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REVIEW ARTICLE Table of Contents   
Year : 2005  |  Volume : 2  |  Issue : 1  |  Page : 127-153
Long-term management of patients with chronic hepatitis B virus infection


Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, MI, USA

Click here for correspondence address and email
 

How to cite this article:
Lok AS. Long-term management of patients with chronic hepatitis B virus infection. Hep B Annual 2005;2:127-53

How to cite this URL:
Lok AS. Long-term management of patients with chronic hepatitis B virus infection. Hep B Annual [serial online] 2005 [cited 2019 Mar 22];2:127-53. Available from: http://www.hepatitisbannual.org/text.asp?2005/2/1/127/29378


Chronic hepatitis B virus (HBV) infection can progress to cirrhosis, hepatic failure and hepatocellular carcinoma (HCC). In most instances, HBV infection is a life-long infection. This concept is important because it implies that reactivation of HBV replication can occur even in patients who have had prolonged periods of undetectable viremia and inactive liver disease and emphasizes the need for life-long follow-up. The clinical course of chronic HBV infection is determined by the interplay between the virus, the host and the environment. An understanding of the natural history of chronic HBV infection and the safety and efficacy of currently available treatments is critical in the long-term management of patients with chronic HBV infection.

HBV infection is a life-long infection

The advent of sensitive molecular virology assays has revolutionized the concept of viral clearance and recovery from HBV infection. Many studies found that serum HBV DNA and vigorous immune response to HBV antigens can be detected more than 10 years after recovery from acute HBV infection - hepatitis B surface antigen (HBsAg) to antibody (anti-HBs) seroconversion.[1],[2] These findings indicate that HBV persists after 'recovery' from acute HBV infection, but is contained by the host immune response. This accounts for reports of reactivation of HBV replication during cancer chemotherapy of patients with serological markers of recovery from HBV infection.[3]

The likelihood of spontaneous viral clearance in patients with chronic HBV infection is more remote because of the presence of extra hepatic reservoirs of HBV, integration of HBV DNA into the host genome and the presence of an intracellular conversion pathway whereby newly replicated HBV DNA is used to amplify covalently closed circular HBV DNA (ccc DNA).[4] This intracellular amplification pathway enables the establishment of a pool of transcriptional templates in the hepatocyte without the need for multiple rounds of re-infection. Thus, spontaneous viral clearance is unlikely to occur once chronic HBV infection is established. Viral clearance is also rarely achieved in patients who have virological response to antiviral therapy because existing treatment has very little direct effect on cccDNA. Thus, withdrawal of antiviral treatment is usually accompanied by rapid viral rebound.

Clinical course of chronic HBV infection is highly variable

The natural course of chronic HBV infection is determined by the interplay between the virus (genotypes, molecular variants, replication level), host (gender, age, immune response, genetic make-up) and environment (alcohol, smoking, carcinogens, coexistent infection with other viruses: hepatitis C, hepatitis D, human immunodeficiency virus [HCV, HDV, HIV]) [Figure - 1]. While the natural course of chronic HCV infection is generally one of step-wise progression, the natural course of chronic HBV infection is characterized by fluctuations in level of HBV replication and activity of liver disease. This difference may be related to the pivotal role of the host immune response in the regulation of HBV replication and pathogenesis of HBV-related liver disease. The unpredictability of the clinical course of chronic HBV infection poses a challenge to physicians and necessitates regular follow-up of all patients with chronic HBV infection.

The clinical course of chronic HBV infection can be considered as comprising of four phases [Figure - 2] although not all patients go through all four phases.[5],[6]

Immune tolerant phase (HBeAg-positive chronic hepatitis with normal ALT) - In patients with perinatally acquired HBV infection, the initial phase is characterized by high levels of HBV replication: presence of hepatitis B e antigen [HBeAg] and high levels of HBV DNA in serum (6-10 log 10 copies/mL) but no evidence of active liver disease as manifested by lack of symptoms, normal serum alanine aminotransferase (ALT) and minimal changes on liver biopsy. A mild degree of liver injury despite high levels of HBV replication is believed to be due to immune tolerance to HBV.

The immune tolerant phase usually lasts 10-30 years, during which there is a very low rate of spontaneous HBeAg clearance. The cumulative rate of spontaneous HBeAg clearance is estimated to be approximately 2% during the first 3 years and only 15% after 20 years of infection. Persistence of high levels of viremia in adolescents and young adults accounts for the high frequency of maternal-infant transmission in Asians. The lack of assistance from immune-mediated viral clearance also contributes to the low rate of treatment-related HBeAg seroconversion.

Immune clearance phase (HBeAg-positive chronic hepatitis) - This phase is characterized by the presence of HBeAg, high levels of serum HBV DNA and active liver disease (elevated ALT and moderate/severe necroinflammation on liver biopsy). In patients with perinatally acquired HBV infection, transition from the immune tolerant to the immune clearance phase usually occurs during the second to fourth decades of life. In patients with childhood or adult acquired HBV infection, the immune tolerant phase is rarely observed or very transient and most patients are already in the immune clearance phase at presentation.

During this phase, immune response to HBV becomes more active. Immune mediated viral clearance leads to elevated ALT and decreased serum HBV DNA levels. In some patients, the immune response results in marked suppression of HBV replication and HBeAg seroconversion. Spontaneous HBeAg clearance has been reported to occur at a rate of 5-20% per year. HBeAg seroconversion is frequently but not always accompanied by biochemical exacerbations (abrupt increases in serum ALT, which may be >1,000 IU/L).[7] Exacerbations are believed to be due to a sudden increase in immune-mediated lysis of infected hepatocytes and are often preceded by an increase in serum HBV DNA level.

Most exacerbations are asymptomatic and are discovered during routine follow-up.[8] However, some are accompanied by symptoms of acute hepatitis and may lead to the incorrect diagnosis of acute hepatitis B in patients who are not previously known to have chronic HBV infection, particularly if there is accompanying increase in IgM hepatitis B core antibody (anti-HBc) titer. Exacerbations may also be associated with an increase in serum alpha-fetoprotein (AFP) level (which may be >5,000 ng/mL) raising concerns about HCC development. Exacerbations are more commonly observed in men than in women. The reason for the gender difference is not clear, but a higher frequency of exacerbations in men may at least in part account for a higher incidence of HBV-related cirrhosis and HCC among men. In a small percent of patients, exacerbations result in hepatic decompensation and rarely death from hepatic failure.[9] Not all exacerbations lead to HBeAg seroconversion or persistent suppression of serum HBV DNA levels, a phenomenon termed abortive immune clearance. These patients may develop recurrent exacerbations with intermittently undetectable serum HBV DNA with or without transient loss of HBeAg.[8] Such repeated episodes of hepatitis may increase the risk of cirrhosis and HCC.

Inactive carrier state Seroconversion from HBeAg to HBe antibody (anti-HBe) is usually accompanied by marked decrease in serum HBV DNA level (<5 log 10 copies/mL) and normalization of ALT. These patients are considered to be in an inactive carrier state. It is now recognized that HBV replication persists during this phase albeit at a lower level. Using sensitive PCR assays, HBV DNA can be detected in the sera of most inactive carriers but levels rarely exceed 4 log 10 copies/mL.[10]

The clinical outcome of inactive carriers depends on the severity of liver damage prior to sustained HBeAg seroconversion and the durability of this "quiescent" phase. Patients who have had minimal liver damage at the time they became inactive carriers and who remain in this phase will most likely have a favorable outcome while patients who had accrued substantial liver damage prior to HBeAg seroconversion and those who had reactivation of HBV replication after HBeAg seroconversion are at risk of progressive liver disease and HCC. Thus, while long-term follow-up of HBsAg positive blood donors who were in the inactive carrier state at presentation revealed excellent prognosis with very low morbidity and mortality from liver disease,[11] longitudinal follow-up of HBeAg positive patients who underwent HBeAg seroconversion reported mixed results.[12]

Approximately, two-thirds of patients will remain in the inactive carrier phase after HBeAg seroconversion; some of these patients ultimately clear HBsAg.[12] These latter patients are said to have resolved HBV infection although HBV DNA still persist in the body and can be detected with sensitive PCR assays. The annual rate of delayed clearance of HBsAg has been estimated to be 1% in Western patients and 0.5% in Asian patients. In most studies, noncirrhotic patients who cleared HBsAg had very good prognosis but HCC development has been reported in patients who were already cirrhotic at the time of HBsAg clearance.[13]

Reactivation of HBV replication (HBeAg-negative chronic hepatitis) - These patients are HBeAg negative and anti-HBe positive, with elevated ALT and high serum HBV DNA levels. Most patients with HBeAg-negative chronic hepatitis harbor HBV variants with mutations in the precore and/or core promoter region that abolish or down-regulate HBeAg production. These HBV variants have been reported in all parts of the world but are most commonly seen in the Mediterranean region, Middle East and South Asia. The prevalence of precore and core promoter variants and HBeAg-negative chronic hepatitis in different parts of the world is related to the predominant HBV genotype(s) in that region.[14] The vast majority of these patients are initially HBeAg-positive and have wild type HBV, but later selection of precore and core promoter mutations occur prior to or around the time of HBeAg seroconversion. One study reported that roughly 25% of patients who underwent HBeAg seroconversion progressed to HBeAg-negative chronic hepatitis after a mean follow-up of 8 years.[12]

Because HBeAg-negative chronic hepatitis represents a later phase in the natural history of chronic HBV infection, these patients tend to be older, to have more advanced liver disease and are more likely to develop adverse clinical outcomes: hepatic decompensation and HCC. A hallmark of HBeAg-negative chronic hepatitis is its fluctuating course. Approximately one third of patients have stable and persistently elevated ALT, one third have elevated but fluctuating ALT and one third have intermittently elevated ALT.[15] Similarly, serum HBV DNA levels may vary from 9 log 10 copies/mL to <2 log 10 copies/mL (undetectable by most PCR assays). Thus, while it has been proposed that a cutoff value of 5 log 10 copies/mL be used to differentiate inactive carriers from patients with HBeAg-negative chronic hepatitis, the distinction should be based on serial testing and not the results of HBV DNA assay at a single time point.[10]

Initial evaluation should aim at determining HBV replication status and activity/stage of liver disease

The initial evaluation should aim at determining which phase of chronic HBV infection the patient is in and if antiviral treatment is indicated [Table - 1]. The evaluation should also include an assessment of other factors that may contribute to liver disease and indications for HCC surveillance, as well as counseling on life-style modifications and prevention of transmission.

A thorough history should be obtained to elicit the likely mode of transmission and age at infection, smoking and alcohol use, risk factors for coinfection with hepatitis C and D virus (HCV, HDV) and human immunodeficiency virus (HIV) and family history of HBV infection and HCC. Despite careful inquiry, >50% patients do not have an identifiable source of infection. Thus, the duration of infection is frequently unknown. Among Asian patients, it is often assumed that infection is acquired perinatally or in early childhood particularly if the mother and one or more siblings are also infected. However, adult acquired infection does occur among Asians and perinatal as well as early childhood infection can occur among Caucasians. A prior history of acute hepatitis or jaundice is frequently absent and when present may be due to other causes such as acute hepatitis A or prior exacerbations of chronic hepatitis B. Symptoms of chronic liver disease such as fatigue, decreased appetite, right upper abdomen discomfort are often absent. Because of the frequent lack of symptoms until patients have hepatic decompensation or advanced HCC and the poor correlation between symptoms and activity of liver disease, the terms asymptomatic carriers and symptomatic carriers should be abandoned. Similarly, the term healthy carriers should be banned as the lack of symptoms is not equivalent to lack of liver injury and all carriers are at risk of cirrhosis and HCC.

Physical examination should be performed on all patients to assess presence of jaundice, stigmata of chronic liver disease, hepatosplenomegaly, ascites and encephalopathy. However, the examination may be unremarkable except for patients with hepatic decompensation or advanced HCC.

Laboratory tests are necessary to determine HBV replication status and activity/stage of liver disease. Tests for HBV replication should include HBeAg, anti-HBe and quantitative HBV DNA level. As discussed earlier, presence of HBeAg denotes earlier phase of HBV infection (immune tolerance or immune clearance) and high levels of HBV replication. Many HBV DNA assays have been used for quantifying serum HBV DNA levels. These assays vary in their sensitivity (lower limit of detection range from 2 log 10 copies/mL to 6 log 10 copies/mL) and range of linearity (upper limit from 5 log 10 copies/mL to 10 log 10 copies/mL). The ideal assay is one that is sensitive and has a broad range of linearity, should be standardized and the results reported using international units (IU). Currently, real time PCR assays are the best. Using sensitive PCR assays, HBV DNA can be detected in the sera of most patients with chronic HBV infection but clinical studies suggest that liver disease remains quiescent and prognosis is favorable in patients with persistently low HBV DNA levels. Because of the uncertain clinical significance of low serum HBV DNA levels, it has been previously proposed that unamplified HBV DNA assays may be used for initial evaluation of patients with chronic HBV infection. However, increasing data indicate that more sensitive assays that can detect HBV DNA levels of 3-4 log 10 copies/mL are needed to evaluate HBeAg-negative patients.

Initial blood tests to assess liver disease should include hepatic panel, complete blood count, prothrombin time and alphafetoprotein (AFP). Aminotransferase levels, particularly ALT, are frequently used as markers of activity (hepatic necroinflammation) although correlation between ALT levels and histologic activity is poor. Albumin and bilirubin concentrations and prothrombin time reflect hepatic synthetic function but often remain normal until patients begin to develop hepatic decompensation. Low platelet count (<100,000/mm 3sub ) and ratios of aspartate/alanine aminotransferase (AST/ALT) <1 have been reported to be reliable indicators of portal hypertension and early cirrhosis. AFP testing should be included in the initial evaluation of all patients, particularly carriers above the age of 40, those with clinical suspicion of cirrhosis and patients with family history of HCC.[5] However, it must be emphasized that normal AFP does not rule out HCC and elevated AFP can be found in patients with cirrhosis and those with severe exacerbations of chronic hepatitis B.

Initial evaluation of adult patients with chronic HBV infection should include an ultrasound examination to evaluate liver and spleen size and liver tumors. An enlarged spleen and/or a small irregular liver suggest the presence of cirrhosis but these findings may be absent in patients with early cirrhosis. Although ultrasound is less sensitive in detecting small tumors compared to computed tomography (CT) and magnetic resonance imaging (MRI) and is subject to observer error, it is less expensive and more readily available.

The most reliable method to assess activity and stage of liver disease is a liver biopsy . However, liver biopsies are expensive, incur pain/discomfort and may be associated with serious albeit rare complications. Furthermore, accuracy of liver histology may be affected by sampling error. Recently, there have been many reports on surrogate markers of liver fibrosis in patients with hepatitis C; these methods remain to be validated in clinical practice. While assessment of liver fibrosis (stage of liver disease) is important in patients with hepatitis B, determination of activity (degree of necroinflammation) is equally important since it has been shown to correlate with response to antiviral therapy. It should also be recognized that liver histology can worsen rapidly in patients with hepatitis flare and improve significantly upon resolution of the flare. Histologic improvement can also be seen in patients with spontaneous or treatment induced HBeAg seroconversion. Thus, the prognostic value of a single liver biopsy must be interpreted with caution.

Carriers should be counseled to decrease disease progression and transmission of infection

Patients with chronic HBV infection should be counseled regarding lifestyle modifications to decrease the rate of progression of liver disease and to prevent transmission of infection [Table - 2]. There are no specific dietary measures that have been shown to have any effect on the progression of chronic hepatitis B, except in countries where consumption of aflatoxin-contaminated food is prevalent. However, heavy drinking has been associated with increased risk of cirrhosis and HCC. More recently, smoking and obesity have also been reported to be associated with increased risk of HCC. All patients with chronic HBV infection will benefit from a balanced diet, regular exercises, no smoking and no or minimal drinking. Patients with chronic hepatitis B are also advised to receive hepatitis A vaccination[16] as superimposed acute hepatitis A in patients with underlying chronic liver disease is associated with increased mortality.

All HBV carriers should be counseled on how to prevent transmission of infection. Counseling should include precautions to prevent sexual transmission, perinatal transmission and risk of inadvertent transmission via environmental contamination from a blood spill. Sharing of personal items such as toothbrushes, razors and nail clippers that are easily contaminated with blood should be discouraged while sharing of eating utensils is generally safe. HBV is a sturdy virus that can survive outside the human body for days. Thus, contaminated environmental surfaces must be properly sterilized using bleach. Household members are at increased risk of HBV infection and should be tested for both HBsAg and anti-HBs. Seronegative household members should receive HBV vaccination, while HBsAg-positive members should be further evaluated. For casual sex partners or steady sex partners who have not been tested, not completed the course of vaccination, or not responded to the full course of vaccine, barrier protection methods should be employed. HBsAg-positive women who become pregnant should be counseled to make sure their newborn receive hepatitis B immune globulin at birth in addition to HBV vaccine. Household members who remain at risk for HBV infection such as infants of HBsAg-positive mothers and sexual partners of carriers should be tested for response to HBV vaccination.

Who and when should hepatitis B treatment be initiated

Ideally, all patients with chronic HBV infection should receive treatment to eradicate the virus. However, virus eradication is not a realistic goal. Thus, the aim of hepatitis B treatment is to achieve sustained virus suppression to a level that is associated with no or minimal liver damage. This threshold level has not been defined. Despite advances in hepatitis B treatment in the past decade, sustained virus suppression is achieved only in a small percent of patients. While approved treatments (standard interferon, lamivudine and adefovir dipivoxil) can reduce HBV replication, the degree and durability of virus suppression varies. Decision regarding treatment should balance the benefits (severity of liver disease and likelihood of durable response) versus risks (side effects, drug-resistant mutations and cost).[17],[18] In most patients, careful monitoring over a period of 3-12 months is needed to correctly determine which phase of chronic HBV infection the patient is in and the severity of liver disease. During this time, patients should be educated on the treatment options including deferred treatment. Details regarding safety and efficacy of hepatitis B treatments and decisions on choice of treatment are discussed by other authors in this series.

Among HBeAg-positive patients , HBeAg seroconversion together with normalization of ALT and decrease in serum HBV DNA to <5 log 10 copies/mL can be achieved in approximately 20-30% of patients after a 4-6 months course of interferon,[19] in 16-18% of patients after 1 year of lamivudine[20],[21] and in 12% of patients after 1 year of adefovir dipivoxil treatment.[22] However, durable response is observed in only 80-90%[23],[24] patients after interferon treatment and in 50-70%[25],[26] patients after lamivudine treatment. Preliminary data suggest that durability of response after adefovir dipivoxil may be as high as 90% but this may be related to a longer duration of consolidated treatment (continuation of treatment after HBeAg seroconversion).[27] These data indicate that only a small percent, 10-20%, of HBeAg-positive patients will have a durable benefit from a finite course of treatment. Increasing the duration of treatment is associated with higher rates of HBeAg seroconversion but also increasing costs and side effects (interferon) and risks of drug-resistant mutations (lamivudine).[28] Although adefovir dipivoxil is associated with a much lower rate of drug resistance, the cost is 3-4 times that of lamivudine and long-term use (>2-3 years) is associated with increasing rate of drug resistance and potential nephrotoxicity.[29] Pre-treatment ALT has been shown to be the best predictor of HBeAg seroconversion.[30] Therefore, current guidelines do not recommend treatment for HBeAg-positive patients with persistently normal ALT (immune tolerance phase) [Table - 3].[17],[31],[32] Patients with ALT >2 times upper limit of normal (ULN) or moderate/severe hepatic inflammation (immune clearance phase) should be considered for treatment if spontaneous HBeAg seroconversion does not ensue after 3-6 months of observation. Patients with icteric flares or hepatic decompensation should receive immediate treatment. Patients with mild hepatitis flares may be observed as these flares may represent immune mediated clearance of infected hepatocytes and precede spontaneous HBeAg seroconversion. Patients with recurrent hepatitis flares and those with minimally elevated ALT but moderate/severe hepatic inflammation and/or advanced fibrosis should also be considered for treatment.

For HBeAg-negative patients , the appropriate endpoint of treatment has not been defined. The initial response is high (approximately 50%) even when response is defined as virus suppression to undetectable levels by PCR assays (< 2-3 log[10] copies/mL) and normalization of ALT.[33],[34],[35],[36],[37] However, post-treatment relapse is frequent (70-90%) when treatment is stopped after 1 year.[33],[38],[39] Thus, long-term (years and possibly life-long) treatment is needed for continued benefit. Treatment is recommended for patients with HBeAg-negative chronic hepatitis but not for inactive carriers [Table - 3].[17],[31],[32] Serial monitoring of ALT and HBV DNA every 1-3 months over a 6-12 months period is often necessary to correctly determine if the patient is in the inactive carrier phase or has HBeAg-negative chronic hepatitis. In some instances, particularly patients with minimally elevated ALT or serum HBV DNA levels between 4-5 log 10 copies/mL, a liver biopsy may help to decide if treatment is indicated.

While serum HBV DNA and ALT/hepatic inflammation are the primary determinants of hepatitis B treatment in patients with compensated liver disease, a recent study showed that lamivudine treatment may prevent liver disease progression and HCC in patients with HBV-cirrhosis.[40] Although the data are very convincing, it is not clear if this approach will benefit cirrhotic patients with low HBV DNA levels (<700,000 copies/mL) and if the benefit can be maintained when treatment is stopped after the virus has been suppressed for a few years.

Patients who are not treatment candidates at presentation may benefit from treatment at a later stage

All patients with chronic HBV infection whether they are treatment candidates or not require long-term monitoring [Table - 4]. The aims of monitoring are to determine if there is disease progression or reactivation of HBV replication , if treatment is indicated and if HCC has developed.

HBeAg-positive patients in the immune tolerance phase should be monitored at 3-6 months intervals. More frequent monitoring should be performed when ALT levels become elevated. Patients who remain HBeAg-positive with HBV DNA levels >5 log 10 copies/mL after 3-6 months of observation should be considered for liver biopsy and treatment. Patients with icteric hepatitis flares and those with recurrent exacerbations should be considered for immediate treatment. Patients who have undergone spontaneous HBeAg seroconversion still require monitoring as a small proportion (5-10%) continues to have high HBV DNA levels and elevated ALT (direct progression to HBeAg-negative chronic hepatitis) and may benefit from antiviral treatment. The vast majority will have marked reduction in HBV DNA levels and normalization of ALT and should be monitored as described below for inactive carriers.

HBeAg-negative patients who are deemed to be inactive carriers based on serial testing should be monitored every 6-12 months. If ALT level is subsequently found to be elevated, more frequent monitoring is needed and an evaluation into the cause of ALT elevation (serum HBV DNA level and other causes of liver disease) should be initiated if it persists or recurs. Patients who meet diagnostic criteria for HBeAg-negative chronic hepatitis should be considered for antiviral treatment.

HCC surveillance with 6-monthly AFP and ultrasound should be implemented for high risk patients. Although prospective data in support of a survival benefit are lacking, patients who undergo surveillance are more likely to have their tumors detected at an earlier stage when curative treatment is feasible. Unlike HCV-related HCC which occurs mostly in the setting of cirrhosis, 30-40% of HBV-related HCC occurs in pre-cirrhotic patients. Thus, all patients with chronic HBV infection are at risk of HCC. However, surveillance of all carriers is not feasible and the yield will be low. Therefore, most guidelines only recommend HCC surveillance of high risk carriers: those above the age of 40, patients with cirrhosis and carriers with family history of HCC.[5],[31],[32]

Patients receiving treatment should be monitored for treatment response, drug resistance and side effects

Patients receiving hepatitis B treatment should be monitored to assess response [Table - 5]. Although histological response has been used as the primary endpoint in many recent licensing trials, virological and biochemical response are used in clinical practice to determine when treatment can be stopped. Patients should also be monitored for treatment related side effects and for antiviral resistance. The frequency of monitoring and the tests to be performed depend on the treatment used and the baseline status of the patient. The following section provides a general guide only.

Virological response is assessed by testing for serum HBV DNA levels, preferably using PCR assays. A sensitive HBV DNA assay is needed to differentiate patients with modest (2-4 log 10 ) versus good (>4 log 10 ) virus suppression and to detect early breakthrough infection (>1 log 10 increase after initial suppression). Testing should be performed at 3-months intervals to determine initial virological response and to detect virological breakthrough. Rapid virus suppression is associated with a lower risk of subsequent drug resistance. One study found that lamivudine-resistant mutation was detected in 63% of patients with serum HBV DNA levels <3 log 10 copies/mL compared to 13% patients who had higher HBV DNA levels after 6 months treatment.[41] HBV DNA testing must be continued throughout treatment to determine if there is further virus suppression after the first few months of treatment and to confirm if virological response is maintained. Because virological breakthrough precedes biochemical breakthrough, HBV DNA monitoring enables drug resistance to be detected earlier such that salvage therapy can be initiated before any hepatitis flare.[42] This is particularly important when treating cirrhotics or immunosuppressed patients.

HBeAg-positive patients should be retested for HBeAg and anti-HBe at 6-month intervals during lamivudine or adefovir dipivoxil treatment; patients who have undergone HBeAg seroconversion should continue treatment for an additional 6 months to decrease the risk of post-treatment relapse.[43] Patients who fail to clear HBeAg after >1 year of treatment despite maintained viral suppression are generally recommended to continue treatment but the decision should be determined by a balance between the likelihood of subsequent HBeAg seroconversion and risk of drug resistance during continued treatment and severity of underlying liver disease. HBeAg and anti-HBe should be tested mid-way and at the end of treatment for patients receiving interferon. The optimal duration of interferon treatment is evolving. Because of the costs and side effects associated with interferon treatment and the fact that interferon-related HBeAg seroconversion may occur after treatment cessation, the duration of interferon treatment is usually predefined and not based on response. Studies using standard interferon have employed 3-6 months treatment. Most studies using pegylated interferon used 48 or 52 week treatment but there are no data to show that the response rates are higher than shorter (e.g., 24 week) duration of treatment. Testing for HBsAg clearance is not necessary except for patients who have undergone HBeAg seroconversion.

For HBeAg-negative patients , testing for HBsAg clearance should be performed annually during lamivudine or adefovir dipivoxil treatment and at the end of interferon treatment. Therapy may be stopped in patients who have cleared HBsAg. For the vast majority of patients who remain HBsAg positive, relapse is frequent (90%) if lamivudine or adefovir dipivoxil is stopped after one year, prompting recommendations on indefinite treatment. However, long durations of treatment are associated with increasing risk of drug resistance (50% for lamivudine and 6% for adefovir dipivoxil after 3 years treatment).[28],[29] One study suggested that lamivudine may be stopped after 2 years in patients who have persistently undetectable HBV DNA by PCR assay.[44] This approach should be validated in larger studies and for other nucleos(t)ides. The optimal duration of interferon treatment for HBeAg-negative patients has not been defined. Studies using standard interferon showed that a minimum of 12 months is needed; whether 24 months is superior is not clear as direct comparisons have not been made. A recent study using pegylated interferon employed 48 week treatment; sustained response (normal ALT and undetectable HBV DNA by PCR assay) was observed in 15% patients 6 months after cessation of treatment.[45] but longer duration of follow-up is needed to determine if late relapse would occur. Currently, there is no data on sustained response rates after 24 months of pegylated interferon therapy.

Biochemical response is defined as normalization of ALT level. For patients with compensated liver disease, monitoring of ALT alone is sufficient. ALT should be checked every 3 months. ALT levels generally decline during treatment in parallel with decrease in serum HBV DNA levels but ALT flares may be observed. ALT elevation during treatment may be temporally related to HBeAg seroconversion. Although this is more common during interferon treatment, it has also been reported in association with lamivudine-related HBeAg seroconversion. ALT elevation may also occur in association with antiviral resistance. ALT elevation associated with HBeAg seroconversion is accompanied by decrease while ALT elevation associated with drug resistance is accompanied by increase in serum HBV DNA level. Treatment may be continued in patients who have ALT elevation and declining HBV DNA level unless the hepatitis flare is accompanied by increased bilirubin or clinical decompensation. However, caution must be exercised particularly if hepatitis flares occur in patients with bridging fibrosis or cirrhosis receiving interferon therapy.

Side effect monitoring includes subjective assessment and laboratory testing. Lamivudine is associated with very few side effects; 6-monthly tests for blood counts and metabolic panel will suffice for most patients. Adefovir dipivoxil is associated with a small risk of nephrotoxicity;[29],[37] serum creatinine should be checked prior to treatment and then every 3 months. Dose adjustments of lamivudine and adefovir dipivoxil are needed for patients with impaired renal function. Interferon is associated with a broad spectrum of side effects; careful evaluation by an experienced provider (physician or allied health provider) at 1-3 months intervals is necessary to assess constitutional and emotional symptoms. Blood counts should be monitored monthly and the dose of interferon reduced if neutrophil count is less than 1,000/mm 3sub or platelet count less than 50,000/mm 3sub . Thyroid dysfunction occurs in as many as 30% of patients receiving interferon; thyroid stimulating hormone level should be checked prior to treatment and at 3-monthly intervals.

HCC surveillance should continue in patients who are in high risk categories.

Patients who have completed treatment should be monitored for post-treatment relapse

Treatment may be stopped because a patient has reached therapeutic endpoint, completed a predefined course of therapy, developed intolerable side effects, experienced treatment failure (primary non-response or breakthrough secondary to drug resistance) or is non-compliant. Regardless of the reason, patients who have stopped treatment should be closely monitored for viral rebound and hepatitis flares [Table - 6].

For patients who have reached therapeutic endpoint , the goal of post-treatment follow-up is to determine if response can be sustained. While most relapse occurs within 3-6 months of treatment cessation, late relapse (after >1 year) can occur, particularly in HBeAg-negative patients. Serum HBV DNA and ALT levels should be tested every 1-3 months for the first 6-12 months and then every 3-6 months; more frequent monitoring is recommended for patients with underlying cirrhosis. Re-treatment should be promptly introduced in patients with severe hepatitis flares.

Patients who have serious side effects should be followed until the adverse events are resolved. Thereafter, treatment with alternative therapies may be considered if serum HBV DNA and ALT levels remain high.

Patients with suboptimal viral suppression or failure to clear HBeAg may be retreated with other approved treatments or combination therapy. Several studies have shown that non-responders to interferon respond similarly to lamivudine and adefovir dipivoxil as treatment-naοve patients.[46] Data on re-treatment of patients who are non-responders to lamivudine or adefovir dipivoxil are lacking.

There are many approaches to the management of patients with antiviral resistance.[42],[47] Additional therapy should be promptly introduced (lamivudine for adefovir resistance and adefovir dipivoxil for lamivudine resistance) in patients with severe hepatitis flares, clinical decompensation, cirrhosis or immunosuppression. The optimal approach for other patients is controversial. Some investigators have recommended withdrawal of treatment; this approach appears to be safe in patients who have compensated liver disease and are not immunosuppressed,[48] and may be the best approach for patients in whom the indication for initial treatment was questionable. Other investigators have recommended maintenance of existing therapy as long as serum HBV DNA and ALT levels are lower than pretreatment. A third approach is to stop existing therapy and switch to another treatment that is not cross-resistant, e.g., switching from lamivudine to adefovir dipivoxil in a patient with lamivudine resistance.[49] Although there are some data to support this approach, the data were derived from a small number of patients with compensated liver disease. Furthermore, this approach is associated with potential risks of ALT elevations during the transition period and resistance to the second treatment. A fourth approach is to maintain existing treatment (such as lamivudine) and to add a second medication (such as adefovir dipivoxil).[50],[51] The main disadvantage of this approach is cost; there is also a potential problem with dual resistance.

HCC surveillance should continue in patients who are in high risk categories.


   Summary Top


In summary, chronic HBV infection is a life-long infection and patients with chronic HBV infection should be monitored for life. Because of the fluctuating course of chronic HBV infection, serial assessment is more informative than evaluation at a single time point. Substantial progress has been made in the treatment of hepatitis B in the past decade, but currently approved treatments have limitations. The long-term management of patients with chronic HBV infection is as much of a science as it is an art.

 
   References Top

1.Michalak TI, Pasquinelli C, Guilhot S, Chisari FV. Hepatitis B virus persistence after recovery from acute viral hepatitis. J Clin Invest 1994;93:230-9.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Rehermann B, Ferrari C, Pasquinelli C, Chisari FV. The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med 1996;2:1104-8.  Back to cited text no. 2  [PUBMED]  
3.Lok AS, Liang RH, Chiu EK, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study. Gastroenterology 1991;100:182-8.  Back to cited text no. 3    
4.Lenhoff RJ, Summers J. Construction of avian hepadnavirus variants with enhanced replication and cytopathicity in primary hepatocytes. J Virol 1994;68:5706-13.  Back to cited text no. 4    
5.Lok AS, McMahon BJ; Practice Guidelines Committee, American Association for the Study of Liver Diseases. Chronic hepatitis B. Hepatology 2001;34:1225-41.  Back to cited text no. 5    
6.Fattovich G. Natural history and prognosis of hepatitis B. Semin Liver Dis 2003;23:47-58.  Back to cited text no. 6    
7.Liaw YF, Chu CM, Su IJ, Huang MJ, Lin DY, Chang-Chien CS. Clinical and histological events preceding hepatitis B e antigen seroconversion in chronic type B hepatitis. Gastroenterology 1983;84:216-9.  Back to cited text no. 7    
8.Lok AS, Lai CL. Acute exacerbations in Chinese patients with chronic hepatitis B virus (HBV) infection. Incidence, predisposing factors and etiology. J Hepatol 1990;10:29-34.  Back to cited text no. 8    
9.Sheen IS, Liaw YF, Tai DI, Chu CM. Hepatic decompensation associated with hepatitis B e antigen clearance in chronic type B hepatitis. Gastroenterology 1985;89:732-5.  Back to cited text no. 9    
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11.Manno M, Camma C, Schepis F, Bassi F, Gelmini R, Giannini F, et al . Natural history of chronic HBV carriers in northern Italy: Morbidity and mortality after 30 years. Gastroenterology 2004;127:756-63.  Back to cited text no. 11    
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13.Chen YC, Sheen IS, Chu CM, Liaw YF. Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection. Gastroenterology 2002;123:1084-9.  Back to cited text no. 13    
14.Funk ML, Rosenberg DM, Lok AS. World-wide epidemiology of HBeAg-negative chronic hepatitis B and associated precore and core promoter variants. J Hepatol 2002;9:52-61.  Back to cited text no. 14    
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16.Prevention of hepatitis A through active or passive immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1999;48:1-37.  Back to cited text no. 16    
17.Lok AS, McMahon BJ; Practice Guidelines Committee, American Association for the Study of Liver Diseases (AASLD). Chronic hepatitis B: Update of recommendations. Hepatology 2004;39:857-61.  Back to cited text no. 17    
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19.Wong DK, Cheung AM, O'Rourke K, Naylor CD, Detsky AS, Heathcote J. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis. Ann Intern Med 1993;119:312-23.  Back to cited text no. 19    
20.Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, et al . Lamivudine as initial treatment for chronic hepatitis B in the United States. New Engl J Med 1999;341:1256-63.  Back to cited text no. 20    
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22.Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, et al . Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003;348:808-16.  Back to cited text no. 22    
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24.Lok AS, Chung HT, Liu VW, Ma OC. Long-term follow-up of chronic hepatitis B patients treated with interferon alfa. Gastroenterology 1993;105:1833-8.  Back to cited text no. 24    
25.Dienstag JL, Cianciara J, Karayalcin S, Kowdley KV, Willems B, Plisek S, et al . Durability of serologic response after lamivudine treatment of chronic hepatitis B. Hepatology 2003;37:748-55.  Back to cited text no. 25    
26.van Nunen AB, Hansen BE, Suh DJ, Lohr HF, Chemello L, Fontaine H, et al . Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: Relation to type of therapy and pretreatment serum hepatitis B virus DNA and alanine aminotransferase. Gut 2003;52:420-4.  Back to cited text no. 26    
27.Chang T, Shiffman M, Tong M. Durability of HBeAg seroconversion after adefovir dipivoxil treatment for chronic hepatitis B. J Hepatol 2004;40:126.  Back to cited text no. 27    
28.Lok AS, Lai CL, Leung N, Yao GB, Cui ZY, Schiff ER, et al . Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 2003;125:1714-22.  Back to cited text no. 28    
29.Hadziyannis S, Tassopoulos N, Chang TT, Heathcote J, Kitis G, Rizzetto M, et al . Three year study of adefovir dipivoxil demonstrates sustained efficacy in presumed precore mutant chronic hepatitis B patients in a long term safety and efficacy study. J Hepatol 2004;40:17.  Back to cited text no. 29    
30.Perrillo RP, Lai CL, Liaw YF, Dienstag JL, Schiff ER, Schalm SW, et al . Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B. Hepatology 2002;36:186-94.  Back to cited text no. 30    
31.de Franchis R, Hadengue A, Lau G, Lavanchy D, Lok A, McIntyre N, et al . EASL International Consensus Conference on Hepatitis B. 13-14 September, 2002 Geneva, Switzerland. Consensus statement (long version). J Hepatol 2003;39:S3-25.  Back to cited text no. 31    
32.Liaw YF, Leung N, Guan R, Lau GK, Merican I; Asian-Pacific Consensus Working Parties on Hepatitis B. Asian-Pacific consensus statement on the management of chronic hepatitis B: An update. J Gastroenterol Hepatol 2003;18:239-45.  Back to cited text no. 32    
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34.Lampertico P, Del Ninno E, Vigano M, Romeo R, Donato MF, Sablon E, et al . Long-term suppression of hepatitis B e antigen-negative chronic hepatitis B by 24-month interferon therapy. Hepatology 2003;37:756-63.  Back to cited text no. 34    
35.Tassopoulos NC, Volpes R, Pastore G, Heathcote J, Buti M, Goldin RD, et al . Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group. Hepatology 1999;29:889-96.  Back to cited text no. 35    
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38.Santantonio T, Mazzola M, Iacovazzi T, Miglietta A, Guastadisegni A, Pastore G. Long-term follow-up of patients with anti-HBe/HBV DNA-positive chronic hepatitis B treated for 12 months with lamivudine. J Hepatol 2000;32:300-6.  Back to cited text no. 38    
39.Hadziyannis S, Tassopoulos N, Heathcote J. Long-term (96) weeks) adefovir dipoxivil in HBeAg-negative chronic hepatitis results in significant virological, biochemical and histological improvement. Hepatology 2003;38:273A.  Back to cited text no. 39    
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45.Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, et al . Peginterferon alfa-2a alone, lamivudine alone and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004;351:1206-17.  Back to cited text no. 45    
46.Schiff ER, Dienstag JL, Karayalcin S, Grimm IS, Perrillo RP, Husa P, et al . Lamivudine and 24 weeks of lamivudine/interferon combination therapy for hepatitis B e antigen-positive chronic hepatitis B in interferon nonresponders. J Hepatol 2003;38:818-26.  Back to cited text no. 46    
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48.Liaw YF, Chien RN, Yeh CT. No benefit to continue lamivudine therapy after emergence of YMDD mutations. Antivir Ther 2004;9:257-62.  Back to cited text no. 48    
49.Peters MG, Hann HW, Martin P, Heathcote EJ, Buggisch P, Rubin R, et al . Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology 2004;126:91-101.  Back to cited text no. 49    
50.Schiff ER, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, et al . Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology 2003;38:1419-27.  Back to cited text no. 50    
51.Perrillo R, Hann HW, Mutimer D, Willems B, Leung N, Lee WM, et al . Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology 2004;126:81-90.  Back to cited text no. 51    

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Correspondence Address:
Anna SF Lok
Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, MI
USA
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