Hepatitis: Philadelphia

Del Vecchio AM, Sarisky RT. · Infectious Diseases Research, Centocor, R&D Inc., 145 King of Prussia Road, Radnor, PA 19087, USA. · Mini Rev Med Chem. · Pubmed #17100638 No free full text.

Abstract: Chronic infection with hepatitis C virus (HCV) remains a global health concern. Using both in vitro and cell-based assays, a series of small molecule agents specific for the viral RNA-dependent RNA polymerase have been shown to interfere with viral RNA replication. Although no agents targeting this viral enzyme have demonstrated sustained efficacy in infected patients as measured by reduction in viral load at 72 weeks post-treatment, proof-of-concept has been achieved in the clinic. A comprehensive account of the structure-activity relationship for nucleoside and non-nucleoside inhibitors of HCV polymerase, as well as consideration of early discovery biologic approaches targeting NS5B are reviewed.

Grossman MD, Stawicki SP. · University of Pennsylvania School of Medicine, Division of Trauma and Surgical Critical Care, St. Lukes Hospital and Health Network, Bethlehem, PA 18015, United States. · Injury. · Pubmed #17081542 No free full text.

Abstract: Since the initial description of a concentrated outbreak of pneumocystis carnii pneumonia in 1981, the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) pandemic has accounted for nearly 25 million deaths worldwide. This review focuses on estimations of prevalence by geographic region and identification of high-risk populations within each region, outcome for trauma patients with HIV and AIDS and risk management for health care workers who sustain occupational exposures. Trauma surgeons are more likely to encounter patients infected with HIV in geographic areas where HIV prevalence is high or in areas where intravenous drug use, high-risk sexual behaviours and penetrating trauma are more common. Patients with HIV may be expected to have higher rates of infectious and respiratory complications if they have active AIDS and/or liver disease caused by one of the hepatitis viruses. Certain aspects of therapy may change in this group of patients. Clinicians should be aware that highly active anti-retroviral therapy (HAART) might produce complications. Occupational exposure among healthcare workers is uncommon. Cases of infection in healthcare workers from needlesticks are rare. Certain precautions regarding body fluid and needlestick exposures have been widely adopted over the past decade. When percutaneous injury results in known exposure to HIV, post-exposure prophylaxis (PEP) should be used and can be expected to be effective in preventing infection in the large majority of cases.

Airoldi J, Berghella V. · Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. · Obstet Gynecol Surv. · Pubmed #16978426 No free full text.

Abstract: Hepatitis C is the most common chronic bloodborne infection in the United States. The diagnosis of vertical transmission is reliably established by a positive serum hepatitis C virus (HCV) RNA on 2 occasions 3 to 4 months apart after the infant is at least 2 months old and/or by the detection of anti-HCV antibodies after the infant is 18 months old. Vertical transmission in HCV RNA-negative pregnant women is approximately 1% to 3% versus approximately 4% to 6% in HCV RNA-positive women. From the standpoint of vertical transmission, no critical HCV RNA titer has been established. Coinfection with HIV has been shown to increase the risk of vertical transmission of HCV, but highly active antiretroviral therapy may decrease the risk significantly. In HIV-negative women, route of delivery does not influence vertical transmission. In HCV/HIV-coinfected women, decisions regarding mode of delivery should be based on HIV status. There is no association between vertical transmission of HCV and gestational age at delivery or the presence of chorioamnionitis. The use of a scalp electrode has been associated with vertical transmission and this practice is discouraged. Data are conflicting regarding duration of ruptured membranes and the risk of vertical transmission of hepatitis C. When the duration of membrane rupture exceeds 6 hours, the risk may be increased. There is no evidence demonstrating an increased risk of HCV transmission in HIV-negative women who breast feed. In HCV/HIV-coinfected women, breast feeding is discouraged in women who have consistent access to safe infant formula. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to recall that vertical transmission of hepatitis C (HCV) does occur, state that coinfection with HIV increases the transmission rate, and summarize that there is no association between gestational age or presence of chorioamnionitis and no evidence that a cesarean delivery prevents transmission.

Zhang T, Li Y, Ho WZ. · Division of Allergy and Immunology, Joseph Stokes, Jr. Research Institute at The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Rev Med Virol. · Pubmed #16933366 No free full text.

Abstract: Since its discovery in 1989, hepatitis C virus (HCV) has become a major public health problem. HCV chronically infects an estimated 170 million people worldwide. The seroprevalence of anti-HCV antibody in the United States has been estimated at 1.8%, which corresponds to approximately 4 million people. HCV is the most common chronic blood borne infection in the United States, and the leading cause of liver transplantation in developed countries. Injection drug use is the dominant mode of HCV transmission and accounts for up to 90% of current infections. Opiates and other drug abuse, such as alcohol, have been implicated as cofactors in the pathogenesis of HCV disease. Injection drug use has been the most common risk factor identified in alcoholics with HCV infection. Both opiates and alcohol contribute significantly to morbidity and mortality from HCV disease. These drugs most likely act synergistically to promote the development and progression of HCV disease. However, there is limited information available concerning the interaction of the drug abuse with the host cell innate immunity against HCV infection, which is a major barrier to fundamental understanding of the immunopathogenesis of HCV disease. Therefore, defining the role of the drug abuse in the development of chronic HCV infection is of crucial importance and should provide practical guidance toward the reduction of risk factors that interfere with therapeutic approaches for HCV infection and disease. This review paper focuses on the interplay between drug abuse (opiates and alcohol), innate immunity and HCV in the context of the development of HCV disease.

Taylor JM. · Fox Chase Cancer Center, Philadelphia, PA 19111-2497, USA. · Curr Top Microbiol Immunol. · Pubmed #16903218 No free full text.

Abstract: While this volume covers many different aspects of hepatitis delta virus (HDV) replication, the focus in this chapter is on studies of the structure and replication of the HDV RNA genome. An evaluation of such studies is not only an integral part of our understanding of HDV infections but it also sheds new light on some important aspects of cell biology, such as the fidelity of RNA transcription by a host RNA polymerase and on various forms of post-transcriptional RNA processing. Representations of the replication of the RNA genome are frequently simplified to a form of rolling-circle model, analogous to what have been described for plant viroids. One theme of this review is that such models, even after some revision, deceptively simplify the complexity of HDV replication and can fail to make clear major questions yet to be solved.

Bloom RD, Lake JR. · Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. · Am J Transplant. · Pubmed #16869798 No free full text.

Abstract: Hepatitis C virus (HCV) infection is a major health care issue in liver and kidney transplantation. Besides negatively affecting both patient and graft survival, HCV is associated with a heightened risk for new onset diabetes mellitus (NODM). The mechanisms underlying the diabetogenicity of HCV are complex but are likely to involve insulin resistance caused by inhibitory actions of the virus on insulin regulatory pathways in the liver. The resultant glucose dysregulation is an important determinant of increased morbidity and mortality in liver and kidney recipients. This review highlights the concerns for outcomes in HCV-positive liver and kidney transplant patients with particular focus on the interrelationship between hepatitis C and diabetes. Data about the potential role of calcineurin inhibitors, corticosteroids and mycophenolate mofetil in HCV infection and HCV-associated NODM will also be discussed.

Samuel R, Bettiker R, Suh B. · Section of Infectious Diseases, Temple University School of Medicine, Philadelphia, PA 19140, USA. · Arch Pharm Res. · Pubmed #16833010 No free full text.

Abstract: As we approach the completion of the first 25 years of the human immunodeficiency virus (HIV) epidemic, there have been dramatic improvements in the care of patients with HIV infection. These have prolonged life and decreased morbidity. There are twenty currently available antiretrovirals approved in the United States for the treatment of this infection. The medications, including their pharmacokinetic properties, side effects, and dosing are reviewed. In addition, the current approach to the use of these medicines is discussed. We have included a section addressing common comorbid conditions including hepatitis B and C along with tuberculosis.

Kotlyar DS, Campbell MS, Reddy KR. · University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. · Am J Gastroenterol. · Pubmed #16771963 No free full text.

Abstract: Long-term graft survival and mortality after liver transplantation continue to improve. However, disease recurrence remains a major stumbling block, especially among patients with hepatitis C. Chronic hepatitis C recurs to varying degrees in nearly all patients who undergo transplantation. Transplantation for hepatitis C is associated with higher rates of graft failure and death compared with transplantation for other indications, and retransplantation for hepatitis C related liver failure remains controversial. Recurrence of hepatitis B has been markedly reduced with improved prophylactic regimens. Further, rates of hepatocellular carcinoma recurrence have also decreased, as improved patient selection criteria have prioritized transplantation for those with a low risk of recurrence. Primary biliary cirrhosis recurs in some patients, but it is often relatively mild. Autoimmune liver disease has also been shown to have a relatively benign post-transplantation course, but some studies have indicated that it slowly progresses in most recipients. It has been recently reported that alcoholic liver disease liver transplant recipients who return to drinking have worsened mortality. In such patients worse outcomes are not due to graft failure, but instead to other comorbidities. Recurrences of other diseases, including nonalcoholic steatohepatitis and primary sclerosing cholangitis, are now being recognized as having potentially detrimental effects on graft survival and mortality. Expert clinical management may help prevent and treat complications associated with disease recurrence.

Mbow ML, Eaton-Bassiri A, Glass WG, Del Vecchio AM, Sarisky RT. · Infectious Diseases Research, Centocor, R&D Inc., 145 King of Prussia Road, Radnor, PA 19087, USA. · Mini Rev Med Chem. · Pubmed #16719827 No free full text.

Abstract: Hepatitis C virus represents a major global health problem, with approximately 3% of the world population infected. Immune-response modifiers represent the standard of care, given the lack of approved antiviral agents having direct activity against the viral proteins. Although in recent years, improvements in therapy have been attained by combined treatment with pegylated interferon and ribavirin, the discovery and development of next-generation small molecule and biologic agents is ongoing. Several of these newer therapeutics are focused on modulating Toll-like receptors, interferon-alpha signaling, and the pro-inflammatory cytokine balance. A comprehensive account of the lead compounds in development, the bioassays used for optimization of these immune response modifiers and their clinical status is presented.

Herrine SK, Rossi S, Navarro VJ. · Division of Gastroenterology and Hepatology, Thomas Jefferson University, Philadelphia, PA 19107, USA. · Clin Exp Med. · Pubmed #16550340 No free full text.

Abstract: Chronic infection with hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality throughout the world. Although reliable figures regarding the global prevalence of HCV infection are wanting, it is likely that HCV prevalence will continue to increase. Injection drug use is the most important source of HCV transmission in the developed world, while unsafe therapeutic injection is an important source of transmission in developing nations. The majority of exposed individuals become chronically infected, of whom 50% develop chronic liver injury. Cirrhosis and hepatocellular carcinoma can arise in those chronically infected over a mean of 20-30 years. Despite this high prevalence and morbidity, recommendations regarding who to screen by antibody testing remain disparate. Quantitative measurement of HCV RNA and HCV genotyping is useful in predicting response to antiviral therapy. Noninvasive methods of detecting liver injury, such as serologic batteries, have not been as informative or predictable as liver biopsy. The current pharmacologic standard of care for chronic HCV infection is the combination of subcutaneous peginterferon and oral ribavirin, which yields sustained virologic response in 54%-56%. Higher rates of SVR are seen in those patients who are infected with HCV genotypes 2 and 3. As intravenous drug use remains the most important source of HCV transmission in the US and Europe, education within this group is an important preventive tool.

Blumberg BS. · Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. · Proc Am Thorac Soc. · Pubmed #16493147 links to  free full text

This publication has no abstract.

Navarro VJ, Senior JR. · Department of Medicine, Division of Gastroenterology and Hepatology, Jefferson Medical College, Philadelphia, USA. · N Engl J Med. · Pubmed #16481640 No free full text.

This publication has no abstract.

Taylor JM. · Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA. · Virology. · Pubmed #16364738 No free full text.

Abstract: Hepatitis delta virus (HDV) is a sub-viral agent that is dependent for its life cycle on hepatitis B virus (HBV). The help it obtains from HBV is limited to the sharing of envelope proteins. These proteins are needed to facilitate the assembly of the HDV genome into new virus particles, and in turn, to allow the attachment and entry of HDV into new host cells. In other respects, the replication of the small single-stranded circular RNA genome of HDV is independent of HBV. HDV genome replication produces two forms of a RNA-binding protein known as the long and small delta antigens (Ag). All other proteins needed for HDV genome replication, especially the RNA-directed RNA polymerase activity, are provided by the host cell. This mini-review article is a mixture of personal perspective and speculations about the future of HDV research. It starts with a brief overview of HDV and its replication, notes some of the major unresolved questions, and directs the interested reader to more detailed reviews.

Metz DC, Vakil N, Keeffe EB, Lichtenstein GR. · Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. · Clin Gastroenterol Hepatol. · Pubmed #16361040 No free full text.

Abstract: The medical management of patients with gastrointestinal diseases is advancing rapidly. At a recent symposium held during Digestive Disease Week in Chicago in May of 2005, specific attention was given to the future prospects for medical management of 3 common gastrointestinal disease areas: antisecretory therapy, chronic hepatitis C, and inflammatory bowel disease. Antisecretory approaches include drug combinations including a proton pump inhibitor, potassium competitive acid blockers, and antigastrin agents. The latter two classes are still experimental, but the former combinations have potential to enhance the highly effective agents currently available. The focus of treatment advances in chronic hepatitis C in the immediate future is the discovery of more effective treatment regimens for nonresponders to prior therapy, who are becoming the largest group of patients seeking treatment of hepatitis C. The combination of peginterferon with ribavirin results in 6%-15% sustained virologic response rates in patients who were prior nonresponders to standard interferon plus ribavirin. Newer strategies to eradicate hepatitis C virus infection using different interferons, such as interferon alfacon-1 or higher doses of peginterferon, or long-term maintenance peginterferon, are undergoing study and show promise based on data from preliminary studies. Several immunomodulators have promise in inflammatory bowel disease, although the risk-benefit ratio and costs of therapy require evaluation. Nevertheless, the success of new biologics such as anti-TNFalpha agents augurs well for effective future therapies.

Nathanson N. · Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA. · Arch Virol Suppl. · Pubmed #16355865 No free full text.

Abstract: In this review, I use the term "perpetuation" for persistence of a virus in a population, since this is a different phenomenon from persistence of a virus in an infected host. Important variables that influence perpetuation differ in small (<1000 individuals) and large (>10,000) populations: in small populations, two important variables are persistence in individuals, and turnover of the population, while in large populations important variables are transmissibility, generation time, and seasonality. In small populations, viruses such as poliovirus that cause acute infections cannot readily be perpetuated, in contrast to viruses such as hepatitis B virus, that cause persistent infections. However, small animal populations can turnover significantly each year, permitting the perpetuation of some viruses that cause acute infections. Large populations of humans are necessary for the perpetuation of acute viruses; for instance, measles required a population of 500,000 for perpetuation in the pre-measles vaccine era. Furthermore, if an acute virus, such as poliovirus, exhibits marked seasonality in large populations, then it may disappear during the seasonal trough, even in the presence of a large number of susceptible persons. Eradication is the converse of perpetuation and can be used as a definitive approach to the control of a viral disease, as in the instance of smallpox. Therefore, the requirements for perpetuation have significant implications for practical public health goals.

Weiss SR, Navas-Martin S. · Department of Microbiology, University of Pennsylvania School of Medicine, 36th Street and Hamilton Walk, Philadelphia, Pennsylvania 19104-6076, USA. · Microbiol Mol Biol Rev. · Pubmed #16339739 links to  free full text

Abstract: Coronaviruses are a family of enveloped, single-stranded, positive-strand RNA viruses classified within the Nidovirales order. This coronavirus family consists of pathogens of many animal species and of humans, including the recently isolated severe acute respiratory syndrome coronavirus (SARS-CoV). This review is divided into two main parts; the first concerns the animal coronaviruses and their pathogenesis, with an emphasis on the functions of individual viral genes, and the second discusses the newly described human emerging pathogen, SARS-CoV. The coronavirus part covers (i) a description of a group of coronaviruses and the diseases they cause, including the prototype coronavirus, murine hepatitis virus, which is one of the recognized animal models for multiple sclerosis, as well as viruses of veterinary importance that infect the pig, chicken, and cat and a summary of the human viruses; (ii) a short summary of the replication cycle of coronaviruses in cell culture; (iii) the development and application of reverse genetics systems; and (iv) the roles of individual coronavirus proteins in replication and pathogenesis. The SARS-CoV part covers the pathogenesis of SARS, the developing animal models for infection, and the progress in vaccine development and antiviral therapies. The data gathered on the animal coronaviruses continue to be helpful in understanding SARS-CoV.

Brent RL. · Laboratory of Clinical and Environmental Teratology, Alfred I. duPont Hospital for Children, Thomas Jefferson University, Wilmington, DE 19899, USA. · Reprod Toxicol. · Pubmed #16290279 No free full text.

Abstract: The medical, social and legal risks of immunizing pregnant women are obstacles preventing the initiation of programs to immunize women for their protection and for their infant's protection. Recent projects devoted to vaccine development have focused on protecting newborns and infants. But there are many other reasons for developing or utilizing vaccines before or during pregnancy, beyond the protection of the newborn. Besides the usual reasons for utilizing immunizations to protect the mother and the neonate, the threat of bio-terrorism adds a new dimension to the necessity for addressing this issue. The potential advantages for thinking about vaccinating pregnant women include an array of possible programs associated with risks and benefits. The immunization of pregnant women or women of reproductive age has multiple purposes: to protect the mother, to protect the newborn and infant and to prevent diseases and complications of pregnancy. (1) Preparation of vaccines against infectious agents that are known to result in reproductive pathology and congenital malformation if the infection of the mother occurs during pregnancy. (2) To utilize vaccines used routinely to protect the non-pregnant population, for administration during pregnancy, i.e., influenza, tetanus and other vaccines. Should these vaccines and other routinely used vaccines for children and non-pregnant adults be administered to women during pregnancy if they are medically indicated? (3) Utilization of vaccines to protect women from diseases to which they are susceptible because of pregnancy (poliomyelitis, hepatitis). (4) Utilization of vaccines for use before or during pregnancy, primarily to protect the newborn and infant via maternal transplacental antibodies, i.e., GBD (group B streptococcus). (5) The prevention of intrauterine infection that has been alleged to initiate premature labor. (6) The preparation of a vaccine for use before or during pregnancy to protect both the mother and the neonate, i.e., botulism toxin vaccine. The regulatory agencies and the vaccine producers will need a great deal of objective scientific advice and support and it is the scientific community's responsibility to provide that support. If the scientific and medical community ignores the opportunity to develop vaccines that could reduce the occurrence of reproductive and developmental problems, then we can be accused of acquiescing to the "risk of doing nothing."

Tedaldi EM. · Comprehensive HIV Program, Temple University School of Medicine, Philadelphia, PA 19140, USA. · Clin Infect Dis. · Pubmed #16265606 No free full text.

Abstract: Current interferon (IFN)-based therapies for hepatitis C in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) may be limited by incomplete virological response, lack of adherence, and poor tolerability. Newer therapies for hepatitis C will target viral replication (e.g., HCV serine protease inhibitors, helicase inhibitors, RNA interference, or an HCV polymerase inhibitor). Other treatments will focus on viral translation (e.g., antisense molecules). Additions to IFN therapy that can modulate the immune response (e.g., thymosin, isatorbine, or injectable histamine) may improve tolerability of treatment. There need to be targets that minimize the inflammatory response by the liver (e.g., IFN-gamma). There are some therapeutic vaccines in early development. Drugs to replace or enhance ribavirin are being studied with IFN-based treatments. Strategic treatment trials that address sequencing of HCV and HIV therapy with current and future therapeutic agents and combination therapy need to be undertaken.

Seeger C. · Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. · Trends Microbiol. · Pubmed #16154356 No free full text.

Abstract: Hepatitis C virus (HCV) is a positive strand RNA virus with a narrow host and tissue tropism. It ranks among the most significant of human pathogens, causing inflammation, scarring and cancer of the liver. Recent investigations have shed light on some of the salient molecular features of this virus. These include a requirement for CD81 (a tetraspanin transmembrane protein for viral entry), a novel mechanism for the initiation of RNA synthesis, phosphorylation of a viral protein in the regulation of RNA amplification and virus assembly and, finally, a viral protease suppressing activation of the innate immune response in infected cells.

Feitelson MA. · Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Room 222 Alumni Hall, 1020 Locust Street, Philadelphia, PA 19107, USA. · Cancer Lett. · Pubmed #16154256 No free full text.

Abstract: Hepatocellular carcinoma (HCC) is one of the most frequent tumor types in the world, with short survival times and few treatment options. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are major etiologic agents of HCC, although the associated mechanisms are incompletely understood. The available evidence suggests that both viruses promote tumorigenesis by up-regulating genes that promote hepatocellular growth and survival, and by down-regulating other genes that act as tumor suppressors and negative growth regulatory molecules. Significantly, a number of the pathways that are altered by these viruses are the same ones that accumulate genetic alterations during tumor progression. This suggests that the pathways that promote virus persistence and replication may also promote cell growth and survival. From the perspective of the virus, this promotes chronic infection, while from the perspective of the host, this promotes tumorigenesis.

Markiewski MM, DeAngelis RA, Lambris JD. · Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical School, Protein Chemistry Laboratory, 401C Stellar-Chance Laboratories, 422 Curie Blvd., Philadelphia, PA 19104, USA. · Mol Immunol. · Pubmed #16002143 No free full text.

Abstract: The anatomic localization and unique vasculature of the liver, along with its cell properties, make this organ an efficient line of defense against blood-borne infections, either systemic or arising in the abdomen. Liver cells can modify the host immune response by releasing immunomodulatory molecules, interacting with cells of the immune system and acting as scavengers for inflammatory mediators. However, these defensive functions do not protect the liver itself from the severe injury that may be caused by pathogens, toxins or pollutant xenobiotics. Therefore, the mammalian liver has developed a unique adaptation in the form of an astonishing regenerative capability. The complexity of regeneration requires a well-orchestrated system to control this process. Growing evidence suggest the importance of immune mechanisms as a part of this system. It seems likely that the mechanisms that serve to eliminate infections (and may simultaneously cause liver injury) are also active in restoring the structural and functional integrity of the damaged liver.

Lo Re V, Kostman JR. · Division of Infectious Diseases, Center for Clinical Epidemiology and Biostatistics, 502 Johnson Pavilion, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Postgrad Med J. · Pubmed #15937203 links to  free full text

Abstract: Hepatitis C virus (HCV) infection is transmitted primarily through percutaneous exposure to blood, and most infections are associated with injection drug use. Progression to chronic HCV occurs in 55% to 86% of infected people, and persistent infection is a major cause of cirrhosis, end stage liver disease, and hepatocellular carcinoma. The detection of HCV antibodies should be performed initially to screen at risk populations. In those who are seropositive, HCV viraemia should be assessed to determine if chronic HCV is present. The HCV genotype should also be determined, as this is the strongest predictor of response to available treatment. A liver biopsy is very often helpful because it can estimate degree of hepatic fibrosis, identify concurrent diseases that might contribute to hepatic injury, and aid in selection of patients for treatment. The decision to start antiviral therapy should take into account potential contraindications to therapy, patient motivation, severity of disease, age, and HCV genotype. Combination therapy with weekly subcutaneous pegylated interferon and daily oral ribavirin is the standard of care for treating patients with chronic HCV.

Strayer DS, Cordelier P, Kondo R, Liu B, Matskevich AA, McKee HJ, Nichols CN, Mitchell CB, Geverd DA, White MK, Strayer MS. · Department of Pathology and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA. · Curr Gene Ther. · Pubmed #15853724 No free full text.

Abstract: The natural function of viruses is to deliver their genetic material to cells. Among the most effective of viruses in doing that is Simian Virus-40 (SV40). The properties that make SV40 a successful virus make it an attractive candidate for use as a gene delivery vehicle: high titer replication, infectivity for almost all nucleated cell types whether the cells are dividing or resting, potential for integration into cellular DNA, a peculiar pathway for entering cells that bypasses the cells' antigen processing apparatus, very high stability, and the apparent ability to activate expression of its own capsid genes in trans. Exploiting these and other characteristics of wild type (wt) SV40, increasing numbers of laboratories are studying recombinant (r) SV40-derived vectors. Among the uses to which these vectors have been applied are: delivering therapy to inhibit HIV, hepatitis C virus (HCV) and other viruses; correction of inherited hepatic and other protein deficiencies; immunizing against lentiviral and other antigens; treatment of inherited and acquired diseases of the central nervous system; protecting the lung and other organs from free radical-induced injury; and many others. The effectiveness of these vectors is a reflection of the adaptive evolution that produced their parent virus, wt SV40. This article explores how and why these vectors work, their strengths and their limitations, and provides a functional model for their exploitation for experimental and clinical applications.

Feitelson MA, Reis HM, Liu J, Lian Z, Pan J. · Department of Pathology, Anatomy and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. <> · Front Biosci. · Pubmed #15769646 No free full text.

Abstract: Hepatitis B and related viruses that infect mammalian hosts encode the "X" protein that has been shown to contribute importantly to the pathogenesis of chronic liver disease (CLD) and to the development of hepatocellular carcinoma (HCC). In a variety of tissue culture systems, hepatitis B virus (HBV) X antigen, or HBxAg, has been shown to trigger apoptosis, while other evidence suggests that HBxAg inhibits apoptosis and stimulates the cell cycle by constitutively activating a number of signaling pathways that are important for hepatocellular growth and survival. These apparently contrasting properties of HBxAg may be associated with differences in the X protein itself, since carboxy-terminal truncated forms of HBxAg appear to be associated with HCC lesions. Alternatively, or in addition, these differences may be due to the cell type, state of cell differentiation, and whether expression occurs in resting or dividing cells. Further, the association between HBxAg expression and chromosomal instability, may also contribute to the apparently contrasting fates of HBxAg positive cells. It is proposed that in many of these systems, the different outcomes of HBxAg expression may be due to the nature of the cellular response to HBxAg, and not due to differences in the fundamental properties of HBxAg, the latter of which promote cell survival, cell cycle progression, and the development of HCC.

Greenbaum LE. · Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, USA. · Cancer Biol Ther. · Pubmed #15662121 links to  free full text

Abstract: Hepatocellular carcinoma (HCC) develops on a background of chronic hepatitis or cirrhosis. The slow progression of this disease has facilitated the identification of discrete pathologic stages. Increased rates of hepatocyte proliferation in preneoplastic nodules is an early event in the progression of HCC. Increased cell turnover results in the selection of monoclonal hepatocyte populations that subsequently undergo genomic alterations that lead to the development of HCC. The heterogeneous nature of genomic alterations identified in tumors from patients with HCC has impeded the identification of regulatory pathways whose disruption are critical for tumor initiation. However, several regulatory networks important for liver cell proliferation have been characterized using the partial hepatectomy model, an in vivo model of liver cell cycle progression, and are likely relevant to the pathogenesis of hepatocellular carcinoma.