.1%) of 9 cases of cytomegalovirus and Eppstein-Barr infection, and in 8 (13.6%) of 59 cases of acute hepatitis of unknown etiology. These positive rates of TTV in various etiologies did not differ significantly amongst each other, and were similar to those of healthy volunteers, i.e. 12.0% (12/100). The comparison of levels of alamine aminotransferase, aspartate aminotransferase, total bilirubin, hepaplastin test and prothrombin time between TT virus-positive and- negative patients did not show any differences. This indicates that TTV is neither a main causative agent of acute sporadic hepatitis of unknown etiology, nor does it affect the clinical features of acute hepatitis with already known etiology.     

The epidemiology of hepatitis C virus infection

The prevalence of hepatitis C virus (HCV) infection varies in different populations, ranging from as low as 0.6% in volunteer blood donors to as high as 80% in injection drug users. The prevalence of HCV in a population can be predicted by risk factors associated with the transmission of infection. These risk factors include injection drug use, blood product transfusion, organ transplantation, hemodialysis, occupational injury, sexual transmission, and vertical transmission. We review the literature regarding the incidence and prevalence of HCV infection and the evidence supporting various modes of HCV transmission.     

TT virus infection during chronic hepatitis C

OBJECTIVE: The pathogenic role of TT virus (TTV) is not well known, especially during chronic hepatitis C virus (HCV) infection. We retrospectively investigated the presence of TTV DNA in the plasma of patients with chronic HCV infection and compared the characteristics of TTV-DNA-positive and -negative groups. METHODS: Between November 1996 and November 1998, 234 patients were included. Inclusion criteria were persistently elevated serum alanine aminotransferase (ALT) levels, anti-HCV and HCV-RNA positivity, and seronegativity for hepatitis B virus and human immunodeficiency virus markers. TTV DNA was amplified in nested polymerase chain reaction with TTV-specific primers, and products were analyzed by agarose-gel electrophoresis. Data were analyzed using the chi2, Fisher's exact test, or Mann-Whitney test, as appropriate. RESULTS: TTV DNA was detected in 19 (8.1%; 95% confidence interval: 4.6-11.6%) patients. TTV-DNA-positive and TTV-DNA-negative patients did not differ statistically for age, gender ratio, source of HCV infection, HCV disease duration, biological parameters, histological grade, HCV-RNA load, or HCV genotype. Although nonsignificant (p = 0.21), there was a trend for a higher prevalence of TTV DNA in patients with an unknown cause of HCV infection (4/22, 18.2%) than in intravenous drug users (4/84; 4.8%), in those exposed to potential risk factors (4/49; 8.2%), or in those having received blood transfusion (7/79; 8.9%). CONCLUSIONS: Because the rates of HCV replication and the severity of liver lesions in TTV-DNA-negative and -positive patients were similar, the hepatic pathogenicity of TTV in chronic hepatitis C patients is questionable.     

Prevalence and persistence of a novel DNA TT virus (TTV) infection in Japanese haemophiliacs

To clarify the clinical implication of a newly discovered 'TT virus (TTV)', we assayed TTV DNA in sera from 50 haemophiliacs by a seminested-PCR. TTV DNA was detected in 75% (35/50), which was a much higher prevalence than for HBV (HBc-Ab), HCV RNA, or HGV RNA. In particular, TTV DNA was found in 44.4% (4/8) of patients who had been treated only with virally inactivated factor VIII concentrates. Elevated ALT levels were observed in patients with HCV RNA and TTV DNA; however, the elevation in TTV DNA was obtained from patients co-infected with HCV RNA (62.9%, 22/35). There was no significant difference in ALT levels between TTV DNA-positive and DNA-negative in patients without HCV RNA. 85.3% (35/41) of TTV DNA-positive sera in 1990 were again positive for TTV DNA in 1995. These findings suggest that many haemophiliacs have been infected with TTV. Although TTV infection was not associated with serum ALT elevation, persistent TTV infection may contribute to cryptogenic hepatic failure in haemophiliacs.     

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感染血清学,原位杂交及干扰素治疗研究

目的了解ＴＴＶ感染状况,探讨ＴＴＶ致病性及对干扰素治疗的应答。方法采用ＰＣＲ和原位杂交方法检测血清和肝组织中ＴＴＶ ＤＮＡ,回顾分析８例ＴＴＶ／ＨＣＶ感染者干扰素治疗后病毒及ＡＬＴ应答状况。结果各型肝病患者（３６．７％～４２．８％）和职业供血员（４３．２％）ＴＴＶ感染率均显著高于义务供血员（健康对照人群,５．６％）。部分感染者采用斑点杂交方法可自血清中检出ＴＴＶ ＤＮＡ（３／３０,１０．０％）,提示存在较高的血清病毒负荷, １６例慢性非甲～戊型肝炎患者及１６例肝炎后肝硬化患者肝组织以原位杂交检测,各６例ＴＴＶ ＤＮＡ阳性（３７．５％）。 ８例ＴＴＶ／ＨＣＶ混合感染者经２４周疗程干扰素治疗后,６例维持持久ＡＬＴ应答（停药后２４周ＡＬＴ正常）,治疗１２周时, ８例血清ＴＴＶ ＤＮＡ均阴转,但 ２例停药后复阳, ＡＬＴ无应答的２例患者, ＨＣＶ ＲＮＡ呈阳性但ＴＴＶ ＤＮＡ阴怀;而ＴＴＶ ＤＮＡ阳转的２例患者ＡＬＴ均维持应答。结论 ＴＴＶ感染在肝病患者和职业供血员中较普遍, ＴＴＶ可在肝组织中活跃复制,其对干扰素治疗反应较敏感,ＴＴＶ／ＨＣＶ重叠感染时ＴＴＶ无明显致肝损伤作用。     

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).

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.     

Spontaneous elimination of hepatitis C virus RNA in individuals with persistent infection in a hyperendemic area of Japan.

The natural course of hepatitis C virus (HCV) carriers is not well understood. We examined the clinical characteristics of individuals exhibiting spontaneous elimination of HCV as part of a cohort study of residents of a HCV hyperendemic area in Japan. In individuals who were judged to have persistent HCV infection in 1995, 302 had at least 4 annual ALT measurements between 1993 and 2000, and had not been treated with IFN. They were tested for the presence of HCV RNA in 2001 and/or 2002 and HCV RNA could not be detected in 20 of the 302 individuals. In these 20 individuals, 7 were confirmed to have detectable HCV RNA and 13 were not until 2000. Thus, 2.4% (7/289) were judged to have spontaneously eliminated the HCV infection during that 6-year period. Although there were no differences in age, sex, ALT levels, or serologically defined HCV genotype between individuals with and without exhibiting spontaneous elimination, there was a significant relationship between the elimination of HCV RNA and a low level of HCVcAg (<20pg/mL) (P<0.001) upon testing in 1995. These results suggest that spontaneous elimination of HCV RNA following persistent infection is rare and appears to be related to viral load.     

The changing epidemiology of hepatitis C virus infection in Europe

The epidemic of hepatitis C virus (HCV) infection in Europe is continuously evolving and epidemiological parameters (prevalence, incidence, disease transmission patterns and genotype distribution) have changed substantially during the last 15 years. Four main factors contribute to such changes: increased blood transfusion safety, improvement of healthcare conditions, continuous expansion of intravenous drug use and immigration to Europe from endemic areas. As a result, intravenous drug use has become the main risk factor for HCV transmission, prevalent infections have increased and genotype distribution has changed and diversified. Hence, prevalence data from studies conducted a decade ago may not be useful to estimate the current and future burden of HCV infection and additional epidemiological studies should be conducted, as well as new preventive strategies implemented to control the silent epidemic. This review summarizes recently published data on the epidemiology of HCV infection in Europe focusing on the factors currently shaping the epidemic.     

Global epidemiology of hepatitis C virus infection

Hepatitis C virus (HCV) is a major cause of liver disease worldwide and a potential cause of substantial morbidity and mortality in the future. The complexity and uncertainty related to the geographic distribution of HCV infection and chronic hepatitis C, determination of its associated risk factors, and evaluation of cofactors that accelerate its progression, underscore the difficulties in global prevention and control of HCV. Because there is no vaccine and no post-exposure prophylaxis for HCV, the focus of primary prevention efforts should be safer blood supply in the developing world, safe injection practices in health care and other settings, and decreasing the number of people who initiate injection drug use.     

Prevalence of hepatitis G virus (HGV) infection in an endemic area of hepatitis C virus (HCV) infection

BACKGROUND/AIMS: We investigated the prevalence of hepatitis G virus infection among inhabitants of a hepatitis C virus endemic area. METHODOLOGY: Two hundred and eighty-eight inhabitants, who underwent medical examinations for health screening, were enrolled in this epidemiological study. HGV RNA and HCV RNA were detected by polymerase chain reaction. We also examined anti-HGV envelope protein (E2) antibodies in all serum samples. RESULTS: In these 288 inhabitants, we found anti-HCV antibodies (HCV-Ab) and HCV RNA in 28.5% and 17.4%, respectively. HGV RNA and anti-HGV E2 were detected in 9 (3.1%) and 16 (5.5%), respectively. One patient was positive for both HGV RNA and anti-HGV E2. The exposure rate, expressed as the percentage of people with HGV RNA and/or anti-HGV E2, was 8.3%, which was significantly lower than the incidence of positive HCV-Ab. Of the 24 patients with HGV RNA and/or anti-HGV E2, 15 (62.5%) were positive for HCV-Ab, of those HCV RNA was detected in 9 (37.5%). Further, we found a higher prevalence of HGV exposure in patients with HCV-Ab than in those without (8.3% vs. 4.4%). CONCLUSIONS: HGV infection was not identical to the epidemic hepatitis C virus infection among inhabitants of this town, suggesting that hepatitis C virus might be less infectious than hepatitis C virus.