Liaw Lancet2009


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Liaw Lancet2009

  1. 1. Seminar Hepatitis B virus infection Yun-Fan Liaw, Chia-Ming Chu Lancet 2009; 373: 582–92 Since the introduction of the hepatitis B vaccine and other preventive measures, the worldwide prevalence of Liver Research Unit, Chang hepatitis B infection has fallen. However, chronic infection remains a challenging global health problem, with more Gung Memorial Hospital, than 350 million people chronically infected and at risk of hepatic decompensation, cirrhosis, and hepatocellular Chang Gung University College carcinoma. An improved understanding of hepatitis B virology, immunology, and the natural course of chronic of Medicine, Taipei, Taiwan (Prof Y-F Liaw MD, infection, has identified hepatitis B virus replication as the key driver of immune-mediated liver injury and disease Prof C-M Chu MD) progression. The approval of potent oral antiviral agents has revolutionised hepatitis B treatment since 1998. Correspondence to: Conventional and pegylated interferon alfa and nucleoside and nucleotide analogues are widely authorised treatments, Prof Yun-Fan Liaw, Liver and monotherapy with these drugs greatly suppresses virus replication, reduces hepatitis activity, and halts disease Research Unit, Chang Gung progression. However, hepatitis B virus is rarely eliminated, and drug resistance is a major drawback during long University and Memorial Hospital, 199 Tung Hwa North term therapy. The development of new drugs and strategies is needed to improve treatment outcomes. Road, Taipei, Taiwan Introduction the viral RNA. The hepatitis B virus replication cycle Hepatitis B virus is one of the most serious and prevalent includes reverse transcription of RNA intermediates to health problems, affecting more than 2 billion people prime DNA synthesis and translation of the hepatitis B worldwide. Although highly effective vaccines against proteins, including hepatitis B surface antigen (HBsAg) hepatitis B virus have been available since 1982, there are and e antigen (HBeAg).2 Thus, cccDNA plays a key part in still more than 350 million chronic carriers, 75% of the maintenance of chronic hepatitis B infection. The whom reside in the Asia Pacific region. People with virus has at least eight major genotypes (A to H), based hepatitis B are at increased risk of developing hepatic on an intergroup divergence of more than 8% in the decompensation, cirrhosis, and hepatocellular carcinoma. complete nucleotide sequence. Apart from The estimated worldwide mortality is 0·5 to 1·2 million genotypes E and G, the genotypes have sub-genotypes deaths a year.1 with a sequence difference of at least 4%.3 Substantial improvement in the understanding of Hepatitis B virus is transmitted parenterally via hepatitis B virology and immunology during past decades, apparent or inapparent percutaneous or permucosal combined with the advent of highly sensitive assays, has exposure to infected blood or other body fluids. Risk led to new insights into the natural history of such factors for infection include transfusion of unscreened infection. Furthermore, the approval of oral antiviral blood, sexual promiscuity, sharing or re-using of syringes agents has revolutionised hepatitis B treatment since 1998, between injection drug users, tattooing, working or and enabled effective clinical management of the disease. residing in a health-care setting, living in a correctional facility, renal dialysis, and long-term household or Viral epidemiology intimate non-sexual contact with an HBsAg-positive Hepatitis B virus is a double-stranded DNA virus of the individual.1,4 In low-prevalence areas, hepatitis B is hepadnaviridae family. The virus is enveloped, and typically a disease of young adults who acquire the contains a viral DNA genome of about 3200 bps within its infection through risky behaviour—such as unprotected core. After the virus enters a hepatocyte, the viral genome sexual contact or sharing syringes with HBsAg-positive is delivered to the nucleus, and the relaxed circular DNA people—and through exposure to contaminated is converted to covalently-closed-circular DNA (cccDNA). equipment used for therapeutic injections and The cccDNA serves as a template for the transcription of procedures. In high-prevalence regions, most infection occurs perinatally or during early childhood. About 90% of HBeAg-seropositive mothers (with high Search strategy and selection criteria viral load) transmit hepatitis B virus to their offspring, Medline and PubMed were searched from 2000 to 2008 using compared with 10–20% of HBeAg-seronegative carrier the terms “hepatitis B virus”, “HBV”, “viral hepatitis”, and mothers.5 The prevalence of HBeAg is higher in Asian “chronic hepatitis” as search terms for hepatitis B virology, than in African HBsAg carrier mothers (40 vs 15%), so immunology, epidemiology, and clinical liver disease status. perinatal transmission is greater in Asians, but mainly Reference lists of the identified articles and review articles horizontal in Africans.6,7 from the past 3 years were also searched. Publications from The prevalence of chronic hepatitis B infection is the past 3–5 years were selected. Earlier publications were not about 5% worldwide, but differs between regions. excluded, however, if they were highly cited or if there were no Infection rates are low (0·1–2·0%) in the USA and recent appropriate publications. Review articles covering western Europe, intermediate (2·0–8·0%) in earlier studies on important issues were selected and cited Mediterranean countries and Japan, and high rather than the earlier original articles. (8·0–20·0%) in southeast Asia and sub-Saharan regions.1 Additionally, hepatitis B virus genotypes have a distinct 582 Vol 373 February 14, 2009
  2. 2. Seminar geographical distribution: genotype A is prevalent in 1990 and 2006, from 8·5 to 1·6 cases per northwestern Europe and the USA; genotypes B and C in 100 000 population, and few cases occurred in blood Asia; genotype D in the Mediterranean basin, Middle East, recipients, dialysis patients, and health-care workers.4 and India; genotype E in west Africa; genotype F in South However, the rate of infection among injection drug and Central America; genotype G in the USA and France; users, people with sexual risk factors, and immigrants and genotype H in Mexico and South America.3 from high-prevalence areas such as Asia has raised the Hepatitis B virus pre-core mutations occur most burden of chronic hepatitis B infection in high-income frequently in genotype D, followed by genotypes C and B, countries, reinforcing the need to improve preventive and are seen least frequently in genotype A.8 Accordingly, efforts aimed at high-risk groups.4,14 Post-exposure HBeAg-negative chronic hepatitis B is most common in prophylaxis with hepatitis B immunoglobulin is effective genotype D dominant regions. The percentage of patients and indicated for newborn infants of HBsAg-positive with chronic hepatitis B who are HBeAg negative mothers, after percutaneous or mucosal exposure to is 80–90% in Mediterranean areas, 30–50% in southeast HBsAg positive blood in health-care settings. Asia, and less than 10% in the USA and northwestern Immunoglobulin is further indicated for prophylaxis Europe.9 after exposure to body fluids (sexual exposure) and for the prevention of hepatitis B recurrence after liver Prevention transplantation.11 Through understanding the routes and modes of hepatitis B transmission, infection can be prevented by Pathophysiology avoidance or interruption of transmission. Since Hepatitis B virus is not cytopathogenic. In acute infection, the 1970s, serological screening of donor blood has clinical hepatitis B becomes apparent after an incubation become progressively routine, resulting in substantial period of 45–180 days. The elimination of hepatitis B reduction of transfusion-associated hepatitis B.1 virus by non-cytopathic mechanisms begins several Syringe-exchange programmes are run in the USA and weeks before the disease onset. Hepatitis B virus DNA other high-income countries, and provide free sterile clearance is mediated largely (up to 90%) by antiviral syringes in exchange for used syringes, reducing cytokines that are produced by cells of the innate and transmission of blood-borne pathogens—including adaptive immune responses—including tumour necrosis hepatitis B—in injection drug users. Operating at fixed factor α, interferon alfa, or interferon beta.15–17 After viral sites and on mobile van routes, the syringe-exchange DNA declines, a cytolytic immune response with programmes can make contact with otherwise hepatocyte apoptosis and necrosis ensues, coincident hard-to-reach populations to deliver social and medical with the onset of clinical hepatitis and a rise in serum services, such as testing for hepatitis B, counselling, and alanine aminotransferase (ALT). The recognition of vaccination.10 infected hepatocytes by virus-specific CD8 cytotoxic An effective hepatitis B vaccine has been available since T cells, via class I human lymphocyte antigen the early 1980s, and in the early 1990s WHO recommended (HLA-I)-presenting hepatitis B virus peptides, is the addition of the hepatitis B vaccination to all national presumed to be the main mechanism causing both liver immunisation programmes. Universal vaccination damage and virus control. Cytotoxic T cells further recruit programmes for newborn babies have been implemented various antigen-non-specific inflammatory cells into the in more than 160 countries, and international financial liver by secreting cytokines, initiating a cascade of support and a reduced cost are facilitating introduction immunological events leading to necroinflammation.18–20 of the vaccine into more low-income countries.11 Some A vigorous, multispecific CD4 and CD8 response is high-income countries with low or very low endemicity associated with viral clearance.21 In individuals with of hepatitis B infection, such as northern European chronic hepatitis B infection, the hepatitis B virus-specific countries, apply a strategy of selective vaccination for CD4 and CD8 response is insufficient;21 and can cause a individuals at high risk of infection, because the low persistent inflammatory response that is ineffective for burden of disease does not warrant the added cost of hepatitis B virus clearance.22 universal vaccination.11,12 Hepatitis B vaccination is the Timely conventional liver biochemical tests are most effective preventive measure in adult populations essential for diagnosis of hepatitis—including with risk factors.1,4,10,11 measurement of ALT for the degree of hepatocellular Since the introduction of hepatitis B vaccination, the damages, bilirubin for conjugation and excretion worldwide rates of infection have fallen. For example, function, and albumin values and prothrombin time for the HBsAg carrier rate in Taiwanese children decreased liver synthesis function. Liver biopsy is important for the from 10% in 1984 to less than 1% in 2004, with a grading of necroinflammation and staging of fibrosis. 68% reduction of fulminant hepatitis in infants Ultrasonography and other imagining methods are (0–1 year), and a 75% decline in hepatocellular carcinoma non-invasive ways to detect cirrhosis and hepatocellular in children (aged 6–14 years).13,14 In the USA the incidence carcinoma23—the judicious use of these methods and of reported acute hepatitis B fell by 81% between assays is crucial to differentiate the nature and severity of Vol 373 February 14, 2009 583
  3. 3. Seminar Persistence of serum HBsAg for more than 6 months ALT in acute infection implies progression to chronic infection. People with ALT in chronic infection Clinical symptoms Acute hepatitis B HBeAg-positive chronic infection usually have high appear Transition from acute to levels of hepatitis B virus DNA, whereas serum chronic hepatitis B concentrations are lower in patients with HBeAg-negative AntiHBs 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 Concentration Serum hepatitis B virus DNA assay is a direct measure of viral load. It is particularly useful for assessment of HBsAg risk of disease progression and candidacy for antiviral therapy, monitoring treatment response, and to HBeAg distinguish active hepatitis B from the inactive carrier state with other causes of high ALT. PCR-based assays, IgM-antiHBc IgG-antiHBc with high sensitivity and a wide dynamic range (10¹–10⁹ IU/mL), are the mainstay for measurement of HBV-DNA hepatitis B viral load. WHO has established an international standard for hepatitis B virus quantification 0 1 2 3 4 5 6 12 24 36 units, in which 1 IU is equal to about five genome Months after hepatitis B virus infection equivalents.27 Assays for hepatitis B virus genotypes and mutations are available and becoming increasingly Figure 1: Serological and clinical changes after acute hepatitis B virus (HBV) infection Shaded bars indicate the duration of seropositivity in self-limited acute hepatitis B infection. Pointed bars indicate important in the clinical field. 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. Natural history The spectrum of acute hepatitis B infection ranges from disease. Testing for hepatitis B virus markers is mandatory asymptomatic infection to self-limited hepatitis, to for the detection and diagnosis of hepatitis B. Serological fulminant hepatitis and it depends on various viral and markers of hepatitis B are HBsAg and its host factors. Symptomatic hepatitis is rare in neonates antibody (antiHBs), HBeAg and its antibody (antiHBe), (less than 1%) and occurs in about 10% of children and immunoglobulins G and M antibody to hepatitis B 1–5 years old.1,22 Fulminant hepatitis is very rare in virus core antigen (IgG antiHBc and IgM antiHBc). paediatric patients, with most reported cases being in HBsAg seropositivity indicates infection, and HBeAg is a infants born to HBeAg-negative, HBsAg-carrier surrogate marker of viral replication with high hepatitis B mothers.28 One proposed explanation is that the absence virus DNA. HBsAg assays should be done in those at risk of HBeAg in maternal blood fails to induce immunological for hepatitis B infection, people with ALT elevation or tolerance,29 thus allowing vigorous immune clearance of evidence of liver disease, and anyone about to receive hepatitis B virus from the infant liver. A third of acute immunosuppressive treatment or chemotherapy. infections in adults are symptomatic,22 and fulminant The first serological marker to appear in acute hepatitis occurs in less than 1% of cases, with a mortality hepatitis B infection is HBsAg, usually 1–6 weeks before of about 70%. Fulminant hepatitis B is related to an the manifestation of clinical symptoms. IgM antiHBc enhanced immune response with rapid viral clearance, appears 1–2 weeks after HBsAg, and persists for up to which means serum HBsAg and hepatitis B virus DNA 6 months after HBsAg is cleared.23 Previously might be undetectable at the time of clinical presentation, undiagnosed chronic HBsAg carriers with acute and the diagnosis is made only by the presence of serum exacerbation of hepatitis B or superinfection with other IgM antiHBc.2 hepatitis virus(es) presenting as clinical acute hepatitis, Resolution of hepatitis B with HBsAg seroclearance are seronegative for IgM antiHBc.24 Serum IgM antiHBc occurs in more than 95% of adult patients. However, assay is, therefore, mandatory for the serodiagnosis of small amounts of hepatitis B virus DNA can still be acute hepatitis B. HBeAg and hepatitis B virus DNA are detected by PCR in serum and peripheral mononuclear present early during acute infection. Both markers cells years after recovery from hepatitis, indicating a usually disappear when serum ALT peaks, or soon state of occult infection.30 Hepatitis B can be transmitted thereafter, and before HBsAg seroclearance, which via organ transplantation, and hepatitis B reactivation occurs within 1–2 months, and are followed by the might occur under immunosuppressive treatment—or appearance of antiHBs several weeks later (figure 1). by chemotherapy in such cases.31 The risk of chronicity Previous infection is diagnosed by the detection of is correlated closely with the patient’s age at the time of antiHBc and antiHBs.23 infection. Infection persists in about 90% of infants Presence of HBeAg for more than 10 weeks indicates a infected at birth, 20–30% of children infected between high likelihood of transition to persistent infection. the ages of 1 and 5 years, 6% of infection in children 584 Vol 373 February 14, 2009
  4. 4. Seminar aged 5–15 years and only 1–5% of patients infected as Hepatitis flares can lead to cirrhosis but will eventually adults.1 One possible explanation for the high chronicity be followed by HBeAg seroconversion to antiHBe. The in infants is that the fetus develops tolerance to the virus estimated yearly proportion of spontaneous HBeAg in utero after the transplacental passage of viral seroconversion is 2–15%, depending on factors such as proteins.32 age, ALT concentrations, and hepatitis B virus The natural course of chronic hepatitis B infection genotype.41–46 In Asia, HBeAg seroconversion occurs at a consists of distinct phases resulting from the interaction mean age of 30–35 years, with most cases between the virus, hepatocytes and host immune (90%) occurring before age 40.45–48 Patients infected with response. Typically, chronic infection acquired perinatally genotype B seroconvert earlier and more frequently or during infancy has three phases: immune tolerant, than do those with genotype C.3,47,49–51 In native Alaskans immune clearance, and inactive residual.33 Hepatitis B with chronic hepatitis B infection, the median age of re-activation can occur in some patients with inactive HBeAg seroclearance is younger than 20 years in disease and trigger immune-mediated liver injury.34,35 patients with genotypes A, B, D, and F, but over 40 years Such patients, therefore, enter a variant phase of immune in patients with genotype C.52 clearance (figure 2).23,36 Adult-acquired chronic infection HBeAg seroconversion is usually followed by clinical has a similar clinical course, except that there is no remission and a life-long inactive state with an excellent obvious initial immune tolerant phase.37 outcome, although a few patients may develop The mechanisms of immune tolerance during the first hepatocellular carcinoma.34,35,53–56 Spontaneous HBsAg phase are not well understood. Work in mice suggests seroclearance can occur, reported at a rate of less than that a transplacental transfer of maternal HBeAg could 1% per year in early studies.53–57 A study with 1965 patients induce a specific unresponsiveness of helper T cells to showed that HBsAg seroclearance occurred at a rate of HBeAg, and result in an ineffective cytotoxic T-cell 1·2% per year, and rose to 1·8% per year in individuals response to nucleocapsid antigens in neonates.32 over age 50; to a 45% cumulative incidence after 25 years Patients in the immune-tolerant phase are usually of follow-up.58 Patients with virus genotype A and B young, asymptomatic, and HBeAg seropositive, with infection have a higher likelihood of HBsAg high viral loads (more than 2×10⁶ to 2×10⁷ IU/mL) but seroclearance than do patients with other genotypes.59,60 normal serum ALT levels and near-normal liver HBsAg seroclearance usually confers an excellent histology. There is usually no, or only minimum, long-term outcome if there is no pre-existing cirrhosis disease progression while serum ALT concentrations or viral superinfection.61,62 However, a small amount of remain normal.38 hepatitis B virus DNA may persist in a state of occult The mechanisms triggering loss of immune tolerance infection.31 are mostly unknown, but a high viral load seems necessary to maintain the tolerant state.39 The immune-clearance phase is associated with falling serum hepatitis B virus DNA concentrations, but their Immune tolerant Immune clearance Inactive residual Reactivation phase phase phase causal relation remains unclear. Other findings that IU/mL characterise the transition from the immune tolerant to 2x109 HBeAg- HBV DNA HBeAg negative the immune clearance phase include a shift of reversion hepatitis hepatocyte expression of hepatitis B virus-core 2x104 HBeAg-positive AntiHBe-positive antigen (HBcAg) from nucleus to cytoplasm,40 and a Pre C/BCP Wild type Wild>mutant Mutant>wild Mutant gradual accumulation of pre-core or core-promoter HBsAg loss mutations.41,42 HCC During the immune-clearance phase, hepatitis activity and intermittent acute ALT increase can flare to over Cirrhosis HCC Cirrhosis five times the upper limit of normal, usually without ALT apparent symptoms. This activity of flares can be complicated by hepatic decompensation. The rises in Liver histology Minimum Active hepatitis Minimum inactive Active hepatitis ALT and flares are attributable to the host’s immune Hepatocyte expression Nucleus Nucleus/cytoplasm Absent Nucleus/cytoplasm response against hepatitis B virus with resultant of liver HBcAg apoptosis and necrosis, thus, higher ALT concentrations 20 35 60 35 usually indicate a more vigorous immune response Age (years) against hepatitis B virus and more extensive hepatocyte damage.43 The occurrence of hepatitis flare varies in Figure 2: Natural course of chronic hepatitis B virus (HBV) infection acquired perinatally and during infancy patient cohorts, but has reached 25% of patients per 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 during year during the first 3–5 years of follow-up in the immune-clearance and reactivation phases could lead to cirrhosis and hepatocellular carcinoma (HCC) (adapted hospital-based studies43–45 The overall occurrence of from Liaw21 with permission). HBeAg=hepatitis B e antigen; antiHBe=hepatitis B e antigen antibody; pre C=pre core; hepatic failure in patients was estimated to be 0·5%.24 BCP=basal core promoter; ALT=serum alanine aminotransferase. Vol 373 February 14, 2009 585
  5. 5. Seminar persistent seropositivity for HBeAg77 or viral DNA;78 Chronic HBV infection persistent raised ALT;79 viral superinfections;80 as well as the severity (hepatic decompensation), extent (bridging HBeAg(+) hepatitis hepatic necrosis), and frequency of hepatitis flare, and the HBV-DNA >2×106-7 IU/mL duration of hepatic lobular alterations.71 ~5% At least a third of patients with cirrhosis are seropositive 2–15%/year for HBeAg or hepatitis B virus DNA at presentation,81 and HBeAg(+) hepatitis 5% HBeAg 90~95% disease progression can continue after cirrhosis HBV-DNA >2×104-5 IU/mL seroconversion development.82 The 5-year probability of hepatic ~4%/year decompensation is 15–20%, and is four-fold higher in ~1·5%/year ~3%/year HBeAg(–) hepatitis Remission patients with active viral replication than in patients HBV-DNA >2×103-4 IU/mL ~0·5%/year ~10% without.83 The yearly rate of hepatocellular carcinoma occurrence is 3–6%.81,82 The estimated 5-year survival rate ~1·5%/year ~1·2%/year Liver cirrhosis HBsAg loss of patients with compensated cirrhosis is 80–85% and ~4%/year ~6%/year 30–50% in patients with decompensated cirrhosis.81 Inactive carrier Hepatocellular carcinoma mostly develops in patients Decompensation ~0·8%/year HCC <0·1%/year with cirrhosis, therefore, hepatocellular carcinoma and cirrhosis share the same risk factors, with a raised risk in ~15%/year patients with a family history of hepatocellular carcinoma.84 Death/transplantation Curative therapy Viral factors also contribute to hepatocellular carcinoma development, including hepatitis B virus DNA level, Figure 3: Hepatitis B virus (HBV) replication and the outcomes of chronic Hepatitis B infection genotypes, and naturally occurring mutations such as Note that Hepatitis B e antigen (HBeAg) seroconversion is followed by remission in most people but that hepatitis B virus pre-S and basal core promoter A1762T/ HBeAg-negative (–) hepatitis (HBV-DNA ≥ 2x10³–2x10⁴ IU/mL) may develop. Patients who remain HBeAg G1764A double mutations.68,85–89 Other contributing factors seropositive or develop HBeAg-negative hepatitis have a high occurrence of cirrhosis (~4 and ~3% per year). Most are habitual alcohol consumption, cigarette smoking, and hepatocellular carcinoma (HCC) develops in patients who have cirrhosis. aflatoxin exposure.90 After HBeAg seroconversion, 1–4% patients have HBeAg seropositive hepatitis again (HBeAg reversion), whereas a Management greater proportion of patients develop HBeAg-negative Acute hepatitis B in adults is selflimiting in more chronic hepatitis B because of reactivation of the hepatitis B than 95% of cases, therefore, antiviral therapy is indicated virus with pre-core or core promoter mutations that only for patients with protracted severe acute hepatitis or abolish or downregulate HBeAg production.34,35,42,63 Results fulminant hepatitis B.25 Management of patients with from Taiwanese studies showed relapse in 2–3% of patients chronic hepatitis B infection should include thorough per year,34,45 with a cumulative rate of 20–25% after 15 years patient assessment and counselling. Although patients of follow-up.64 The proportion of relapse was very low in are usually asymptomatic, they can be anxious and patients who HBeAg-seroconverted before age 30,55,64 but attribute a wide range of negative psychological, social, was raised in men, patients with genotype C, those who and physical symptoms to their condition.91 Counselling HBeAg-seroconverted after age 40,65 and in patients with should include dietary and lifestyle advice, including serum hepatitis B virus DNA concentrations greater than guidance to increase physical activity and control alcohol 10 000 copies per mL.66 These age-related findings show use. Further, health-care providers and patients should that early HBeAg seroconversion, or a short HBeAg-positive discuss the behaviours that lead to superinfection, phase, are associated with an improved chance of sustained prevention of such infection and preventive measures remission.48 against transmission of hepatitis B to intimate contacts. Cirrhosis or hepatocellular carcinoma, or both, can The importance of the long term hepatocellular develop during the natural course of chronic hepatitis B carcinoma surveillance, with ultrasonography infection. Results of large population-based studies with supplemented with α-fetoprotein assay, should be mostly (85%) HBeAg-negative, HBsAg-positive people emphasised to patients older than 40 years, with advanced older than 30 years at recruitment have shown that the fibrosis or cirrhosis, and with a family history of risk of cirrhosis, hepatocellular carcinoma, and mortality hepatocellular carcinoma.25,36,81 increases proportionally with increasing viral DNA Hepatitis B virus replication is key to liver injury and concentrations, starting with at least 1×104 copies per mL.67–69 disease progression,70 and, therefore, the main aims of The study findings suggest hepatitis B virus replication, treatment are to suppress the virus to achieve HBeAg with subsequent immune-mediated liver injuries, is the seroconversion or undetectable viral-DNA levels, or both; main driver of disease progression70 (figure 3). Further risk stop or reduce hepatic necroinflammation; and prevent factors for the development of cirrhosis include: male sex; the development of hepatic decompensation. Long term increasing age;67–69,71,72 HBeAg positivity;72 virus genotype C goals are to reduce cirrhosis and hepatocellular carcinoma (vs B);47,49,73–76 HBeAg reversion or virus reactivation;34,47 development, and ultimately extend survival. Viraemic 586 Vol 373 February 14, 2009
  6. 6. Seminar Lamivudine Adefovir Entecavir Telbivudine Tenofovir Pegylated interferon alfa-2a e+ e– e+ e– e+ e– e+ e– e+ e– e+ e– Dose/route 10 mg/ 10 mg/ 10 mg/ 10 mg/ 0–5 mg/ 0–5 mg/ 600 mg/ 600 mg/ 300 mg/ 300 mg/ 180 μg/week 180 μg/week day orally day orally day orally day orally day orally day orally day orally day orally day orally day orally subcutaneous subcutaneous Cost (US$/year per person)* 2482 2482 6647 6647 8694 8694 5924 5924 5811 5811 18 480 18 480 HBV-DNA (PCR) Log reduction at year 1† 5·4 4·5 3·6 (1·0) 3·7 (1·4) 6·9 5·0 5·7 4·4 6·5 4·5 4·5 4·1 Undetectable at year 1† 40% 72% 21% (0%) 61% (0%) 67% 90% 60% 88% 76% 93% 25% 63% HBeAg seroconversion at 20% – 12% (6%) – 21% – 23% – 21% – 32% – year 1† Drug resistance Year 1 11–14% 6–27% 0% 0% 0% 0% 5% 2% 0 0 0 0 Year 2 40% 26–54% ·· 3% 0% 0% 25% 11% 0 0 – – Year 3 56% 57% ·· 11% ~1% ~1% ·· ·· ·· ·· – – Year 5 69% 65% 20% 29% 1·2% 1·2% ·· ·· ·· ·· – – Other side-effects Negligible Negligible Creatinine Creatinine Negligible Negligible Increase Increase Negligible Negligible Various, Various, increase increase in CK in CK unpleasant unpleasant CK=creatine kinase. e=hepatitis B e antigen. –=not applicable. *From Hoofnagle and colleagues.130 †Data in brackets refer to untreated controls. Table: Comparison of the drugs used in treatment-naive patients with chronic hepatitis B patients with an ALT concentration of twice the upper 32% when assessed 24 weeks after completion of limit of normal or more, or substantial liver disease, are therapy.95–97 Patients with genotype A (vs D) or B (vs C) candidates for drug therapy. Of note, ALT flare may infection tend to have a better response to interferon or precede spontaneous HBeAg seroconversion.43 Obser- pegylated interferon.3,95–97 HBeAg seroconversion response vation for 3 months before considering drug therapy is is sustained in more than 80% of people, and can be acceptable.25,36 Liver biopsy is recommended to assess the followed by HBsAg loss,77,98,99 which is the desired end necroinflammation grade and fibrosis stage, because point. significant fibrosis could have developed in patients with Patients with HBeAg-negative chronic hepatitis B normal ALT, except during the immunotolerant phase.92 respond to interferon alfa therapy but often relapse after Before drug therapy is initiated, the efficacy, advantages treatment completion.78,100 The combined response to and disadvantages, and cost of available therapies should pegylated interferon therapy (normal ALT+hepatitis B be discussed with the patient.36 virus DNA concentration less than 2×10⁴ copies per mL) Approved and widely used agents are conventional in HBeAg-negative patients is 36% at 6 months post interferon alfa and pegylated interferon-alfa-2a; the treatment.101,102 Improved response rates are achieved in nucleoside analogues lamivudine, entecavir, and patients with low serum viral DNA, raised ALT and low telbivudine; and the nucleotide analogue adefovir HBeAg concentrations at baseline, and low HBeAg after dipivoxil. Tenofovir, another nucleotide analogue 24 weeks’ treatment.102–104 HBsAg seroconversion occurs in approved for the treatment of HIV infection, was more 3% of the pegylated interferon treated patients,96,97,101 and effective than adefovir in hepatitis B,93 it has been the rate increases to 10% at 4 years after therapy.105 These approved in European countries and USA, and will response figures are better than those of lamivudine probably be approved worldwide. Drug therapy should be monotherapy. Results from follow-up studies suggest selected according to the patient’s condition, the drug’s that interferon alfa therapy has long term benefits by mechanism, rapidity of action, potency, convenience of promoting cumulative HBeAg seroconversion, administration, adverse effect profile, and cost (see increasing HBsAg loss, reducing development of table). cirrhosis and hepatocellular carcinoma, and extending survival—especially in responders.70,77,98–100 Further Interferon-based therapy advantages of interferon-based therapy are the finite Interferon alfa and pegylated interferon have treatment duration and that patients do not develop drug immunomodulating activity. Theoretically, interferons resistance. Eventually, pegylated interferon treatment will are the ideal treatment for patients with chronic replace interferon alfa because of its improved hepatitis B, but the response rate after 4–6 months of effectiveness and convenient once a week interferon alfa is only 30–40% in HBeAg-positive administration.36,95 Interferon-based therapy is associated patients, with a risk difference of 23–25% against with many adverse events; including influenza-like untreated controls.94 48 weeks of pegylated interferon symptoms, fatigue, anorexia, weight loss, hair loss, therapy yields a sustained HBeAg seroconversion rate of thyroid dysfunction, emotional instability, and bone Vol 373 February 14, 2009 587
  7. 7. Seminar marrow suppression. Patients might need symptomatic upper limit of normal, but in only 5% of patients with treatment, and some require dose modification or ALT values less than twice the upper limit of normal.111,112 discontinuation of therapy.95 Most patients are able to Thus, patients with a stronger endogenous immune complete 48 weeks of pegylated interferon treatment response to the hepatitis B virus might have an improved despite the side-effects.96,97,101 chance of reducing cccDNA and HBeAg translation.111 Additionally, patients with ALT values more than five Nucleoside or nucleotide analogues times the upper limit of normal could be developing Oral antiviral agents have fast and potent inhibitory severe hepatitis or hepatic decompensation, especially if effects on hepatitis B virus polymerase and reverse they have advanced fibrosis.43 These patients should be transcriptase activity, and are safe and effective for monitored every week or every two weeks so that hepatitis B virus DNA suppression, ALT normalisation, fast-acting antiviral drugs can be started to arrest the and histological improvement. Results from cross-trial development, or deterioration, of hepatic de- 1 year treatment data suggest entecavir is the most potent compensation.113 Similarly, nucleoside and nucleotide of the drugs, followed by tenofovir, telbivudine, analogues might rescue patients with decompensated lamivudine, and adefovir. However, the antiviral potency cirrhosis by increasing serum albumin concentrations, of these drugs does not result in an increase in HBeAg and stabilising bilirubin values and prothrombin time, seroconversion—which was seen at a rate of around removing the need for transplantation and prolonging 20% after 1 year of treatment (see table)—and HBsAg survival.114,115 loss is very rare.106–110 After 1 year of lamivudine treatment 20–50% of patients who have HBeAg seroconversion an HBeAg seroconversion was achieved in more than will relapse with HBeAg reversion within 6–12 months half of patients with ALT values more than five times the off therapy, and more patients may relapse if the duration of consolidation therapy after HBeAg seroconversion is less than 6 months.25,36 In Chronic HBV infection HBeAg-negative patients, there is no end point such as HBeAg seroconversion, so treatment duration is HBeAg(+) HBeAg(–) indefinite, and stopping drug therapy after 1 year is associated with a 90% relapse rate.116 Relapses are characterised by increasing hepatitis B virus DNA level HBV-DNA >2×104 IU/mL HBV-DNA >2×103 IU/mL HBV-DNA <2×103 IU/mL followed by rising ALT or a hepatitis flare which could be life threatening.117 Therefore, continuing long-term ALT<ULN ALT>ULN ALT<ULN ALT<ULN ALT>ULN drug therapy is usually necessary to maintain a virological response. Results of a large randomised Other causes? controlled trial in patients with advanced fibrosis or <2× ULN cirrhosis showed the benefits of long-term therapy after 3-month 3-month 6-month 6-month 3 years of lamivudine therapy were reduced dis- >2× 1–3-month follow-up follow-up follow-up follow-up follow-up ease progression and hepatocellular carcinoma development.118 The emergence of drug-resistant genotypic mutations >40 years Concern of <2× ULN >40 years >40 years of hepatitis B virus in long term therapy is a major decompensation problem. Clinically, emergence of drug resistance is indicated by viral breakthrough—an increase of serum Biopsy/therapy + Yes No Biopsy/therapy + HCC surveillence hepatitis B virus DNA to more than ten-fold increase HCC surveillence HCC surveillence in HBV concentrations from the nadir of initial response—with subsequent biochemical breakthrough 3–6 months or raised ALT values in more than 90% of patients.119 Hepatitis flares develop frequently, sometimes NA IFN or NA associated with hepatic decompensation during continued antiviral therapy,120 and, the initial clinical and histological benefits of antiviral therapy Response Non-response diminish.118,121,122 The occurrence of drug resistance rises with increasing therapy duration, although the generation of Stop/monitor Consider other strategies nucleoside and nucleotide analogues has improved potency and raised the genetic barrier to resistant Figure 4: Management of patients with chronic hepatitis B virus (HBV) infection mutations (see table). Drug resistance occurs most HBeAg=hepatitis B e antigen. ULN=upper limit of normal. NA=nucleoside or nucleotide analogues. frequently with lamivudine, followed by telbivudine, IFN=interferon-based therapy. HCC=hepatocellular carcinoma. adefovir and tenofovir, and is very low with entecavir.106–110 588 Vol 373 February 14, 2009
  8. 8. Seminar Studies have shown that suppression of the hepatitis B Hepatitis B virus re-activation is a serious complication virus to undetectable level at 24 weeks of telbivudine in patients undergoing transplantation, immuno- and lamivudine therapy is associated with low incidence suppression, or chemotherapy. Patients should be of drug resistance at week 48.110 Rescue therapy for drug screened for HBsAg and, if positive, prophylactic therapy resistance is now available and, therefore, monitoring with a direct antiviral agent should be started before the hepatitis B virus DNA levels during drug treatment to beginning of and at least 12 weeks after the end of the detect drug resistance early enough to start rescue immunosuppressive treatment or chemotherapy.36,131 For therapy before serum hepatitis B virus DNA increases all patients with hepatitis B virus-associated liver failure over 1×10⁶ copies per mL123,124 is very important. In who are listed for transplantation, nucleoside or nucleotide patients with drug resistance, add-on therapy without analogues should be started and continued after cross-resistance (adefovir and tenofovir vs lamivudine, transplantation as prophylaxis against re-infection of the telbivudine and entecavir) should be instituted.123,125 allograft.25,36 Switching to interferon-based therapy can be a further Conflict of interest statement option.126 Yun-Fan Liaw has been involved in clinical trials or served as a global advisory board member of Roche, BMS, GSK, Novartis, Gilead Sciences. Chia-Ming Chu declares that he has no conflict of interest. Drug treatment strategies In view of the array of drugs available, physician and Acknowledgments We thank Chang-Gung Medical Research Fund and the Prosperous patient should decide which drug should be used, and Foundation, Taipei, Taiwan, for long term grant support; when to start and stop treatment. 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