https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1002/hep.23190

Chronic hepatitis B: Update 2009

Cells termed myofibroblasts are prominent in the injury response of all epithelial tissues. They exhibit proliferation, migration, production of collagen and other extracellular matrix (ECM) molecules, and contraction, all for containing the injury and closing the wound. When the injury is limited in time, the final stage of the repair involves a dismantling of the cellular apparatus and restoration of normal tissue structure. With multiple cycles of repair, however, there is net accumulation of ECM, to the detriment of tissue structure and function. Repair-related ECM coalesces into fibrous bundles and, over time, undergoes changes that render it resistant to degradation. The result is a scar. In the skin, a scar may have cosmetic importance only. In the liver, however, extensive scarring is the setting for unregulated growth and neoplasia; also, fibrous bands disrupt normal blood flow, leading to portal hypertension and its complications. With regard to therapy for fibrosis, the first consideration is elimination of the injury factor. However, given that many liver diseases do not have effective therapies at present, strategies targeting fibrogenesis per se are under development. The main source of myofibroblast-like cells and ECM production in the liver is the perisinusoidal stellate cell, which responds to injury with a pleiotypic change termed activation. Activation is orchestrated by cytokines and the ECM itself. Among the cytokines involved in this process, transforming growth factor-beta (TGF-β) is particularly prominent. The early changes in ECM include de novo production of a specific “fetal” isoform of fibronectin, which arises from sinusoidal endothelial cells. It is stimulated by TGF-β and acts directly on stellate cells to promote their activation. Based on these and other advances in understanding the fundamentals of the injury response, several strategies now exist for altering fibrogenesis, ranging from agents that block TGF-β to traditional Chinese herbal extracts. Arrest of fibrogenesis, even with underlying cirrhosis, is likely to extend life or prolong the time to transplant. Whether it reduces the risk of hepatocellular carcinoma remains to be proven. Although TGF-β antagonists are effective anti-fibrogenic agents, they will require detailed safety testing because of the finding that several forms of epithelial neoplasia are associated with altered regulation of TGF-β.

/pdf/chronic-liver-injury-tgf-beta-and-cancer-18jh7in1dx.pdf

Chronic liver injury, TGF-beta, and cancer.

Patients chronically infected with hepatitis B virus (HBV) run the risk of developing cirrhosis and hepatocellular carcinoma in later life. Antiviral treatment offers the only means of preventing such an undesirable outcome. To date, interferon-alpha (IFN-alpha), an immunomodulator, and two synthetic nucleoside analogues, lamivudine and adefovir dipivoxil, are the only licensed antiviral agents for the treatment of chronic HBV infection. However, the standard treatment endpoints of loss of HBeAg with or without seroconversion to anti-HBe, normalization of serum transaminase levels, loss of HBV-DNA and improvement in liver histology following monotherapy with either types of agent are only achievable in approximately 20-30% of those treated. Long-term treatment with lamivudine is effective in suppressing viral replication, but drug-resistant mutants arise with increased length of treatment. Nevertheless, such mutants appear to be susceptible to adefovir and other nucleoside analogues that are undergoing Phase II/III clinical trials at the moment. Therapeutic vaccination and other molecular approaches such as antisense oligonucleotides, ribozymes, DNA vaccines, dominant-negative proteins and aptamers are possible future antiviral therapies, which will supplement our armamentarium against chronic HBV infection. It seems certain that combination therapies involving two or more nucleoside analogues, immunomodulators or gene therapies will be the future treatment regimens for chronic HBV infection.

/pdf/hepatitis-b-virus-old-new-and-future-approaches-to-antiviral-2nk7zq11kj.pdf

Hepatitis B virus: old, new and future approaches to antiviral treatment

Several government and nongovernment organizations held a consensus conference on the management of acute and chronic viral hepatitis to update previous management recommendations. The conference became necessary because of the introduction of new forms of therapy for both hepatitis B and hepatitis C. The conference issued recommendations on the investigation and management of chronic hepatitis B, including the use of lamivudine, adefovir and interferon. The treatment of hepatitis B in several special situations was also discussed. There were also recommendations on the investigation and treatment of chronic hepatitis C and hepatitis C-HIV coinfection. In addition, the document makes some recommendations about the provision of services by provincial governments to facilitate the delivery of care to patients with hepatitis virus infection. The present document is meant to be used by practitioners and other health care providers, including public health staff and others not directly involved in patient care.

/pdf/the-management-of-chronic-viral-hepatitis-a-canadian-4q9j08ipel.pdf

The management of chronic viral hepatitis: a Canadian consensus conference 2004.

Treatment of chronic hepatitis B has improved substantially over the past five years. Pegylated interferon alpha2a and entecavir have been approved by the FDA and joined the armamentarium of therapies that includes inteferon alpha (IFN-alpha), lamivudine, and adefovir dipivoxil. Several key questions come to mind regarding treatment. Who should receive treatment? Which agent should they be given? How long should treatment last? Treatment is indicated for patients with a high pretreatment alanine aminotransferase level, detectable HBV DNA, and active inflammation on liver biopsy. When selecting an agent, the likelihood of achieving a sustained response should be weighed against long-term risks. IFN-alpha, lamivudine, and adefovir dipivoxil are equally efficacious; however, even though IFN-alpha and pegylated IFN-alpha have a durable response, both are associated with unpleasant side effects. Long-term lamivudine therapy has a high rate of drug resistance compared with adefovir dipivoxil, which has a low rate of drug resistance and a small risk of reversible nephrotoxicity. Entecavir reduces HBV load more effectively than the other therapies, but it is associated with increased drug resistance in patients with lamivudine-resistant HBV. The key to therapy seems to be some combination of therapies--both existing and those in development--that has yet to be determined.

Treatment of chronic hepatitis B

Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B

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Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B