Hepatitis B virus infection

SeminarHepatitis B virus infectionYun-Fan Liaw, Chia-Ming ChuSince the introduction of the hepatitis B vaccine and other preventive measures, the worldwide prevalence ofhepatitis B infection has fallen. However, chronic infection remains a challenging global health problem, with morethan 350 million people chronically infected and at risk of hepatic decompensation, cirrhosis, and hepatocellularcarcinoma. An improved understanding of hepatitis B virology, immunology, and the natural course of chronicinfection, has identifi ed hepatitis B virus replication as the key driver of immune-mediated liver injury and diseaseprogression. The approval of potent oral antiviral agents has revolutionised hepatitis B treatment since 1998.Conventional and pegylated interferon alfa and nucleoside and nucleotide analogues are widely authorised treatments,and monotherapy with these drugs greatly suppresses virus replication, reduces hepatitis activity, and halts diseaseprogression. However, hepatitis B virus is rarely eliminated, and drug resistance is a major drawback during longterm therapy. The development of new drugs and strategies is needed to improve treatment outcomes.IntroductionHepatitis B virus is one of the most serious and prevalent health problems, affecting more than 2 billion people worldwide. Although highly effective vaccines against hepatitis B virus have been available since 1982, there are still more than 350 million chronic carriers, 75% of whom reside in the Asia Pacific region. People with hepatitis B are at increased risk of developing hepatic decompensation, cirrhosis, and hepatocellular carcinoma. The estimated worldwide mortality is 0·5 to 1·2 million deaths a year.1Substantial improvement in the understanding of hepatitis B virology and immunology during past decades, combined with the advent of highly sensitive assays, has led to new insights into the natural history of such infection. Furthermore, the approval of oral antiviral agents has revolutionised hepatitis B treatment since 1998, and enabled eff ective clinical management of the disease. Viral epidemiologyHepatitis B virus is a double-stranded DNA virus of the hepadnaviridae family. The virus is enveloped, and contains a viral DNA genome of about 3200 bps within its core. After the virus enters a hepatocyte, the viral genome is delivered to the nucleus, and the relaxed circular DNA is converted to covalently-closed-circular DNA (cccDNA). The cccDNA serves as a template for the transcription of the viral RNA. The hepatitis B virus replication cycle includes reverse transcription of RNA intermediates to prime DNA synthesis and translation of the hepatitis B proteins, including hepatitis B surface antigen (HBsAg) and e antigen (HBeAg).2 Thus, cccDNA plays a key part in the maintenance of chronic hepatitis B infection. The virus has at least eight major genotypes (A to H), based on an intergroup divergence of more than 8% in the complete nucleotide sequence. Apart from genotypes E and G, the genotypes have sub-genotypes with a sequence diff erence of at least 4%.3Hepatitis B virus is transmitted parenterally via apparent or inapparent percutaneous or permucosal exposure to infected blood or other body fl uids. Risk factors for infection include transfusion of unscreened blood, sexual promiscuity, sharing or re-using of syringes between injection drug users, tattooing, working or residing in a health-care setting, living in a correctional facility, renal dialysis, and long-term household or intimate non-sexual contact with an HBsAg-positive individual.1,4In low-prevalence areas, hepatitis B is typically a disease of young adults who acquire the infection through risky behaviour—such as unprotected sexual contact or sharing syringes with HBsAg-positive people—and through exposure to contaminated equipment used for therapeutic injections and procedures. I n high-prevalence regions, most infection occurs perinatally or during early childhood. About 90% of HBeAg-seropositive mothers (with high viral load) transmit hepatitis B virus to their off spring, compared with 10–20% of HBeAg-seronegative carrier mothers.5 The prevalence of HBeAg is higher in Asian than in African HBsAg carrier mothers (40 vs 15%), so perinatal transmission is greater in Asians, but mainly horizontal in Africans.6,7The prevalence of chronic hepatitis B infection is about 5% worldwide, but differs between regions. nfection rates are low (0·1–2·0%) in the USA and western Europe, intermediate (2·0–8·0%) in Mediterranean countries and Japan, and high (8·0–20·0%) in southeast Asia and sub-Saharan regions.1 Additionally, hepatitis B virus genotypes have a distinctLancet 2009; 373: 582–92Liver Research Unit, ChangGung Memorial Hospital,Chang Gung University Collegeof Medicine, Taipei, Taiwan(Prof Y-F Liaw MD,Prof C-M Chu MD)Correspondence to:Prof Yun-Fan Liaw, LiverResearch Unit, Chang GungUniversity and MemorialHospital, 199 Tung Hwa NorthRoad, Taipei, Taiwanliveryfl @.twSearch strategy and selection criteriaMedline and PubMed were searched from 2000 to 2008 usingthe terms “hepatitis B virus”, “HBV”, “viral hepatitis”, and“chronic hepatitis” as search terms for hepatitis B virology,immunology, epidemiology, and clinical liver disease status.Reference lists of the identifi ed articles and review articlesfrom the past 3 years were also searched. Publications fromthe past 3–5 years were selected. Earlier publications were notexcluded, however, if they were highly cited or if there were norecent appropriate publications. Review articles coveringearlier studies on important issues were selected and citedrather than the earlier original articles.Seminargeographical distribution: genotype A is prevalent in northwestern Europe and the USA; genotypes B and C in Asia; genotype D in the Mediterranean basin, Middle East, and India; genotype E in west Africa; genotype F in South and Central America; genotype G in the USA and France; and genotype H in Mexico and South America.3Hepatitis B virus pre-core mutations occur most frequently in genotype D, followed by genotypes C and B, and are seen least frequently in genotype A.8 Accordingly, HBeAg-negative chronic hepatitis B is most common in genotype D dominant regions. The percentage of patients with chronic hepatitis B who are HBeAg negative is 80–90% in Mediterranean areas, 30–50% in southeast Asia, and less than 10% in the USA and northwestern Europe.9PreventionThrough understanding the routes and modes of hepatitis B transmission, infection can be prevented by avoidance or interruption of transmission. Since the 1970s, serological screening of donor blood has become progressively routine, resulting in substantial reduction of transfusion-associated hepatitis B.1 Syringe-exchange programmes are run in the USA and other high-income countries, and provide free sterile syringes in exchange for used syringes, reducing transmission of blood-borne pathogens—including hepatitis B—in injection drug users. Operating at fi xed sites and on mobile van routes, the syringe-exchange programmes can make contact with otherwise hard-to-reach populations to deliver social and medical services, such as testing for hepatitis B, counselling, and vaccination.10An eff ective hepatitis B vaccine has been available since the early 1980s, and in the early 1990s WHO recommended the addition of the hepatitis B vaccination to all national immunisation programmes. Universal vaccination programmes for newborn babies have been implemented in more than 160 countries, and international fi nancial support and a reduced cost are facilitating introduction of the vaccine into more low-income countries.11 Some high-income countries with low or very low endemicity of hepatitis B infection, such as northern European countries, apply a strategy of selective vaccination for individuals at high risk of infection, because the low burden of disease does not warrant the added cost of universal vaccination.11,12 Hepatitis B vaccination is the most eff ective preventive measure in adult populations with risk factors.1,4,10,11Since the introduction of hepatitis B vaccination, the worldwide rates of infection have fallen. For example, the HBsAg carrier rate in Taiwanese children decreased from 10% in 1984 to less than 1% in 2004, with a 68% reduction of fulminant hepatitis in infants (0–1 year), and a 75% decline in hepatocellular carcinoma in children (aged 6–14 years).13,14 In the USA the incidence of reported acute hepatitis B fell by 81% between 1990 and 2006, from 8·5 to 1·6 cases per 100 000 population, and few cases occurred in blood recipients, dialysis patients, and health-care workers.4 However, the rate of infection among injection drug users, people with sexual risk factors, and immigrants from high-prevalence areas such as Asia has raised the burden of chronic hepatitis B infection in high-income countries, reinforcing the need to improve preventive efforts aimed at high-risk groups.4,14 Post-exposure prophylaxis with hepatitis B immunoglobulin is eff ective and indicated for newborn infants of HBsAg-positive mothers, after percutaneous or mucosal exposure to HBsAg positive blood in health-care settings.I mmunoglobulin is further indicated for prophylaxis after exposure to body fl uids (sexual exposure) and for the prevention of hepatitis B recurrence after liver transplantation.11PathophysiologyHepatitis B virus is not cytopathogenic. In acute infection, clinical hepatitis B becomes apparent after an incubation period of 45–180 days. The elimination of hepatitis B virus by non-cytopathic mechanisms begins several weeks before the disease onset. Hepatitis B virus DNA clearance is mediated largely (up to 90%) by antiviral cytokines that are produced by cells of the innate and adaptive immune responses—including tumour necrosis factor α, interferon alfa, or interferon beta.15–17 After viral DNA declines, a cytolytic immune response with hepatocyte apoptosis and necrosis ensues, coincident with the onset of clinical hepatitis and a rise in serum alanine aminotransferase (ALT). The recognition of infected hepatocytes by virus-specifi c CD8 cytotoxic T cells, via classIhuman lymphocyte antigen (HLA-I)-presenting hepatitis B virus peptides, is presumed to be the main mechanism causing both liver damage and virus control. Cytotoxic T cells further recruit various antigen-non-specifi c infl ammatory cells into the liver by secreting cytokines, initiating a cascade of immunological events leading to necro i nfl ammation.18–20A vigorous, multispecific CD4 and CD8 response is associated with viral clearance.21n individuals with chronic hepatitisB infection, the hepatitis B virus-specifi c CD4 and CD8 response is insuffi cient;21 and can cause a persistent infl ammatory response that is ineff ective for hepatitis B virus clearance.22Timely conventional liver biochemical tests are essential for diagnosis of hepatitis—including measurement of ALT for the degree of hepatocellular damages, bilirubin for conjugation and excretion function, and albumin values and prothrombin time for liver synthesis function. Liver biopsy is important for the grading of necroinflammation and staging of fi brosis. Ultrasonography and other imagining methods are non-invasive ways to detect cirrhosis and hepatocellular carcinoma23—the judicious use of these methods and assays is crucial to diff erentiate the nature and severity ofSeminardisease. Testing for hepatitis B virus markers is mandatory for the detection and diagnosis of hepatitis B. Serological markers of hepatitis B are HBsAg and its antibody (antiHBs), HBeAg and its antibody (antiHBe), and immunoglobulins G and M antibody to hepatitis B virus core antigen (I gG antiHBc and I gM antiHBc). HBsAg seropositivity indicates infection, and HBeAg is a surrogate marker of viral replication with high hepatitis B virus DNA. HBsAg assays should be done in those at risk for hepatitis B infection, people with ALT elevation or evidence of liver disease, and anyone about to receive immunosuppressive treatment or chemotherapy.The first serological marker to appear in acute hepatitis B infection is HBsAg, usually 1–6 weeks before the manifestation of clinical symptoms. I gM antiHBc appears 1–2 weeks after HBsAg, and persists for up to 6 months after HBsAg is cleared.23 Previously undiagnosed chronic HBsAg carriers with acute exacerbation of hepatitis B or superinfection with other hepatitis virus(es) presenting as clinical acute hepatitis, are seronegative for IgM antiHBc.24 Serum IgM antiHBc assay is, therefore, mandatory for the serodiagnosis of acute hepatitis B. HBeAg and hepatitis B virus DNA are present early during acute infection. Both markers usually disappear when serum ALT peaks, or soon thereafter, and before HBsAg seroclearance, which occurs within 1–2 months, and are followed by the appearance of antiHBs several weeks later (fi gure 1). Previous infection is diagnosed by the detection of antiHBc and antiHBs.23Presence of HBeAg for more than 10 weeks indicates a high likelihood of transition to persistent infection. Persistence of serum HBsAg for more than 6 months implies progression to chronic infection. People with HBeAg-positive chronic infection usually have high levels of hepatitis B virus DNA, whereas serum concentrations are lower in patients with HBeAg-negative infection. Serial testing showing a hepatitis B virus DNA concentration of less than 2×10³ IU/mL and normal ALT values is needed to verify an inactive carrier state.25,26 Serum hepatitis B virus DNA assay is a direct measure of viral load. I t is particularly useful for assessment of risk of disease progression and candidacy for antiviral therapy, monitoring treatment response, and to distinguish active hepatitis B from the inactive carrier state with other causes of high ALT. PCR-based assays, with high sensitivity and a wide dynamic range (10¹–10⁹ I U/mL), are the mainstay for measurement of hepatitis B viral load. WHO has established an international standard for hepatitis B virus quantifi cation units, in which 1 I U is equal to about fi ve genome equivalents.27 Assays for hepatitis B virus genotypes and mutations are available and becoming increasingly important in the clinical fi eld.Natural historyThe spectrum of acute hepatitis B infection ranges from asymptomatic infection to self-limited hepatitis, to fulminant hepatitis and it depends on various viral and host factors. Symptomatic hepatitis is rare in neonates (less than 1%) and occurs in about 10% of children 1–5 years old.1,22 Fulminant hepatitis is very rare in paediatric patients, with most reported cases being in infants born to HBeAg-negative, HBsAg-carrier mothers.28 One proposed explanation is that the absence of HBeAg in maternal blood fails to induce immunological tolerance,29 thus allowing vigorous immune clearance of hepatitis B virus from the infant liver. A third of acute infections in adults are symptomatic,22 and fulminant hepatitis occurs in less than 1% of cases, with a mortality of about 70%. Fulminant hepatitis B is related to an enhanced immune response with rapid viral clearance, which means serum HBsAg and hepatitis B virus DNA might be undetectable at the time of clinical presentation, and the diagnosis is made only by the presence of serum IgM antiHBc.2Resolution of hepatitis B with HBsAg seroclearance occurs in more than 95% of adult patients. However, small amounts of hepatitis B virus DNA can still be detected by PCR in serum and peripheral mononuclear cells years after recovery from hepatitis, indicating a state of occult infection.30 Hepatitis B can be transmitted via organ transplantation, and hepatitis B reactivation might occur under immunosuppressive treatment—or by chemotherapy in such cases.31 The risk of chronicity is correlated closely with the patient’s age at the time of infection. I nfection persists in about 90% of infants infected at birth, 20–30% of children infected between the ages of 1 and 5 years, 6% of infection in childrenFigure 1: Serological and clinical changes after acute hepatitis B virus (HBV) infectionShaded bars indicate the duration of seropositivity in self-limited acute hepatitis B infection. Pointed bars indicate that HBV-DNA and HbeAg can become seronegative during chronic infection. Only IgG antiHBc is detectable after resolution of acute hepatitis or during chronic infection. Y axis is schematic concentration of ALT and antiHBs.Seminaraged 5–15 years and only 1–5% of patients infected as adults.1One possible explanation for the high chronicity in infants is that the fetus develops tolerance to the virus in utero after the transplacental passage of viral proteins.32The natural course of chronic hepatitis B infection consists of distinct phases resulting from the interaction between the virus, hepatocytes and host immune response. Typically, chronic infection acquired perinatally or during infancy has three phases: immune tolerant, immune clearance, and inactive residual.33 Hepatitis B re-activation can occur in some patients with inactive disease and trigger immune-mediated liver injury.34,35 Such patients, therefore, enter a variant phase of immune clearance (fi gure 2).23,36 Adult-acquired chronic infection has a similar clinical course, except that there is no obvious initial immune tolerant phase.37The mechanisms of immune tolerance during the fi rst phase are not well understood. Work in mice suggests that a transplacental transfer of maternal HBeAg could induce a specifi c unresponsiveness of helper T cells to HBeAg, and result in an ineff ective cytotoxic T-cell response to nucleocapsid antigens in neonates.32 Patients in the immune-tolerant phase are usually young, asymptomatic, and HBeAg seropositive, with high viral loads (more than 2×10⁶ to 2×10⁷ IU/mL) but normal serum ALT levels and near-normal liver histology. There is usually no, or only minimum, disease progression while serum ALT concentrations remain normal.38The mechanisms triggering loss of immune tolerance are mostly unknown, but a high viral load seems necessary to maintain the tolerant state.39 The immune-clearance phase is associated with fallingserum hepatitis B virus DNA concentrations, but their causal relation remains unclear. Other fi ndings thatcharacterise the transition from the immune tolerant to the immune clearance phase include a shift ofantigen (HBcAg) from nucleus to cytoplasm,40 and agradual accumulation of pre-core or core-promoter mutations.41,42During the immune-clearance phase, hepatitis activity and intermittent acute ALT increase can fl are to over fi ve times the upper limit of normal, usually withoutapparent symptoms. This activity of fl ares can be complicated by hepatic decompensation. The rises inALT and fl ares are attributable to the host’s immuneresponse against hepatitis B virus with resultant apoptosis and necrosis, thus, higher ALT concentrationsusually indicate a more vigorous immune response against hepatitis B virus and more extensive hepatocyte damage.43 The occurrence of hepatitis fl are varies in patient cohorts, but has reached 25% of patients per year during the fi rst 3–5 years of follow-up in hospital-based studies 43–45 The overall occurrence of hepatic failure in patients was estimated to be 0·5%.24 Hepatitis fl ares can lead to cirrhosis but will eventuallybe followed by HBeAg seroconversion to antiHBe. The estimated yearly proportion of spontaneous HBeAg seroconversion is 2–15%, depending on factors such as age, ALT concentrations, and hepatitis B virus genotype.41–46 In Asia, HBeAg seroconversion occurs at a mean age of 30–35 years, with most cases (90%) occurring before age 40.45–48 Patients infected with genotype B seroconvert earlier and more frequently than do those with genotype C.3,47,49–51 In native Alaskans with chronic hepatitis B infection, the median age of HBeAg seroclearance is younger than 20 years in patients with genotypes A, B, D, and F, but over 40 years in patients with genotype C.52HBeAg seroconversion is usually followed by clinical remission and a life-long inactive state with an excellent outcome, although a few patients may develop hepatocellular carcinoma.34,35,53–56 Spontaneous HBsAg seroclearance can occur, reported at a rate of less than 1% per year in early studies.53–57 A study with 1965 patients showed that HBsAg seroclearance occurred at a rate of 1·2% per year, and rose to 1·8% per year in individuals over age 50; to a 45% cumulative incidence after 25 years of follow-up.58 Patients with virus genotype A and B infection have a higher likelihood of HBsAg seroclearance than do patients with other genotypes.59,60 HBsAg seroclearance usually confers an excellent long-term outcome if there is no pre-existing cirrhosis or viral superinfection.61,62 However, a small amount of hepatitis B virus DNA may persist in a state of occult infection.31Figure 2: Natural course of chronic hepatitis B virus (HBV) infection acquired perinatally and during infancy The reactivion phase is similar in every aspect to the immune-clearance-phase, except for HBeAg status.Adult-acquired infection usually presents in the immune-clearance or reactivation phase (inset). The events duringthe immune-clearance and reactivation phases could lead to cirrhosis and hepatocellular carcinoma (HCC) (adapted from Liaw 21with permission). HBeAg=hepatitis B e antigen; antiHBe=hepatitis B e antigen antibody; pre C=pre core; BCP=basal core promoter; ALT=serum alanine aminotransferase.SeminarAfter HBeAg seroconversion, 1–4% patients have HBeAg seropositive hepatitis again (HBeAg reversion), whereas a greater proportion of patients develop HBeAg-negative chronic hepatitis B because of reactivation of the hepatitis B virus with pre-core or core promoter mutations that abolish or downregulate HBeAg production.34,35,42,63 Results from Taiwanese studies showed relapse in 2–3% of patients per year,34,45 with a cumulative rate of 20–25% after 15 years of follow-up.64 The proportion of relapse was very low in patients who HBeAg-seroconverted before age 30,55,64 but was raised in men, patients with genotype C, those who HBeAg-seroconverted after age 40,65 and in patients with serum hepatitis B virus DNA concentrations greater than 10 000 copies per mL.66 These age-related fi ndings show that early HBeAg seroconversion, or a short HBeAg-positive phase, are associated with an improved chance of sustained remission.48Cirrhosis or hepatocellular carcinoma, or both, can develop during the natural course of chronic hepatitis B infection. Results of large population-based studies with mostly (85%) HBeAg-negative, HBsAg-positive people older than 30 years at recruitment have shown that the risk of cirrhosis, hepatocellular carcinoma, and mortality increases proportionally with increasing viral DNA concentrations, starting with at least 1×104 copies per mL.67–69 The study fi ndings suggest hepatitis B virus replication, with subsequent immune-mediated liver injuries, is the main driver of disease progression70 (fi gure 3). Further risk factors for the development of cirrhosis include: male sex; increasing age;67–69,71,72 HBeAg positivity;72 virus genotype C (vs B);47,49,73–76 HBeAg reversion or virus reactivation;34,47persistent seropositivity for HBeAg77 or viral DNA;78 persistent raised ALT;79 viral superinfections;80 as well as the severity (hepatic decompensation), extent (bridging hepatic necrosis), and frequency of hepatitis fl are, and the duration of hepatic lobular alterations.71At least a third of patients with cirrhosis are seropositivefor HBeAg or hepatitis B virus DNA at presentation,81 and disease progression can continue after cirrhosis development.82 The 5-year probability of hepatic decompensation is 15–20%, and is four-fold higher in patients with active viral replication than in patients without.83 The yearly rate of hepatocellular carcinoma occurrence is 3–6%.81,82 The estimated 5-year survival rateof patients with compensated cirrhosis is 80–85% and 30–50% in patients with decompensated cirrhosis.81 Hepatocellular carcinoma mostly develops in patients with cirrhosis, therefore, hepatocellular carcinoma and cirrhosis share the same risk factors, with a raised risk in patients with a family history of hepatocellular carcinoma.84 Viral factors also contribute to hepatocellular carcinoma development, including hepatitis B virus DNA level, genotypes, and naturally occurring mutations such as hepatitis B virus pre-S and basal core promoter A1762T/G1764A double mutations.68,85–89 Other con t ributing factors are habitual alcohol consumption, cigarette smoking, andafl atoxin exposure.90ManagementAcute hepatitis B in adults is selflimiting in more than 95% of cases, therefore, antiviral therapy is indicated only for patients with protracted severe acute hepatitis or fulminant hepatitis B.25 Management of patients with chronic hepatitis B infection should include thorough patient assessment and counselling. Although patients are usually asymptomatic, they can be anxious and attribute a wide range of negative psychological, social, and physical symptoms to their condition.91 Counselling should include dietary and lifestyle advice, including guidance to increase physical activity and control alcohol use. Further, health-care providers and patients should discuss the behaviours that lead to superinfection, prevention of such infection and preventive measures against transmission of hepatitis B to intimate contacts. The importance of the long term hepatocellular carcinoma surveillance, with ultrasonography supplemented with α-fetoprotein assay, should be emphasised to patients older than 40 years, with advancedfibrosis or cirrhosis, and with a family history of hepatocellular carcinoma.25,36,81Hepatitis B virus replication is key to liver injury and disease progression,70 and, therefore, the main aims of treatment are to suppress the virus to achieve HBeAg seroconversion or undetectable viral-DNA levels, or both; stop or reduce hepatic necroinfl ammation; and prevent the development of hepatic decompensation. Long term goals are to reduce cirrhosis and hepatocellular carcinoma development, and ultimately extend survival. ViraemicFigure 3: Hepatitis B virus (HBV) replication and the outcomes of chronic Hepatitis B infectionNote that Hepatitis B e antigen (HBeAg) seroconversion is followed by remission in most people but that HBeAg-negative (–) hepatitis (HBV-DNA ≥ 2x10³–2x10⁴ IU/mL) may develop. Patients who remain HBeAg seropositive or develop HBeAg-negative hepatitis have a high occurrence of cirrhosis (~4 and ~3% per year). Most hepatocellular carcinoma (HCC) develops in patients who have cirrhosis.Seminarpatients with an ALT concentration of twice the upper limit of normal or more, or substantial liver disease, are candidates for drug therapy. Of note, ALT fl are may precede spontaneous HBeAg seroconversion.43 Obser-vation for 3 months before considering drug therapy is acceptable.25,36 Liver biopsy is recommended to assess the necroinflammation grade and fibrosis stage, because signifi cant fi brosis could have developed in patients with normal ALT, except during the immunotolerant phase.92 Before drug therapy is initiated, the effi cacy, advantages and disadvantages, and cost of available therapies should be discussed with the patient.36Approved and widely used agents are conventional interferon alfa and pegylated interferon-alfa-2a; the nucleoside analogues lamivudine, entecavir, and telbivudine; and the nucleotide analogue adefovir dipivoxil. Tenofovir, another nucleotide analogue approved for the treatment of HIV infection, was more effective than adefovir in hepatitis B,93 it has been approved in European countries and USA, and will probably be approved worldwide. Drug therapy should be selected according to the patient’s condition, the drug’s mechanism, rapidity of action, potency, convenience of administration, adverse eff ect profile, and cost (see table).Interferon-based therapyInterferon alfa and pegylated interferon have immunomodulating activity. Theoretically, interferons are the ideal treatment for patients with chronic hepatitis B, but the response rate after 4–6 months of interferon alfa is only 30–40% in HBeAg-positive patients, with a risk difference of 23–25% against untreated controls.94 48 weeks of pegylated interferon therapy yields a sustained HBeAg seroconversion rate of 32% when assessed 24 weeks after completion of therapy.95–97 Patients with genotype A (vs D) or B (vs C) infection tend to have a better response to interferon or pegylated interferon.3,95–97 HBeAg seroconversion responseis sustained in more than 80% of people, and can be followed by HBsAg loss,77,98,99 which is the desired end point.Patients with HBeAg-negative chronic hepatitis B respond to interferon alfa therapy but often relapse after treatment completion.78,100 The combined response to pegylated interferon therapy (normal ALT+hepatitis B virus DNA concentration less than 2×10⁴ copies per mL)in HBeAg-negative patients is 36% at 6 months post treatment.101,102 I mproved response rates are achieved in patients with low serum viral DNA, raised ALT and low HBeAg concentrations at baseline, and low HBeAg after 24 weeks’ treatment.102–104 HBsAg seroconversion occurs in 3% of the pegylated interferon treated patients,96,97,101 and the rate increases to 10% at 4 years after therapy.105 These response figures are better than those of lamivudine monotherapy. Results from follow-up studies suggest that interferon alfa therapy has long term benefi ts by promoting cumulative HBeAg seroconversion, increasing HBsAg loss, reducing development of cirrhosis and hepatocellular carcinoma, and extending survival—especially in responders.70,77,98–100 Further advantages of interferon-based therapy are the fi nite treatment duration and that patients do not develop drug resistance. Eventually, pegylated interferon treatment will replace interferon alfa because of its improved effectiveness and convenient once a week administration.36,95 Interferon-based therapy is associated with many adverse events; including infl uenza-like symptoms, fatigue, anorexia, weight loss, hair loss, thyroid dysfunction, emotional instability, and bone。