Hepatitis: Coffin CS

Coffin CS, Lee SS. · Liver Unit, University of Calgary, Calgary, AB, Canada. · Liver Int. · Pubmed #19207974 No free full text.

Abstract: The two main goals of hepatitis B therapy are durable viral suppression and avoidance of antiviral resistance. Recent treatment guidelines now recognize the importance of these treatment endpoints in the prevention of end-stage liver disease and hepatocellular carcinoma rather then other surrogate markers such as HBeAg seroconversion and serum alanine aminotransferase normalization, especially in patients who acquired hepatitis B virus infection early in life. A variety of therapeutic options are now available for the treatment of chronic hepatitis B infection, including four nucleos/tide analogues (i.e lamivudine, adefovir, entecavir and telbivudine), along with standard and pegylated interferon. Newer oral nucleos/tide analogues that include tenofovir, emtricitabine and clevudine are soon likely to be approved worldwide. Given the wide array of choices and the complex nature of chronic hepatitis B infection, selection of the appropriate therapeutic agent can be challenging for clinicians. Effective treatment decisions require an understanding of the natural history of hepatitis B and knowledge of its life cycle and molecular biology. This review includes the range of treatment options and criteria for determining when and how to most effectively intervene with antiviral therapy for chronically infected patients positive for the HBeAg.

Coffin CS, Terrault NA. · Department of Medicine, University of California at San Francisco, San Francisco, CA 94143, USA. · J Viral Hepat. · Pubmed #17958641 No free full text.

Abstract: Advances in hepatitis B virus (HBV) antiviral prophylaxis have dramatically improved graft and patient survival for patients undergoing liver transplantation for hepatitis B related end-stage liver disease. In particular, the availability of hepatitis B immune globulin (HBIg) in combination with nucleos(t)ide analogues such as lamivudine and adefovir, have transformed outcomes. The availability of newer antivirals such as adefovir, tenofovir and entecavir either as monotherapy or in combination offer an increasing number of antiviral options. Despite these advances, significant challenges remain. Factors that affect the efficacy of anti-viral therapy include detectable HBV viraemia at the time of transplant and emergence of HBV mutants (especially in patients with prior exposure to lamivudine). HBV prophylaxis protocols are expensive especially with use of high-dose HBIg and newer nucleos(t)ide analogues. This review summarizes current HBV prophylaxis protocols and management of recurrent disease post-transplantation. There is an increasing need for individualization of therapy based on prior drug exposures, level of HBV DNA at time of transplantation and type of prophylaxis used.

Coffin CS, Lee SS. · Liver Unit, Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada. · MedGenMed. · Pubmed #16915205 links to  free full text

Abstract: Hepatitis B virus (HBV) can cause both acute and chronic infection and is an important human pathogen, with an estimated 350 million individuals chronically infected worldwide. HBV carriers are at risk for the development of cirrhosis and hepatocellular carcinoma (HCC), and patients with chronic infection require life-long monitoring. Effective hepatitis B antiviral treatment is important given the significant associated global morbidity and mortality from liver-related complications. The goals of treatment are to achieve sustained suppression of HBV replication and remission of liver disease. In the past decade, great progress has been made in the treatment of chronic HBV infection. Interferon alfa, longer-acting pegylated interferon, and nucleos(t)ide analogs such as lamivudine, adefovir dipivoxil, and entecavir are currently available for treatment of HBV infection. Effective treatment decisions require an understanding of the natural history of hepatitis B and the range of treatment options. This review includes criteria for determining when and how to most effectively intervene with antiviral therapy for chronically infected patients.

Coffin CS, Mulrooney-Cousins PM, Lee SS, Michalak TI, Swain MG. · Liver Unit, Division of Gastroenterology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. · Liver Int. · Pubmed #17498260 No free full text.

Abstract: BACKGROUND: Hepatitis B virus (HBV) and hepatitis C virus (HCV) share similar transmission routes; thus, coinfection is frequent. The consequences of acute HBV infection in patients with chronic hepatitis C are unknown. METHODS: We describe a 47-year-old male with chronic hepatitis C who acquired HBV and then spontaneously and apparently completely cleared HCV but developed chronic hepatitis B. Five serum samples collected over 14 months and lymphoid cells obtained after acquiring HBV were tested for HCV and HBV by both standard assays and ultra-sensitive polymerase chain reaction/nucleic acid hybridization (PCR/NAH) (sensitivity approximately 2 IU/ml). RESULTS: After superinfection with HBV, HBV surface antigen-positive chronic hepatitis developed with readily detectable HBV DNA. All sera collected after acquisition of HBV, which tested negative for HCV RNA by standard laboratory assay, were positive for HCV genomes when analysed by PCR/NAH. Peripheral lymphoid cells carried HBV DNA and covalently closed circular DNA, but were negative for HCV. CONCLUSIONS: This is the first reported case of profound suppression of chronic hepatitis C after superinfection with HBV and establishment of chronic hepatitis B. It is hypothesized that HBV infection precipitated generalized and/or virus-specific cellular immune responses that profoundly suppressed HCV replication and yet failed to inhibit progression to chronic hepatitis B.

Coffin CS, Burak KW, Hart J, Gao ZH. · Department of Medicine, University of Calgary, Calgary, AB, Canada. · Mod Pathol. · Pubmed #16575397 links to  free full text

Abstract: We studied the impact of pathologist experience on liver transplant biopsy interpretation for cases designated 'nonspecific' by pathologists at a nontransplant center. Among 102 consecutive liver transplant biopsies from 92 patients performed at the Foothills Medical Center, 30 liver biopsies from 23 patients were designated 'nonspecific' by the local pathologist. These biopsy slides were independently reviewed by an expert in liver transplant pathology at a major US transplant center. The expert pathologist was given only the information on the original requisition. In seven biopsies from five patients, there was full agreement between the external expert and the local pathologist. In 10 biopsies from six patients, the expert concurred with the initial assessment but emphasized critical negatives such as 'no evidence of rejection or recurrent hepatitis'. A discrepant diagnosis was found in 13 biopsies from 12 patients. In five biopsies from four patients, the revised diagnoses were inaccurate due to insufficient or misleading clinical information on the requisition. In eight biopsies from eight patients, the revised diagnoses were proven to be correct by clinicopathologic correlation. Our study shows that pathology expertise helped to clarify the diagnosis in about 27% of cases, which justifies the cost of obtaining a second opinion in difficult biopsies. Misinterpretation by the expert pathologist in up to 17% of biopsies highlights the importance of direct communication between hepatologist and pathologist in order to achieve a correct diagnosis. Familiarity with those cases with relatively uncommon histology, a diligent search for subtle morphologic changes, and use of standard terminology could improve the quality of liver transplant biopsy interpretation in a nontransplant center.

Pham TN, Macparland SA, Coffin CS, Lee SS, Bursey FR, Michalak TI. · Molecular Virology and Hepatology Research, Division of Basic Medical Science, Faculty of Medicine, Health Sciences Centre, Memorial University, St John's, Newfoundland, Canada A1B 3V6. · J Gen Virol. · Pubmed #15722526 links to  free full text

Abstract: Considering growing evidence indicating that hepatitis C virus (HCV) replicates in lymphoid cells, establishment of a reliable and sensitive method for detection of HCV in these cells may provide means for monitoring the infection and the efficacy of sterilizing antiviral therapy. In this study, conditions for ex vivo augmentation and detection of the HCV genome in peripheral blood mononuclear cells (PBMCs) from patients with chronic hepatitis C (CHC) or after a sustained virological response (SVR) to antiviral treatment were assessed. Following stimulation with combinations of mitogens and/or cytokines, PBMCs and, in certain cases, affinity-purified T and B cells were examined for HCV positive- and negative-strand RNA by using RT-PCR followed by nucleic acid hybridization, while the presence of viral NS3 protein was determined by flow cytometry. HCV RNA augmentation was assessed by quantification of Southern and dot-blot hybridization signals. The results showed that treatment of peripheral lymphoid cells with mitogens stimulating T- and B-cell proliferation and with cytokines supporting their growth significantly increased HCV RNA detection in patients with both CHC and SVR. This enhancement was up to 100-fold for the HCV genome and fivefold for the NS3 protein compared with untreated cells. In conclusion, HCV RNA can be readily detected in circulating lymphoid cells in progressing hepatitis C and following SVR after ex vivo cell stimulation. As such, this method offers a new investigative tool to study HCV lymphotropism and to monitor virus presence during the course of HCV infection.

Coffin CS, Pham TN, Mulrooney PM, Churchill ND, Michalak TI. · Molecular Virology and Hepatology Research, Division of Basic Medical Sciences, Memorial University of Newfoundland, St. John's, Newfoundland A1B 3V6, Canada. · Hepatology. · Pubmed #15382154 No free full text.

Abstract: Antibodies against virus nucleocapsid (anticore) normally accompany hepadnaviral hepatitis but they may also occur in the absence of symptoms and other serological indicators of the infection. This situation can be encountered following a clinically and serologically unapparent exposure to hepatitis B virus (HBV) or after recovery from hepatitis B. In this study, woodchucks inoculated with woodchuck hepatitis virus (WHV) were investigated to determine the relationship between anticore detection and the molecular status of virus replication in a primary WHV surface antigen (WHsAg)-negative infection or long-after resolution of WHV hepatitis. Serial, parallel samples of sera, peripheral blood mononuclear cells (PBMC) and liver tissue, collected for more than 5 years after inoculation with virus, were examined for WHV DNA by highly sensitive polymerase chain reaction (PCR)/nucleic acid hybridization assays. Sera were also tested for WHV DNA after DNase treatment and for WHV DNA and WHsAg after concentration in sucrose. Liver and PBMC were examined for WHV covalently closed circular DNA and viral RNA transcripts by PCR-based techniques to assess virus replication status. The study showed that anticore antibodies existing in the absence of other serological markers are a reliable indicator of occult WHV infection. This state can be accompanied by traces of circulating particles behaving as intact virions and by intermittent minimal-to-mild liver inflammation. In conclusion, the long-term presence of anticore antibodies alone is a consequence of sustained restimulation of the immune system by virus nucleocapsid produced during low-level hepadnaviral assembly.

Michalak TI, Mulrooney PM, Coffin CS. · Molecular Virology and Hepatology Research, Division of Basic Medical Sciences, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John's, Newfoundland A1B 3V6, Canada. · J Virol. · Pubmed #14747538 links to  free full text

Abstract: Woodchuck hepatitis virus (WHV), which is closely related to human hepatitis B virus and is considered to be principally hepatotropic, invades the host's lymphatic system and persists in lymphoid cells independently of whether the infection is symptomatic and serologically evident or concealed. In this study, we show, with the woodchuck model of hepatitis B, that hepadnavirus can establish an infection that engages the lymphatic system, but not the liver, and persists in the absence of virus serological markers, including antiviral antibodies. This primary occult infection is caused by wild-type virus invading the host at a quantity usually not greater than 10(3) virions. It is characterized by trace virus replication progressing in lymphatic organs and peripheral lymphoid cells that, with time, may also spread to the liver. The infection is transmissible to virus-naive hosts as an asymptomatic, indefinitely long, occult carriage of small amounts of biologically competent virus. In contrast to residual silent WHV persistence, which normally endures after the resolution of viral hepatitis and involves the liver, primary occult infection restricted to the lymphatic system does not protect against reinfection with a large, liver-pathogenic WHV dose; however, the occult infection is associated with a swift recovery from hepatitis caused by the superinfection. Our study documents that the lymphatic system is the primary target of WHV infection when small quantities of virions invade a susceptible host.

Coffin CS, Michalak TI. · Molecular Virology and Hepatology Research, Division of Basic Medical Sciences, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, Canada. · J Clin Invest. · Pubmed #10411550 links to  free full text

Abstract: Mother-to-child transmission is an important route for hepatitis B virus (HBV) dissemination. It has been established that HBV traces persist for years after complete clinical recovery from hepatitis B. Similarly, resolution of hepatitis caused by HBV-related woodchuck hepatitis virus (WHV) is followed by occult lifelong carriage of pathogenic virus. In this study, we documented that WHV persisting after termination of acute hepatitis is transmittable to newborns as an asymptomatic long-term infection. All 11 offspring from 4 dams studied carried transcriptionally active WHV genomes for 3.5 years after birth without immunovirological markers of infection. WHV genomes and mRNA were detected both in the liver and lymphoid tissue in the majority of offspring; WHV covalently closed circular DNA was detected in some samples. In 4 offspring, however, the virus was restricted to the lymphatic system. In the circulation, WHV DNA-reactive particles were DNase resistant and of comparable size and density to complete virions. Importantly, the virus in offspring with or without hepatic WHV DNA expression was infectious to WHV-naive woodchucks. Finally, offspring challenged with WHV were not protected against reinfection. These findings show that mothers with occult hepadnaviral carriage transmit pathogenic virus to their offspring, inducing a persistent infection invariably within the lymphatic system but not always in the liver.

Michalak TI, Pardoe IU, Coffin CS, Churchill ND, Freake DS, Smith P, Trelegan CL. · Molecular Virology and Hepatology Research, Division of Basic Medical Sciences, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John's, Canada. · Hepatology. · Pubmed #10051500 No free full text.

Abstract: Traces of hepatitis B virus (HBV) genome can persist for years following recovery from hepatitis B. To determine overall duration, molecular characteristics, and pathological implications of this serologically undetectable form of hepadnaviral carriage, we have analyzed the expression of transcriptionally active virus genomes, their infectivity, and examined liver alterations during the natural lifespan of woodchucks convalescent from acute infection with HBV- related woodchuck hepatitis virus (WHV). In this study, we document lifelong persistence of scanty amounts of replicating virus both in the liver and lymphatic system after spontaneous resolution of an episode of experimental hepadnaviral hepatitis. Antibodies to virus nucleocapsid (core) were found to be the most reliable immunovirological marker coexisting with occult infection. In the majority of convalescent woodchucks, serial liver biopsies showed protracted minimal to mild necroinflammation with periods of normal morphology; however, hepatocellular carcinoma (HCC) ultimately developed in 2 of 9 animals studied. Inocula derived from lymphoid cells of convalescent animals induced classical acute hepatitis in virus-naive woodchucks that progressed to chronic hepatitis and HCC in 1 of the animals, demonstrating infectivity and pathogenic competence of the carried virus. Our results reveal that low levels of infectious WHV and residual hepatic inflammation usually continue for life after resolution of hepatitis and that this recovery does not avert HCC development. They also demonstrate that, in addition to the liver, the lymphatic system is the site of the occult lifelong maintenance of replicating hepadnavirus.