MicrobiologyBytes

A recent edition of Archives of Medical Research is devoted to hepatitis B (HBV) and hepatitis C (HCV) viruses. Among the highlights are:

• Viral Hepatitis: Historical Perspectives from the 20th to the 21st Century: The spectacular progress of medicine that we have seen during the last half of the century first established that diverse forms of hepatitis exist, which result from infection with different etiological agents, usually by different routes. This, in turn, led to the implementation of preventive measures, to the development of vaccines and passive immunization approaches and, more recently, at least for some forms of hepatitis, to promising or effective treatments. Yet, hepatitis continues to be a serious health threat that should be present in the mind of every practitioner. This review discusses the major research accomplishments that led to the current understanding of the etiology and natural history of the various types of viral hepatitis, as well as the contributions of molecular biology to hepatitis research that have elucidated the structural features and the life cycle of the different viruses, which have been essential for the design of effective treatments and preventive measures. We also discuss the current applications to hepatitis treatment of the antiviral cytokine, interferon alpha (IFN-alpha), as well as the more recently introduced antiviral drugs, i.e., nucleoside and nucleotide analogs, which interfere with the replication of viral genomes.

• Epidemiology of Hepatitis Virus B and C: Hepatitis B and C virus infections constitute a significant health problem in Latin America. Approximately 400,000 new cases of hepatitis B per year and 10 million people infected with hepatitis C are estimated to occur. HBV and HCV genotype distribution may reflect the different patterns of migration to the Americas: Genotype F and H of HBV correspond to the Amerindian genotype. Overall, Genotype 1 is the most prevalent HCV genotype in the Caribbean and in South and Central America. Hepatitis B and C epidemiology needs to be considered in the context of dissimilar social and economic aspects among the countries of the region. Behaviors, cultural and ethical aspects, as well as environmental and organizational processes affect directly the way these diseases are approached in their diagnosis, treatment and prevention.

• Viral Hepatitis and Hepatocellular Carcinoma: Hepatocellular carcinoma (HCC) is the fifth most common tumor worldwide, and one of the fastest rising tumors as a result of chronic hepatitis B and C infection. The patients at risk for developing HCC are those with underlying cirrhosis secondary to viral hepatitis. External factors such as alcohol, tobacco, obesity, and diabetes increase the risk of HCC among those with chronic viral hepatitis. Surveillance of patients with cirrhosis with α-fetoprotein and ultrasound has been shown to reduce survival. The diagnosis of HCC is established by the presence of an arterially enhancing mass in the presence of cirrhosis. Viral hepatitis represents an opportunity for prevention of HCC.

• Current Therapy of Chronic Hepatitis B: In recent years, significant progress has been made in the treatment of chronic hepatitis B, and several antiviral drugs are already available. There are host and viral factors associated with the likelihood of virological response to treatment, such as age, gender, baseline ALT level, HBV DNA levels, and HBV genotype. The first antiviral drug used in chronic hepatitis B was interferon (IFN) alfa, which is effective but has frequent side effects. Recently, the efficacy of IFN alfa has improved with the new pegylated interferon (PEG-IFN). This new form of IFN has better efficacy than conventional IFN alfa in chronic hepatitis B, as well as having better patient acceptance. The introduction of lamivudine as the first oral agent approved for the treatment of chronic hepatitis B was a landmark in the management of this disease. This nucleoside analogue has also proved efficacy but is limited by the high rate of occurrence of viral resistance related to mutations.

• Current and Future Hepatitis C Therapies: Treatment of chronic hepatitis C patients has evolved significantly in the past 15 years. With a better knowledge of viral kinetics and molecular virology of the hepatitis C virus, we have gone from a low chance of viral eradication to a chance as high as 50%. Despite this, current therapies are not ideal and are associated with side effects, complications, and poor patient tolerability. Therefore, an urgent need to look for better strategies to treat this disease is imperative. Thanks to the current knowledge and ongoing research, we know the way we treat hepatitis C today will change dramatically in the next 5–10 years. This focuses on current therapies for hepatitis C and the most recent advances in the search for new therapies.

• Recurrent Viral Liver Disease (Hepatitis B and C) after Liver Transplantation: Hepatitis C represents more than 35% of liver transplant candidates worldwide. Meanwhile, hepatitis B continues to be an important cause of end-stage liver disease and hepatocellular carcinoma in Asia and Africa. Recurrent viral liver disease is a significant event after liver transplantation and continues to be one of the main causes of graft dysfunction and loss in the middle and long-term follow-up. Mechanisms of liver reinfection and disease recurrence vary between these two viruses and pre-emptive as well as the therapeutic approaches are different. Hepatitis B patients can be managed with immune globulin immediately after liver transplant and various agents such as nucleotide and nucleoside analogues can be associated. As a result, disease recurrence has been delayed or prevented in these patients. Individuals transplanted for hepatitis C are known to have universal reinfection and a high rate of disease recurrence has been reported in the literature. Strategies to treat hepatitis C recurrence are limited to the use of pegylated interferon and ribavirin when disease is demonstrated histologically and biochemically, although other strategies have been described with limited or no success. We review the mechanisms of disease recurrence and the current as well as the future therapeutic approaches to prevent and to treat these diseases.

• Treatment of Viral Hepatitis in Children: Hepatitis B and hepatitis C are important causes of chronic liver disease in children and adolescents, and later on for potential cirrhosis and primary hepatocellular carcinoma. The risk of developing chronic hepatitis B (HB) infection ranges from 90% in neonates to <5% in adults. Hepatitis C induces chronic infection in at least 85% of affected persons. HBV and HCV associated liver damage appears to be less severe in children than in adults. At the present time, lamivudine and a combination of interferon and lamivudine seem to be the best options for HB infection treatment in the pediatric population, even though they induce the presence of drug-resistant mutations, and new therapies have to be developed to improve reduction and cessation of viral replication and decrease the emergence of mutations. Therapy with interferon and ribavirin seems to offer the best results for children and adolescents. Results from a study on pegylated interferon in a pediatric population might lead to better therapeutic responses. Cost of treatment for chronic viral hepatitis is very high and efforts have to continue to extend hepatitis B vaccination to the general population worldwide to reduce vertical and horizontal transmission of hepatitis C.

All worth checking out, and while I’m on the hepatitis theme:

Reduced expression of Jak-1 and Tyk-2 proteins leads to interferon resistance in Hepatitis C virus replicon. Virology Journal 2007, 4: 89
Alpha interferon in combination with ribavirin is the standard therapy for hepatitis C virus infection. Unfortunately, a significant number of patients fail to eradicate their infection with this regimen. The mechanisms of IFN-resistance are unclear. The aim of this study was to determine the contribution of host cell factors to the mechanisms of interferon resistance using replicon cell lines. HCV replicons with high and low activation of the IFN-promoter were cultured for a prolonged period of time in the presence of interferon-alpha2b. Stable replicon cell lines with resistant phenotype were isolated and characterized by their ability to continue viral replication in the presence of IFN-alpha2b. Interferon resistant cell colonies developed only in replicons having lower activation of the IFN promoter and no resistant colonies arose from replicons that exhibit higher activation of the IFN promoter. Individual cell clones were isolated and nine IFN resistant cell lines were established. HCV RNA and protein levels in these cells were not altered by IFN-alpha2b Reduced signaling and IFN-resistant phenotype was found in all Huh-7 cell lines even after eliminating HCV, suggesting that cellular factors are involved. Resistant phenotype in the replicons is not due to lack of interferon receptor expression. All the cell lines show defect in the JAK-STAT signaling and phosphorylation of STAT 1 and STAT 2 proteins were strongly inhibited due to reduced expression of Tyk2 and Jak-1 protein. This in vitro study provides evidence that altered expression of the Jak-Stat signaling proteins can cause IFN resistance using HCV replicon cell clones.

This entry was posted on Thursday, September 20th, 2007 at 6:26 am and is filed under Biology, Health, Medicine, Microbiology, Science, Vaccines, Virology. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed.