Texas Liver Coalition: Guest Column

Hepatitis B: A Primer
by John C. Hoefs, MD
UCI Medical Center
Irvine, CA

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Hepatitis B virus (HBV) is a DNA virus that can chronically infect hepatocytes causing a wide spectrum of clinical liver disease that includes cirrhosis and hepatocellular carcinoma (HCC). All of the other hepatitis viruses are of the RNA variety such as hepatitis A, C, D and E. Only HBV (+/- HDV) and HCV cause chronic infection placing the patient at significant risk for the complications of chronic liver disease and HCC.

Parenteral or sexual exposure is the most common modes of transmission in the western countries such as the USA whereas childhood exposure (before the age of 5) is most common in Asia and Africa. Vertical exposure from an infected mother to child is frequent in this instance.

Exposure to HBV as an adult usually produces an intense immunologic reaction to the virus that results in the killing of infected hepatocytes and clearance of the virus from the body. Clinically, this produces high levels of SGOT and SGPT in blood accompanied in some patients by hepatic dysfunction with jaundice and even liver failure. However, the final result is clearance of the virus from the body and permanent immunity. Chronic infection due to inadequate clearance following acute exposure is found in < 5% of adult patients. The result in these patients is a persistent immunologic attack that is inadequate to clear the virus, varies over time, and may produce ongoing fibrogenesis that leads to cirrhosis.

Neonatal exposure does not produce an intense immunologic reaction and, in general, an individual tends to be immune tolerant to the virus. Thus, a majority of patients exposed as a neonate become chronically infected (>90%). However, the immunologic reaction may cause sufficient inflammation over time to cause progressive liver disease or develop an immunologic attack with age. Puberty tends to be a time of enhanced immune attack, particularly in females. Thus, inactive immune tolerant liver disease can be activated during this time to chronic active hepatitis.

There are over 350 million carriers of HBV in the world most of them living in Asia and Africa. The high incidence in these areas is related to childhood exposure, often by vertical transmission in which clearance of the virus from the body in uncommon. Some areas of the Asia ( Taiwan, Vietnam, Cambodia, some Islands in the Phillipines, and some provinces in southern china) have 20 % of the population infected with HBV whereas the incidence in the USA is .3 %. High incidence pockets in the USA often reflect immigration from high risk areas.

The life-time risk of dying of HBV related cirrhosis or HCC is 8 – 35% in these high incidence areas with childhood exposure. HCC is much less common in cirrhosis due to adult acquired HBV.

Hepatitis B viruses can differ from one another by small differences in the DNA genome (genotypes A –H) similar to the varieties of hepatitis C RNA genome (genotypes 1-6). The HBV genotypes are primarily B/C in Asia and A/D predominates in Caucasians and blacks. The HCV genotypes have become clinically useful primarily in determining the likelihood of a sustained virologic response to treatment and are routinely obtained in HCV patients. The value of HBV genotypes have not been clearly identified and, therefore, are not routinely obtained. However, data is accumulating that genotype C and F are particularly predisposed to HCC and, perhaps, a more aggressive course. Therefore, there is potential in the future to use this test to identify patients who need more aggressive treatment and surveillance for HCC.

HBV mutant viruses are a special category that is increasing as treatment options are increasing. During HBV replication, the infected hepatocyte manufactures hepatitis e antigen (HBeAg) proportionate to DNA production. Both tests are positive with the wild type virus. However, 2 mutants can be selected in response to immunologic attack during the course of HBV that eliminate HBeAg production (precore mutant) or markedly reduce HBeAg production (promoter region mutant) relative to DNA replication. Thus, the HBeAg may be absent with high levels of DNA in the Blood. These patients represent the E antigen negative (HBV-E-) variants of HBV chronic active hepatitis. These mutants may be more clinically aggressive and less responsive to therapy than wild type virus.

The relationship of DNA to HBeAg production is variable even in the wild type infection and, therefore, low levels of DNA (<10 5 copies/ml by quantitative PCR) can be associated with a negative HBeAg without one of the mutants mentioned above. Conclusive evidence for a HBeAg mutant virus can only be made by DNA analysis or if the HBeAg is negative with DNA levels >10 5 copies/ml by Quantitative PCR.

Both HBV-E+ and HBV-E- forms of HBV can develop mutants in response to treatment with Lamivudine or Adefovir. The mutant to Lamivudine is an YMDD mutant, occurs at a rate of 10-20% per year of treatment and these mutants respond very well to adeforvir. The mutant to Adefovir is N236T mutant, a rate of .8% per year, and the mutant strain responds very well to Lamivudine.

Hepatitis B is produced in hepatocytes, but inflammation is caused by the immunologic attack directed against hepatocytes containing the virus. The virus does not directly damage the liver in the non-immunosuppressed patient. The clinical patterns of liver disease are dependent on the load of virus in the liver and the intensity of the immunologic attack.

All forms of active liver disease due to hepatitis B are associated with a positive hepatitis B surface antigen (HBsAg) indicating some level of virus production. Conversion of HBsAg from positive to negative in blood particularly when associated with conversion to a positive hepatitis B surface antibody (HBsAb) is thought to represent clinical cure. The HBsAb is a protective antibody that can also be stimulated by the hepatitis B vaccine as well as natural infection. Seroconversion following acute hepatitis B infection is thought to leave no residual virus in the body. However, seroconversion after a period of chronic infection leaves some individuals with cccDNA remnants in the hepatocyte nucleus that could be reactivated at some later time (usually during immunosuppression). In general, the absence of HBsAg in someone with active liver disease indicates that some other agent is responsible for the liver injury even when HBsAb or hepatitis core antibody indicates prior exposure and cccDNA fragments may be present in the nucleus.

Patients with neonatal exposure characterize this group. The virus was never identified by the immune system as abnormal. Thus, high levels of HBV DNA (10 7 – 10 10 copies/ml) can be found with normal liver tests and no evident liver disease. Liver biopsy usually shows a normal liver. The high levels of virus do not form an indication for treatment since progressive liver disease is uncommon. However, some patients will later develop an immunologic attack and patients have a higher incidence of HCC than normal individuals.

Individuals with Chronic hepatitis develop an immunologic attack that is inadequate to clear the virus. The DNA level is positive, AST and ALT are elevated due to inflammation in the liver, and progressive fibrogenesis leading to cirrhosis is possible. In wild type virus, the HBeAg is positive. The rate at which cirrhosis develops is related to the degree of inflammation and other factors such as alcohol intake or co-infection with HDV, HCV and HIV. Although the activity of inflammation may vary over time, the liver disease tends to be progressive.

This is the most clinically important form of the liver disease causing progression to cirrhosis and the highest level of risk for HCC. The complications such as ascites, variceal bleeding and hepatic encephalopathy occur in the patients with cirrhosis.

The wild type infection with HBV-E+ virus has viral levels >10 5 when the liver disease is active. The HBV-E- variant has lower viral levels >10 4 with active liver disease. The average viral levels are a log lower with the HBV-E- variant compared to the wild type.

An intense immunologic response following acute exposure to HBV may nearly clear the virus from the liver during the resolution or 1-2% per year of patients with CAH (even those with cirrhosis) convert to this quiescent stage of hepatitis B. In this inactive stage, the viral load in the liver is minimal, the blood DNA is negative or at least <10 5 copies/ml (<10 4 the HBV-E- variant), and liver tests are normal. Liver disease does not tend to be progressive although cirrhosis previously developed as a result of CAH may not resolve.

Increase in liver tests during the course of HBV infection may be due to co-infection with HDV or HCV or even development of HCC, but more likely is due to factors related to HBV infection. The activity of the liver disease can fluctuate over time with substantial increase or decrease in liver tests (AST and ALT). An increase in liver tests can be due to a flare during which the serum DNA levels may decrease (although generally not to <10 5 copies/ml) and HBeAg remains positive in wild type virus infections.

An increase in liver tests can also be seen with conversion from chronic hepatitis to inactive hepatitis with seroconversion of the HBeAg to HBeAb in chronic hepatitis patients who are initially positive for HBeAg. In this instance, the HBV DNA decreases to <10 5 copies/ml usually becoming negative with time and liver tests normalize. Typically, the alfa-fetoprotein (AFP) increases substantially (range of slight increase to > 1000 ng/ml) during a deactivation sequence with a lag in the peak AFP of 3-6 weeks after the peak of the AST and ALT. The final result is the inactive phase with low DNA and normal liver test.

Liver tests can also increase when a person in the inactive phase has an increase in DNA to >10 5 copies/ml (>10 4 the HBV-E- variant). This reactivation to chronic hepatitis is characterized by elevated AST and ALT followed by a flare in the AFP similar to the conversion from active to inactive phase. The final result is chronic hepatitis, elevated DNA, and positive HBeAg.

Presumably, the elevated liver tests during a deactivation or activation sequence are due to severe necrosis and the elevated AFP to hepatic regeneration as a response. In that sense, the elevated AFP is a good prognostic sign. The amount of necrosis can be severe enough to cause jaundice and even the appearance of fulminant hepatic failure. These periods of elevated liver tests are similar to that seen with acute viral hepatitis. In fact, such patients caused an over-estimation of the chronicity (to 10 %) following acute viral hepatitis when such episodes were considered due to acute exposure.

In general, the hepatitis B virus does not directly damage the liver. However, intense immunosuppression allows the virus to proliferate and fill most of the hepatocytes of the liver producing toxicity. The overwhelming load of virus produces direct damage in this setting resulting in profound damage and a clinical syndrome known a cholestatic fibrosing hepatitis B. It occurs primarily in the setting of intense immunosuppression with hepatic or renal transplant and during chemotherapy that nearly wipes out the immune system. HBsAg positive patients who are started on intense chemotherapy should have Epivir or Hepsera initiated prior to the start of chemotherapy or transplant. The alternate strategy of following HBV DNA levels closely may allow the patient to become severely ill or even die before therapy can become effective.
The clinical difference between a flare or activation / deactivation sequence compared to cholestatic fibrosing HBV is the very high DNA levels (often > than a billion) and severe hepatocyte dysfunction with jaundice and elevated prothrombin time out of proportion to the elevation of AST and ALT.

Patients with immune tolerant HBV regardless of the level of DNA (range: 10 6 to10 11 copies/ml) and inactive HBV probably do not need to be treated since progressive liver disease is unlikely. A liver biopsy is appropriate if the stage of liver disease or activity is unclear. However, some patients with cirrhosis and inactive hepatitis B may be considered for such therapy.
The goal of all forms of hepatitis B treatments is a deactivation sequence resulting in inactive HBV. This can occur naturally over time at a rate of 1-2 % per year and is more likely with high levels of AST and ALT. However, it is unlikely that the HBsAg will become negative or that the virus will be cleared from the body. Therapy is designed to increase the rate at which chronic hepatitis becomes inactive.

The approved treatments of HBV are interferon (alpha 2 b) and the antivirals, Epivir and Adefovir. Interferon Alpha 2 b is given in 10,000,000 units SC every other day or 5,000,000 units daily for 4 – 12 months. The patient is generally sick with the usual side effects of high dose interferon. The advantage of short term interferon therapy is that seroconversion may be permanent in the absence of continued therapy. Furthermore, up to 40% of patients who seroconvert in response to interferon may eventually lose their HBsAg and be cured of the Hepatitis B virus infection. Interferon is the only approved therapy in which cure of infection is likely.

Patient with high baseline levels of AST and ALT are more likely to have permanent seroconversion and eventual loss of HBsAg. Patients with neonatal acquired HBV are less likely to have seroconversion or cure than patients with adult acquired HBV.

Two nucleoside analogues are available for HBV treatment, Lamivudine and Adefovir. Neither have many side effects and both are highly effective with the at least a 3 log decrease in viral DNA levels within 4-8 weeks with at least 40% becoming negative for DNA within a year. The rate of seroconversion from HBsAg to HBsAb is 20% for Lamivudine and 10% for Adefovir. However, seroconversion from Lamivudine is stable after the first year whereas the serocoversion rate continues to increase at approximately 10% per year for Adefovir reaching 30% at 3 years. The rate of YMDD mutation is 20% per year for Lamivudin (peaking at 60-70 % in 3 years) compared to .8% for the N236T mutant on Adefovir. Mutants from one drug are treated effectively with the other drug. HBeAg seroconversion that has been stable for 1 year on antivirals becomes a durable seroconversion when the drug is stopped in at least 86% of patients with Lamivudine and nearly 100% of patients with Adefovir.

Although the low mutation rate of adefovir might make this drug preferable for initiation of treatment in HBV-E+ patients, the monthly cost is three times that of Lamivudine, the rate of seroconversion in the first year is slow, resistance to Lamivudine may take up to 5 years to appear and Lamivudine resistance can be treated with Adefovir. Furthermore, renal insufficiency is an unlikely, but serious potential side effect of adefovir. HBV-E- patients may benefit from initiation with Adefovir since long term treatment is required in all patients and the low rate of resistant mutants is more likely to confer long term benefit.

HBV is a serious viral infection of the liver that has the potential to cause cirrhosis and HCC. Numerous factors affect the outcome including adult vs. childhood exposure, mutant virus related to immunologic pressure and treatment, and activity of the liver disease. Patients with advanced or very active liver disease should be treated whereas patients with immunotolerant and inactive disease rarely need treatment.