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.     

Hepatitis C in chronic liver disease: an epidemiological study based on 566 consecutive patients undergoing liver biopsy during a 10-year period

We analysed the presence of hepatitis C virus (HCV) antibodies in 566 patients undergoing liver biopsy. While over 20% of the patients were anti-HCV positive according to elisa, only 13.8% had HCV antibodies when tested with a four-antigen recombinant immunoblot assay (RIBA 2). At the time of inclusion in the study, most patients were asymptomatic, irrespective of whether they were HCV-positive. Histological findings in anti-HCV-positive patients were chronic persistent hepatitis, chronic active hepatitis or cirrhosis in > 75% of cases. Only four of the patients who were anti-HCV-positive according to the RIBA 2 had autoimmune chronic active hepatitis. Risk behaviour could be identified in the majority of cases. Community-acquired sporadic cases were rare (12%). Of the 153 patients who died during follow-up, 23 subjects were anti-HCV positive. Although age- and sex-adjusted survival was not shorter in anti-HCV-positive patients than in anti-HCV-negatives, the risk of hepatocellular cancer was higher (P = 0.01). We conclude that HCV infection is associated with chronic liver disease, even when critical evidence of viral aetiology is slight. Truly sporadic cases are rare. Patients infected with HCV are at increased risk of developing hepatocellular cancer.     

Long-term outcome of kidney transplantation in patients with hepatitis C virus infection

BACKGROUND/AIMS: The impact of HCV (hepatitis C virus) infection on the long-term outcome of kidney transplant patients is controversial. METHODOLOGY: Eighty-four renal allograft recipients who were seronegative for hepatitis B surface antigen and had been screened for antibody to hepatitis C virus (anti-HCV) were included. The outcome and survival were compared between anti-HCV-positive (n = 30, group 1) and anti-HCV-negative (n = 54, group 2) kidney transplant patients. Group 1 patients were further compared to 52 anti-HCV-positive end-stage renal disease patients (group 3) who were on chronic dialysis. RESULTS: Group 1 patients had a higher prevalence of chronic hepatitis than group 2 and group 3 patients did (67% vs. 2% and 31%). Liver-related complications and deaths between group 1 and group 2, and group 1 and group 3 patients were not significantly different. The comparisons of the long-term survival between these groups showed no significant differences, despite group 3 patients had a higher overall mortality rate. Cox regression analysis confirmed that age more than 45 years was the only independent factor that affected survival in anti-HCV-positive end-stage renal disease patients with or without kidney transplantation. CONCLUSIONS: HCV infection is not a contraindication to kidney transplantation. For anti-HCV-positive end stage renal disease patients, survival is better in younger patients, and is not influenced by kidney transplantation or continuing dialysis.     

Risk of hepatitis C virus infection among household contacts of Saudi patients with chronic liver disease

SUMMARY. To evaluate the intrafamilial transmission of heptitis C virus and related risk factors among the Saudi population, two groups were investigated: 120 index patients with chronic liver disease and their 127 family contacts, and 220 blood donors who were anti-HCV-positive but with no chronic liver disease and their 91 family contacts. After a questionnaire on the risk factors for parenteral exposure, blood samples were obtained and tested for liver biochemistry and antibody to HCV (anti-HCV) by a third-generation enzyme immunoassay (UBI HCV HA4.0). Only two spouses of 20 index patients were anti-HCV-positive while the remaining 125 family contacts were anti-HCV-negative. None of the 91 family contacts of the 20 anti-HCV-positive blood donors was anti-HCV-positive. The two spouses were wives of index patients but had a history of blood transfusion on at least two different occasions. Our results clearly indicate the intrafamilial transmission of HCV is not the route of transmission of HCV among Saudis and our results argue against sexual transmission of hepatitis C virus despite a relatively long duration of marriage.     

Antibody to hepatitis C virus in patients with chronic schistosomiasis.

To clarify the effect of hepatitis C virus (HCV) infection in patients with chronic schistosomiasis, 96 patients with schistosomiasis and 137 patients with chronic liver disease without schistosomal infection were analysed by domination of antibody to HCV (anti-HCV). In 45 of 96 schistosomiasis patients, the serum alanine aminotransferase (ALT) level was continuously elevated, and the positive rate of anti-HCV was 52.9%, which is almost the same prevalence rate as in patients with chronic liver disease (48.9%). In contrast, in the remaining 51 schistosomiasis patients, serum ALT level was continuously within the normal range and the positive rate of anti-HCV was 0%. Histological investigation showed that the positive rate of anti-HCV in HBsAg-negative schistosomiasis patients was 14% for hepatic fibrosis, 71% for chronic hepatitis, 80% for liver cirrhosis and 56% for hepatocellular carcinoma. In all anti-HCV-positive patients, serum ALT level was continuously elevated. The serum transaminase levels in anti-HCV-positive patients were higher than those in anti-HCV-negative patients. These data suggest that in patients with chronic schistosomiasis, HCV infection accelerates the derangement of liver function, and may be a major aetiological factor in the development of chronic hepatitis and liver cirrhosis, supporting a causative association between HCV infection and hepatocellular carcinoma.     

Molecular evidence that the hepatitis C virus replicates in the oral mucosa

BACKGROUND/AIMS: Patients infected with the hepatitis C virus (HCV) often have extrahepatic manifestations, which significantly contribute to HCV-related morbidity, but whose pathogenesis is largely unknown. Our aim was to evaluate the HCV replication in oral mucosa of chronic hepatitis C patients. METHODS: We collected oral mucosa specimens from 17 anti-HCV-positive and four anti-HCV-negative patients. Fifteen had oral lichen (12 anti-HCV-positive). Total mucosa RNA was extracted and analyzed for presence and titer of genomic and negative-strand HCV RNA. Findings were compared with clinical and pathological features. RESULTS: Genomic and negative-strand HCV RNA were detected, respectively, in 12 of 17 (70.6%) and four of 17 (23.5%) specimens from the chronic hepatitis C patients. No negative-strand HCV RNA was detected in five anti-HCV-positive patients without lichen (including three with normal mucosa). Presence and titer of the negative-strand HCV RNA were independent of HCV genotype, serum viral load, and histological diagnosis of liver lesions. The phylogenetic analysis of the envelope 2 region cloned from a normal mucosa and the corresponding serum further suggested that only lichen tissues appear to harbor replicating HCV. CONCLUSIONS: HCV may occasionally replicate in oral lichen tissue, possibly contributing to the pathogenesis of mucosa damage.     

Hepatitis C virus viremia increases the incidence of chronic kidney disease in HIV-infected patients

BACKGROUND:: Several studies have reported on an association between hepatitis C virus (HCV) antibody status and the development of chronic kidney disease (CKD), but the role of HCV viremia and genotype are not well defined. METHODS:: Patients with at least three serum creatinine measurements after 1 January 2004 and known HCV antibody status were included. Baseline was defined as the first eligible estimated glomerular filtration rate (eGFR) (Cockcroft-Gault equation), and CKD was either a confirmed (>3 months apart) eGFR of 60?ml/min per 1.73?m or less for patients with a baseline eGFR more than 60?ml/min per 1.73?m or a confirmed 25% decline in eGFR for patients with a baseline eGFR of 60?ml/min per 1.73?m or less. Incidence rates of CKD were compared between HCV groups (anti-HCV-negative, anti-HCV-positive with or without viremia) using Poisson regression. RESULTS:: Of 8235 patients with known anti-HCV status, 2052 (24.9%) were anti-HCV-positive of whom 983 (47.9%) were HCV-RNA-positive, 193 (9.4%) HCV-RNA-negative and 876 (42.7%) had unknown HCV-RNA. At baseline, the median eGFR was 97.6 (interquartile range 83.8-113.0) ml/min per 1.73?m. During 36123 person-years of follow-up (PYFU), 495 patients progressed to CKD (6.0%) with an incidence rate of 14.5 per 1000 PYFU (95% confidence interval 12.5-14.9). In a multivariate Poisson model, patients who were anti-HCV-positive with HCV viremia had a higher incidence rate of CKD, whereas patients with cleared HCV infection had a similar incidence rate of CKD compared with anti-HCV-negative patients. There was no association between CKD and HCV genotype. CONCLUSION:: Compared with HIV-monoinfected patients, HIV-positive patients with chronic rather than cleared HCV infection were at increased risk of developing CKD, suggesting a contribution from active HCV infection toward the pathogenesis of CKD.     

Antibody to Hepatitis C Is Common among Patients with Alcoholic Liver Disease with and without Risk Factors

Thirty-seven patients with clinically suspected alcoholic liver disease were retrospectively studied for the prevalence of antibody to hepatitis C virus (HCV) by enzyme-linked immunosorbent assay (ELISA) and immunoblot assay. Twenty-four had biopsy-proven cirrhosis. Nineteen had identifiable risk factors for non-A, non-B viral hepatitis, and 18 did not. Five of 19 high-risk (26%) and 6 of 18 low-risk (33%) patients had positive antibody, compared with two of 179 healthy blood donors (p less than 0.01 for either group of alcoholics compared with blood donors). Nine of 11 ELISA-positive patients were also either positive or indeterminable by immunoblot testing. Histologic scores for parameters commonly associated with chronic viral hepatitis were numerically worse among anti-HCV-positive patients, but none reached statistical significance. Clinically, seven of 11 (64%) of anti-HCV-positive patients versus 14 of 26 (54%) anti-HCV-negative patients were Child's class C. Among the 21 Child's class C patients, seven (33%) were anti-HCV-positive versus four of 16 (25%) of Child's class A/B patients. A weak correlation between IgG and ELISA optical density was observed (r = 0.52). We conclude that antibody to hepatitis C by ELISA and immunoblot is common among alcoholics with liver disease even in the absence of known or suspected risk factors for viral hepatitis. Although hepatitis C-positive patients tended to have more severe histologic disease, neither histologic parameters nor clinical findings were adequate to predict antibody seropositivity.     

Assessment of long-term outcomes of community-acquired hepatitis C infection in a cohort with sera stored from 1971 to 1975

The aim of this study was to examine the long-term effects of hepatitis C virus (HCV) infection on a cohort of patients admitted with acute viral hepatitis from 1971 through 1975. The availability of stored sera from this time enabled testing to identify those who were anti-HCV-positive on admission. Sixteen percent (n = 238) of the cohort tested anti-HCV-positive. The unexposed group was selected from those who were anti-HCV-negative. Systematic approaches were used to locate the cohort and health outcomes assessed by a study-specific questionnaire and clinical, serological, virological, and biochemical assessment. Complete follow-up was achieved on 98 anti-HCV-positive individuals and 201 negatives. Injecting drug use (IDU) was the presumed route of infection. At a mean of 25 years' follow-up, 54% of the anti-HCV-positive group had evidence of chronic HCV infection (both anti-HCV- and HCV-RNA-positive); the remainder were HCV-RNA-negative. Sixty-nine percent of those chronically infected had elevated serum alanine transaminase (ALT) levels, but only 8% had progressed to overt cirrhosis, and no cases of hepatocellular carcinoma (HCC) were identified. In summary, anti-HCV-positive subjects were 8 times more likely to have died from suicide or drug overdose than from HCV-related disease. Anti-HCV-positive study subjects were at increased risk of liver-related pathology after 25 years' follow-up, but few had progressed to overt cirrhotic liver disease. Excess mortality in this group was not the result of liver disease. This suggests that the natural history of community-acquired HCV may be more benign than previously thought.     

Hepatitis C virus-related chronic liver disease with autoantibodies to liver-kidney microsomes (LKM). Clinical characterization from idiopathic LKM-positive disorders.

This study was carried out on 33 patients who were sero-positive for liver-kidney microsomal antibodies (LKM) in order to examine clinical features and the presence of underlying hepatitis C virus infection. Twenty-four sera were positive for antibodies against HCV (anti-HCV) as detected by enzyme immunoassay and confirmed by recombinant immunoblot assay. These patients had chronic liver disease and the majority of those treated with interferon responded favourably. Three of the nine anti-HCV-negative patients had idiopathic chronic hepatitis and two responded favourably to steroids. Two patients were diagnosed as having toxic hepatitis and the other four had various extrahepatic disorders without evidence of liver involvement. The immunoblotting analysis showed reactivity with a 50 kDa microsomal protein which presumably corresponded to cytochrome P-450 db1 both in anti-HCV-positive and -negative sera. In addition a few anti-HCV-positive sera also reacted with a 35 kDa microsomal antigen. Autoimmune markers different from LKM were absent in both groups. The high prevalence of antibodies to the hepatitis C virus among LKM-positive sera confirms that this infection plays a role in forms of chronic hepatitis that had previously been labelled autoimmune. In patients with LKM the presence of anti-HCV may help to forecast a therapeutic response to interferon, while its absence may forecast response to steroid therapy.     

Hepatitis C virus (HCV) genotypes and chronic liver disease in Pakistan

Hepatitis C virus (HCV) is classified into different types depending on nucleotide sequence variability. Detailed information on the distribution of various HCV genotypes in some geographical areas is available but little is known about Pakistan. In this study, a 5’ non-coding region (NCR)-based restriction fragment length polymorphism (RFLP) genotyping assay was used to investigate the genotype distribution in a large series of HCV-infected patients in Karachi, Pakistan. Serum samples from 74 hepatitis B surface antigen (HBsAg)-negative patients with a clinical diagnosis of chronic liver disease (60 patients) and hepatocellular carcinoma (HCC) (14 patients) were assayed for anti-HCV antibody by second generation enzyme immunoassay and 48 were confirmed anti-HCV-positive (33 males, 15 females). Other causes of chronic liver disease (e.g. haemochromatosis, Wilson's disease and immunemediated injury) were ruled out. Liver biopsy was done in 27/48 anti-HCV-positive patients and in all HCC patients. Genotypes were determined for 45/48 anti-HCV-positive study patients; 39/45 (87%) were type 3; four (9%) were type 1; one was type 2; and one was type 5. Past blood transfusion was the main identifiable risk factor found in 10 patients, all type 3. Seven of the 14 HCC patients were anti-HCV positive, (six were type 3). Most patients with hepatitis C presented with established cirrhosis and complications of portal hypertension and liver failure. In conclusion: (i) genotype 3 is the most common isolate in HCV-associated chronic liver disease in Pakistan; (ii) a significant proportion of HBsAg-negative cirrhotics are non-B, non-C in aetiology; and (iii) half of the patients with HCC have serological evidence of HCV infection.     

Hepatitis G virus infection in haemodialysis patients and its relationship with hepatitis C virus RNA positivity

A novel RNA virus designated hepatitis G virus (HGV) was identified recently in patients with acute and chronic liver disease. Since HGV may be transmitted parenterally, chronic haemodialysis (HD) patients are at increased risk for acquiring this infection. 110 chronic HD patients were studied (56 HCV-RNA and anti-HCV-positive, and 54 HCV-RNA and anti-HCV-negative). HGV-RNA and HCV-RNA were studied by RT-PCR. HCV genotype determination was applied to all 56 HCV-RNA-positive patients. 28 of 110 (25%) patients were found be HGV-RNA-positive. HCV-RNA-positive patients had higher rate of HGV-RNA positivity compared with HCV-RNA-negative patients. The HCV genotypes of HGV-RNA-positive patients were mostly 4 (48%) and 1b (33%). HGV was not linked with HBsAg positivity. While there was a significant correlation between HCV-RNA positivity and the number of blood transfusions and duration of HD, we did not observe this relationship in HGV-RNA-positive patients. These results indicate that the prevalence of HGV is high in HD patients and that HGV-RNA positivity is higher in HCV-RNA-positive patients.     

HCV genotypes in patients with liver disease of different stages and severity

Aims/Material: Hepatitis C virus (HCV) genotyping was performed in 213 anti-HCV-positive patients with chronic liver disease ranging from minimal histological changes to hepatocellular carcinoma. One hundred and twenty-two patients had non-cirrhotic chronic active or persistent hepatitis (including 29 who were asymptomatic with persistently normal ALT levels) (chronic liver disease group). The other 91 had hepatocellular carcinoma and, in all but three cases, cirrhosis (hepatocellular carcinoma group).Results: The overall prevalence of HCV variants was: 54.9% type 1b, 37.8% type 2, 2.5% type 1a, 2.0% type 3a, 2.0% type 4a. The genotype distribution showed no relation to the stage (chronic liver disease vs. hepatocellular carcinoma) or severity (chronic active vs. chronic persistent hepatitis) of the liver disease, or to the duration of the disease (<10 years vs. >10 years). Within the hepatocellular carcinoma group, the duration of type-1b disease was similar to that of type-2 infections. Ages at the time of infection and genotype were both independently associated with progression to cirrhosis and hepatocellular carcinoma, but multivariate analysis revealed that the effect of age was much stronger than that of genotype 1b.Conclusions: The predominance of HCV type 1b in this study reflects the higher frequency of this variant in our area. Our findings indicate that infections caused by each HCV genotype are capable of progressing to hepatocellular carcinoma.     

A comparison of hepatitis C virus (HCV) RNA and – antibody as markers of infection and predictors of infectivity

Background: The diagnosis of hepatitis C virus (HCV) infection currently relies on the detection of antibody to HCV (anti-HCV). However, anti-HCV positivity may indicate past infection, current infection or possibly non-specific reactivity. For confirmation of current infection the virus needs to be assayed directly and this is possible by the polymerase chain reaction (PCR). Aims: The aims were to compare HCV RNA and anti-HCV as markers of infection in two groups of individuals: (i) a heterogeneous group with suspected HCV infection and (ii) a small group of blood and bone marrow donors, and their respective recipients. Methods: Serum samples were tested for alanine aminotransferase (ALT) as part of a liver function screen, for anti-HCV by ELISAII, and HCV RNA was detected by PCR. Single round and nested PCR was performed using primers designed from the sequence of the 5′-untranslated region of the HCV genome. Results: Of the 36 subjects in the heterogeneous group, 19/22 anti-HCV-positive patients with chronic non-A non-B hepatitis (NANBH) were viraemic, and the majority (17/19) demonstrated elevated ALT. However, HCV RNA was undetected in seven anti-HCV-positive patients, four of whom suffered autoimmune hepatitis Type I and three were low risk blood donors. Of the remaining subjects (seven/36) who were anti-HCV-negative, three/seven were HCV-RNA-positive and included two with acute post-transfusion (PT) NANBH and a recent needlestick victim who contracted HCV. In the second group, four individuals (donors), including a mother with a history of drug use, were implicated in transmission to three recipients. ALT levels were normal in all donors but raised in two of the recipients. PCR determined which of two anti-HCV-negative blood donors was infectious, confirmed transmission between a bone marrow donor and recipient, and indicated that anti-HCV detected in a newborn child represented passive transfer of antibody. Conclusions: Anti-HCV detected by ELISA II is a useful marker of chronic HCV infection, particularly in association with raised ALT. However, HCV RNA is a superior marker of acute HCV infection, a more reliable predictor of infectivity and is more specific.     

HCV RNA in serum of asymptomatic blood donors involved in post-transfusion hepatitis (PTH).

A group of blood donors involved in post-transfusion hepatitis was investigated for the presence of the anti-HCV antibody and of HCV RNA as a more direct infection marker. RNA was extracted from serum, reverse transcribed and amplified using primers which belonged to the non structural region. The amplified product of the PCR reaction was 582 base pairs. Seven (25.9%) of the 27 blood donors examined were found anti-HCV-positive by ELISA; five (71.4%) of these were HCV RNA positive. Among the 20 anti-HCV-negative blood donors, four (20.0%) were HCV RNA positive. ALT levels were below 45 UI/l in 18 donors, while the other nine had ALTs over the limit accepted for transfusion. The anti-HCV-negative HCV RNA-positive blood donors had normal ALTs. Our study offers a direct explanation for the substantial proportion of residual cases of anti-HCV-positive post-transfusion hepatitis and suggests the necessity of creating a register of blood donors who have at some time presented blood enzyme abnormalities and for whom second level investigations such as HCV RNA should be used.     

Hepatitis A virus infection suppresses hepatitis C virus replication and may lead to clearance of HCV

BACKGROUND/AIMS: The significance of hepatitis A virus (HAV) super-infection in patients with chronic hepatitis C had been a matter of debate. While some studies suggested an incidence of fulminant hepatitis A of up to 35%, this could not be confirmed by others. METHODS: We identified 17 anti-HCV-positive patients with acute hepatitis A from a cohort of 3170 anti-HCV-positive patients recruited at a single center over a period of 12 years. RESULTS: Importantly, none of the anti-HCV-positive patients had a fulminant course of hepatitis A. HCV-RNA was detected by PCR in 84% of the anti-HCV-positive/anti-HAV-IgM-negative patients but only in 65% of anti-HCV-positive patients with acute hepatitis A (p=0.03), indicating suppression of HCV replication during hepatitis A. Previous HAV infection had no effect on HCV replication. After recovery from hepatitis A, an increased HCV replication could be demonstrated for 6 out of 9 patients with serial quantitative HCV-RNA values available while 2 patients remained HCV-RNA negative after clearance of HAV throughout follow-up of at least 2 years. CONCLUSIONS: HAV super-infection is associated with decreased HCV-RNA replication which may lead to recovery from HCV in some individuals. Fulminant hepatitis A is not frequent in patients with chronic hepatitis C recruited at a tertiary referral center.     

Superinfection with hepatitis C virus in patients with symptomatic chronic hepatitis B.

11/323 patients (3.4%) with symptomatic chronic hepatitis B were positive for antibody to hepatitis C virus (anti-HCV). The positive rate of anti-HCV in patients with serum alanine aminotransferase (ALT) levels greater than 200 U/l (n = 219) did not exceed that of the patients with ALT less than or equal to 200 U/l (n = 104) (2.7% vs. 4.8%). Of the 219 patients who were positive for hepatitis B e antigen (HBeAg) and/or hepatitis B virus-DNA (HBV-DNA), 5 (2.3%) had anti-HCV, while 6/104 patients (5.8%) who were positive for antibody to HBeAg (anti-HBe) had anti-HCV (p greater than 0.1). In contrast to the anti-HCV-negative patients, the patients with anti-HCV had a higher percentage of cirrhosis in their liver histological findings (36.4% vs 5.4%, p less than 0.005). In conclusion, the prevalence of HCV superinfection in symptomatic chronic hepatitis B patients is low and HCV superinfection is not an important factor in acute exacerbation of chronic hepatitis B. However, the superinfection with HCV may exacerbate the existing liver disease and accelerate its progression.