Antiviral therapy to prevent carcinogenesis

( Mark Thursz ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-

Whenever treatment decisions are made for patients with chronic viral hepatitis the clinician should keep in mind the therapeutic goals that they are trying to achieve. As trials of antiviral therapy are invariably based on relatively short term surrogate endpoints we tend to lose sight of the long term goals; suppression of viral replication is encouraging but can we extrapolate this endpoint to the avoidance of premature mortality which is our ultimate aim. In chronic hepatitis B virus (HBV) infection the development of potent nucleos (t) ide analogues (NA) has revolutionised the treatment of patients with chronic HBV infection. These agents allow us to suppress viral replication very effectively with minimal side effects. We have also recently seen that therapy can result in HBeAg to anti HBe seroconversion and, in patients who are HBeAg positive, prolonged therapy may result in HBsAg loss. A series of histologically based studies now show us that NAs will reverse fibrosis and even ``reverse`` cirrhosis. However, in clinical practice we still see the development of hepatocellular carcinoma (HCC) in patients where viral replication has been effectively suppressed. Does this mean that the NAs do not influence the development of HCC? Only one placebo controlled trial provides us with evidence that Lamivudine reduces the risk of HCC. For ethical reasons this can never be repeated and as a result other evidence of benefit is circumstantial. Nevertheless it is probably safe to conclude that NA treatment reduces the risk of HCC but does not eliminate it. The exact magnitude of the reduction is a little hard to estimate but probably depends on the stage of disease and the age of the patient at the time that treatment was initiated. In chronic hepatitis C virus (HCV) infection the situation is similarly confused. It is now clear that elimination of the virus (sustained virological response) is associated with improvement of liver fibrosis and a reduction in the risk of developing HCC. However, in a proportion of patients with cirrhosis at the time they started treatment there is little resolution of the fibrosis and the risk of HCC persists after viral elimination. The important clinical point is that whilst virological control is important and will reduce risk of HCC it is still vital to maintain patients under surveillance.

Host genomics in viral hepatitis

( Mark Thursz ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-

The outcome of viral hepatitis infection varies substantially in different individuals. This is particularly marked in hepatitis B virus (HBV) and hepatitis C virus (HCV) infections where the clinical course may vary from asymptomatic self limited infection to chronic infection progressing to cirrhosis, liver failure and / or hepatocellular carcinoma. Family clustering and twin studies indicate that some of the variability in the outcomes of these infections is determined by the host genetic background. Over the last 20 years a number of the genes which exert influence on the outcome of infection have been identified. In HBV infection both candidate gene studies and genome wide association studies have demonstrated the importance of the genes in the major histocompatibility region and in particular to the HLA class II alleles. In HCV infection recent excitement has focussed on a series of genome wide association studies revealing the importance of specific single nucleotide polymorphisms in the IL 28b gene which influence both response to treatment and spontaneous resolution of infection. Genetic association studies have also addressed variation in the rate of liver fibrosis and susceptibility to cancer. Polymorphisms in the coagulation system proteins have highlighted the importance of thrombin in fibrogenesis and therefore indicated a potential therapeutic approach for patients with progressive disease. A number of genome wide association studies have identified susceptibility loci for hepatocellular carcinoma but there is, at present, a lack of consistency in these findings.

Antiviral therapy to prevent carcinogenesis

( Mark Thursz ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.1

Whenever treatment decisions are made for patients with chronic viral hepatitis the clinician should keep in mind the therapeutic goals that they are trying to achieve. As trials of antiviral therapy are invariably based on relatively short term surrogate endpoints we tend to lose sight of the long term goals; suppression of viral replication is encouraging but can we extrapolate this endpoint to the avoidance of premature mortality which is our ultimate aim. In chronic hepatitis B virus (HBV) infection the development of potent nucleos(t)ide analogues (NA) has revolutionised the treatment of patients with chronic HBV infection. These agents allow us to suppress viral replication very effectively with minimal side effects. We have also recently seen that therapy can result in HBeAg to anti?HBe seroconversion and, in patients who are HBeAg positive, prolonged therapy may result in HBsAg loss. A series of histologically based studies now show us that NAs will reverse fibrosis and even ‘reverse’ cirrhosis. However, in clinical practice we still see the development of hepatocellular carcinoma (HCC) in patients where viral replication has been effectively suppressed. Does this mean that the NAs do not influence the development of HCC? Only one placebo controlled trial provides us with evidence that Lamivudine reduces the risk of HCC. For ethical reasons this can never be repeated and as a result other evidence of benefit is circumstantial. Nevertheless it is probably safe to conclude that NA treatment reduces the risk of HCC but does not eliminate it. The exact magnitude of the reduction is a little hard to estimate but probably depends on the stage of disease and the age of the patient at the time that treatment was initiated. In chronic hepatitis C virus (HCV) infection the situation is similarly confused. It is now clear that elimination of the virus (sustained virological response) is associated with improvement of liver fibrosis and a reduction in the risk of developing HCC. However, in a proportion of patients with cirrhosis at the time they started treatment there is little resolution of the fibrosis and the risk of HCC persists after viral elimination. The important clinical point is that whilst virological control is important and will reduce risk of HCC it is still vital to maintain patients under surveillance.

Host genomics in viral hepatitis

( Mark Thursz ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.1

The outcome of viral hepatitis infection varies substantially in different individuals. This is particularly marked in hepatitis B virus (HBV) and hepatitis C virus (HCV) infections where the clinical course may vary from asymptomatic self limited infection to chronic infection progressing to cirrhosis, liver failure and / or hepatocellular carcinoma. Family clustering and twin studies indicate that some of the variability in the outcomes of these infections is determined by the host genetic background. Over the last 20 years a number of the genes which exert influence on the outcome of infection have been identified. In HBV infection both candidate gene studies and genome wide association studies have demonstrated the importance of the genes in the major histocompatibility region and in particular to the HLA class II alleles. In HCV infection recent excitement has focussed on a series of genome wide association studies revealing the importance of specific single nucleotide polymorphisms in the IL?28b gene which influence both response to treatment and spontaneous resolution of infection. Genetic association studies have also addressed variation in the rate of liver fibrosis and susceptibility to cancer. Polymorphisms in the coagulation system proteins have highlighted the importance of thrombin in fibrogenesis and therefore indicated a potential therapeutic approach for patients with progressive disease. A number of genome wide association studies have identified susceptibility loci for hepatocellular carcinoma but there is, at present, a lack of consistency in these findings.