2. Hepatitis B
Kathrin van Bremen, Christoph Boesecke and Jan-Christian Wasmuth
Introduction
Approximately one third of the world’s population has serological evidence of past or present infection with the hepatitis B virus (HBV). Despite the availability of HBV vaccines, the global prevalence of chronic HBV infection is estimated to be 3.7% (Lok 2016). The World Health Organization estimates that in 2015 257 million people were living with chronic HBV (defined as HBsAg positive) resulting in approximately 887.000 deaths mostly due to cirrhosis and hepatocellular carcinoma (WHO 2017, WHO 2019).
Since the discovery of HBV by Blumberg in 1965, progress has been impressive, with the availability of vaccines in the 1980s and the development of potent antiviral drugs two decades later. Nevertheless, the global burden of chronic HBV remains substantial and healing of chronic HBV still remains almost impossible.
There is a wide range of HBV prevalence rates in different parts of the world (from 0.1% up to 20%). Low prevalence areas (<2%) represent 12% of the global population and include Western Europe, the United States and Canada, Australia and New Zealand. In these regions, the lifetime risk of infection is less than 20%. Intermediate prevalence is defined as 2% to 7%, with a lifetime risk of infection of 20–60% and includes the Mediterranean countries, Japan, Central Asia, the Middle East, and Latin and South America, representing about 43% of the global population. High prevalence areas (≥8%) include Southeast Asia, China, and sub-Saharan Africa, where a lifetime likelihood of infection is greater than 60%. The diverse prevalence rates are probably related to differences in age at infection, which correlates with the risk of chronicity. The progression rate from acute to chronic HBV infection decreases with age. Approximately 90% of infections acquired perinatally will progress compared to 5% or less for adult infections (Stevens 1975, Wasley 2008, Pan 2016).
The incidence of new HBV infections has decreased in most high-income countries, most likely due to the implementation of vaccination strategies (Rantala 2008, Leroy 2015). However, exact data is difficult to generate as many cases remain undetected due to the asymptomatic nature of the infection. In Germany, 4.507 cases (acute or chronic) of HBV were documented in 2018, corresponding to an incidence rate of 5.4 per 100,000 inhabitants (RKI 2019). From 2001 until 2009 there was a stable decrease in infections which then stagnated until 2014. Since 2015 there has been a rise in the number of infections mostly due to migration and boosted testing as well as a change in the definition of diagnosis (RKI 2019). Likewise, the incidence of acute HBV in the United States has decreased considerably in the last two decades (Wasley 2008, CDC 2012). Due to the persisting opioid crisis the number of acute HBV infections in the US slightly increased in 2017 (CDC 2017). Moreover, in Germany as well as in the US the major number of infections is found in foreign born people, presenting 2/3 of all reported cases in Germany (RKI 2019). Although estimates are difficult due to a continuously growing migration from high to low prevalence areas, a further drop in prevalence is expected due to the implementation of vaccination programmes (Belongia 2008). In Germany, 84,4% of all children starting school in 2017 were fully vaccinated against HBV, with a trend toward increasing coverage (RKI 2019).
Thus screening instruments are most important in diagnosing chronic HBV in migrants, especially facing an increased risk for HCC in those patients. (ECDC 2019).
Although the incidence of acute HBV infection is decreasing in most countries, overall HBV-related complications are still on the rise (Gomaa 2008, Hatzakis 2011, Zhang 2013). Reasons for this increase may be the delay of vaccination effects and the improved diagnosis rate of HBV cases. When looking at the age-adjusted rate ratios of HBV-related HCC incidence, a continuous decline can be observed following the launch of vaccination programmes. Published results of a large population-based controlled trial in Chinese newborns show that HCC incidence was significantly lower in the vaccinated group compared to the control group, with a hazard ratio of 0.16 (Qu 2014). A mathematic model from 2005 found that routine infant hepatitis B vaccination, with 90% coverage and the first dose administered at birth would prevent 84% of global HBV-related deaths (Goldstein 2005).
Transmission
The predominance of transmission modes varies considerably in different geographic areas. For example, in Western Europe (a low prevalence area), the main routes are unprotected sexual intercourse and intravenous drug use. In sub-Saharan Africa (a high prevalence area), perinatal infection is the predominant mode of transmission. Horizontal transmission, particularly in early childhood, is regarded as the major route of transmission in intermediate prevalence areas.
Sexual transmission
Sexual transmission of HBV in people who are unvaccinated largely occurs among heterosexual men or women who either have multiple sex partners or contact with sex workers, or among men who have sex with men (MSM). In low prevalence areas, sexual transmission is the major route of transmission. In the United States, heterosexual contacts amount up to 40% of newly diagnosed HBV infections, MSM approximately 25% (Wasley 2008), in Germany in 2018 27% of newly diagnosed HBV infections were due to sexual intercourse with 58% in heterosexual contacts and 42% in MSM (RKI 2019). Comparatively high rates of HIV/HBV coinfections are observed in German MSM, as less than half of HIV positive patients are vaccinated against HBV (Jansen 2015). However, as noted above, infection in adulthood leads to chronic hepatitis in less than 5% of cases. Measures to prevent sexual HBV transmission are vaccination – especially of risk groups – and safer sex practices.
Percutaneous inoculation
Percutaneous inoculation seems to be an effective mode of HBV transmission, with an estimated risk as up to 30% in individuals without post-exposure prophylaxis (PEP) or adequate vaccination (Deisenhammer 2006, Hofmann 2002). The most important percutaneous transmission route is sharing syringes and needles by people who inject drugs (PWID), representing about 15% of newly diagnosed HBV infections in low prevalence areas such as Europe and the United States (Wasley 2008). Sharing razors or toothbrushes are other potential ways of percutaneous transmission, although absolute risk remains unknown. In addition, practices like acupuncture, tattooing, and body piercing have been associated with transmission of HBV. Public health education and the use of disposable needles or equipment are important methods of prevention.
Perinatal transmission
Perinatal transmission is the major route of HBV transmission in many parts of the world, and an important factor in maintaining the reservoir of the infection, particularly in high prevalence areas. In the absence of prophylaxis, chronic HBV infection will develop in 80 to 90% of infants born to mothers who are positive for HBV e antigen (HBeAg) (Lee 2006). Neonatal vaccination has demonstrated high efficacy, indicating that transmission mostly occurs at or shortly before birth. On the other hand, cesarean section seems less protective than for other vertically transmitted diseases such as HIV.
The risk of transmission from mother to infant is related to the mother’s HBV replicative rate. There seems to be a direct correlation between maternal HBV DNA levels and the likelihood of transmission. In mothers with highly replicating HBV the risk of transmission may be up to 85 or 90%. This risk steadily drops at lower HBV DNA levels (Burk 1994, Zhang 2012). Some studies report that perinatal transmission is rare if the mother has HBV DNA <105 log copies/mL (Li 2004).
All women should be tested for HBsAg at the first prenatal visit/first trimester and this should be repeated later in pregnancy if appropriate (CDC 2011, EASL 2017). Newborns born to HBV positive mothers can be effectively protected by passive-active immunisation (>90% protection rate) (Del Canho 1997, Dienstag 2008, WHO 2015). HBV immunoglobulin for passive immunisation should be given as early as possible (within 12 hours), but can be given up to seven days after birth if replicative HBV infection of the mother is detected later. Active immunisation follows a standard regimen and is given at three time points (10 µg at day 0, month 1, and month 6). However, immunoprophylaxis fails in 10 to 30% of infants born to mothers with an HBV DNA level greater than 106 log copies/mL (Zou 2012). In a Chinese cohort study, no HBV infection was observed in infants born to HBeAg negative mothers who received HBV vaccine, independently of immunoglobulin administration (Zhang 2014).
Anti-HBV treatment of the mother with nucleoside analogues may be considered, especially in mothers with high HBV DNA levels. The use of telbivudine, lamivudine, and tenofovir appears to be safe in pregnancy with no increased adverse maternal or fetal outcome (Brown 2016). Adefovir and entecavir are not recommended in pregnancy (Cornberg 2011). Treatment of mothers with telbivudine prevented almost all cases of vertical transmission compared to a vertical transmission rate of about 10% in the arm receiving only active-passive immunisation (Han 2011, Wu 2014). Tenofovir starting from 30 weeks of gestation until postpartum week 4 combined with immunoprophylaxis demonstrated significantly lower transmission rates in HBeAg positive mothers with viral loads >200.000 IU/mL compared to immunoprophylaxis alone (Pan 2016). In women with lower viral load a recently study from Thailand reported that additional use of Tenofovir from 28 weeks of gestation on, did not result in a lower mother-to-child HBV transmission in HBeAg-positive mothers together with the administration of HBV immune globulin and HBV vaccine (Jourdain 2018). Lamivudine seems to be another safe, low cost and equally effective option to prevent vertical transmission in highly viraemic HBV-infected pregnant women (Jackson 2014, Zhang 2014). A meta-analysis showed that the use of any antiviral therapy reduced mother-to-child transmission, as defined by infant HBV surface antigen seropositivity (risk ratio = 0.3, 95% CI 0.2–0.4) or infant HBV DNA seropositivity (risk ratio 5 0.3, 95% CI 0.2–0.5) at 6–12 months (Brown 2016).
As mentioned earlier, cesarean section should not be performed routinely. If the child is vaccinated, (s)he may be breastfed (Hill 2002). Taking lamivudine or tenofovir during breastfeeding results in lower exposure to drugs than due to in utero exposure during pregnancy and thus does not support contraindicating their use during breastfeeding (Ehrhardt 2014).
Horizontal transmission
Horizontal transmission includes household, intrafamiliar and child-to-child transmission via minor breaks in the skin or mucous membranes. At least 50% of infections in children cannot be accounted for by mother-to-infant transmission and, in many endemic regions, before the introduction of neonatal vaccination, the prevalence peaked in children 7 to 14 years of age (Papatheodoridis 2008). HBV remains viable outside the human body for a prolonged period and is infectious in the environment for at least 7 days (Lok 2007). Although HBV DNA has been detected in various body fluids of HBV carriers, there is no firm evidence of HBV transmission via body fluids other than blood.
In one study, family members of inactive HBsAg carriers had a higher HBsAg positivity rate than the general population over a 10-year period. Despite negative HBV DNA levels, transmission risk was not negligible in these patients, and horizontal transmission seems to be independent of the HBV DNA level (Demirturk 2014).
Blood transfusion
Blood donors are routinely screened for HBV surface antigen (HBsAg). Therefore incidence of transfusion-related HBV has significantly decreased. The risk of acquiring post-transfusion HBV depends on factors like prevalence and donor testing strategies. In low prevalence areas it was estimated to be one to four per million blood components transfused (Dodd 2000, Polizzotto 2008). In high prevalence areas it is considerably higher (around 1 in 20,000) (Shang 2007, Vermeulen 2011).
There are different strategies for donor screening. Most countries use HBsAg screening of donors. Others, including the United States, use both HBsAg and anti-HBc. Routine screening of anti-HBc remains controversial, as the specificity is low and patients with cleared hepatitis have to be excluded. Some countries e.g. the USA, Germany, Spain and Singapure use mini-pool nucleic acid testing for HBV DNA screening. Through this testing the risk of HBV transmission through transfusion has been lowered to 1 in 1 million (Busch 2019, Stramer 2013). With increasing implementation of NAT in high prevalence countries, the risk of transmission through blood transfusion will be extremely diminished in those countries.
Nosocomial infection
Nosocomial infection can occur from patient to patient, from patient to health care worker and vice versa. HBV is considered the most commonly transmitted blood-borne virus in the healthcare setting. Despite implementation of prevention strategies (including the use of disposable needles and equipment, sterilisation of surgical instruments, and vaccination of healthcare workers) documented cases of nosocomial infections occur (Williams 2004, Amini-Bavil-Olyaee 2012). However, the exact risk of nosocomial infection is unknown. The numbers of cases reported from this route is likely to be underestimated as many infections might be asymptomatic and only a fraction of exposed patients is recalled for testing.
The incidence of HBV infection in health care workers is lower than in the general population due to routine vaccination (Duseja 2002, Mahoney 1997). Therefore, transmission from healthcare workers to patients is rare, while the risk of transmission from an HBV positive patient to a health care worker seems to be higher.
Healthcare workers who are HBV positive are not generally prohibited from working. HBeAg negative healthcare workers are not considered to be infectious, whereas HBeAg positive healthcare workers should wear double gloves and not perform certain activities, to be defined on an individual basis (Gunson 2003, Cornberg 2011). However, cases of transmission from HBsAg positive, HBeAg negative surgeons to their patients have been reported (Teams 1997) and a precore stop codon mutation was found responsible for HBeAg non-expression despite active HBV replication (Borzooy 2015). Therefore, HBV DNA testing has been implemented in some settings, although this may not always be reliable due to fluctuating levels of HBV DNA. In most high-income countries, guidelines for HBV positive healthcare workers have been established and should be consulted (Cornberg 2011).
The risk of transmission of HBV through sharps injuries (when the patient is HBeAg positive) is estimated with 1:3 (Riddell 2015). Despite HBV being highly infectious, only 15 cases of occupational transmission by sharps injuries have been reported in Germany during 2018 (RKI 2019). This low number probably relates to the high percentage of healthcare workers who are immunised against HBV. Based on vaccination history, previous response to vaccination, type of exposure, and the HBV status of the source patient a vaccine can be given shortly after exposure either as the first dose of a primary course or as a booster. The additional use of immunoglobulin aims to provide passive immunity if the source patient is known to be at high risk of HBV infection and the recipient has not been previously adequately immunised or is a known non-responder to the vaccine.
Organ transplantation
Transmission of HBV infection has been reported after transplantation of extrahepatic organs from HBsAg positive donors (e.g., kidney, cornea) (Dickson 1997). Organ donors are therefore routinely screened for HBsAg. The role of anti-HBc is controversial, as it is in screening of blood donors. Reasons are the possibility of false positive results, the potential loss of up to 5% of donors even in low endemic areas, and the uncertainty about the infectivity of organs, especially extrahepatic organs, from donors who have isolated anti-HBc (Dickson 1997). Although an increased risk of HBV infection for the recipient of anti-HBc positive organs has been postulated, no donor-derived HBV transmission has been observed in a recent case series of anti-HBc positive donors (Horan 2014, Niu 2014). Evidence exists that patients who have recovered from HBV may benefit from preemptive antiviral therapy in the case of profound immunosuppression (e.g., chemotherapy involving monoclonal antibodies such as rituximab or immunosuppressive treatment) because of the risks associated with a form of HBV reactivation referred to as reverse seroconversion (Di Bisceglie 2014).
Postexposure prophylaxis
In case of exposure to HBV in any of the circumstances mentioned above, post-exposure prophylaxis is recommended for all non-vaccinated persons. A passive-active immunisation is recommended. The first dose of passive and active immunisation should be given as early as possible. 12 hours after the exposure is usually considered the latest time point for effective post-exposure prophylaxis. One dose of HBV-immunoglobulin (HBIG) should be administered at the same time, if the source is known to be HBsAg positive. The other two doses of vaccine should be administered after 4 and 12–24 weeks.
Vaccinated individuals with a documented response do not need post-exposure prophylaxis. Individuals who have had no post-vaccination testing should be tested for anti-HBs titre as soon as possible. If this is not possible, or the anti-HBs titre is insufficient (<100 IU/L), they will require a second course of vaccination.
Individuals who are documented non-responders will require two doses of HBIG given one month apart.
Natural history and clinical manifestations
The spectrum of clinical manifestations of HBV infection varies in both acute and chronic disease. During the acute phase, manifestations range from subclinical or anicteric hepatitis to icteric hepatitis, and in some cases fulminant hepatitis. During the chronic phase, manifestations range from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Extrahepatic manifestations can occur in both acute and chronic infection.
Acute hepatitis
After HBV infection, the incubation period lasts from one to four months. A prodromal phase may appear before acute hepatitis develops. During this period a serum sickness-like syndrome may develop. This syndrome manifests with fever, skin rash, arthralgia and arthritis. It will usually cease with the onset of hepatitis. At least 70% of patients then have subclinical or anicteric hepatitis, while less than 30% will develop icteric hepatitis. The most prominent clinical symptoms of hepatitis are right upper quadrant discomfort, nausea, jaundice and other unspecific constitutional symptoms. In case of coinfection with other hepatitis viruses or other underlying liver disease the clinical course may be more severe. Symptoms – including jaundice – generally disappear after one to three months, but some patients have prolonged fatigue even after normalisation of serum aminotransferase concentrations.
During the acute phase, alanine and aspartate aminotransferase levels (ALT and AST) may increase to 1000–2000 IU/L. ALT is typically higher than AST. Bilirubin levels may be normal in a substantial portion of patients. In patients who recover, normalisation of serum aminotransferases usually occurs within one to four months. Persistent elevation of serum ALT for more than six months indicates progression to chronic hepatitis.
The rate of progression from acute to chronic HBV is primarily determined by the age at infection (Ganem 2004, McMahon 1985). In adult-acquired infection the chronicity rate is 5% or less, whereas it is higher if acquired at younger ages. Approximately 90% for perinatal acquired infection (up to six months of age) become chronic, but this rate decreases to 20–60% for infections acquired between the age of six months and five years (Caredda 1989, Smedile 1982).
For decades it was assumed that the virus is cleared in patients who recover from acute HBV. However, even in patients positive for anti-HBs and anti-HBc, HBV DNA may persist lifelong in the form of covalently closed circular DNA (cccDNA) and this latent infection maintains the T cell response that enables viral control (Yotsuyanagi 1998, Guner 2011, Gerlich 2013, Zhong 2014). It is now accepted that complete eradication rarely occurs. This is important, as immunosuppression can lead to reactivation of the virus, e.g., after organ transplant or during chemotherapy (Di Bisceglie 2014).
Fulminant hepatic failure is rare, only occurring in approximately 0.1–0.5% of patients. Reasons and risk factors for fulminant HBV are not well understood (Garfein 2004). This may correlate with substance use or coinfections with other viruses. Fulminant HBV is believed to be due to massive immune-mediated lysis of infected hepatocytes. This is why many patients with fulminant HBV have no evidence of HBV replication at presentation (Wright 1992).
Antiviral treatment of patients with acute HBV usually is not recommended (Cornberg 2011). In adults, the likelihood of fulminant HBV is less than 1%, and the likelihood of progression to chronic HBV is less than 5%. Therefore, treatment of acute HBV is mainly supportive in the majority of patients. Antiviral treatment with HBV polymerase inhibitors can be considered in certain subsets of patients, e.g., patients with a severe or prolonged course of HBV, patients coinfected with other hepatitis viruses or underlying liver diseases, patients with immunosuppression, or patients with fulminant liver failure undergoing liver-transplantation (Kondili 2004, Tillmann 2006).
In addition, patient contacts should be tested for HBV and vaccinated if appropriate.
Chronic hepatitis
In adult-acquired infection, HBV chronicity is 5% or lower, as mentioned earlier. In perinatally acquired infection it is estimated to be approximately 90%, and 20–50% for infections between the age of one and five years (Ganem 2004, McMahon 1985). Most patients will not have a history of acute hepatitis.
Most patients with chronic HBV (CHB) are clinically asymptomatic. Some may have nonspecific symptoms such as fatigue. In most instances, significant clinical symptoms will develop only if liver disease progresses to decompensated cirrhosis. In addition, extrahepatic manifestations may cause symptoms.
Accordingly, a physical exam will be normal in most instances. In advanced liver disease there may be clinical signs of chronic liver disease including splenomegaly, spider angioma, caput medusae, palmar erythema, testicular atrophy, gynecomastia. In patients with decompensated cirrhosis, jaundice, ascites, peripheral edema, and encephalopathy may be present.
Laboratory testing shows mild to moderate elevation in serum AST and ALT in most patients, whereas normal transaminases occur rarely. During exacerbation, serum ALT concentration may be as high as 50 times the upper limit of normal. Alpha-fetoprotein concentrations correlate with disease activity. In exacerbations of HBV, concentrations as high as 1000 ng/mL may be seen (Lok 1989).
The natural course of CHB infection is determined by the interplay of viral replication and the host immune response. Other factors that may play a role in the progression of HBV-related liver disease include gender, alcohol consumption, and concomitant infection with other hepatitis viruses. The outcome of CHB infection depends upon the severity of liver disease at the time HBV replication is suppressed (UpToDate 2020). Liver fibrosis is potentially reversible once HBV replication is controlled.
There are several typical patterns of CHB acquired in adult or later childhood:
First, infection with a wildtype HBV variant: There is the classic necroinflammatory state with high HBV DNA, HBeAg positive, high ALT and active liver disease.
Second, infection with a precore mutant, which has become much more common than wildtype virus in the recent years. After infection with a precore mutant HBeAg is negative despite considerable HBV DNA replication and elevated ALT.
Third, a low or non-replicative phase, where serum ALT is normal, HBeAg is negative and anti-HBe antibodies are usually present and HBV DNA is low or not detectable. This status is characterised by partial immune control of the HBV infection.
In perinatally acquired chronic HBV infection there are three different states: (i) an immune tolerance phase, (ii) an immune clearance phase, and (iii) a late non-replicative phase.
The immune tolerance phase, which usually lasts 10 to 30 years, is characterised by high levels of HBV replication, as manifested by the presence of HBeAg and high levels of HBV DNA in serum. However, there is no evidence of active liver disease as seen by normal serum ALT concentrations and minimal changes in liver biopsy. It is thought that this lack of liver disease despite high levels of HBV replication is due to immune tolerance to HBV (Dienstag 2008), although the exact mechanisms are unknown. This phenomenon of immune tolerance is believed to be the most important reason for the poor response to interferon therapy in HBeAg positive patients with normal ALT levels. During this phase there is a very low rate of spontaneous HBeAg clearance. It is estimated that the rate of spontaneous HBeAg clearance is only 15% after 20 years of infection.
During the second to third decade, the immune tolerant phase may convert to immune clearance. The spontaneous HBeAg clearance rate increases – estimated to be 10 to 20% annually. If HBeAg seroconversion occurs, exacerbations of hepatitis with abrupt increases in serum ALT are very often observed. These exacerbations follow an increase in HBV DNA and might be due to a sudden increase in immune-mediated lysis of infected hepatocytes. Most often there are no clinical symptoms during exacerbation, and ALT increase is only detected by routine examinations. Some patients may develop symptoms mimicking acute hepatitis. Anti-HBc IgM titres and alpha-fetoprotein may increase. If such patients are not known to be HBV-infected, misdiagnosis of acute HBV can be made. HBeAg seroconversion and HBV DNA clearance from serum is not always achieved after exacerbation. In these patients, recurrent exacerbation with intermittent disappearance of serum HBV DNA with or without HBeAg loss may occur. The non-replicative phase is usually characterised by the absence of HBV DNA and normalisation of serum ALT, like in adult chronic HBV.
Very few patients with chronic HBV infection become HBsAg negative in the natural course of infection. The annual rate of HBsAg clearance has been estimated to be less than 2% in patients from high-income countries and even lower (0.1–0.8%) in patients of Asian origin (Liaw 1991) following an accelerated decrease in HBsAg levels during the three years before HBsAg seroclearance (Chen 2011). If loss of HBsAg occurs, prognosis is considered favourable. However, clearance of HBsAg does not exclude development of cirrhosis or hepatocellular carcinoma in some patients, although the exact rate of these complications is unknown. This phenomenon is thought to be linked to the fact that HBV DNA may still be present in hepatocytes despite HBsAg loss.
Prognosis and survival
There is a wide variation in clinical outcome and prognosis of chronic HBV infection. Recent data showed that in France about three-quarters of patients with chronic HBV who progressed to a liver-related complication had an additional liver-related risk factor (Mallet 2016). The risk of progression appears to be higher if immune activation occurs. Moreover, increased all-cause mortality in HBsAg positive patients was observed (Montuclard 2015). The lifetime risk of liver-related death has been estimated to be 40 to 50% for men and 15% for women in a Chinese cohort (Beasley 1982). However, it has to be noted that these data are based from pre-nucleos(t)ide analogue era and prognosis of patients with CHB have markedly improved during the last decade.
Estimated five-year rates of progression (Fattovich 2008) are:
- Chronic hepatitis to cirrhosis – 10 to 20%
- Compensated cirrhosis to hepatic decompensation – 20 to 30%
- Compensated cirrhosis to hepatocellular carcinoma – 5 to 15%
Survival rates are:
- Compensated cirrhosis – 85% at five years
- Decompensated cirrhosis – 55 to 70% at one year and 15 to 35% at five years
Viral replication
Survival is consistently worse in patients with signs of substantial viral replication compared to patients who are HBV DNA negative or who have very low HBV DNA levels. During the natural course of chronic infection, the appearance of the precore stop codon and basal core promoter variants initiates the seroconversion from HBeAg to anti-HBe positivity and leads to the awakening of the immune response. However, variants may emerge and lead to HBeAg negative CHB with high viraemia levels. The prevalence of HBeAg negative CHB has been increasing over the last decades. Acute exacerbations accompanied by high viral replication, elevated ALT levels and histological activity are a common feature of HBeAg negative CHB leading to cirrhosis and HCC much faster than in HBeAg positive CHB patients (Alexopoulou 2014, Papatheodoridis 2001).
In recent years, HBV DNA levels have been linked to disease progression and has replaced HBeAg positivity as a marker for disease activity (Chen 2006). This is true both for progression to cirrhosis and risk of HCC. Therefore, most treatment guidelines are based on HBV viraemia. A reasonable cut-off to distinguish patients with a low compared to high risk of progression and indication for antiviral treatment is 104 log copies/mL (corresponding to approximately 2 x 103 IU/mL) (Cornberg 2011), although other cut-offs may be used.
Duration of viral replication is linked with the risk of development of cirrhosis and HCC. As necroinflammation may persist longer in patients with a prolonged replicative phase, the risk of disease progression is elevated. Conversely, even in patients with decompensated cirrhosis, suppression of HBV replication and delayed HBsAg clearance can improve liver disease (Fung 2008).
Alcohol use
Heavy alcohol use is associated with faster HBV progression to liver injury and an elevated risk of developing cirrhosis and HCC (Bedogni 2008, Marcellin 2008). Survival is reduced compared to heavy alcohol users who are HBV negative. However, there is no clear evidence that heavy alcohol use is associated with an enhanced risk of chronic HBV infection, although prevalence of HBV is estimated to be fourfold higher than in controls (Laskus 1992) with variation among regions and cohorts (Rosman 1996).
Hepatitis C (HCV) coinfection
In patients with HBV/HCV coinfection, HCV usually predominates. This may lead to lower levels of transaminases and HBV DNA (Jardi 2001). The rate of HBsAg seroconversion even appears to be increased, as there is a well-known entity of occult HBV infection (patients with negative HBsAg but detectable serum HBV DNA) in patients with chronic HCV (Cacciola 1999, Torbenson 2002, Raimondo 2005). Despite lower aminotransferases and HBV DNA levels, liver damage is worse in most cases. The risks of severe hepatitis and fulminant hepatic failure seem to be elevated if both infections occur simultaneously regardless of whether it is an acute coinfection of HBV and HCV or acute HCV in chronic HBV (Liaw 2004).
Hepatitis D coinfection
An acute HBV/HDV coinfection tends to be more severe than an acute HBV infection alone. It is more likely to result in fulminant hepatitis. If HDV superinfection occurs in patients with CHB, HDV usually dominates, and HBV replication is suppressed (Jardi 2001). Severity of liver disease is worse and progression to cirrhosis is accelerated (Fattovich 2000, Grabowski 2010, Heidrich 2012) (see Chapter 10).
Extrahepatic manifestations
The two major extrahepatic complications of chronic HBV are polyarteritis nodosa and renal impairment due to glomerular disease. They occur in up to 10% of patients with chronic HBV and are thought to be mediated by circulating immune complexes (Han 2004).
Polyarteritis nodosa
The clinical manifestations are similar to those in patients with polyarteritis who are HBV negative. There may be some clinical benefit to antiviral therapy.
Nephropathy/Glomerulonephritis
HBV can induce both membranous nephropathy and, less often, membranoproliferative glomerulonephritis. Most cases occur in children. The clinical hallmark is proteinuria. In contrast to polyarteritis nodosa, there is no significant benefit of antiviral treatment.
For further details, please refer to extrahepatic manifestations in chapter 13.
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