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Hepatitis B and D
LIVER INFECTIONS
Hepatitis B and D
What’s new?
Ye Htun Oo C
David J Mutimer C
Abstract Hepatitis B virus (HBV) infection is a global health problem. 400 million people are chronically infected with HBV, which is a major cause of liver cirrhosis and liver failure. The global distribution has changed due to migration. Immunization programs have resulted in a dramatic decline in the incidence and prevalence of HBV and hepatitis D virus (HDV) infection in many countries. Host immune responses to the viruses define the clinical course of infection, which varies from an asymptomatic carrier state to fulminant hepatic failure. The timing of treatment and the choice of antiviral therapy depend on the patient profile. The main goal of antiviral therapy is to prevent liver cirrhosis. Antiviral treatment can suppress HBV to undetectable levels. However, the HBV genome can persist in hepatocytes despite sustained and potent suppression. HDV requires coexisting HBV for its proliferation. Around 20 million people are co-infected with HDV and HBV. In general, HBV/HDV co-infection causes more severe liver disease than is observed in HBV alone. Interferon is the current accepted treatment option of HBV/HDV infection, though treatment results are disappointing. For selected patients with decompensated liver cirrhosis due to HBV or HBV/HDV infection, liver transplantation may be appropriate.
C
C
C
Migration of population from endemic to low prevalence areas across the world has changed the epidemiology of HBV infection in many countries The epidemiology of HDV infection has been affected by HBV vaccination and by population migration Universal vaccination programmes have reduced the incidence of acute HBV infection, the prevalence of HBV in younger patients and the incidence of childhood hepatocellular carcinoma. An eventual impact of vaccination on deaths from chronic liver disease is predicted Non-invasive means of assessing liver fibrosis are being validated and will reduce the need for liver biopsy in chronic HBV Potent antivirals with low rates of emergence of resistance are an option for treatment of chronic HBV
Between 15 and 20 million HBV-infected individuals are coinfected with hepatitis D. HDV prevalence and distribution in Europe are changing as a result of HBV vaccination programmes (reducing the prevalence of both HBV and HDV infection) and recent migration patterns (tending to increase the prevalence of both infections in some countries).2 Worldwide prevalence and distribution of HBV and HDV are shown in Figure 1.
Keywords Antiviral therapy; cirrhosis; hepatitis B; hepatitis D; hepatocellular carcinoma; liver transplantation; recurrence; vaccination
Virology Human HBV is a member of the Hepadnaviridae family and humans and higher primates are the only hosts for HBV infection. The intact virion is composed of the viral DNA surrounded by a nucleocapsid (core protein or antigen) and an outer layer comprising the HBV surface protein or antigen (HBsAg). The viral genome is a 3.2-kb, partially double-stranded DNA with four overlapping reading frames (ORF). The viral genome encodes the viral polymerase (which includes the reverse transcriptase function), the core and surface proteins, and the nonstructural proteins (HBV e antigen and X protein). The cccDNA (co-valently closed circular DNA), which acts as the major transcriptional template for the virus, is central to the durability of HBV infection and persists as an episome in infected hepatocytes. It can persist after antiviral therapy and even after the apparent clearance of infection. There are eight distinct HBV genotypes, which have well-defined geographical distribution (see Figure 1). They differ in some important respects, including their natural history and response to interferon-based antiviral therapy. In Europe, genotypes A and D are most common. In eastern Asia, genotypes B and C are prevalent. Hepatitis D is a spherical particle, 36 nm in diameter. It is a defective satellite RNA virus of the Deltaviridae family. It requires HBsAg for viral assembly and propagation, so HDV infection can occur only in HBV patients. The single-stranded circular RNA genome of HDV is transcribed in hepatocytes during infection.3,4 The virion is composed of an outer coat containing HBV envelope proteins and host lipids, which surround the nucleocapsid; the latter comprises a single stranded RNA and hepatitis D antigen. Eight genotypes of HDV exist. The
Epidemiology Approximately 350e400 million persons have chronic HBV infection1 and more than 1 million deaths annually are due to end-stage liver disease or hepatocellular cancer (HCC). HCC is the fifth most common cancer in the world and third leading cause of cancer-related death. HBV infection is highly prevalent in Asia, Africa, and parts of southern and eastern Europe. In the UK, more than 300,000 people may have chronic HBV infection.2 HBV is the indication for transplantation in fewer than 5% of transplant cases in the UK. Migration from high-prevalence to low-prevalence countries influences the distribution, incidence and prevalence of HBV infection in low-prevalence countries, especially in Western Europe, North America and Australia.
Ye Htun Oo MBBS PhD MRCP is a Medical Research Council Clinician Scientist and an Honorary Consultant in Hepatology at the Queen Elizabeth Hospital Liver Unit, UK. His research interests include viral and autoimmune hepatitis, liver transplantation, and hepatic immune tolerance. Competing interests: none. David J Mutimer MBBS MD FRCP is a Professor of Clinical Hepatology at the Queen Elizabeth Hospital Liver Unit & University of Birmingham, UK. His main interests include viral hepatology and liver transplantation. Competing interests: he has acted as advisor to Gilead and BMS, the manufacturers of tenofovir and entecavir respectively.
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LIVER INFECTIONS
Geographic distribution of HBV and HDV a HBV
A,G
A D
D
B,C
E
F,H
B E
F
C
A
HBsAg prevalence > 8%: High 2–7%: Intermediate < 2%: Low Red = high endemic area; blue = intermediate; green = low. Hepatitis is highly prevalent in Asia and Africa. The arrows show the effect of migration from developing countries to Europe, North America and Australia. HBsAg, hepatitis B surface antigen. b HDV Genotype 1
Genotype 1 Genotype 1 Genotype 1/2/4 Genotype 1/3
Genotype 5–8
High Intermediate Low Very low Insufficient data Two subtypes–1A and 1B–have been identified in HDV genotype 1. 1A is predominant in Asia and 1B in the USA. Both are common in the Mediterranean. HDV genotype 2 occurs in the Far East. HDV genotype 3 occurs exclusively in the northern part of South America and is linked to HBV genotype F. Genotypes 5–8 have been identified primary in patients from Africa. HDV=hepatitis D virus. Figure 1(b). reproduced from Hughes SA, Wedemeyer H, Harrison PM. Hepatitis delta virus. The Lancet 2011; 378:73−85, with permission from Elsevier. Figure 1 (a) Prevalence of hepatitis B. (b) Prevalence of hepatitis D.
infection and the severity of the liver damage are determined by the balance between viral replication and host immune response mechanisms. HBV-specific cytotoxic CD8 T cells play a critical role in HBV clearance. However, suppressor or regulatory T cells (Treg) inhibit HBV-specific CD8 T-cell function in chronic HBV infection. This contributes to viral persistence. Large numbers of Treg are found in both the circulation and in the liver of chronic HBV patients.
combination of HDV genotype 1 and HBV genotype C appears to be associated with a worse outcome.5 HDV genotype 1 is most frequent genotype throughout the world (Figure 1).
Pathogenesis and natural history HBV The pathogenesis of liver disease in HBV is related to the persistence and magnitude of viral replication. The course of the
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LIVER INFECTIONS
The natural history of chronic HBV is diverse and non-linear. Chronically infected patients range from inactive carriers with low levels of replication to those patients with higher levels of virus and active inflammation, which may progress to cirrhosis and HCC. Following acute HBV infection of adults, 95% recover spontaneously with viral clearance not needing treatment. Perinatal infection and infection at a young age are strongly associated with failure to clear the virus and with the development of chronic infection. Chronic infection is defined as the persistence of HBsAg in serum for at least 6 months after infection. Liver inflammation requires both high levels of replication and targeted inflammatory responses. Chronic infection may be associated with production and secretion by infected hepatocytes of the HBV e antigen (HBeAg). In that case, the level of viral replication is almost invariably very high. Eventually, the production of HBeAg stops, which usually coincides with a reduction in viral replication. However, the subsequent level of viral replication may be low or high. When HBeAg-negativity is associated with high levels of replication, the associated hepatitis may be referred to as e-negative hepatitis. Under that circumstance, sequencing of the viral DNA frequently shows that specific mutations have emerged in the pre-core or core promoter regions of the viral DNA. Thus, e-negative hepatitis is also known as pre-core mutant hepatitis (see Figure 2a). Classically, four phases of chronic HBV infection have been described: the immune tolerant phase, the immune reactive phase, the inactive/resolution phase and reactivation phase. High levels of replication (usually associated with a serum titre
greater than 10 million IU/ml) may be observed in the absence of inflammatory response (normal alanine aminotransferase (ALT) with minimal or no inflammation on liver biopsy), the so-called immune tolerant phase. Immune tolerance is more frequently associated with HBeAg-positive infection and is seen most often in those infected at birth or at a young age. During this phase there is little cytotoxic T cell reaction to virus. However, this phase is seldom maintained for life. When the virus is recognized as foreign antigen by the immune system, the immune reactive phase occurs and is characterized by elevated or fluctuating ALT, HBeAg-positivity and moderate to severe inflammation on liver biopsy. During this phase, serum HBV DNA falls and HBeAg secretion may stop (called HBeAg seroconversion). After HBeAg seroconversion, the majority of patients will become inactive hepatitis B carriers with HBeAg-negativity, low serum HBV (<2000 IU/ml) and normal ALT. This phase may persist for life with sustained and effective cytotoxic T cell responses. For those that remain inactive, 1e3% per annum will achieve resolution phase with clearance of HBsAg from serum. These HBsAgnegative patients may still have detectable HVB DNA in the liver but not in serum. However, some patients revert from the inactive phase to a reactivation phase, with reappearance of higher levels of virus despite HBeAg-negativity (sequencing may demonstrate pre-core or core promoter mutations). There is resumed liver inflammation and progressive fibrosis. In general, the majority of patients with high levels of replication sustained for a long duration will eventually develop progressive liver damage leading to cirrhosis and/or HCC. This
Site of hepatitis B virus DNA mutations pre-S1
pre-S2
Mutations
S
HBV-DNA
C P pre-C Mutations
Mutations X
HBV viral DNA is partially double stranded and encodes four proteins: a DNA polymerase for viral replication (P), a surface protein (S), a core protein (C) and an X protein. The pre-C and C regions encode a core protein and an e antigen. Pre-C encodes a signal sequence needed for the C protein to be secreted from the hepatocytes into serum as e antigen. Mutation in pre-C region leads to a failure of secretion of e antigen into serum, thus e antigen is negative despite a high level of DNA. Mutations in the surface protein can lead to vaccination failure, and mutations in the DNA polymerase can occur during antiviral treatment. Figure 2
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LIVER INFECTIONS
a. Stages of infection in patients infected with HBe-positive virus Phase1 Immune tolerance
Viraemia
Phase 2 Immune clearance
HBeAg-positive viraemia (HBV DNA-positive; >10 5 IU/ml)
Phase 3 Immune control or latent
Phase 4 Emergence of HBe-negative variant
(HBV DNA <10 5 IU/ml)
HBeAg-positive viraemia (HBV DNA-positive; >10 5 IU/ml)
Alanine aminotransferase
0
50
Time (years) Liver histology
Chronic hepatitis
Minimal lobular
Chronic lobular/ hepatitis Cirrhosis
Inactive cirrhosis
Chronic hepatitis Active cirrhosis
Hepatocellular carcinoma
Four different phases of chronic HBV infection is shown. The best time to treat with either interferon or nucleoside/nucleotide analogues is in immune reactive and reactivation phases. (Figure used is from Prof Howard Thomas; Hepatitis B and D; Medicine 35(1); 2006). b. Typical evolution of serological and virological measures in HDV infection A HBsAG HDV RNA ALT
Anti-HBc IgG Anti-HBc IgM Anti-HD IgG Anti-HD IgM
B
C
Time after exposure (weeks) (A) Simultaneous co-infection with HBV and HDV, resulting in clearance of both viruses in almost all patients. (B) HDV superinfection of an HBV carrier with self-limited outcome. The spontaneous clearance of HDV RNA might take years to occur (indicated by break on x axis) and, in few cases, can herald the loss of HBsAg (not depicted). (C) HDV superinfection of a HBV carrier with chronic persistent viral replication; the more common outcome after superinfection. HDV, hepatitis delta virus; ALT, alanine aminotransferase; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen.
Figure 3(b). reproduced from Hughes SA, Wedemeyer H, Harrison PM. Hepatitis delta virus. The Lancet 2011; 378:73−85, with permission from Elsevier. Figure 3 (a) Clinical course of HBV infection. (b) Virological and serological evolution in HDV infection.
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LIVER INFECTIONS
Serologic markers of HBV and HDV infection and their clinical interpretation Viral serology markers
Definition
Clinical significance
HBsAg
HBV surface antigen
Anti-HBs
Antibody to HBV surface antigen
Anti-HBc
Antibody to HBV core antigen
HBeAg Anti-HBe
Non-structural protein measured in serum Antibody to HBe antigen
HBV DNA
Viral genomic material measured in serum
Anti-HDV IgG Anti-HDV IgM
Antibody to HDV antigen Antibody to HDV antigen
HDV RNA
Viral genomic material measured in serum
Diagnosis of HBV infection Must be positive in HDV infection Presence without anti-HBc implies vaccine induced immunity. Also present in naturally cleared infection but titres fall and often is reported as negative IgM positive in acute infection, IgG alone implies resolved infection Usually associated with high HBV DNA titre Can be found with high-level or low-level viral replication Reflects viral replication and indicates response to therapy Indicator of past or present HDV infection Serum marker of recent acute infection, and persists in chronic infection as a marker of ongoing viral replication (can be applied as a surrogate for HDV RNA positivity) Reflects viral replication
HBV, hepatitis B virus; HDV, Hepatitis D virus; Ig, immunoglobulin.
Table 1
Clinical presentation and diagnosis
natural history of HBV can be transformed by antiviral agents. Successful treatment prevents progressive fibrosis and hepatic decompensation, reduces the risk for HCC and prevents liverrelated deaths. Hepatitis serology, HBV DNA titres, serum ALT and expected liver histology findings in different phases of HBV infection are shown in Figure 3.
Both viruses are transmitted via the parenteral route by exposure to infected blood or body fluids. Vertical transmission from mother-to-infant or child-to-child infection is the most common routes worldwide. Transmission can also occur via sexual contact, poor medical practice or self-injection of drugs. Acute HBV infection is characterized by arthralgia, fever, urticaria and flulike symptoms, followed by jaundice. More than 90% recover with acquired immunity but a small proportion is persistently infected; fulminant hepatitis is rare. Globally, most infection is acquired at a young age, the majority of infection is asymptomatic, and a high proportion becomes chronic. Thus, the majority of diagnoses are made in those with asymptomatic chronic infection when blood tests are performed for HBV screening or for other reasons. The clinical outcome of HDV depends on the mode of infection and on the host response to HBV and HDV (Figure 3). HBV is essential for HDV virion assembly and replication, so that HDV infection is always associated with HBV infection. Acute coinfection is a simultaneous infection with both viruses that leads to acute hepatitis B and D. This is clinically
HDV Hepatitis D antigen is not directly cytopathic to human hepatocytes. Hepatitis D virus induces innate and adaptive immune response in the infected host, including the production of IgM and IgG antibodies. Evidence so far has suggested that innate and adaptive cellular immune responses to HDV via both NK cells and CD4/CD8 responses could play an important role in the pathogenesis of liver damage, and in predicting the response to antiviral therapy.6e8 HDV infection can occur as a result of simultaneous coinfection with both HDV and HBV or by superinfection of individuals with established chronic HBV infection with HDV (Figure 3). Compared with chronic HBV mono-infection, chronic infection with both HDV and HBV is associated with accelerated fibrosis progression, higher rates of cirrhosis development, and increased risk of HCC and hepatic decompensation. The clinical profile of HDV infection can range from symptom-free to fulminant hepatitis.9 The diagnosis is frequently made when a patients presents with complications of cirrhosis.10 Around 70e80% of chronic HDV patients may develop cirrhosis within 5e10 years of diagnosis and, compared with HBV mono-infection, HBV and HDV co-infection is twice as likely to result in cirrhosis.11
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HBV treatment (oral antivirals) L-nucleosides
Deoxyguanosine analogues
Nucleotides
Lamivudine Telbivudine
Entecavir
Adefovir Tenofovir
Table 2
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LIVER INFECTIONS
Assessment of fibrosis A liver biopsy can determine the degree of hepatic necroinflammation (grading) and fibrosis (staging).15 The use of noninvasive methods such as serum markers and transient elastography may provide a measurement of liver fibrosis, and some centres use these as an alternative to liver biopsy.
Anti-viral resistance in chronic HBV Anti-viral drug
Addition of second anti-viral or change to tenofovir
HBV DNA (IU/ml)
10 10
Monitoring cirrhosis and surveillance of HCC Liver ultrasound scanning demonstrates cirrhosis and features of portal hypertension (splenomegaly, ascites and varices) and monitors the appearance of primary liver cancer. It should be performed at first assessment for all patients and every 6 months for patients with high risk of liver cancer.
10 10
Drug resistance
10
Detectable limit
10 10 0
Time since antiviral therapy started
Management HBV management The management of HBV may include the use of interferon or oral antiviral nucleoside/nucleotide analogues. The goal of therapy is to prevent the progression to cirrhosis and to reduce risk of HCC. Antiviral efficacy is measured by the degree of HBV DNA suppression and by rates of HBeAg and HBsAg loss, and is reflected by improvement in liver histology.
Figure 4 HBV DNA titre is well suppressed following potent antiviral therapy. However, over the years, there may be selection and emergence of drug resistance, characterized by a rise in HBV DNA titre. Drug resistance HBV DNA sequencing should be checked if this rise in titre is observed. These patients need to be treated with addition of a second drug, or by switching to appropriate monotherapy (usually either tenofovir or entecavir).
Treatment strategy HBV treatment is recommended for those patients who have moderate hepatic necroinflammation or fibrosis and high serum HBV DNA. Patients with established cirrhosis should be given oral antiviral therapy regardless of HBV DNA titre.16 The choice between nucleoside/nucleotide and interferon (IFN) depends on patient and viral characteristics, and on patient and physician preference. IFN therapy has both immunomodulatory and antiviral effects. IFN treatment is of finite duration, and the ideal candidate is the young patient with HBeAg-positivity who is infected with HBV genotype A (the genotype most sensitive to IFN treatment). Successful outcome for this patient is defined as HBeAg loss, acquisition of anti-HBe, and low serum HBV DNA (all sustained after cessation of treatment). Occasional patients will lose serum HBsAg. Nucleoside/nucleotide analogues are oral antiviral agents that inhibit HBV DNA synthesis by acting as DNA chain terminators and are well tolerated. Both types of analogue comprise a nitrogenous base and ribose/deoxyribose, but nucleotides also have 1e3 phosphate groups. Among agents in common use for this indication, entecavir, lamivudine and telbivudine are nucleoside analogues, whereas tenofovir is a nucleotide analogue. They fall into three groups as shown in (Table 2). First-line therapy for the treatment-naı¨ve non-cirrhotic patient is either IFN or an oral antiviral. Entecavir and tenofovir both have potent antiviral activity (90% of treated patients have undetectable serum HBV DNA at 12 months of therapy), good safety profiles, and very low rates of emergence of resistance. Lamivudine and telbivudine should not be used as first-line therapy because the risk of drug resistance is high. Patients taking oral antiviral therapy need to understand the importance of treatment adherence to prevent disease progression and to minimize the risk of drug resistance. In normal practice, the emergence of drug resistance is recognized by a rise in viral load of at least 1 log10 IU/ml from nadir titre in a compliant patient.
indistinguishable from acute hepatitis B although it may be more severe and two peaks of serum ALT may be noted. Superinfection by HDV of an individual chronically infected with HBV leads to severe acute hepatitis, which progresses to chronicity in up to 80% of patients.12 Once chronic HDV infection is established, it usually exacerbates the pre-existing liver disease due to HBV.13 However, HBV replication is usually suppressed to low levels during the acute phase of HDV infection and this suppression persists in chronic HDV/HBV infection.14 The incubation period of acute HBV (with or without HDV) infection ranges from 3 to 7 weeks with prodromal symptoms of fatigue, lethargy, anorexia or nausea followed by biochemical evidence of hepatitis with a rise in serum ALT.
Investigations Viral serology Those patients who present with acute HBV typically have both HBsAg and immunoglobulin M (IgM) antibodies to HBV in serum (IgM reactivity to the core antigen is typically measured). Chronic HBV patients who present to clinics should be checked for HBsAg, HBeAg and HBV DNA titre. HBV DNA quantification is a key determinant for selection of patients for therapy, and its measurement is necessary to monitor response to antiviral therapy (Table 1). HBV infection can be associated with HDV infection, so HDV serology should be routinely performed. AntiHDV antibody should be tested and, if positive, ongoing HDV infection should be confirmed by the detection of HDV RNA (Table 1). Liver biochemistry Assessment of liver damage requires routine biochemical liver function tests, including serum albumin, and international normalized ratio.
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LIVER INFECTIONS
Immunosuppressed patients Reappearance of serum HBsAg or HBV DNA in a patient with previous resolved or inactive HBV infection is sometimes observed in immunosuppressed states. cccDNA, which resides within the infected hepatocytes, plays a significant role in reactivation of HBV during cancer chemotherapy, during the use of some biological agents (particularly anti-CD20 rituximab) and following organ transplantation. Patients should be screened for HBV before being given any immunosuppressive therapy. Under these circumstances, prophylaxis with oral antiviral drugs is frequently indicated.
HBV resistance can be confirmed by genetic sequencing of the virus (Figure 4). Treatment options for HDV are limited since the viral RNA does not encode any viral enzymes. Thus no virus-specific directly acting antivirals are available and nucleoside/nucleotide analogues used for HBV infection are ineffective against HDV. Administration of pegylated (polyethylene glycolconjugated) interferon-a induces HDV-RNA negativity in about one quarter of patients but therapy for a year or 18 months is required,17 which is often poorly tolerated. Addition of oral nucleoside/nucleotide is of no greater benefit than IFN monotherapy alone. Regular blood count and thyroid function monitoring is recommended for patients on IFN therapy and renal function and phosphate level monitoring should be performed in patients on Tenofovir therapy. Potential novel treatments for the future may include hepatocyte entry inhibitors, viron assembly inhibitors and prenylation inhibitors.18
Prevention HBV vaccination Vaccination is the most effective way to achieve global HBV control and to prevent cirrhosis, liver failure and liver cancer. Most countries include HBV vaccination as part of the routine universal childhood vaccination schedule. Universal vaccination has been shown to reduce the incidence of both HBV and HDV infection, the frequency of childhood chronic infection, and the risk of childhood liver cancer. Some low-prevalence countries have not implemented universal vaccination, but prefer to target vaccination to specific high-risk groups. Most countries undertake maternal screening for HBsAg, and vaccinate the neonate born to the HBV carrier mother.9 If HBV infection is detected, members of the infected person’s family should be screened and vaccination offered to household members and close contacts who are HBsAg negative.
Follow-up and HCC surveillance It is estimated that more than 50% of liver cancers worldwide are due to HBV and the majority of these occur in developing countries. African or Asian ethnicity, male gender, age over 40 years, family history of HCC, high HBV DNA titre and coinfection with other viruses including HDV19 are the risk factors which are associated with increased risk of HCC development.20,21 Most cancer is seen after development of cirrhosis, so prevention of cirrhosis dramatically reduces the risk of cancer.
HBV infection in special circumstances Liver transplantation
Pregnancy Vaccination of the offspring of carrier mothers prevents neonatal infection in the majority of cases. Occasional vaccine failure is observed, most commonly in association with very high maternal viral titre. Antiviral therapy for the pregnant mother with very high titres may further reduce the risk of transmission to the baby. Current recommendations suggest that either lamivudine (Category C) or tenofovir (Category B) can be taken by the pregnant mother during the third trimester to further reduce the risk of transmission to the developing fetus and neonate. Breastfeeding by an HBV-positive mother is safe and there is a low risk of infection (so long as the baby has been vaccinated).
Liver transplantation is the preferred treatment for HBV-infected individuals who present with fulminant liver failure, decompensated liver disease and HBV-related HCC. Oral antiviral therapy alone or in combination with hyperimmune immunoglobulin can prevent graft re-infection.22 Prevention of HBV recurrence will also prevent HDV recurrence in transplanted patients with HBV/HDV co-infection. A REFERENCES 1 Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 2004; 11: 97e107. 2 Gaeta GB, Stroffolini T, Smedile A, Niro G, Mele A. Hepatitis delta in Europe: vanishing or refreshing? Hepatology 2007; 46: 1312e3. 3 Chen PJ, Kalpana G, Goldberg J, et al. Structure and replication of the genome of the hepatitis delta virus. Proc Natl Acad Sci U. S. A 1986; 83: 8774e8. 4 Rizzetto M, Canese MG, Arico S, et al. Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut 1977; 18: 997e1003. 5 Su CW, Huang YH, Huo TI, et al. Genotypes and viremia of hepatitis B and D viruses are associated with outcomes of chronic hepatitis D patients. Gastroenterology 2006; 130: 1625e35. 6 Nisini R, Paroli M, Accapezzato D, et al. Human CD4þ T-cell response to hepatitis delta virus: identification of multiple epitopes and
Infants and children HBV infection is seldom associated with significant liver damage during childhood years. Antivirals can be used under specialist care. Healthcare worker HBV-infected healthcare workers who undertake exposure-prone procedures (e.g. surgeons, obstetricians) can take antivirals to reduce the risk of inadvertent transmission from doctor to patient. Co-infection with HIV HIV and HBV co-infection is frequently observed. Inclusion of tenofovir in the HIV treatment regimen ensures excellent suppression of the HBV. Co-infection leads to severe hepatitis compared to HBV mono-infected patients.12
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characterization of T-helper cytokine profiles. J Virol 1997; 71: 2241e51. Actis GC, Maran E, Saracco G, et al. Interferon treatment of chronic hepatitis B surface antigen (HBsAg) carriers. A description of the activation profiles of natural killer cells obtained with different schedules of administration in three subsets of carriers. Ric Clin Lab 1987; 17: 331e41. Wedemeyer H, Heidrich B, Manns MP. Hepatitis D virus infectionenot a vanishing disease in Europe!. Hepatology 2007; 45: 1331e2. author reply 1332e1333. Bonino F, Negro F, Baldi M, et al. The natural history of chronic delta hepatitis. Prog Clin Biol Res 1987; 234: 145e52. Rizzetto M, Verme G, Recchia S, et al. Chronic hepatitis in carriers of hepatitis B surface antigen, with intrahepatic expression of the delta antigen. An active and progressive disease unresponsive to immunosuppressive treatment. Ann Intern Med 1983; 98: 437e41. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 2008; 48: 335e52. Smedile A, Farci P, Verme G, et al. Influence of delta infection on severity of hepatitis B. Lancet 1982; 2: 945e7. Smedile A, Dentico P, Zanetti A, et al. Infection with the delta agent in chronic HBsAg carriers. Gastroenterology 1981; 81: 992e7.
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14 Krogsgaard K, Kryger P, Aldershvile J, Andersson P, Sorensen TI, Nielsen JO. Delta-infection and suppression of hepatitis B virus replication in chronic HBsAg carriers. Hepatology 1987; 7: 42e5. 15 Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22: 696e9. 16 EASL clinical practice guidelines. Management of chronic hepatitis B virus infection. J Hepatol 2012; 57: 167e85. 17 Farci P, Mandas A, Coiana A, et al. Treatment of chronic hepatitis D with interferon alfa-2a. N. Engl J Med 1994; 330: 88e94. 18 Glenn JS, Watson JA, Havel CM, White JM. Identification of a prenylation site in delta virus large antigen. Science 1992; 256: 1331e3. 19 Romeo R, Del Ninno E, Rumi M, et al. 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and hepatocellular carcinoma. Gastroenterology 2009; 136: 1629e38. 20 Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22,707 men in Taiwan. Lancet 1981; 2: 1129e33. 21 Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006; 130: 678e86. 22 Freshwater DA, Dudley T, Cane P, Mutimer DJ. Viral persistence after liver transplantation for hepatitis B virus: a cross-sectional study. Transplantation 2008; 85: 1105e11.
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Hepatitis B and D
What’s new?
Ye Htun Oo C
David J Mutimer C
Abstract Hepatitis B virus (HBV) infection is a global health problem. 400 million people are chronically infected with HBV, which is a major cause of liver cirrhosis and liver failure. The global distribution has changed due to migration. Immunization programs have resulted in a dramatic decline in the incidence and prevalence of HBV and hepatitis D virus (HDV) infection in many countries. Host immune responses to the viruses define the clinical course of infection, which varies from an asymptomatic carrier state to fulminant hepatic failure. The timing of treatment and the choice of antiviral therapy depend on the patient profile. The main goal of antiviral therapy is to prevent liver cirrhosis. Antiviral treatment can suppress HBV to undetectable levels. However, the HBV genome can persist in hepatocytes despite sustained and potent suppression. HDV requires coexisting HBV for its proliferation. Around 20 million people are co-infected with HDV and HBV. In general, HBV/HDV co-infection causes more severe liver disease than is observed in HBV alone. Interferon is the current accepted treatment option of HBV/HDV infection, though treatment results are disappointing. For selected patients with decompensated liver cirrhosis due to HBV or HBV/HDV infection, liver transplantation may be appropriate.
C
C
C
Migration of population from endemic to low prevalence areas across the world has changed the epidemiology of HBV infection in many countries The epidemiology of HDV infection has been affected by HBV vaccination and by population migration Universal vaccination programmes have reduced the incidence of acute HBV infection, the prevalence of HBV in younger patients and the incidence of childhood hepatocellular carcinoma. An eventual impact of vaccination on deaths from chronic liver disease is predicted Non-invasive means of assessing liver fibrosis are being validated and will reduce the need for liver biopsy in chronic HBV Potent antivirals with low rates of emergence of resistance are an option for treatment of chronic HBV
Between 15 and 20 million HBV-infected individuals are coinfected with hepatitis D. HDV prevalence and distribution in Europe are changing as a result of HBV vaccination programmes (reducing the prevalence of both HBV and HDV infection) and recent migration patterns (tending to increase the prevalence of both infections in some countries).2 Worldwide prevalence and distribution of HBV and HDV are shown in Figure 1.
Keywords Antiviral therapy; cirrhosis; hepatitis B; hepatitis D; hepatocellular carcinoma; liver transplantation; recurrence; vaccination
Virology Human HBV is a member of the Hepadnaviridae family and humans and higher primates are the only hosts for HBV infection. The intact virion is composed of the viral DNA surrounded by a nucleocapsid (core protein or antigen) and an outer layer comprising the HBV surface protein or antigen (HBsAg). The viral genome is a 3.2-kb, partially double-stranded DNA with four overlapping reading frames (ORF). The viral genome encodes the viral polymerase (which includes the reverse transcriptase function), the core and surface proteins, and the nonstructural proteins (HBV e antigen and X protein). The cccDNA (co-valently closed circular DNA), which acts as the major transcriptional template for the virus, is central to the durability of HBV infection and persists as an episome in infected hepatocytes. It can persist after antiviral therapy and even after the apparent clearance of infection. There are eight distinct HBV genotypes, which have well-defined geographical distribution (see Figure 1). They differ in some important respects, including their natural history and response to interferon-based antiviral therapy. In Europe, genotypes A and D are most common. In eastern Asia, genotypes B and C are prevalent. Hepatitis D is a spherical particle, 36 nm in diameter. It is a defective satellite RNA virus of the Deltaviridae family. It requires HBsAg for viral assembly and propagation, so HDV infection can occur only in HBV patients. The single-stranded circular RNA genome of HDV is transcribed in hepatocytes during infection.3,4 The virion is composed of an outer coat containing HBV envelope proteins and host lipids, which surround the nucleocapsid; the latter comprises a single stranded RNA and hepatitis D antigen. Eight genotypes of HDV exist. The
Epidemiology Approximately 350e400 million persons have chronic HBV infection1 and more than 1 million deaths annually are due to end-stage liver disease or hepatocellular cancer (HCC). HCC is the fifth most common cancer in the world and third leading cause of cancer-related death. HBV infection is highly prevalent in Asia, Africa, and parts of southern and eastern Europe. In the UK, more than 300,000 people may have chronic HBV infection.2 HBV is the indication for transplantation in fewer than 5% of transplant cases in the UK. Migration from high-prevalence to low-prevalence countries influences the distribution, incidence and prevalence of HBV infection in low-prevalence countries, especially in Western Europe, North America and Australia.
Ye Htun Oo MBBS PhD MRCP is a Medical Research Council Clinician Scientist and an Honorary Consultant in Hepatology at the Queen Elizabeth Hospital Liver Unit, UK. His research interests include viral and autoimmune hepatitis, liver transplantation, and hepatic immune tolerance. Competing interests: none. David J Mutimer MBBS MD FRCP is a Professor of Clinical Hepatology at the Queen Elizabeth Hospital Liver Unit & University of Birmingham, UK. His main interests include viral hepatology and liver transplantation. Competing interests: he has acted as advisor to Gilead and BMS, the manufacturers of tenofovir and entecavir respectively.
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Geographic distribution of HBV and HDV a HBV
A,G
A D
D
B,C
E
F,H
B E
F
C
A
HBsAg prevalence > 8%: High 2–7%: Intermediate < 2%: Low Red = high endemic area; blue = intermediate; green = low. Hepatitis is highly prevalent in Asia and Africa. The arrows show the effect of migration from developing countries to Europe, North America and Australia. HBsAg, hepatitis B surface antigen. b HDV Genotype 1
Genotype 1 Genotype 1 Genotype 1/2/4 Genotype 1/3
Genotype 5–8
High Intermediate Low Very low Insufficient data Two subtypes–1A and 1B–have been identified in HDV genotype 1. 1A is predominant in Asia and 1B in the USA. Both are common in the Mediterranean. HDV genotype 2 occurs in the Far East. HDV genotype 3 occurs exclusively in the northern part of South America and is linked to HBV genotype F. Genotypes 5–8 have been identified primary in patients from Africa. HDV=hepatitis D virus. Figure 1(b). reproduced from Hughes SA, Wedemeyer H, Harrison PM. Hepatitis delta virus. The Lancet 2011; 378:73−85, with permission from Elsevier. Figure 1 (a) Prevalence of hepatitis B. (b) Prevalence of hepatitis D.
infection and the severity of the liver damage are determined by the balance between viral replication and host immune response mechanisms. HBV-specific cytotoxic CD8 T cells play a critical role in HBV clearance. However, suppressor or regulatory T cells (Treg) inhibit HBV-specific CD8 T-cell function in chronic HBV infection. This contributes to viral persistence. Large numbers of Treg are found in both the circulation and in the liver of chronic HBV patients.
combination of HDV genotype 1 and HBV genotype C appears to be associated with a worse outcome.5 HDV genotype 1 is most frequent genotype throughout the world (Figure 1).
Pathogenesis and natural history HBV The pathogenesis of liver disease in HBV is related to the persistence and magnitude of viral replication. The course of the
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The natural history of chronic HBV is diverse and non-linear. Chronically infected patients range from inactive carriers with low levels of replication to those patients with higher levels of virus and active inflammation, which may progress to cirrhosis and HCC. Following acute HBV infection of adults, 95% recover spontaneously with viral clearance not needing treatment. Perinatal infection and infection at a young age are strongly associated with failure to clear the virus and with the development of chronic infection. Chronic infection is defined as the persistence of HBsAg in serum for at least 6 months after infection. Liver inflammation requires both high levels of replication and targeted inflammatory responses. Chronic infection may be associated with production and secretion by infected hepatocytes of the HBV e antigen (HBeAg). In that case, the level of viral replication is almost invariably very high. Eventually, the production of HBeAg stops, which usually coincides with a reduction in viral replication. However, the subsequent level of viral replication may be low or high. When HBeAg-negativity is associated with high levels of replication, the associated hepatitis may be referred to as e-negative hepatitis. Under that circumstance, sequencing of the viral DNA frequently shows that specific mutations have emerged in the pre-core or core promoter regions of the viral DNA. Thus, e-negative hepatitis is also known as pre-core mutant hepatitis (see Figure 2a). Classically, four phases of chronic HBV infection have been described: the immune tolerant phase, the immune reactive phase, the inactive/resolution phase and reactivation phase. High levels of replication (usually associated with a serum titre
greater than 10 million IU/ml) may be observed in the absence of inflammatory response (normal alanine aminotransferase (ALT) with minimal or no inflammation on liver biopsy), the so-called immune tolerant phase. Immune tolerance is more frequently associated with HBeAg-positive infection and is seen most often in those infected at birth or at a young age. During this phase there is little cytotoxic T cell reaction to virus. However, this phase is seldom maintained for life. When the virus is recognized as foreign antigen by the immune system, the immune reactive phase occurs and is characterized by elevated or fluctuating ALT, HBeAg-positivity and moderate to severe inflammation on liver biopsy. During this phase, serum HBV DNA falls and HBeAg secretion may stop (called HBeAg seroconversion). After HBeAg seroconversion, the majority of patients will become inactive hepatitis B carriers with HBeAg-negativity, low serum HBV (<2000 IU/ml) and normal ALT. This phase may persist for life with sustained and effective cytotoxic T cell responses. For those that remain inactive, 1e3% per annum will achieve resolution phase with clearance of HBsAg from serum. These HBsAgnegative patients may still have detectable HVB DNA in the liver but not in serum. However, some patients revert from the inactive phase to a reactivation phase, with reappearance of higher levels of virus despite HBeAg-negativity (sequencing may demonstrate pre-core or core promoter mutations). There is resumed liver inflammation and progressive fibrosis. In general, the majority of patients with high levels of replication sustained for a long duration will eventually develop progressive liver damage leading to cirrhosis and/or HCC. This
Site of hepatitis B virus DNA mutations pre-S1
pre-S2
Mutations
S
HBV-DNA
C P pre-C Mutations
Mutations X
HBV viral DNA is partially double stranded and encodes four proteins: a DNA polymerase for viral replication (P), a surface protein (S), a core protein (C) and an X protein. The pre-C and C regions encode a core protein and an e antigen. Pre-C encodes a signal sequence needed for the C protein to be secreted from the hepatocytes into serum as e antigen. Mutation in pre-C region leads to a failure of secretion of e antigen into serum, thus e antigen is negative despite a high level of DNA. Mutations in the surface protein can lead to vaccination failure, and mutations in the DNA polymerase can occur during antiviral treatment. Figure 2
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a. Stages of infection in patients infected with HBe-positive virus Phase1 Immune tolerance
Viraemia
Phase 2 Immune clearance
HBeAg-positive viraemia (HBV DNA-positive; >10 5 IU/ml)
Phase 3 Immune control or latent
Phase 4 Emergence of HBe-negative variant
(HBV DNA <10 5 IU/ml)
HBeAg-positive viraemia (HBV DNA-positive; >10 5 IU/ml)
Alanine aminotransferase
0
50
Time (years) Liver histology
Chronic hepatitis
Minimal lobular
Chronic lobular/ hepatitis Cirrhosis
Inactive cirrhosis
Chronic hepatitis Active cirrhosis
Hepatocellular carcinoma
Four different phases of chronic HBV infection is shown. The best time to treat with either interferon or nucleoside/nucleotide analogues is in immune reactive and reactivation phases. (Figure used is from Prof Howard Thomas; Hepatitis B and D; Medicine 35(1); 2006). b. Typical evolution of serological and virological measures in HDV infection A HBsAG HDV RNA ALT
Anti-HBc IgG Anti-HBc IgM Anti-HD IgG Anti-HD IgM
B
C
Time after exposure (weeks) (A) Simultaneous co-infection with HBV and HDV, resulting in clearance of both viruses in almost all patients. (B) HDV superinfection of an HBV carrier with self-limited outcome. The spontaneous clearance of HDV RNA might take years to occur (indicated by break on x axis) and, in few cases, can herald the loss of HBsAg (not depicted). (C) HDV superinfection of a HBV carrier with chronic persistent viral replication; the more common outcome after superinfection. HDV, hepatitis delta virus; ALT, alanine aminotransferase; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen.
Figure 3(b). reproduced from Hughes SA, Wedemeyer H, Harrison PM. Hepatitis delta virus. The Lancet 2011; 378:73−85, with permission from Elsevier. Figure 3 (a) Clinical course of HBV infection. (b) Virological and serological evolution in HDV infection.
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Serologic markers of HBV and HDV infection and their clinical interpretation Viral serology markers
Definition
Clinical significance
HBsAg
HBV surface antigen
Anti-HBs
Antibody to HBV surface antigen
Anti-HBc
Antibody to HBV core antigen
HBeAg Anti-HBe
Non-structural protein measured in serum Antibody to HBe antigen
HBV DNA
Viral genomic material measured in serum
Anti-HDV IgG Anti-HDV IgM
Antibody to HDV antigen Antibody to HDV antigen
HDV RNA
Viral genomic material measured in serum
Diagnosis of HBV infection Must be positive in HDV infection Presence without anti-HBc implies vaccine induced immunity. Also present in naturally cleared infection but titres fall and often is reported as negative IgM positive in acute infection, IgG alone implies resolved infection Usually associated with high HBV DNA titre Can be found with high-level or low-level viral replication Reflects viral replication and indicates response to therapy Indicator of past or present HDV infection Serum marker of recent acute infection, and persists in chronic infection as a marker of ongoing viral replication (can be applied as a surrogate for HDV RNA positivity) Reflects viral replication
HBV, hepatitis B virus; HDV, Hepatitis D virus; Ig, immunoglobulin.
Table 1
Clinical presentation and diagnosis
natural history of HBV can be transformed by antiviral agents. Successful treatment prevents progressive fibrosis and hepatic decompensation, reduces the risk for HCC and prevents liverrelated deaths. Hepatitis serology, HBV DNA titres, serum ALT and expected liver histology findings in different phases of HBV infection are shown in Figure 3.
Both viruses are transmitted via the parenteral route by exposure to infected blood or body fluids. Vertical transmission from mother-to-infant or child-to-child infection is the most common routes worldwide. Transmission can also occur via sexual contact, poor medical practice or self-injection of drugs. Acute HBV infection is characterized by arthralgia, fever, urticaria and flulike symptoms, followed by jaundice. More than 90% recover with acquired immunity but a small proportion is persistently infected; fulminant hepatitis is rare. Globally, most infection is acquired at a young age, the majority of infection is asymptomatic, and a high proportion becomes chronic. Thus, the majority of diagnoses are made in those with asymptomatic chronic infection when blood tests are performed for HBV screening or for other reasons. The clinical outcome of HDV depends on the mode of infection and on the host response to HBV and HDV (Figure 3). HBV is essential for HDV virion assembly and replication, so that HDV infection is always associated with HBV infection. Acute coinfection is a simultaneous infection with both viruses that leads to acute hepatitis B and D. This is clinically
HDV Hepatitis D antigen is not directly cytopathic to human hepatocytes. Hepatitis D virus induces innate and adaptive immune response in the infected host, including the production of IgM and IgG antibodies. Evidence so far has suggested that innate and adaptive cellular immune responses to HDV via both NK cells and CD4/CD8 responses could play an important role in the pathogenesis of liver damage, and in predicting the response to antiviral therapy.6e8 HDV infection can occur as a result of simultaneous coinfection with both HDV and HBV or by superinfection of individuals with established chronic HBV infection with HDV (Figure 3). Compared with chronic HBV mono-infection, chronic infection with both HDV and HBV is associated with accelerated fibrosis progression, higher rates of cirrhosis development, and increased risk of HCC and hepatic decompensation. The clinical profile of HDV infection can range from symptom-free to fulminant hepatitis.9 The diagnosis is frequently made when a patients presents with complications of cirrhosis.10 Around 70e80% of chronic HDV patients may develop cirrhosis within 5e10 years of diagnosis and, compared with HBV mono-infection, HBV and HDV co-infection is twice as likely to result in cirrhosis.11
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HBV treatment (oral antivirals) L-nucleosides
Deoxyguanosine analogues
Nucleotides
Lamivudine Telbivudine
Entecavir
Adefovir Tenofovir
Table 2
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Assessment of fibrosis A liver biopsy can determine the degree of hepatic necroinflammation (grading) and fibrosis (staging).15 The use of noninvasive methods such as serum markers and transient elastography may provide a measurement of liver fibrosis, and some centres use these as an alternative to liver biopsy.
Anti-viral resistance in chronic HBV Anti-viral drug
Addition of second anti-viral or change to tenofovir
HBV DNA (IU/ml)
10 10
Monitoring cirrhosis and surveillance of HCC Liver ultrasound scanning demonstrates cirrhosis and features of portal hypertension (splenomegaly, ascites and varices) and monitors the appearance of primary liver cancer. It should be performed at first assessment for all patients and every 6 months for patients with high risk of liver cancer.
10 10
Drug resistance
10
Detectable limit
10 10 0
Time since antiviral therapy started
Management HBV management The management of HBV may include the use of interferon or oral antiviral nucleoside/nucleotide analogues. The goal of therapy is to prevent the progression to cirrhosis and to reduce risk of HCC. Antiviral efficacy is measured by the degree of HBV DNA suppression and by rates of HBeAg and HBsAg loss, and is reflected by improvement in liver histology.
Figure 4 HBV DNA titre is well suppressed following potent antiviral therapy. However, over the years, there may be selection and emergence of drug resistance, characterized by a rise in HBV DNA titre. Drug resistance HBV DNA sequencing should be checked if this rise in titre is observed. These patients need to be treated with addition of a second drug, or by switching to appropriate monotherapy (usually either tenofovir or entecavir).
Treatment strategy HBV treatment is recommended for those patients who have moderate hepatic necroinflammation or fibrosis and high serum HBV DNA. Patients with established cirrhosis should be given oral antiviral therapy regardless of HBV DNA titre.16 The choice between nucleoside/nucleotide and interferon (IFN) depends on patient and viral characteristics, and on patient and physician preference. IFN therapy has both immunomodulatory and antiviral effects. IFN treatment is of finite duration, and the ideal candidate is the young patient with HBeAg-positivity who is infected with HBV genotype A (the genotype most sensitive to IFN treatment). Successful outcome for this patient is defined as HBeAg loss, acquisition of anti-HBe, and low serum HBV DNA (all sustained after cessation of treatment). Occasional patients will lose serum HBsAg. Nucleoside/nucleotide analogues are oral antiviral agents that inhibit HBV DNA synthesis by acting as DNA chain terminators and are well tolerated. Both types of analogue comprise a nitrogenous base and ribose/deoxyribose, but nucleotides also have 1e3 phosphate groups. Among agents in common use for this indication, entecavir, lamivudine and telbivudine are nucleoside analogues, whereas tenofovir is a nucleotide analogue. They fall into three groups as shown in (Table 2). First-line therapy for the treatment-naı¨ve non-cirrhotic patient is either IFN or an oral antiviral. Entecavir and tenofovir both have potent antiviral activity (90% of treated patients have undetectable serum HBV DNA at 12 months of therapy), good safety profiles, and very low rates of emergence of resistance. Lamivudine and telbivudine should not be used as first-line therapy because the risk of drug resistance is high. Patients taking oral antiviral therapy need to understand the importance of treatment adherence to prevent disease progression and to minimize the risk of drug resistance. In normal practice, the emergence of drug resistance is recognized by a rise in viral load of at least 1 log10 IU/ml from nadir titre in a compliant patient.
indistinguishable from acute hepatitis B although it may be more severe and two peaks of serum ALT may be noted. Superinfection by HDV of an individual chronically infected with HBV leads to severe acute hepatitis, which progresses to chronicity in up to 80% of patients.12 Once chronic HDV infection is established, it usually exacerbates the pre-existing liver disease due to HBV.13 However, HBV replication is usually suppressed to low levels during the acute phase of HDV infection and this suppression persists in chronic HDV/HBV infection.14 The incubation period of acute HBV (with or without HDV) infection ranges from 3 to 7 weeks with prodromal symptoms of fatigue, lethargy, anorexia or nausea followed by biochemical evidence of hepatitis with a rise in serum ALT.
Investigations Viral serology Those patients who present with acute HBV typically have both HBsAg and immunoglobulin M (IgM) antibodies to HBV in serum (IgM reactivity to the core antigen is typically measured). Chronic HBV patients who present to clinics should be checked for HBsAg, HBeAg and HBV DNA titre. HBV DNA quantification is a key determinant for selection of patients for therapy, and its measurement is necessary to monitor response to antiviral therapy (Table 1). HBV infection can be associated with HDV infection, so HDV serology should be routinely performed. AntiHDV antibody should be tested and, if positive, ongoing HDV infection should be confirmed by the detection of HDV RNA (Table 1). Liver biochemistry Assessment of liver damage requires routine biochemical liver function tests, including serum albumin, and international normalized ratio.
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Immunosuppressed patients Reappearance of serum HBsAg or HBV DNA in a patient with previous resolved or inactive HBV infection is sometimes observed in immunosuppressed states. cccDNA, which resides within the infected hepatocytes, plays a significant role in reactivation of HBV during cancer chemotherapy, during the use of some biological agents (particularly anti-CD20 rituximab) and following organ transplantation. Patients should be screened for HBV before being given any immunosuppressive therapy. Under these circumstances, prophylaxis with oral antiviral drugs is frequently indicated.
HBV resistance can be confirmed by genetic sequencing of the virus (Figure 4). Treatment options for HDV are limited since the viral RNA does not encode any viral enzymes. Thus no virus-specific directly acting antivirals are available and nucleoside/nucleotide analogues used for HBV infection are ineffective against HDV. Administration of pegylated (polyethylene glycolconjugated) interferon-a induces HDV-RNA negativity in about one quarter of patients but therapy for a year or 18 months is required,17 which is often poorly tolerated. Addition of oral nucleoside/nucleotide is of no greater benefit than IFN monotherapy alone. Regular blood count and thyroid function monitoring is recommended for patients on IFN therapy and renal function and phosphate level monitoring should be performed in patients on Tenofovir therapy. Potential novel treatments for the future may include hepatocyte entry inhibitors, viron assembly inhibitors and prenylation inhibitors.18
Prevention HBV vaccination Vaccination is the most effective way to achieve global HBV control and to prevent cirrhosis, liver failure and liver cancer. Most countries include HBV vaccination as part of the routine universal childhood vaccination schedule. Universal vaccination has been shown to reduce the incidence of both HBV and HDV infection, the frequency of childhood chronic infection, and the risk of childhood liver cancer. Some low-prevalence countries have not implemented universal vaccination, but prefer to target vaccination to specific high-risk groups. Most countries undertake maternal screening for HBsAg, and vaccinate the neonate born to the HBV carrier mother.9 If HBV infection is detected, members of the infected person’s family should be screened and vaccination offered to household members and close contacts who are HBsAg negative.
Follow-up and HCC surveillance It is estimated that more than 50% of liver cancers worldwide are due to HBV and the majority of these occur in developing countries. African or Asian ethnicity, male gender, age over 40 years, family history of HCC, high HBV DNA titre and coinfection with other viruses including HDV19 are the risk factors which are associated with increased risk of HCC development.20,21 Most cancer is seen after development of cirrhosis, so prevention of cirrhosis dramatically reduces the risk of cancer.
HBV infection in special circumstances Liver transplantation
Pregnancy Vaccination of the offspring of carrier mothers prevents neonatal infection in the majority of cases. Occasional vaccine failure is observed, most commonly in association with very high maternal viral titre. Antiviral therapy for the pregnant mother with very high titres may further reduce the risk of transmission to the baby. Current recommendations suggest that either lamivudine (Category C) or tenofovir (Category B) can be taken by the pregnant mother during the third trimester to further reduce the risk of transmission to the developing fetus and neonate. Breastfeeding by an HBV-positive mother is safe and there is a low risk of infection (so long as the baby has been vaccinated).
Liver transplantation is the preferred treatment for HBV-infected individuals who present with fulminant liver failure, decompensated liver disease and HBV-related HCC. Oral antiviral therapy alone or in combination with hyperimmune immunoglobulin can prevent graft re-infection.22 Prevention of HBV recurrence will also prevent HDV recurrence in transplanted patients with HBV/HDV co-infection. A REFERENCES 1 Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 2004; 11: 97e107. 2 Gaeta GB, Stroffolini T, Smedile A, Niro G, Mele A. Hepatitis delta in Europe: vanishing or refreshing? Hepatology 2007; 46: 1312e3. 3 Chen PJ, Kalpana G, Goldberg J, et al. Structure and replication of the genome of the hepatitis delta virus. Proc Natl Acad Sci U. S. A 1986; 83: 8774e8. 4 Rizzetto M, Canese MG, Arico S, et al. Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut 1977; 18: 997e1003. 5 Su CW, Huang YH, Huo TI, et al. Genotypes and viremia of hepatitis B and D viruses are associated with outcomes of chronic hepatitis D patients. Gastroenterology 2006; 130: 1625e35. 6 Nisini R, Paroli M, Accapezzato D, et al. Human CD4þ T-cell response to hepatitis delta virus: identification of multiple epitopes and
Infants and children HBV infection is seldom associated with significant liver damage during childhood years. Antivirals can be used under specialist care. Healthcare worker HBV-infected healthcare workers who undertake exposure-prone procedures (e.g. surgeons, obstetricians) can take antivirals to reduce the risk of inadvertent transmission from doctor to patient. Co-infection with HIV HIV and HBV co-infection is frequently observed. Inclusion of tenofovir in the HIV treatment regimen ensures excellent suppression of the HBV. Co-infection leads to severe hepatitis compared to HBV mono-infected patients.12
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characterization of T-helper cytokine profiles. J Virol 1997; 71: 2241e51. Actis GC, Maran E, Saracco G, et al. Interferon treatment of chronic hepatitis B surface antigen (HBsAg) carriers. A description of the activation profiles of natural killer cells obtained with different schedules of administration in three subsets of carriers. Ric Clin Lab 1987; 17: 331e41. Wedemeyer H, Heidrich B, Manns MP. Hepatitis D virus infectionenot a vanishing disease in Europe!. Hepatology 2007; 45: 1331e2. author reply 1332e1333. Bonino F, Negro F, Baldi M, et al. The natural history of chronic delta hepatitis. Prog Clin Biol Res 1987; 234: 145e52. Rizzetto M, Verme G, Recchia S, et al. Chronic hepatitis in carriers of hepatitis B surface antigen, with intrahepatic expression of the delta antigen. An active and progressive disease unresponsive to immunosuppressive treatment. Ann Intern Med 1983; 98: 437e41. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 2008; 48: 335e52. Smedile A, Farci P, Verme G, et al. Influence of delta infection on severity of hepatitis B. Lancet 1982; 2: 945e7. Smedile A, Dentico P, Zanetti A, et al. Infection with the delta agent in chronic HBsAg carriers. Gastroenterology 1981; 81: 992e7.
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14 Krogsgaard K, Kryger P, Aldershvile J, Andersson P, Sorensen TI, Nielsen JO. Delta-infection and suppression of hepatitis B virus replication in chronic HBsAg carriers. Hepatology 1987; 7: 42e5. 15 Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22: 696e9. 16 EASL clinical practice guidelines. Management of chronic hepatitis B virus infection. J Hepatol 2012; 57: 167e85. 17 Farci P, Mandas A, Coiana A, et al. Treatment of chronic hepatitis D with interferon alfa-2a. N. Engl J Med 1994; 330: 88e94. 18 Glenn JS, Watson JA, Havel CM, White JM. Identification of a prenylation site in delta virus large antigen. Science 1992; 256: 1331e3. 19 Romeo R, Del Ninno E, Rumi M, et al. 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and hepatocellular carcinoma. Gastroenterology 2009; 136: 1629e38. 20 Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22,707 men in Taiwan. Lancet 1981; 2: 1129e33. 21 Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006; 130: 678e86. 22 Freshwater DA, Dudley T, Cane P, Mutimer DJ. Viral persistence after liver transplantation for hepatitis B virus: a cross-sectional study. Transplantation 2008; 85: 1105e11.
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