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Viral hepatitis: how to manage type C and D infections.

Hepatitis C and D are relative newcomers to the study of viral hepatitis. Their transmission is mainly parenteral. The 0.5 to 2.2% prevalence of hepatitis C in the United States does not vary by patient age. Often, hepatitis C is asymptomatic. In older patients, symptomatic infection has a cholesteatic appearance, and progress to chronic hepatitis and cirrhosis is more rapid than in younger adults. Hepatitis D virus is a defective single-stranded RNA that presents as a co-infection or superinfection of hepatitis B. Prevalence varies by geographic region. The rate of progression to chronic disease and cirrhosis is high in superinfection.

Acute Disease↗

Alpha-interferon therapy in chronic hepatitis due to active dual infection with hepatitis B and C viruses.

BACKGROUND: Nearly 14% of non-alcoholic chronic liver disease in India is related to hepatitis B virus (HBV) and hepatitis C virus (HCV) dual infection. There are no clear data available from the literature on the therapeutic management of these patients who often suffer an unfavourable course. METHODS: Fourteen consecutive cases of biopsy-proven chronic liver disease fulfilling the following criteria were included: Child's A or B liver disease, hepatitis B surface antigen positive, HBV-DNA positive, antibody to HCV positive and HCV-RNA positive. Seven patients had chronic liver disease (group I), while the remaining seven patients (group II) had additional disorders (non-Hodgkin's lymphoma (two), acute leukaemia (two), thalassaemia (two), chronic renal failure (one). Interferon alpha-2b (IFN) was given in a dose of 6 MIU thrice weekly for 6 months. Complete response was defined as loss of HBV-DNA and HCV-RNA at 6 months and sustained response (SR) as the sustained loss of HBV-DNA and HCV-RNA for more than 6 months during the follow-up period. RESULTS: At the end of 6 months, alanine aminotransferase (ALT) levels remained unchanged (120 +/- 40 vs 136 +/- 64 IU/L), but six of the seven (86%) patients in group I lost HBV-DNA. All three hepatitis Be antigen (HBeAg)-positive patients lost HBeAg with an early flare of ALT (at 45 +/- 12 therapy days). Two of these patients (29%) lost HCV-RNA. Thus, SR was seen in 29%, while HBV-DNA loss was found in 100% during the follow-up period. In group II patients, there was a significant decrease in ALT (308 +/- 14 vs 65 +/- 25 IU/L, P < 0.001), but only three (43%) patients lost HBV-DNA and two (29%) lost HCV-RNA. One patient with acute leukaemia and another with renal failure had a complete response to IFN, but none of the lymphoma patients showed any antiviral response. CONCLUSIONS: In chronic hepatitis due to dual infection with HBV and HCV, interferon therapy is: (i) safe; (ii) effective (more so in clearing HBV); (iii) often associated with early ALT flare; and (iv) may be less effective if non-Hodgkin's lymphoma is present.

Adult↗

Role of CD4+ and CD8+ T cells in mouse hepatitis virus infection in mice.

Viral growth and histopathological changes in the liver after intraperitoneal infection with mouse hepatitis virus, strain JHM were compared among normal C57BL/6 mice, those depleted of CD4+ T cells, CD8+ T cells and both T cell subsets. Viral growth in mice depleted of CD4+ T cells increased slightly, but pathological changes resembled those in normal mice. In contrast, the hepatitis was exacerbated in mice depleted of CD8+ T cells and those depleted of both T cell subsets. These results suggest that CD8+ T cells play a key role although both T cell subsets are involved in protection against mouse hepatitis virus infection in mice.

Animals↗

Antiamoebic activity of 3,3'-fluro-4,4'-di-(pyrrolidine-2-ylidene amino)-diphenyl (liroldine), against experimentally infected intestinal and hepatic amoebiasis.

HL 707, Liroldine, a novel synthetic compound, was found effective against both extraintestinal and intestinal amoebiasis in animal models. Its activity against hepatic infection in golden hamsters is comparable with that of different derivatives of nitroimidazoles used for human treatment. Against intestinal amoebiasis in Wistar rats, the activity was superior to nitroimidazoles and chloroquine. Paramomycin was comparable and diloxanide furoate was marginally superior. The comparative in vitro and in vivo studies with standard marketed drugs and Liroldine indicate an excellent profile of the compound against experimental amoebiasis. LD50 of Liroldine determined in mice is 910 mg/kg x 1, po and 940 mg/kg x 1 ip).

Amebiasis↗

Infected solitary hepatic cyst.

An unusual case involving an infected hepatic cyst in which the correct diagnosis was made without operation is reported. A 93-year-old woman presented with acute onset of right upper quadrant abdominal pain, mild left lower quadrant abdominal pain, diarrhea, and fever. On admission, computed tomography revealed a 15 cm solitary hepatic cyst in the anterior-superior segment of the liver with a thickened wall that enhanced with contrast media. Ultrasonography demonstrated a 15 cm anechoic lesion with a hypoechoic area in the dependent portion of the cyst and a thickened wall. The serum concentration of C-reactive protein was 24.3 mg/dL, and the white blood cell count was 13,800/microL. A diagnosis of infected hepatic cyst was suspected, and percutaneous transhepatic drainage of the cyst was performed. Milky yellow fluid was obtained and the patient's right upper quadrant abdominal pain resolved after drainage. Klebsiella pneumoniae was cultured from the drainage fluid. The patient was discharged 20 days after drainage. Infection has not recurred and the hepatic cyst has not enlarged after 18 months.

Aged↗

Lack of intrafamilial transmission of hepatitis C virus in family members of children with chronic hepatitis c infection.

Intrafamilial transmission of hepatitis C virus (HCV) was studied in family members of 44 children with chronic hepatitis C infection (index cases). There were 22 males and the mean age of all patients was 9.5 years (range, 1.5 to 16 years). Eleven index patients were multitransfused because of thalassemia major. Aminotransferase serum concentrations and anti-HCV antibodies were evaluated in 77 parents (38 fathers) and 56 siblings (28 males; mean age, 11.2 years; range, 2.5 to 18 years). No sibling showed evidence of liver disease or HCV infection. Eight parents (14%) were found to be anti-HCV positive, but only one of them acquired HCV infection from an index case through an accidental needle stick injury. A nonsexual person-to-person transmission of HCV was conceivable only in a girl (index case) who had no risk factor other than the contact with anti-HCV-positive father. Vertical transmission played a role in five children (index cases) (three males) from five different mothers. Among the eight children belonging to these mothers, three did not show evidence of HCV infection although born after their HCV-infected siblings. Furthermore, we have not identified factors related to activity of disease or to duration of contact with index cases or to peculiar features of family members capable of favoring the spreading of HCV infection. Different from hepatitis b, pediatric age does not seem to represent a reservoir for HCV infection since the majority of children acquired HCV infection through parenteral routes and no HCV-infected child transmitted HCV infection horizontally.

Adolescent↗

Temporal pathogenesis of experimental neonatal woodchuck hepatitis virus infection: increased initial viral load and decreased severity of acute hepatitis during the development of chronic viral infection.

Acute hepatitis B virus (HBV) infections either resolve or progress to chronicity. Identification of early deviations in host-virus responses associated with these outcomes can further differentiate cause-effect mechanisms that initiate and maintain chronicity. Neonatal woodchucks were infected experimentally with the woodchuck hepatitis virus (WHV) at 3 days of age. At 8 or 14 weeks of age (i.e. , the early- or mid-acute stage of infection), whole blood and large surgical biopsies of the liver were obtained from infected animals and uninfected controls. These were stored for later correlating histopathologic responses and viral load with the subsequently determined outcome of infection. As of 1 year postinfection, half of the surgically treated infected woodchucks had developed self-limited infections, while the other half developed chronic infections. The self-limited outcome was characterized by decreased viral load in acute-phase liver and plasma and a generally robust acute hepatic inflammatory response. Comparisons at the same early time points revealed that the chronic outcome was characterized by increasing initial viral load in liver and plasma, and a detectable, but diminished, acute hepatic inflammation. These cotemporal comparisons indicate that there is an early host-response deviation during the acute phase of a developing chronic infection. Continued analysis of the tissues banked from this study will facilitate further temporal characterization of acute-phase mechanisms that determine resolution versus chronicity in WHV infection. Understanding such mechanisms may be useful in the rational design of therapy for established chronic HBV infection.

Acute Disease↗

Combination therapy with lamivudine and adenovirus causes transient suppression of chronic woodchuck hepatitis virus infections.

Treatment of hepatitis B virus carriers with the nucleoside analog lamivudine suppresses virus replication. However, rather than completely eliminating the virus, long-term treatment often ends in the outgrowth of drug-resistant variants. Using woodchucks chronically infected with woodchuck hepatitis virus (WHV), we investigated the consequences of combining lamivudine treatment with immunotherapy mediated by an adenovirus superinfection. Eight infected woodchucks were treated with lamivudine and four were infected with approximately 10(13) particles of an adenovirus type 5 vector expressing beta-galactosidase. Serum samples and liver biopsies collected following the combination therapy revealed a 10- to 20-fold reduction in DNA replication intermediates in three of four woodchucks at 2 weeks after adenovirus infection. At the same time, covalently closed circular DNA (cccDNA) and viral mRNA levels both declined about two- to threefold in those woodchucks, while mRNA levels for gamma interferon and tumor necrosis factor alpha as well as for the T-cell markers CD4 and CD8 were elevated about twofold. Recovery from adenovirus infection was marked by elevation of sorbitol dehydrogenase, a marker for hepatocyte necrosis, as well as an 8- to 10-fold increase in expression of proliferating cell nuclear antigen, a marker for DNA synthesis, indicating significant hepatocyte turnover. The fact that replicative DNA levels declined more than cccDNA and mRNA levels following adenovirus infection suggests that the former decline either was cytokine induced or reflects instability of replicative DNA in regenerating hepatocytes. Virus titers in all four woodchucks were only transiently suppressed, suggesting that the effect of combination therapy is transient and, at least under the conditions used, does not cure chronic WHV infections.

Adenoviridae↗

Control of HBV and HDV infection in an isolated Pacific Island: 1. Pattern of infection.

Hepatitis B virus (HBV) and hepatitis delta virus (HDV) infections are known to be hyperendemic in Nauru. Because of the consequences of chronic HBV infection, the Nauruan Government has commenced a program that aims to reduce and eventually eliminate hepatitis B infection by immunizing susceptible adults and children on the island and every newborn baby. At the outset of this program, a national seroepidemiological survey was undertaken. Eighty-eight percent of the population were tested, of whom 69.1% had markers of HBV infection. Evidence of superinfection with HDV was found in 22.7% of HBV carriers, with the highest prevalence in adolescents and young adults. All seronegative individuals were offered three doses of plasma derived hepatitis B vaccine. A post-vaccination survey of 64% of those vaccinated showed that 98% had developed circulating antibodies.

Adolescent↗

Hepatocarcinogenesis in viral Hepatitis B infection: the role of HBx and p53.

Infection of Hepatitis B Virus (HBV) is a risk factor of chronic active hepatitis (CAH), hepatic cirrhosis and hepatocellular carcinoma (HCC). Infection of HBV may develop to HCC without antecedent hepatic cirrhosis. Pathogenesis of HBV causing malignant changes has not been fully understood. HBx, a protein of HBV, is an activator of transcription process involved in hepatocarcinogenesis. Most of human cancer associated with mutation of p53, a Tumor Suppressor Genes, a protein serves as cellular protection for growth and cell division, which is one of predisposition factor of hepatocarcinoma. Some studies indicate the correlation between mutation / inactivation of p53 and HBV protein x (HBx) in hepatocarcinogenesis. In that process, HBx will suppress p53 function, which will lead to ineffective liver cell division and resulting in HCC.

Carcinoma, Hepatocellular↗

Severe hepatitis C infection in a renal transplant recipient following hepatitis C genotype mismatch transplant.

We report a case of a 32-year-old female with histologically and clinically inactive chronic hepatic C infection, who received a cadaveric renal transplant from a hepatitis C-positive donor with a different genotype. The genotype mismatch (genotype 1 to genotype 2) and change to tacrolimus-based immunosuppression resulted in severe hepatitis C infection characterized by a 10-fold increase in transaminase levels and grade 3 inflammation histologically. Our report highlights the risk of genotype-mismatch transplants in solid organ transplantation.

Adult↗

[Seroprevalence of delta virus and hepatitis C virus in patients with chronic infection with hepatitis B virus].

OBJECTIVE: To study the prevalence of hepatitis delta and hepatitis C viruses (HDV and HCV) in patients infected with hepatitis B virus (HBV) with and without risk behaviors for the infection by these viruses and by the human immunodeficiency virus (HIV). MATERIALS AND METHODS: Clinical and serological study (January 1990-December 1992) at Medicine Service at Galdacano Hospital of 109 patients with positive hepatitis B surface antigen and without clinical or serological evidence of acute hepatitis, 60 without risk behaviors for the infection, 45 parenteral drug abusers (PDA) and 4 homosexual males. RESULTS: Chronic HDV infection was observed in 60% of PDA and more frequently among HIV-positive patients (p < 0.05). In six of these patients the serological determination of HDV-Ag was positive. Chronic HDV and HCV infection rates in patients without risk behaviors were 1.6% and 16%, respectively. Eighty-eight percent of PDA had anti-HCV; no differences were observed between HIV-positive and HIV-negative patients (p = 0.64). CONCLUSIONS: HDV was particularly associated with parenteral drug abuse, with a similar prevalence to other surveys conducted in Spain. The higher frequency of HDV and HDV-Ag among HIV-positive patients could indicate a greater susceptibility to HDV in clinical conditions associated with immunosuppression. HCV infection occurs at early stages and is common among PDA infected with HBV, with no apparent association with patient's age, years of drug abuse or HIV infection.

Adolescent↗

Cell-mediated immune response to liver tissue antigen and hepatitis B surface antigen after infection with hepatitis B virus in humans.

The in vitro correlates of cell-mediated immunity to liver tissue antigens and hepatitis B surface antigen (HBsAg) were studied in groups of subjects with acute and chronic hepatitis B virus (HBV) infection and in a population of HBV-seronegative controls. The technique of in vitro lymphocyte transformation (LTF) was employed in these studies. No LTF response to liver-specific antigen and HBsAg was observed in the control population. LTF activity in response to HBsAg was present in 11 of the 14 subjects with acute type B viral hepatitis during the early phase of the disease, and eight of these subjects also had LTF reactivity to liver antigen. During the convalescent phase the LTF reactivity to these antigens usually disappeared. More than 70% of patients with chronic carriage of HBsAg who had elevated levels of liver enzymes showed LTF responses to HBsAg, and a significant number of these subjects also exhibited LTF response to liver-specific antigen. On the other hand, chronic HBsAg carriers who persistently showed normal liver enzyme values (asymptomatic carriers) failed to show significant responses to liver antigen or HBsAg. It is suggested that the persistence of cellular reactivity to liver antigens may lead to the establishment of chronic liver disease.

Acute Disease↗

Effect of tumour necrosis factor alpha antagonists on serum transaminases and viraemia in patients with rheumatoid arthritis and chronic hepatitis C infection.

BACKGROUND: Tumour necrosis factor alpha (TNF alpha) antagonists are effective for the treatment of rheumatoid arthritis (RA), but concerns remain about the safety of these agents in the presence of chronic infections, including hepatitis C virus (HCV) infection. OBJECTIVE: To examine the influence of treatment with TNF alpha antagonists on levels of HCV viraemia and serum transaminases in patients with RA and HCV. METHODS: In a retrospective survey the course of 16 HCV infected patients with RA who had received the TNF alpha antagonists etanercept or infliximab was analysed. Eight additional patients with RA and HCV were also enrolled into a three month prospective trial of etanercept. Serum concentrations of albumin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and HCV were followed. RESULTS: Viraemia was measured in 22 patients receiving a TNF alpha antagonist at the start of treatment and after 1-34 months (median 9 months follow up). Twenty four patients had serial tests of liver related enzymes and albumin. None of the differences between liver related tests at baseline and at follow up achieved significance (p>0.05). Similarly, the mean HCV measurement at 1-3, 4-6, 7-12, and 13-34 months did not differ significantly from baseline (p>0.05). CONCLUSION: In this study, liver related blood tests and HCV viral load measurements did not change substantially. These findings suggest that TNF alpha antagonists merit further study for the treatment of RA in HCV infected patients. Larger and longer term studies are still needed.

Adult↗

Interferon-gamma-associated responses to woodchuck hepatitis virus infection in neonatal woodchucks and virus-infected hepatocytes.

Acute hepatitis and recovery from woodchuck hepatitis virus (WHV) infection involves increased intrahepatic expression of interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) mRNAs. In the present study, recovery correlated with increased intrahepatic expression of mRNAs for major histocompatibility complex class 1 (MHC1), beta(2)-microglobulin, 2'5'-oligoadenylate synthetase (2'5'-OAS), and indoleamine dioxygenase (IDO). By comparison, acute WHV infection progressing to chronicity was associated with diminished expression of these IFN-gamma-associated mRNAs in liver. Transfection of WHV-infected primary hepatocytes (WPH) from WHV carriers with an IFN-gamma-expressing plasmid (pIFN-gamma) resulted in dose-dependent accumulations of MHC1, TNF-alpha, 2'5'-OAS, and IDO mRNAs within 96 h. Markers of T cells and immune-mediated cytotoxicity that accumulate in recovering liver were not apparent in WPH based on the relative lack of CD3, CD4, Fas ligand, perforin, and granzyme B mRNAs. Expression of pIFN-gamma, and TNF-alpha-expressing plasmid (pTNF-alpha), did not affect total WHV RNA, or fully double-stranded WHV DNA in WPH, but each reduced some of the replicative intermediate (RI) species of WHV DNA synthesis. WPH treated with recombinant IFN-alpha protein had a higher fold induction of 2'5'-OAS mRNA associated with partial reductions in WHV RNAs and the major RI species. Thus, IFN-gamma expression in carrier WPH induced several host responses often observed in liver of recovering woodchucks, and impaired a stage of WHV DNA synthesis by a non-cytolytic mechanism mediated by TNF-alpha. Local enhancement of IFN-gamma-associated responses in chronic WHV-infected hepatocytes may promote therapeutic antiviral effects, but additional effector mechanisms evident during recovery appear necessary for more complete clearance of WHV infection.

2',5'-Oligoadenylate Synthetase↗

[Hepatitis virus infection and bone marrow transplantation].

Hepatitis virus infection is a special problem in China and the role of Hepatitis virus infection in allogeneic bone marrow transplantation (BMT) is not well-defined. In this study, 106 BMT patients were included for analysis of the role of virus infection in allo-BMT. Seven and 65 of 106 patients were found to have HBV infection and HCV infection, respectively. Neither HBV infection and HCV infection interfered with the engraftment of bone marrow cells nor increased the rate of AGVHD, CGVHD, VOID. Neither HBV infection nor HCV infection prohibited allo-BMT. But Hepatitis virus infection can cause mild to moderate liver dysfunction, even death because of acute liver function failure, active prevention and treatment of hepatitis virus infection remains necessary. In this respect, rh-interferon is useful.

Adolescent↗

Lamivudine treatment for fulminant hepatic failure due to acute exacerbation of chronic hepatitis B infection.

BACKGROUND: Exacerbation of chronic hepatitis B infection can lead to fulminant hepatic failure with a mortality of up to 90%. AIM: To evaluate the efficacy of lamivudine in the treatment of this subgroup of patients. METHODS: Twenty-four patients with exacerbation of chronic hepatitis B infection and fulminant hepatic failure were treated with lamivudine, 100 mg daily. Hepatitis A, C, D and human immunodeficiency virus co-infections and hepatocellular carcinoma were excluded. RESULTS: The median age was 53 years (range, 24-77 years) with a male predominance of 20:4. Seventeen patients were hepatitis B e antigen positive. Mean hepatitis B virus DNA was 2079 Meq/mL. Eight patients (33%) survived (group A). Thirteen patients died and three patients received liver transplantation (67%) (group B). Baseline laboratory results were comparable between the two groups, including serum albumin, bilirubin, alanine aminotransferase, prothrombin time and creatinine. Group B patients had significantly more comorbid illnesses at baseline and more complications, including sepsis and renal failure, compared with group A patients. Six out of eight survivors (75%) had full hepatitis B e antigen seroconversion, but this was not sustained in four patients. CONCLUSIONS: Lamivudine may be useful in treating patients with fulminant hepatic failure due to exacerbation of chronic hepatitis B. Hepatitis B e antigen seroconversion was less durable in this subgroup of patients and long-term therapy may be required.

Administration, Oral↗

Hepatitis C infection in risk groups.

Hepatitis C infection is important global health problem with wide spectrum of health, social and economic consequences. The goal of this research was to estimate prevalence of hepatitis C virus infection in risk groups, and to determine association hepatitis C virus (HCV) infection and risk factors. Research included 4627 subjects divided in two groups. Test group included 2627 subjects divided in 4 subgroups with risk for HCV infection: those who received blood transfusion without screening on HCV (it was introduced in 1995) (700); intravenous drug users (60); patients on hemodialysis (168) and health care workers (1699). Control group included 2000 healthy volunteer blood donors. In all subjects anti-HCV antibodies were tested with third generation ELISA test. Positive serum samples were tested for presence of HCVRNA, using reaction of reverse transcription and polymerase chain reaction. In all anti-HCV positive subjects further epidemiological and clinical workup was performed. Prevalence of HCV infection in risk groups was: 4.6% in subjects who have received blood transfusions without HCV blood screening, 35% in intravenous drug users, 58.9% in patients on chronic dialysis, and 0.4% in health care workers. In control group prevalence was low (0.2%). In the group of 158 anti-HCV positive subjects, 73.4% had HCVRNA. The largest number of subjects with HCV infection was in the age group of 30-49 years (45.8%). This study showed that multiple blood transfusions before introducing the blood screening for HCV, longer duration of intravenous drug abuse, longer duration of hemodialysis treatment, larger number of accidental injuries in health care workers are independent and statistically significant risk factors for those groups examined. Results of this study confirm that general screening for HCV infection is recommended in risk groups for HCV infection in order to identify to prevent and to treat it.

Adolescent↗