Treatment of Hepatitis B

Treatment of Hepatitis B

Vivek Raj, MD, MRCP (UK), Assistant Professor, Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas

[Clinical Cornerstone 3(6):24-36, 2001. ฉ 2001 Excerpta Medica, Inc.]

Abstract and Introduction

Abstract

Hepatitis B virus (HBV) is a major world health problem and a common cause of cirrhosis and hepatocellular carcinoma. The natural history of HBV varies with many factors, including age of acquisition. Persistent elevation of alanine aminotransferase (ALT) levels and presence of hepatitis B surface antigen for >6 months after infection suggest chronic HBV. Presence of hepatitis B e antigen (HBeAg) and HBV DNA in serum indicate active disease. Treatment is indicated for chronic active HBV. The aim of treatment is to suppress viral replication and eliminate the virus. Endpoints of treatment are normalization of ALT levels and elimination of HBeAg and HBV DNA from the blood. Available treatments are interferon alfa and lamivudine. Interferon is effective in 25% to 40% of patients, but has serious side effects. Lamivudine is effective in a similar percentage of patients and has fewer side effects; however, it is associated with the emergence of viral mutations and drug-resistant strains.

Introduction

Chronic hepatitis B virus (HBV) affects >5% of the world's population -- it is the primary cause of cirrhosis and hepatocellular carcinoma and the ninth leading cause of death worldwide. In the United States, ~1 million persons are chronically infected with HBV. The HBV carrier rate in the United States, Western Europe, and Australia is 0.1% to 0.2%, but is as high as 10% to 20% in China, Southeast Asia, and sub-Saharan Africa. An effective vaccine has been available since 1982, but its use has been primarily restricted to high-risk groups. Since 1991 the vaccine has been given to all newborns in the United States. Because treatment of chronic active HBV can prevent cirrhosis and liver cancer, effective therapy and universal immunization are highly desirable goals. To treat HBV, it is important to understand the epidemiology, natural history, and serologic markers of the disease.

Natural History

The clinical presentation of acute HBV ranges from subclinical hepatitis (70%) to icteric hepatitis (30%) with rare cases of fulminant hepatitis (0.1% to 0.5%). Elevation of liver enzyme levels, primarily alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with levels typically up to 1000 to 2000 IU/L (ALT > AST), is a hallmark of acute HBV. Elevation of bilirubin levels occurs after an increase in liver enzymes. In acute HBV the best indicators of prognosis are parameters of hemostasis (prothrombin time). In patients who recover, ALT levels normalize within 1 to 4 months. Persistent elevation (>6 months) of serum ALT levels usually indicates progression to chronic HBV.

The outcome of acute HBV depends on age of acquisition, immune status of the host, and rate of replication of the virus. In the perinatal period or childhood, infection is usually associated with mild or no symptoms but a high risk of chronicity. In adults, infection is usually symptomatic with a low risk of chronicity. With perinatal infection, the initial phase is characterized by high levels of HBV replication, hepatitis B e antigen (HBeAg) in serum, and high levels of HBV DNA, but no evidence of active liver disease. The patient is asymptomatic, has normal ALT levels, and minimal changes on liver biopsy. Minimal liver disease, despite high levels of HBV replication, may be caused by immune tolerance in infants and children. These patients usually experience an immune-clearance phase during the second and third decade when spontaneous HBeAg seroconversion to antibody to HBeAg (anti-HBe) increases to an annual rate of 10% to 20%.

Chronic HBV ranges from the asymptomatic carrier, to chronic active HBV, to cirrhosis and hepatocellular carcinoma. The rate of progression from acute to chronic HBV is ~90% for perinatal infection, 20% to 50% for infection acquired between the ages of 1 to 5 years, and <5% for adult-acquired infection. Of these adults, some develop chronic active HBV while others are asymptomatic carriers.

In healthy hepatitis B surface antigen (HBsAg) carriers, prognosis is very good with a low rate of progression to cirrhosis. However, in HBV patients from endemic areas and in patients with chronic HBV, the risk of progression over 5 years from chronic hepatitis to cirrhosis is 12% to 20%, from cirrhosis to decompensation 20% to 23%, and from compensated cirrhosis to hepatocellular carcinoma 6% to 15%.

Serologic Diagnosis

Serologic tests used to diagnose HBV infection are shown in the Table.

HBsAg and Anti-HBs

HBsAg is the serologic hallmark of HBV infection. HBsAg appears 1 to 10 weeks after acute infection and before the onset of symptoms or elevation of ALT levels. In patients who recover, HBsAg becomes negative 4 to 6 months later. Persistence of HBsAg beyond 6 months suggests progression to chronic HBV. Antibody to HBsAg (anti-HBs) appears as HBsAg disappears, and in most cases anti-HBs persists and confers lifelong immunity. In 25% of cases the titers of anti-HBs are not sufficient to neutralize circulating virions, and HBsAg and anti-HBs coexist. Individuals with this combination are considered carriers.

HBcAg and Anti-HBc

Hepatitis B core antigen (HBcAg) is an intracellular antigen in infected hepatocytes and is not detectable in serum. Antibody to HBcAg (anti-HBc) appears early in the infection and is then detected throughout the course of infection. In the acute phase, it is primarily an immunoglobulin (Ig) M antibody. In patients who recover, the anti-HBc changes to IgG and remains detectable with anti-HBs. It is also detectable in patients with chronic active HBV with HBsAg. IgM anti-HBc may be detectable during HBV exacerbations.

HBeAg and Anti-HBe

HBeAg is a marker of active HBV replication and infectivity. HBeAg is usually associated with high titers of HBV DNA in the serum, active liver disease, and high rates of infectivity; however, patients with perinatal HBV infection can be HBeAg positive but have minimal liver inflammation and normal ALT levels. Seroconversion from HBeAg to anti-HBe is associated with recovery and the disappearance of serum HBV DNA. Although rare, some patients have a viral mutation in the precore region that prevents expression of HBeAg; these patients have active liver disease and HBV DNA in the serum but are HBeAg negative.

Serum HBV DNA

The presence of serum HBV DNA is sensitive and specific for viral replication. Hybridization or signal amplification (branched DNA) assays detect 10⁵ to 10⁶ viral equivalents/mL, while the more sensitive polymerase chain reaction (PCR)-based assays detect 10² to 10³ viral equivalents/mL. Recovery from acute HBV and HBeAg seroconversion in chronic HBV is associated with the disappearance of HBV DNA by non-PCR-based assays. PCR-based assays may remain positive for many years, which suggests the persistence of small numbers of virions that are contained by the host immune system. The main use of HBV DNA assays is to assess chronic active HBV patients for treatment and to evaluate their response.

Patterns of Serologic Tests for HBV

Acute HBV is diagnosed by the presence of elevated ALT, HBsAg, and IgM anti-HBc levels. Similar changes may be seen with exacerbation of chronic HBV, reactivation of HBV, superinfection of an HBV carrier with hepatitis C virus (HCV) or hepatitis D virus (HDV), and acute drug- or toxin-induced hepatitis (eg, alcohol) in an HBV carrier.

HBV infection with spontaneous recovery is characterized by the presence of anti-HBs and IgG anti-HBc. Following successful HBV vaccination, the only serologic marker detected is anti-HBs.

Chronic HBV is characterized by the persistence of HBsAg for >6 months. During active viral replication, HBeAg and HBV DNA (by non-PCR-based assay) are positive, and ALT levels are usually elevated. These tests are necessary to decide if therapy is warranted. A carrier state is characterized by positive HBsAg and anti-HBs, negative HBeAg, normal ALT levels, and undetectable HBV DNA (by non-PCR-based assays).

Liver biopsy is helpful in assessing the severity of liver damage, predicting prognosis, determining treatment, and monitoring response. Liver biopsy is generally indicated if any of the parameters for chronic active HBV are present -- HBsAg along with either elevated ALT levels, HBeAg, or HBV DNA, or all 3 of them. In most cases all 3 parameters are present but in some the ALT levels may be normal or HBeAg may be negative.

Treatment of HBV

In compensated patients with chronic HBV, antiviral therapy is indicated for active viral replication, elevated ALT levels, and histologic evidence of chronic liver injury. Two agents are FDA-approved for treatment of chronic HBV -- interferon alfa (IFN-

) and lamivudine (a nucleoside analogue). The mechanism of action of the 2 drugs is different as is patient selection for treatment.

IFN-alfa

Mechanism of action. IFNs are proteins produced by host cells in response to viral infection. Three different types have been identified -- IFN-

produced by B lymphocytes and monocytes, IFN-b by fibroblasts, and IFN-

by helper T and natural killer cells. Of these, only IFN-

is effective against HBV. HBV is a noncytopathic virus. Liver injury is caused by the host immune response. IFN-

has both immunoregulatory and antiviral activity and therefore is effective in suppressing viral replication and augmenting the host immune response. IFN-

responders have a rapid increase in ALT levels during the second or third month of therapy (Figure 1). This increase is commonly associated with seroconversion from HBeAg to anti-HBe and is thought to reflect immune stimulating properties of IFN. IFN-

also has an antifibrogenic effect that may decrease the progression to fibrosis and cirrhosis.

Patient selection and indications for IFN therapy. Patients suitable for treatment with IFN have: (1) active viral replication by presence of HBeAg or HBV DNA (non-PCR-based assay) for >6 months; (2) elevated ALT levels; and (3) active HBV on biopsy. Because 5% to 10% of patients who are HBeAg positive will convert spontaneously to anti-HBe, patients should be screened for >6 months before initiating therapy. IFN is contraindicated in patients with decompensated cirrhosis because there is a risk of a hepatitis flare with seroconversion from HBeAg to anti-HBe (seen in 60% of patients treated with IFN) that can precipitate liver failure.

Predictors of response to IFN therapy. Clinical and serologic parameters associated with a good response to IFN include high pretreatment ALT levels (>3 to 4 x normal), low HBV DNA (<200 pg/mL by solution hybridization), and active disease on liver biopsy. Other variables associated with a better response include adult infection, female sex, short duration of infection, and heterosexuality. Because the precore/core region of the virus is the major target for the host immune response, mutations in this region are associated with a poor response to IFN therapy and a higher relapse rate. These factors help to assess prognosis, but "poor response" factors should not deter treatment with alternative strategies, such as lamivudine.

Efficacy of IFN therapy. The goal of IFN therapy is permanent suppression of viral replication or elimination of infection. In most trials of antiviral therapy, the endpoint of successful therapy was the disappearance of HBeAg and HBV DNA and normalization of ALT levels for >6 months after therapy. This result was seen in 25% to 40% of patients treated with IFN for 4 to 6 months. In a meta-analysis of 15 clinical trials, the overall response rate (disappearance of HBeAg) was 33% with IFN compared with 12% in controls.

In patients who become HBeAg negative at the end of therapy, remission is usually sustained and results in an inactive HBsAg carrier state. About one third of these patients eventually lose HBsAg. In about 80% of patients who become HBsAg negative, serum HBV DNA is not detectable even by PCR. Virologic response after IFN treatment has been maintained for 3 to 11 years. Patients who respond to IFN have improvement in symptoms and liver histology. Long-term IFN treatment results in a decreased risk of mortality, liver transplantation, and complications of cirrhosis. Few patients undergo HBV reactivation within the first year of completion of therapy.

Dose and side effects. IFN is given as 5 million units daily or as 10 million units 3 times a week subcutaneously for 4 months. Therapy should be monitored closely. Patients should be seen at 2- to 4-week intervals and ALT and AST levels monitored and a complete blood cell count taken. HBsAg, HBeAg, and HBV DNA should be tested at initiation, end of therapy, and 6 months later. Figure 1 shows typical courses of responders and nonresponders. Treatment with IFN is associated with frequent side effects. Most patients experience influenza-like illness with fever, chills, myalgia, and headache after IFN injection. These symptoms, however, tend to improve after the first few days of therapy. Psychiatric side effects, especially depression, occur in 15% of patients. Although rare, suicidal ideation and delirium can occur. IFN frequently causes a 30% to 50% reduction in platelet count, 20% to 40% reduction in white blood cell count, and a slight fall (3% to 5%) in hematocrit. IFN can also induce an autoimmune diathesis and can unmask or worsen preexistent autoimmune conditions. Both hypothyroidism and hyperthyroidism have been reported, but in most cases there is no clinically significant change. If adverse effects are not very severe, then dose reduction by 50% is advised and should be adjusted back to the original dose once any side effects disappear. Dose reduction is necessary in ~20% of patients. Discontinuation of treatment due to severe adverse events is necessary in <5% of patients.

HDV and HBV coinfection. Patients who are coinfected with HDV tend to have rapidly progressive disease and earlier decompensation compared with patients who have HBV alone. Unfortunately, results with IFN therapy in these patients are disappointing. IFN has been shown to decrease ALT levels and suppress HBV replication but the virus is not eradicated, and when treatment is stopped, almost all patients relapse.

HIV and HBV coinfection. Improved survival in HIV patients has led to increased interest in the treatment of HBV in these patients. HIV coinfection may result in a poor response to IFN because of high levels of HBV DNA, relatively low serum ALT levels, and depressed immune function. Data on the treatment of these patients with IFN are limited. A better response with fewer side effects may be seen with lamivudine.

HCV and HBV coinfection. Coinfection with HCV and HBV is associated with severe liver injury and poor response to IFN. In one study, loss of HBV DNA and HBeAg was seen in only 6.7% of patients.

Nucleoside Analogue Therapy

Mechanism of action. Nucleoside analogues block HBV replication by inhibiting HBV DNA polymerase; therefore, unlike IFN, the activity of these drugs is independent of host immune responses. These agents are highly bioavailable by oral administration and are well tolerated. Of these, lamivudine is the most extensively studied, most effective, and the only one that is FDA-approved.

Efficacy of lamivudine. Lamivudine is associated with a 4-log suppression of HBV DNA. Lamivudine treatment, 100 mg PO daily for 1 year, results in HBeAg seroconversion in 17% of patients; HBeAg loss in 32%; sustained normalization of ALT levels in 41%; and histologic improvement in 52% (Figure 2). Moreover, lamivudine is effective in patients not usually responsive to IFN and in those who have failed IFN. Prolonging lamivudine therapy increases the likelihood of a sustained response. Of patients who lost HBeAg after treatment with lamivudine, 80% maintained their response for ฃ2 years. However, patients without an HBeAg response invariably returned to pretreatment levels of HBV DNA and ALT.

Dose, duration of treatment, and side effects. The standard dose of lamivudine is 100 mg PO daily for 1 year. It is recommended that lamivudine be stopped after a sustained period (>2 months) of HBeAg loss or seroconversion. Patients are then monitored closely to identify reactivation, which is an indication for retreatment. Lamivudine is remarkably free of side effects and discontinuation of therapy due to side effects is rarely necessary.

Lamivudine in patients with predictors of poor response to IFN. Patients who respond poorly to IFN, including those with perinatal acquisition of HBV, normal ALT levels, precore-mutant strains of HBV, and immunosuppression by HIV or organ transplantation, tend to respond well to lamivudine. Lamivudine has been used safely in some patients with hepatic decompensation and also may be effective in patients who fail IFN therapy.

Resistance to lamivudine. Emergence of resistance, commonly associated with a mutation in the YMDD motif of the polymerase gene, is a major limitation of lamivudine therapy. The frequency ranges from 15% to 30% after 1 year of therapy to 50% after 3 years. In immunocompetent patients, continued treatment with lamivudine has maintained improvement, but in immunosuppressed liver transplant patients, YMDD mutation has resulted in hepatic decompensation in 50% of cases.

IFN or Lamivudine as First-Line Therapy?

IFN requires only 4 months of therapy, achieves a 30% to 40% HBeAg loss, about a 10% HBsAg loss, and long-term improvement in histology and natural history. However, IFN requires uncomfortable injections, is associated with many side effects, and is of limited value in the subgroups discussed earlier.

On the other hand, lamivudine is safe, convenient to administer, achieves a >30% HBeAg loss, shows histologic improvement in the majority of patients, and is effective in treating patients with poor response indicators to IFN treatment such as precore mutants or normal ALT levels. However, lamivudine requires a long duration of treatment and is associated with the emergence of viral variants and resistance. These factors also can hamper consideration for liver transplantation.

The choice of drug, therefore, should be tailored to the patient, taking into account factors such as the likelihood of response to therapy, compliance, cost, and follow-up. The algorithm shown in Figure 3 indicates a reasonable approach to stratification for therapy. As shown in the figure, elevated ALT levels (>3 to 4 x normal), HBeAg positive, and HBV DNA positive are all indicators of good response to IFN treatment, while patients with normal ALT levels or absence of HBeAg do not respond well to treatment with IFN. However, the efficacy of lamivudine is similar in both groups of patients. For patients who have good predictors of response to IFN, the author's preference is to use IFN if the patient can tolerate it since it has a 30% to 40% sustained response rate and is not associated with the emergence of drug-resistant mutations.

Combination Therapy with IFN and Lamivudine

Data on combination therapy are limited. In a randomized controlled trial of 230 patients, HBeAg seroconversion rates were higher with combination therapy (29%) than with IFN (19%) or lamivudine (18%) monotherapy. However, the difference was not statistically significant by intention-to-treat analysis (P = .12 and .10, respectively). More studies are needed to define the role of combination therapy.

HBV and Liver Transplantation

For patients with acute fulminant liver failure or liver failure caused by chronic HBV, liver transplantation is necessary. Early experience with liver transplantation in HBV-related liver failure was disappointing. The recurrence rates of HBV and progression of liver damage in the graft were high, leading to early rejection, high mortality, and reluctance to perform liver transplant in HBV-related liver failure. However, with the advent of options such as the use of HBV Ig, lamivudine, and famciclovir, in most centers HBV is no longer a contraindication for liver transplantation.

Hepatocellular Carcinoma Screening

There are no clear guidelines for screening patients for hepatocellular cancer who are HBsAg carriers or have chronic active HBV. Most of the recommendations for screening are for patients with cirrhosis or severe chronic active HBV. In these patients, annual or semi-annual serum alpha fetoprotein and ultrasound of the liver are recommended. It is hoped that screening will detect tumors at an earlier stage, resulting in better cure rates. Even in this group, reduction in mortality from hepatocellular cancer has not been well demonstrated. There are some data that favor a similar screening strategy for patients with chronic active HBV and for HBsAg carriers in high endemic areas like Japan.

HBV Vaccine

Since HBV is one of the leading causes of liver cancer in the world, vaccination prevents not only hepatitis and cirrhosis due to HBV but also liver cancer. Universal vaccination for HBV has been adopted in 80 countries in the world. In the United States, universal vaccination for HBV with recombinant vaccine that consists of HBsAg particles was introduced in 1991.

In adults, the vaccine is given as three 10-mg doses at 0, 1 to 2 months, and 6 months. Seroprotective levels (>10 mIU/mL) are achieved in 95% of people who complete the schedule. Efficacy in individuals who develop anti-HBs approaches 100%. Immunity lasts >10 years and may be lifelong, even though anti-HBs levels disappear in a large number of individuals after 10 years.

The vaccine is indicated for all infants, children, and adolescents through 18 years of age. Among adults, it is indicated for high-risk groups (high-risk occupation, sexually active adults with multiple partners, homosexual men, IV drug users, patients attending sexually transmitted disease clinics, and patients needing clotting factor preparations). Neonates born to HBsAg-positive mothers also should be vaccinated.

Postexposure Prophylaxis of Health Care Workers

Previously unvaccinated health care workers who are exposed to infection by needle stick or splash and the source is HBsAg-positive should be given HBV Ig (0.06 mL/kg) and the first of 3 doses of the HBV vaccine as soon as possible. The second and third doses of the vaccine should be given at 1 and 6 months. If the health care worker has been previously vaccinated for HBV and is a responder, no further treatment is necessary.

Summary

Progression to cirrhosis and liver cancer occurs in patients with chronic HBV who have active viral replication characterized by presence in the serum of HBeAg and HBV DNA. Depending on the likelihood of response, compliance, cost, and other factors, these patients should be treated with either IFN or lamivudine. In the future, universal HBV vaccination is likely to decrease the burden of cirrhosis and liver cancer from this disease.

Key Points

The rate of progression from acute to chronic HBV is ~90% for perinatal infection, but <5% for adult infection.
Serologic markers that indicate active viral replication and suggest the need for therapy are elevated ALT levels, HBeAg, and HBV DNA (non-PCR-based assay). Liver biopsy assesses degree of inflammation and fibrosis.
The goal of IFN therapy is suppression of viral replication or elimination of infection. Serologic markers suggesting therapeutic response are normalization of ALT levels, HBeAg loss, HBV DNA loss, seroconversion to anti-HBe, and in some cases loss of HBsAg. IFN therapy is successful in 25% to 40% of cases.
Lamivudine is effective in patients who respond poorly to IFN. It is well tolerated; however, it is associated with a high incidence of resistance and mutations in the virus.
Since HBV is one of the leading causes of liver cancer, vaccination prevents not only hepatitis and cirrhosis due to HBV but also liver cancer.

Sidebar: Dialogue Box

ADVISORY BOARD
Please elaborate on the relationship between HBsAg and HBV DNA. For example, if the HBsAg is positive, can the HBV DNA be negative?

RAJ
HBsAg arises from excess surface particles produced by virions multiplying in liver cells. Since HBV DNA arises from hepatitis virions replicating in the liver, one would expect it to be positive in patients with positive HBsAg. Having said that, the less sensitive non-PCR-based HBV DNA assays can be negative in such a patient, but the more sensitive PCR-based assay will always be positive. The PCR assays are so sensitive that they can remain positive for years after the virus is cleared from the blood.
ADVISORY BOARD
Do patients infected with HBV ever completely eliminate the virus?

RAJ
Probably not. Even in patients with positive antibody to HBsAg and negative HBsAg and DNA in the blood, the PCR-based assays in liver cells will still likely be positive. In the vast majority of patients, HBV infection is best viewed as
a continuum, which at any given time reflects the degree of viral replication, the immune response mounted by the patient, and our ability to detect or measure it. For example, the HBsAg carrier is a patient who at that moment is mounting sufficient immune response to suppress active replication but not enough to completely eliminate the production of surface antigen. However, this is a dynamic situation; thus, it is possible that if the immune response were to change, the carrier state could reactivate and result in a state of chronic active hepatitis.
ADVISORY BOARD
Why not simply use quantitative PCR DNA measurements as the metric to follow chronic HBV patients as opposed to relying on a composite of ALT levels and various viral replication markers?

RAJ
Primarily because of the great fluctuations seen in this measurement. For example, a patient may one day have a high number of virions, such as 6 million viral equivalents/mL; 5 days later have only 3 million; and a few days later have up to 5 million. Second, the number of circulating virions measured doesn't consistently correlate well with the histologic picture of the liver. Unlike HIV where viral replication and the number of virions correlate well with CD-4 counts and prognosis, in HBV it has not been as good. As a result, it is necessary to put 4 or 5 pieces of the puzzle together to arrive at an accurate picture.

It is important to appreciate that any single piece of the puzzle is not likely to give you a complete, accurate picture. For example, with respect to HBeAg, recognize that there are some patients with viral mutations in the precore region of the virus in whom this antigen is negative, yet these patients can have a lot of virus replicating and inflicting damage. Similarly, if you rely solely on ALT levels, you'll find there are some patients who have normal ALT levels and viral replication going on and others who have higher ALT levels and relatively low viral replication.
ADVISORY BOARD
What is the recommended follow-up in the HBsAg carrier?

RAJ
Normally we follow patients who are carriers on a 6- to 12-month basis. In addition to ordering a full panel of liver tests that includes an ALT value, we check HBeAg as well.
ADVISORY BOARD
What about the patient who has a positive HBsAg with an elevated ALT level but negative viral replication markers (ie, HBeAg and hybridization DNA assay)?

RAJ
Typically we would recommend a liver biopsy and offer medical therapy. If the patient declines, then close follow-up is indicated since the patient has not been able to suppress the infection enough to achieve a carrier state.
ADVISORY BOARD
What screening protocol for hepatocellular carcinoma do you follow in patients with chronic HBV infections?

RAJ
Let me begin by stating there are no definitive studies to guide you in this regard. Having said that, for patients who are carriers -- that is HBsAg positive and surface antibody positive, HBeAg negative, with no DNA detected by hybridization assay -- I probably wouldn't screen. For patients with chronic active hepatitis -- regardless if mild, moderate, or severe -- I would screen every 2 to 3 years with an ultrasound of the liver and a serum alpha fetoprotein. For the patient with evidence of cirrhosis, I would screen with these studies on an annual basis.
ADVISORY BOARD
Why is screening for hepatocellular carcinoma more aggressive in Southeast Asia?

RAJ
Since HBV DNA lives within cells, patients with HBV do not have to progress in a sequential fashion from chronic active hepatitis to cirrhosis to liver cancer. This seems to be the case in high endemic areas in Southeast Asia where patients who have chronic active hepatitis with mild activity have developed liver cancer without first having cirrhosis. That is why health practitioners in China and Japan are very aggressive about screening and recommend screening every 6 months in all patients with chronic HBV. For reasons not entirely clear, the incidence of such a rapid progression is much lower in Western Europe and the United States. As a result, in the United States we screen less aggressively in patients with mild disease or who are carriers and reserve frequent screening for those patients who have more active liver disease and cirrhosis or for those patients who have failed medical therapy.
ADVISORY BOARD
Why do you favor IFN therapy only in those patients with elevated ALT levels and positive HBeAg and hybridization DNA assays and lamivudine if even 1 of these 3 parameters is negative?

RAJ
The answer lies in the observation that the best response to IFN is seen in patients who have 3- to 4-fold elevations in ALT levels and are both HBV DNA and HBeAg positive. For such patients the main reason I favor IFN over lamivudine is that IFN avoids the risk of viral resistance emerging and the risk that if these patients were to require
a liver transplant 2 or 3 years down the line they would have a mutated virus that might cause them to get turned down for the transplant. IFN is a more toxic treatment than lamivudine, but it represents a sure-shot treatment since there are more data and experience to support its use. However, for patients who don't have all of these positive markers, the response rate for IFN falls from 30% to 40% to 10% to 20%, which seems to me to be a very low response rate for such a toxic treatment. In those cases, I prefer lamivudine.
ADVISORY BOARD
Do you have difficulty convincing people with normal ALT levels to undergo a liver biopsy?

RAJ
It's usually not a problem. I tell them that although having a normal ALT level is an indicator of inactive disease, it by no means guarantees it.
I then inform them that a liver biopsy is the only sure way of determining the degree of liver damage and whether medical therapy is warranted.
ADVISORY BOARD
Should patients with chronic HBV infections, including carriers, be vaccinated against hepatitis A (HAV)?

RAJ
Yes, vaccination against HAV is recommended even in carriers. The bottom line is that coinfection with another hepatitis virus is bad news. Consequently, for HCV patients we vaccinate against HAV and HBV. For HBV, we recommend vaccinating only against HAV simply because there's no vaccine available for HCV.
ADVISORY BOARD
What are your thoughts with regard to the need for an interval booster for HBV for people who have been vaccinated in the past?

RAJ
Although by no means definitive, most of the vaccination data up to this point show that at 10 years antibody levels may fall off but you continue to be protected.
ADVISORY BOARD
In health professionals who have been vaccinated, should we test their B surface antibody at some point, say after 10 years?

RAJ
I would not routinely check it since I really wouldn't know how to interpret it. However, if significant time has elapsed since the vaccination series and the patient then has significant exposure to HBV, I would probably check the serology to see if the antibody titer is low. If it is, I would give a booster. It should be noted, though, that the general opinion is that if someone has already been vaccinated and has developed a good antibody response, then you don't need to do any testing even if the person is exposed to HBV.
ADVISORY BOARD
For health care professionals who have completed the vaccination series, do you routinely check titers to make sure they've responded?

RAJ
Yes, I do, because they are a group at high risk of exposure. But once seroconversion is demonstrated, routine follow-up titers are not needed regardless of the elapsed interval.
ADVISORY BOARD
What do you do in the 5% of patients who don't form an antibody to HBsAg following the immunization?

RAJ
I do 2 things. First, I repeat the entire immunization series. Second, I switch to a different vaccine product. If they don't seroconvert after this, I advise them to take extra precautions and inform them that in the event of a significant exposure, HBV immunoglobulin should be administered immediately after exposure.
ADVISORY BOARD
How well has it been demonstrated that current medical therapy can favorably impact the development of cirrhosis, the development of hepatocellular cancer, and/or mortality due to liver failure in a patient with chronic HBV?

RAJ
A lot of prospective data have been collected on treated patients on rates of progression to cirrhosis, the need for liver transplantation, and death from hepatocellular cancer. Long-term follow-up of patients treated for hepatitis B has shown that responders have improved overall survival as well as survival free of hepatic decompensation and/or hepatocellular carcinoma. (See Niederau C, Heintges T, Lang S, et al. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med. 1996;334:1422-1427 and Papatheodoridis GV, Manesis E, Hadziyannis SJ. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B.

Table. Serologic Tests for Hepatitis B Virus

Serologic Test	HBsAg	Anti-HBs	Anti-HBc	HBeAg	Anti-HBe	HBV DNA
Acute infection
Early phase	+	-	IgM	+	-	+
Window phase	-	-	IgM	-	-	-
Recovery	-	+	IgG	-	+	-
Chronic infection
Active replication	+	-	IgG	+	-	+
Low replication	+	-	IgG	-	+	-
Precore mutant	+	-	IgG	-	+	+
HBV vaccination	-	+	-	-	-	-

HBsAg = hepatitis B surface antigen; anti-HBs = antibody to HBsAg; anti-HBc = antibody to hepatitis B core antigen; HBeAg = hepatitis B e antigen; anti-HBe = antibody to HBeAg; HBV = hepatitis B virus; IgM = immunoglobulin M; IgG = immunoglobulin G; + = positive; - = negative. Reprinted with permission from Chan HLY, Lok ASF. Hepatitis B in adults -- a clinical perspective. Clin Liver Dis. 1999;3:291-307.