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The Natural History of Chronic HBV Infection and Geographical Differences

The Natural History of Chronic HBV Infection and Geographical Differences Antiviral Therapy 2010 15 Suppl 3:25–33 (doi: 10.3851/IMP1621) Review The natural history of chronic HBV infection and geographical differences 1 2 3 Yun-Fan Liaw *, Maurizia R Brunetto , Stephanos Hadziyannis Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan UO Epatologia, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy Department of Medicine and Hepatology, Henry Dunant Hospital, Athens, Greece *Corresponding author e-mail: [email protected] Although chronic HBV infection is a global health issue, patients. This occurs more frequently in males and in there are geographical differences in the mode of trans- patients infected with genotypes D, C and B. mission, prevalence and HBV genotype distribution. The effort of active HBV replication-triggered immune Chronic HBV infection is a dynamic state of interac- clearance is the driving force of liver injury and subse- tions between HBV, hepatocytes and immune cells of quent disease progression in patients with hepatitis B e the host. Accordingly, the natural history of chronic antigen (HBeAg)-positive or HBeAg-negative hepatitis. HBV infection typically starts with an immune toler- Clinical studies have shown that chronic HBV infection ant phase, followed by an immune clearance phase and in western countries is associated with a higher inci- finally an inactive phase. The duration of the immune dence of cirrhosis, but lower incidence of hepatocellu- tolerant phase is usually long in chronic HBV infection lar carcinoma, than in Asian countries. The geographical acquired perinatally or in early childhood, otherwise the differences in age at the time of infection and predomi- duration is very short. During the inactive phase, spon- nant HBV genotype could account for the variance in taneous hepatitis B surface antigen (HBsAg) seroclear- the natural history of chronic HBV infection; however, ance might occur at an annual rate of 1–2%; however, some of these differences might actually result from HBV reactivation with hepatitis activity could occur over comparisons between cohorts with different age, gen- time in one-quarter to one-third of HBsAg-seropositive der distribution or fibrosis stage. Introduction Chronic HBV infection is a global public health issue and Alaska, whereas in other areas with high HBV because of its worldwide distribution and its poten- prevalence, 40–50% of chronic HBV infection origi- tial adverse sequelae, including cirrhosis, hepatic nates from perinatal transmission [4,5]. In areas of decompensation and development of hepatocellular intermediate endemicity, chronic HBV infection is gen- carcinoma (HCC). The prevalence of chronic HBV erally caused by transmission during early childhood, infection is approximately 5% globally, but differs mostly through household contact by ‘non-parenteral’ greatly from area to area (Figure 1) [1,2]. The preva- [6] or unclear parenteral mechanisms [7,8]. In low lence of hepatitis B surface antigen (HBsAg) carriage is prevalence areas, hepatitis B is typically a disease of low (0.1–2.0%) in the United States, North and West- young adults, who acquire the infection through risky ern Europe, intermediate (2.0–8.0%) in the Mediterra- behaviour, such as unprotected sexual contact or shar- nean countries, Eastern Europe, Central Asia, Middle ing of injection needles [4,5]. HBV genotypes also have East, South America and Japan, and high (8.0–20.0%) distinct geographical distribution (Figure 1): genotype in Southeast Asia, China, Taiwan, Alaska and sub- A is prevalent in Africa (A and A ), in Northwestern 1 3 Saharan regions [3]. In high-prevalence areas, HBV Europe (A ) and in the United States; genotypes B and infection usually occurs perinatally or during infancy C are prevalent in Asia or among Asian immigrants to, and early childhood. Close contact among toddlers is for example, the United States, Europe, Australia and considered to contribute to the maintenance of the high New Zealand; genotype D is prevalent in the Medi- prevalence of HBsAg carriage in sub-Saharan areas terranean basin, Middle East, Central Asia and India; ©2010 International Medical Press 1359-6535 (print) 2040-2058 (online) 25 AVT-10-SA-1003_Liaw.indd 25 28/7/10 11:25:36 Y-F Liaw et al. Figure 1. Geographical differences in the prevalence of chronic HBV infection and genotype distribution Prevalence of HBsAg carriage ≥8% = high 2–7% = intermediate <2% = low When two genotypes are common in a region, the more dominant genotype is shown in a larger font size. Adapted and modified from [1]. HBsAg, hepatitis B surface antigen. genotype E is prevalent in Western Africa; genotype F usually has a very short or no obvious immune toler- is prevalent in South and Central America; genotype ant phase [5]. G is prevalent in the United States and France; and genotype H is prevalent in Mexico and Latin America Hepatitis activity and HBeAg seroconversion during [9]. Along with these geographical differences, the the immune clearance phase natural history of chronic HBV infection also displays The mechanisms triggering the loss of immune toler- geographical variation. ance are largely unknown. The majority of patients enter the immune clearance phase after the age of 20 years. During this phase, hepatitis activity and inter- Natural history of chronic HBV infection mittent acute ALT flares > 5× the upper limit of normal Chronic HBV infection is a dynamic state involving (ULN) might occur and a few (<3%) might be com- interactions between the virus itself, the host hepato- plicated by hepatic decompensation [11]. These ALT cyte and immune response. Accordingly, the natural increases and flares are considered to be the result of course of chronic HBV infection consists of changing the host immune response against HBV with result- phases. Chronic HBV infection acquired perinatally ant apoptosis and necrosis; thus, higher ALT levels or during infancy typically has a long and uneventful usually reflect a more vigorous endogenous immune immune tolerant phase. Patients in the immune toler- response against HBV and more extensive hepatocyte ant phase are usually young, asymptomatic, hepati- damage [12]. The incidence of hepatitis flares varies tis B e antigen (HBeAg)-seropositive with high viral between patient cohorts, but has reached 25% per 6 7 loads (approximately >2×10 –2×10 IU/ml of HBV year during the first 3–5 years of follow-up in hospi- DNA), normal serum alanine aminotransferase (ALT) tal-based studies [12–14]. These events could lead to levels and near normal liver histology [4,5]. Providing a decrease in serum HBV DNA levels and a gradual that serum ALT levels remain normal, there is usu- accumulation of precore or core promoter mutations ally no or only minimal disease progression [10]. By [15–17], and could eventually be followed by HBeAg contrast, chronic HBV infection acquired in later life clearance and appearance of its antibody (anti-HBe), 26 ©2010 International Medical Press AVT-10-SA-1003_Liaw.indd 26 28/7/10 11:25:42 Geographical variations in the natural history of chronic hepatitis B defined as HBeAg seroconversion [12]. The estimated accelerate after longer follow-up or in individuals annual incidence of spontaneous HBeAg seroconver- over the age of 40–50 years to a cumulative incidence sion is 2 –15%, depending on factors such as age, of 25% after 20 years of follow-up [36]. Besides being ALT levels and HBV genotype [12–17]. In Taiwan, related to age, patients infected with genotypes A or approximately 90% of children remain HBeAg-pos- B HBV have a higher chance of HBsAg seroclearance itive until 10–15 years of age and HBeAg serocon- compared with other genotypes [37,38]. The annual version occurs at a mean age of 30–35 years, with rate of spontaneous HBsAg clearance in genotype-D- 90% of HBeAg seroconversion occurring before the infected HBsAg-positive individuals in the inactive age of 40 years [18]. Patients infected with genotype anti-HBe-positive phase in Greece has recently been B HBV seroconvert earlier and more frequently than calculated to be 1.79% [39]. HBsAg seroclearance patients infected with genotype C HBV [9,18–24]. In usually confers an even better long-term outcome Alaskan natives with chronic HBV infection, the 50th compared with that of inactive HBsAg carriers, pro- percentile age of HBeAg seroclearance is <20 years in vided that there is no pre-existing cirrhosis or viral patients with genotypes A, B, D and F, but >40 years superinfection; however, small amounts of HBV DNA in patients with genotype C [23]. In Mediterranean might persist in a state of occult HBV infection. One countries, where HBV genotype D infection is pre- study involving 34 consecutive patients with HBsAg dominant, the mean age of adult patients at the time seroclearance showed that 30 were still seropositive of HBeAg seroconversion was 30 years (range 13–65) for HBV DNA (all 30 patients had HBV DNA<10 in one Italian study [25]. However, several field studies copies/ml with 27 patients who had <10 copies/ml) in Greece, where genotype D prevails by >90%, have and that some harboured defective pre-S/S sequences, shown repeatedly that almost 80% of the HBsAg-pos- including G149R, whereas the ‘a’ determinant region itive individuals are already HBeAg-negative and anti- was conserved [40]. HBe-positive by the second decade of life [8,26–28]. Moreover, follow-up studies in Greek communities Reactivation of hepatitis B with endemic HBV infection have revealed large-scale After spontaneous HBeAg seroconversion, approxi- horizontal spread of HBV among infants and chil- mately 5–10% of patients still have high HBV DNA dren with clinically silent HBeAg clearance, and that levels and persistently abnormal ALT levels, indicat- development of the HBeAg-negative/anti-HBe-posi- ing direct transition from HBeAg-positive to HBeAg- tive HBsAg carrier state occurs before reaching adult- negative hepatitis [29,31,41]. This could either be hood in the vast majority of patients [7,8,29]. A study short-lived or persistent [42]. The remaining 90–95% in the early 1970s found that most HBsAg-positive of patients initially achieve remission, but could individuals aged 18–23 years (mainly Hellenic army relapse either because of HBeAg reversion (HBeAg- recruits) had normal levels of hepatic enzymes, nor- seropositive hepatitis) in 1–4% of patients or, in the mal liver histology and numerous ground glass hepa- majority of patients, because of reactivation of HBV tocytes with cytoplasmic HBsAg [30], but no hepatitis with precore or core promoter mutations that abolish B core antigen (HBcAg) expression in the liver [27]. or down-regulate HBeAg production (HBeAg-neg- Subsequent studies of HBeAg status and serum HBV ative chronic hepatitis) [17,25,26,29,31,41,43]. In DNA levels have confirmed that chronic HBV infec- Taiwanese studies, the estimated incidence of hepa- tion in this population had already progressed to the titis relapse was 1–3% per year [14,31,41], with a HBeAg-negative carrier state [28]. cumulative incidence of up to 30% after 15 years of follow-up – mostly within 10 years of HBeAg sero- Inactive phase and spontaneous HBsAg conversion [31,41]. The incidence was very low in seroclearance patients who HBeAg seroconverted before the age of HBeAg seroconversion marks the transition from the 30 years [24,34,41,44], but was significantly higher active to the inactive phase of chronic HBV infection. in males, patients with genotype C infection, patients It is usually followed by a phase with low viral load who HBeAg seroconverted after the age of 40 years 4 5 (<10 –10 copies/ml), sustained clinical remission and [45] and in patients with serum HBV DNA levels a lifelong inactive state with an excellent outcome >10 copies/ml within 1 year of HBeAg seroconver- [24,25,31–35]. Spontaneous HBsAg seroclearance sion [41] or at entry of the so called ‘inactive carrier might occur after a prolonged period of sustained state’ [33,45,46]. These age-related findings sug- remission [32,36,37]. It occurs at an incidence of gest that earlier HBeAg seroconversion or a shorter 0.7–2.4% per year in studies with a follow-up dura- HBeAg-positive phase is associated with a higher tion >5 years, being higher in studies with a mean chance of sustained remission [18]. A Spanish study or median age >40 years at time of entry. The inci- showed that patients infected with genotypes D or F dence of spontaneous HBsAg seroclearance might HBV had a lower chance of sustained remission after Antiviral Therapy 15 Suppl 3 27 AVT-10-SA-1003_Liaw.indd 27 28/7/10 11:25:43 Y-F Liaw et al. HBeAg seroconversion (61% and 50%, respectively) alterations [55]. Accordingly, patients in the inactive compared with a rate of 86% in genotype-A-infected phase have a very low incidence of cirrhosis develop- patients [38]. ment [24,25,31–35]. A recent study in 4,376 HBeAg- HBV precore mutations occur most frequently in negative patients with persistent ALT<2×ULN showed genotype D infection, followed by genotypes C and a low rate of cirrhosis (2.7%) and HCC (0.5%) during B, and are seen least frequently in genotype A [47]. long-term follow-up (median 13 years, range 3–29). Long-term follow-up data from Greece have shown The rates were even lower in those who maintained recently that HBV reactivation in genotype-A-infected normal ALT [35]. Similarly, an Italian study showed patients following HBeAg clearance is associated with that the adjusted hazard ratios (95% confidence inter - HBeAg seroreversion; however, this might escape val [CI]) for liver-related death were 33 (3.01–363) detection if the duration of observation and serologi- for persistently HBeAg-positive patients and 38.73 cal testing are limited. In a recent study, all properly (4.65–322) for those with HBeAg-negative chronic documented cases of HBeAg-negative chronic hepa- hepatitis B or HBeAg reversion relative to inactive car- titis B exhibiting persistent HBeAg-negativity/anti- riers. These data suggest that the risk of liver-related HBeAg positivity were found to harbour genotype D. mortality in Caucasian adults with chronic hepatitis It is, therefore, suggested that HBeAg-negative geno- B is strongly related to sustained disease activity and type A chronic HBV infection is either extremely rare ongoing high levels of HBV replication independent or non-existent [48]. Accordingly, HBeAg-negative of HBeAg status [25]. chronic HBV infection is most common in regions Approximately 50% of patients are seropositive for where genotype D infection dominates. The percent- HBeAg or for HBV DNA (measured by hybridization age of patients with chronic HBV infection who are assays) at the onset of cirrhosis [60,61], suggesting HBeAg-negative is 80–90% in genotype-D-dominant that disease progression might continue after cirrho- Mediterranean areas, 30–50% in Southeast Asia and sis develops [61]. The 5-year probability of hepatic <10% in the United States and Northwestern Europe, decompensation is 15–20%, being fourfold higher in where genotype A is prevalent and genotype D infec- patients with active HBV replication than in patients tion is relatively rare [49]. The higher incidence of without [62]. The estimated 5-year survival rate of HBeAg-negative hepatitis was well demonstrated in a patients with compensated and decompensated cir- Greek study involving 85 ‘inactive carriers’. During a rhosis is 80–85% and 30–50%, respectively [60]. mean follow-up period of 36 months (range 12–48), The risk of HCC correlates with underlying liver the cumulative incidence was 24% at the end of year disease and most cases of HCC develop in patients 4 [50]. This rate was much higher than the 9.7% at with cirrhosis; therefore, HCC and cirrhosis share year 5 and 21.6% at year 20 of follow-up reported in the same risk factors. Patients with a family history 1,965 inactive carriers from Taiwan [44]. of HCC are at increased risk [63]. Cohort studies showed that the incidence of HCC was <0.2% per year in inactive HBsAg carriers and <0.6% per year Long-term outcomes of infection in patients with chronic hepatitis B [64]. The annual Cirrhosis, HCC or both might develop during the incidence of HCC in patients with cirrhosis is 2–6% natural course of chronic HBV infection. Large [60,61,63]. Of the viral factors, HBV DNA level, geno- population-based studies involving primarily (85%) type and naturally occurring mutations, such as HBV HBeAg- negative HBsAg-positive patients over the pre-S and basal core promoter A1762T/G1764A dou- age of 30 years (67% of patients were >39 years) at ble mutations, are also associated with HCC develop- recruitment have shown that the risk of cirrhosis, ment [9,52,65,66]. A multivariate analysis involving HCC and mortality increases proportionally with 2,762 Taiwanese HBsAg carriers with 33,847 person- HBV DNA levels ≥10 copies/ml [51–53]. These find- years of follow-up showed that A1762T/G1764A and ings suggest that HBV replication, with subsequent genotype C were independent factors with an adjusted immune-mediated liver injuries, is the primary driving hazard ratio of 1.73 (P=0.013) and 1.76 (P=0.005), force of disease progression [54]. Other risk factors respectively [66]. Investigators noted that the associa- for the development of cirrhosis include male gender, tion between HBV mutations and HCC development increasing age [51–56], HBV genotype [7,16,20], per- was most profound in patients who had a pre-S dele- sistent HBeAg seropositivity or reversion [31,55,57], tion followed by basal core promoter mutations, and HBV reactivation [22,31,41,44], persistent HBV DNA that combination of these mutations had a synergistic seropositivity [58] and persistent ALT abnormality effect on the development of HCC [67]. Concurrent [59], as well as the severity (hepatic decompensation), infection with HCV, HDV or HIV also increased the extent (bridging hepatic necrosis) and frequency of risk of cirrhosis and HCC [68]. Other factors that hepatitis flares, and the duration of hepatic lobular contribute to HCC development include habitual 28 ©2010 International Medical Press AVT-10-SA-1003_Liaw.indd 28 28/7/10 11:25:43 Geographical variations in the natural history of chronic hepatitis B alcohol consumption, cigarette smoking and aflatoxin predictive of cirrhosis were similar between western exposure [68]. Studies in Africa and China showed and Asian countries, including older age, histological a significant association between urinary aflatoxin evidence of bridging hepatic necrosis and persistent levels and HCC, and a synergistic interaction with HBeAg and/or HBV DNA seropositivity [55,64]. In HBsAg carrier status [69]. addition, the incidence of cirrhosis varied among dif- ferent cohorts, being lowest in inactive HBsAg car- riers [24,25,31–35], lower in HBeAg-positive young Geographical differences patients with normal baseline ALT [14] and consider- In addition to the geographical differences in age at ably higher in patients with active hepatitis at entry the time of HBV infection and the incidence of the [17,55,57,58,64,70]. Even in patients with active major HBV genotypes, there are also geographical hepatitis, the incidence was different between HBeAg- differences in the natural history of chronic HBV positive and HBeAg-negative cohorts and also dif- infection (Table 1). Firstly, chronic HBV infection ferent between younger and older cohorts [64]. For acquired perinatally or in infancy usually has a pro- example, an Italian study showed that the cumulative longed uneventful immune tolerant phase, whereas probability of cirrhosis development after 5 and 10 HBV infections acquired later in life have no or a very years of follow-up was 5% and 46%, respectively, in short immune tolerant phase [4,5]. Secondly, patients patients younger than 36 years, but it was 28% and infected with genotypes A, B and D HBV undergo 93%, respectively, in those older than 36 years [58]. earlier HBeAg seroconversion [9,19,23], but patients Another Italian study showed that none of the 85 pae- infected with genotypes C and D have a higher inci- diatric patients developed cirrhosis during 15 years dence of HBeAg-negative hepatitis after spontaneous of follow-up [34]. Similarly, in a study from Taiwan, HBeAg seroconversion [22,29,50]. Accordingly, areas the incidence of cirrhosis in HBeAg-negative patients where genotypes C or D HBV are predominant have aged >50 years was 4.14%, but only 0.5% per year more HBeAg-negative hepatitis [17]. Thirdly, Euro- in those aged <30 years [44]. The calculated differ- pean patients predominantly (>90%) infected with ences might reflect differences in the study cohorts; genotype D seem to have a higher incidence of cir- therefore, age, gender and stage of fibrosis should be rhosis development despite early HBeAg seroconver- considered in such comparisons. sion. This finding suggests that genotype is a more HBV hepatocarcinogenesis is a multistage proc- crucial factor for the difference between geographical ess involving many factors and it usually takes dec- locations. As mentioned earlier, patients infected with ades for HCC to develop. Chronic HBV infection genotype D have a higher incidence of HBeAg-neg- acquired in adults has a much lower risk of HCC ative hepatitis [50], which is an important risk fac- development than infections resulting from maternal– tor for cirrhosis development. The calculated annual neonatal transmission, possibly reflecting differences incidence of cirrhosis in patients with HBeAg-positive in the duration of infection. The risk of HCC among hepatitis was 3.8% in western countries compared White asymptomatic carriers from North America with 1.6% in Asian countries. The corresponding and Europe is low, with an estimated annual risk of 0 figures in HBeAg-negative patients were 9.7% and and 13 per 100,000 individuals, respectively [70–72]. 2.8% per year, respectively [64]. Of note, the factors These figures are much lower than the annual risk of Table 1. Comparisons among representative studies from geographical areas of different HBsAg prevalences Southeast Asia Mediterranean Basin United States HBsAg prevalence High Intermediate Low Age of infection Perinatal or <2 years Childhood Adolescent/adult Major HBV genotype B and C D A, C and D Immune tolerant phase Long Short Short Age of HBeAg seroconversion, 30–35 <20 50th percentile <20 years (genotypes A and D) HBeAg-negative/chronic HBV infection, % 30 80–90 <10 (genotype A) Cirrhosis, % per year 0.07, 1.6, 2.8 0.01, 3.8, 9.7 – c d d e HCC, % per year 0.2, 0.6, 3.7 0.02, 0.3, 2.2 0.01, 0.9, 3.3 a b Abstracted from [2] and [3]. Data expressed in the sequence of inactive hepatitis B surface antigen (HBsAg) carriers, hepatitis B e antigen (HBeAg)-positive and c d HBeAg-negative chronic HBV infection [64]. Data expressed in the sequence of inactive HBsAg carriers, chronic HBV infection and compensated cirrhosis. Data from [64]. Data from [70]. Antiviral Therapy 15 Suppl 3 29 AVT-10-SA-1003_Liaw.indd 29 28/7/10 11:25:43 Y-F Liaw et al. 494 [55] and 324–1,169 [73] per 100,000 reported in the long-term outcomes of chronic HBV infection. two Taiwanese studies, 240 per 100,000 reported in Geographical differences in the age of acquisition of Japan [74] and 256 per 100,000 reported in Alaska HBV infection and in major HBV genotypes might [75]. The overall annual incidence of HCC in seven be responsible for the geographical differences in the studies involving 732 patients with chronic hepatitis natural history of chronic HBV infection. However, from Europe and the United States was calculated to some of the observed geographical differences might be 300 per 100,000. By contrast, the annual incidence actually result from comparisons between cohorts calculated from nine studies involving 5,661 patients with different distribution in age, gender or fibrosis from Taiwan, China, Korea and Japan was 600 per stage – all of which also affect outcome. Finally, there 100,000 [64]. The risk of HCC increases further in is one other variable that must be considered: namely, patients with cirrhosis: in a European study involv- the progressive change in the way we have looked at ing 161 patients (89% male) with a median age of 48 HBeAg-negative and anti-HBe-positive carriers over years (range 17–78) who remained untreated during a the years. Prior to the 1980s, all such patients were follow-up period of 6.4 years, the 5-year risk of HCC considered to be healthy; however, more recently, was 9% and the annual incidence was 2.2% [62]. The approximately 25% of patients in the Mediterra- overall annual incidence of HCC in seven studies from nean area were found to be viraemic (based on an Europe and the United States involving 540 patients HBV DNA cutoff of 10 copies/ml – the limit of assay followed for 6 years was calculated to be 2.2% (95% sensitivity at the time) and have a distinct form of CI 1.71–2.71) [64]. These figures are lower than a cal- HBeAg-negative/anti-HBe-positive chronic hepatitis. culated annual rate of 3.7% (95% CI 3.2–4.14) [64], In the 1990s, improvements in the sensitivity of diag- based on reports from Taiwan, Japan and Asia where nostic tools (for example, PCR for HBV DNA detec- genotypes B and C HBV are predominant [52,76–78]. tion) lowered the HBV DNA threshold to 10 copies/ A recent study has shown that the intracellular expres- ml to confirm HBV-replication-associated liver dis- sion of HBV DNA, HBcAg and cellular stress proteins ease in these patients and, more recently, population- are highest for genotypes B and C followed by geno- based studies have identified 10 copies/ml as the type D and lowest in genotype A HBV [79]. Intracellu- new threshold for HBeAg-negative/anti-HBe-positive lar accumulation of HBV DNA, of HBV antigens and chronic HBV infection. increased cellular stress might promote hepatocyte International studies comparing cohorts that are damage and inflammation, which could contribute well matched in terms of these factors are warranted to hepatocarcinogenesis [80]. In South Africa, HCC to elucidate the actual role of age of infection and of occurs in younger men who are anti-HBe-positive and HBV genotypes in the observed geographical differ- non-cirrhotic. Aflatoxin exposure could also be a fac- ences in the natural history of chronic HBV infection. tor in increasing the risk of HCC [69] as could infec- tion with genotype A , which is associated with a 4.5- Acknowledgements fold increased risk of HCC [81]. Y-FL thanks Chang Gung Medical Research Fund and the Prosperous Foundation (Taipei, Taiwan) for Summary and perspectives the long-term grant support and Su-Chiung Chu for It is clear that chronic HBV infection is a global health secretarial administration. Editorial support was pro- issue, although there are geographical differences in the vided by Liesje Thomas at Elements Communications mode of transmission, prevalence and HBV genotype and was funded by F Hoffmann–La Roche (Basel, distribution. Typically, the natural history of chronic Switzerland). HBV infection starts with an immune tolerant phase followed by an immune clearance phase and finally by Disclosure statement an inactive phase. The duration of the immune toler- ant phase varies and is usually long in chronic HBV Y-FL has been involved with clinical trials or has infection acquired perinatally or in infancy, but very served as a global advisory board member for Roche, short in infections acquired in later life. Bristol–Myers Squibb, Novartis and Gilead Sci- During the inactive phase, HBV reactivation fol- ences. MRB is a member of the speakers’ bureaus lowed by immune-mediated hepatocytolysis or by for F Hoffmann– La Roche, Gilead Sciences, Bristol– active hepatitis might occur in one-quarter to one- Myers Squibb, Novartis and Abbott Laboratories. SH third of HBsAg-seropositive patients. Immune clear- has received research grants from Gilead Sciences and ance of reactivated HBV occurs more frequently in F Hoffmann–La Roche, has participated in clinical tri- genotype D- and C-infected patients. Clinical stud- als and has been in global advisory boards of Roche, ies suggest that there are geographical differences in Gilead Sciences, Bristol– Myers Squibb and Novartis. 30 ©2010 International Medical Press AVT-10-SA-1003_Liaw.indd 30 28/7/10 11:25:43 Geographical variations in the natural history of chronic hepatitis B 21. Yuen MF, Sablon E, Tanaka Y, et al. 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N Engl J Med 2004; 351:1521–1531. 32 ©2010 International Medical Press AVT-10-SA-1003_Liaw.indd 32 28/7/10 11:25:43 Geographical variations in the natural history of chronic hepatitis B 79. Sugiyama M, Tanaka Y, Kato T, et al. Influence of 81. Kew MC, Kramvis A, Yu MC, Arakawa K, Hodkinson J. hepatitis B virus genotypes on the intra- and extracellular Increased hepatocarcinogenic potential of hepatitis B virus expression of viral DNA and antigens. Hepatology 2006; genotype A in Bantu-speaking sub-Saharan Africans. 44:915–924. J Med Virol 2005; 75:513–521. 80. Manigold T, Rehermann B. Chronic hepatitis B and hepatocarcinogenesis: does prevention of ‘collateral damage’ bring the cure? Hepatology 2003; 37:707–710. Accepted for publication 5 March 2010 Antiviral Therapy 15 Suppl 3 33 AVT-10-SA-1003_Liaw.indd 33 28/7/10 11:25:43 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antiviral Therapy SAGE

The Natural History of Chronic HBV Infection and Geographical Differences

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Antiviral Therapy 2010 15 Suppl 3:25–33 (doi: 10.3851/IMP1621) Review The natural history of chronic HBV infection and geographical differences 1 2 3 Yun-Fan Liaw *, Maurizia R Brunetto , Stephanos Hadziyannis Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan UO Epatologia, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy Department of Medicine and Hepatology, Henry Dunant Hospital, Athens, Greece *Corresponding author e-mail: [email protected] Although chronic HBV infection is a global health issue, patients. This occurs more frequently in males and in there are geographical differences in the mode of trans- patients infected with genotypes D, C and B. mission, prevalence and HBV genotype distribution. The effort of active HBV replication-triggered immune Chronic HBV infection is a dynamic state of interac- clearance is the driving force of liver injury and subse- tions between HBV, hepatocytes and immune cells of quent disease progression in patients with hepatitis B e the host. Accordingly, the natural history of chronic antigen (HBeAg)-positive or HBeAg-negative hepatitis. HBV infection typically starts with an immune toler- Clinical studies have shown that chronic HBV infection ant phase, followed by an immune clearance phase and in western countries is associated with a higher inci- finally an inactive phase. The duration of the immune dence of cirrhosis, but lower incidence of hepatocellu- tolerant phase is usually long in chronic HBV infection lar carcinoma, than in Asian countries. The geographical acquired perinatally or in early childhood, otherwise the differences in age at the time of infection and predomi- duration is very short. During the inactive phase, spon- nant HBV genotype could account for the variance in taneous hepatitis B surface antigen (HBsAg) seroclear- the natural history of chronic HBV infection; however, ance might occur at an annual rate of 1–2%; however, some of these differences might actually result from HBV reactivation with hepatitis activity could occur over comparisons between cohorts with different age, gen- time in one-quarter to one-third of HBsAg-seropositive der distribution or fibrosis stage. Introduction Chronic HBV infection is a global public health issue and Alaska, whereas in other areas with high HBV because of its worldwide distribution and its poten- prevalence, 40–50% of chronic HBV infection origi- tial adverse sequelae, including cirrhosis, hepatic nates from perinatal transmission [4,5]. In areas of decompensation and development of hepatocellular intermediate endemicity, chronic HBV infection is gen- carcinoma (HCC). The prevalence of chronic HBV erally caused by transmission during early childhood, infection is approximately 5% globally, but differs mostly through household contact by ‘non-parenteral’ greatly from area to area (Figure 1) [1,2]. The preva- [6] or unclear parenteral mechanisms [7,8]. In low lence of hepatitis B surface antigen (HBsAg) carriage is prevalence areas, hepatitis B is typically a disease of low (0.1–2.0%) in the United States, North and West- young adults, who acquire the infection through risky ern Europe, intermediate (2.0–8.0%) in the Mediterra- behaviour, such as unprotected sexual contact or shar- nean countries, Eastern Europe, Central Asia, Middle ing of injection needles [4,5]. HBV genotypes also have East, South America and Japan, and high (8.0–20.0%) distinct geographical distribution (Figure 1): genotype in Southeast Asia, China, Taiwan, Alaska and sub- A is prevalent in Africa (A and A ), in Northwestern 1 3 Saharan regions [3]. In high-prevalence areas, HBV Europe (A ) and in the United States; genotypes B and infection usually occurs perinatally or during infancy C are prevalent in Asia or among Asian immigrants to, and early childhood. Close contact among toddlers is for example, the United States, Europe, Australia and considered to contribute to the maintenance of the high New Zealand; genotype D is prevalent in the Medi- prevalence of HBsAg carriage in sub-Saharan areas terranean basin, Middle East, Central Asia and India; ©2010 International Medical Press 1359-6535 (print) 2040-2058 (online) 25 AVT-10-SA-1003_Liaw.indd 25 28/7/10 11:25:36 Y-F Liaw et al. Figure 1. Geographical differences in the prevalence of chronic HBV infection and genotype distribution Prevalence of HBsAg carriage ≥8% = high 2–7% = intermediate <2% = low When two genotypes are common in a region, the more dominant genotype is shown in a larger font size. Adapted and modified from [1]. HBsAg, hepatitis B surface antigen. genotype E is prevalent in Western Africa; genotype F usually has a very short or no obvious immune toler- is prevalent in South and Central America; genotype ant phase [5]. G is prevalent in the United States and France; and genotype H is prevalent in Mexico and Latin America Hepatitis activity and HBeAg seroconversion during [9]. Along with these geographical differences, the the immune clearance phase natural history of chronic HBV infection also displays The mechanisms triggering the loss of immune toler- geographical variation. ance are largely unknown. The majority of patients enter the immune clearance phase after the age of 20 years. During this phase, hepatitis activity and inter- Natural history of chronic HBV infection mittent acute ALT flares > 5× the upper limit of normal Chronic HBV infection is a dynamic state involving (ULN) might occur and a few (<3%) might be com- interactions between the virus itself, the host hepato- plicated by hepatic decompensation [11]. These ALT cyte and immune response. Accordingly, the natural increases and flares are considered to be the result of course of chronic HBV infection consists of changing the host immune response against HBV with result- phases. Chronic HBV infection acquired perinatally ant apoptosis and necrosis; thus, higher ALT levels or during infancy typically has a long and uneventful usually reflect a more vigorous endogenous immune immune tolerant phase. Patients in the immune toler- response against HBV and more extensive hepatocyte ant phase are usually young, asymptomatic, hepati- damage [12]. The incidence of hepatitis flares varies tis B e antigen (HBeAg)-seropositive with high viral between patient cohorts, but has reached 25% per 6 7 loads (approximately >2×10 –2×10 IU/ml of HBV year during the first 3–5 years of follow-up in hospi- DNA), normal serum alanine aminotransferase (ALT) tal-based studies [12–14]. These events could lead to levels and near normal liver histology [4,5]. Providing a decrease in serum HBV DNA levels and a gradual that serum ALT levels remain normal, there is usu- accumulation of precore or core promoter mutations ally no or only minimal disease progression [10]. By [15–17], and could eventually be followed by HBeAg contrast, chronic HBV infection acquired in later life clearance and appearance of its antibody (anti-HBe), 26 ©2010 International Medical Press AVT-10-SA-1003_Liaw.indd 26 28/7/10 11:25:42 Geographical variations in the natural history of chronic hepatitis B defined as HBeAg seroconversion [12]. The estimated accelerate after longer follow-up or in individuals annual incidence of spontaneous HBeAg seroconver- over the age of 40–50 years to a cumulative incidence sion is 2 –15%, depending on factors such as age, of 25% after 20 years of follow-up [36]. Besides being ALT levels and HBV genotype [12–17]. In Taiwan, related to age, patients infected with genotypes A or approximately 90% of children remain HBeAg-pos- B HBV have a higher chance of HBsAg seroclearance itive until 10–15 years of age and HBeAg serocon- compared with other genotypes [37,38]. The annual version occurs at a mean age of 30–35 years, with rate of spontaneous HBsAg clearance in genotype-D- 90% of HBeAg seroconversion occurring before the infected HBsAg-positive individuals in the inactive age of 40 years [18]. Patients infected with genotype anti-HBe-positive phase in Greece has recently been B HBV seroconvert earlier and more frequently than calculated to be 1.79% [39]. HBsAg seroclearance patients infected with genotype C HBV [9,18–24]. In usually confers an even better long-term outcome Alaskan natives with chronic HBV infection, the 50th compared with that of inactive HBsAg carriers, pro- percentile age of HBeAg seroclearance is <20 years in vided that there is no pre-existing cirrhosis or viral patients with genotypes A, B, D and F, but >40 years superinfection; however, small amounts of HBV DNA in patients with genotype C [23]. In Mediterranean might persist in a state of occult HBV infection. One countries, where HBV genotype D infection is pre- study involving 34 consecutive patients with HBsAg dominant, the mean age of adult patients at the time seroclearance showed that 30 were still seropositive of HBeAg seroconversion was 30 years (range 13–65) for HBV DNA (all 30 patients had HBV DNA<10 in one Italian study [25]. However, several field studies copies/ml with 27 patients who had <10 copies/ml) in Greece, where genotype D prevails by >90%, have and that some harboured defective pre-S/S sequences, shown repeatedly that almost 80% of the HBsAg-pos- including G149R, whereas the ‘a’ determinant region itive individuals are already HBeAg-negative and anti- was conserved [40]. HBe-positive by the second decade of life [8,26–28]. Moreover, follow-up studies in Greek communities Reactivation of hepatitis B with endemic HBV infection have revealed large-scale After spontaneous HBeAg seroconversion, approxi- horizontal spread of HBV among infants and chil- mately 5–10% of patients still have high HBV DNA dren with clinically silent HBeAg clearance, and that levels and persistently abnormal ALT levels, indicat- development of the HBeAg-negative/anti-HBe-posi- ing direct transition from HBeAg-positive to HBeAg- tive HBsAg carrier state occurs before reaching adult- negative hepatitis [29,31,41]. This could either be hood in the vast majority of patients [7,8,29]. A study short-lived or persistent [42]. The remaining 90–95% in the early 1970s found that most HBsAg-positive of patients initially achieve remission, but could individuals aged 18–23 years (mainly Hellenic army relapse either because of HBeAg reversion (HBeAg- recruits) had normal levels of hepatic enzymes, nor- seropositive hepatitis) in 1–4% of patients or, in the mal liver histology and numerous ground glass hepa- majority of patients, because of reactivation of HBV tocytes with cytoplasmic HBsAg [30], but no hepatitis with precore or core promoter mutations that abolish B core antigen (HBcAg) expression in the liver [27]. or down-regulate HBeAg production (HBeAg-neg- Subsequent studies of HBeAg status and serum HBV ative chronic hepatitis) [17,25,26,29,31,41,43]. In DNA levels have confirmed that chronic HBV infec- Taiwanese studies, the estimated incidence of hepa- tion in this population had already progressed to the titis relapse was 1–3% per year [14,31,41], with a HBeAg-negative carrier state [28]. cumulative incidence of up to 30% after 15 years of follow-up – mostly within 10 years of HBeAg sero- Inactive phase and spontaneous HBsAg conversion [31,41]. The incidence was very low in seroclearance patients who HBeAg seroconverted before the age of HBeAg seroconversion marks the transition from the 30 years [24,34,41,44], but was significantly higher active to the inactive phase of chronic HBV infection. in males, patients with genotype C infection, patients It is usually followed by a phase with low viral load who HBeAg seroconverted after the age of 40 years 4 5 (<10 –10 copies/ml), sustained clinical remission and [45] and in patients with serum HBV DNA levels a lifelong inactive state with an excellent outcome >10 copies/ml within 1 year of HBeAg seroconver- [24,25,31–35]. Spontaneous HBsAg seroclearance sion [41] or at entry of the so called ‘inactive carrier might occur after a prolonged period of sustained state’ [33,45,46]. These age-related findings sug- remission [32,36,37]. It occurs at an incidence of gest that earlier HBeAg seroconversion or a shorter 0.7–2.4% per year in studies with a follow-up dura- HBeAg-positive phase is associated with a higher tion >5 years, being higher in studies with a mean chance of sustained remission [18]. A Spanish study or median age >40 years at time of entry. The inci- showed that patients infected with genotypes D or F dence of spontaneous HBsAg seroclearance might HBV had a lower chance of sustained remission after Antiviral Therapy 15 Suppl 3 27 AVT-10-SA-1003_Liaw.indd 27 28/7/10 11:25:43 Y-F Liaw et al. HBeAg seroconversion (61% and 50%, respectively) alterations [55]. Accordingly, patients in the inactive compared with a rate of 86% in genotype-A-infected phase have a very low incidence of cirrhosis develop- patients [38]. ment [24,25,31–35]. A recent study in 4,376 HBeAg- HBV precore mutations occur most frequently in negative patients with persistent ALT<2×ULN showed genotype D infection, followed by genotypes C and a low rate of cirrhosis (2.7%) and HCC (0.5%) during B, and are seen least frequently in genotype A [47]. long-term follow-up (median 13 years, range 3–29). Long-term follow-up data from Greece have shown The rates were even lower in those who maintained recently that HBV reactivation in genotype-A-infected normal ALT [35]. Similarly, an Italian study showed patients following HBeAg clearance is associated with that the adjusted hazard ratios (95% confidence inter - HBeAg seroreversion; however, this might escape val [CI]) for liver-related death were 33 (3.01–363) detection if the duration of observation and serologi- for persistently HBeAg-positive patients and 38.73 cal testing are limited. In a recent study, all properly (4.65–322) for those with HBeAg-negative chronic documented cases of HBeAg-negative chronic hepa- hepatitis B or HBeAg reversion relative to inactive car- titis B exhibiting persistent HBeAg-negativity/anti- riers. These data suggest that the risk of liver-related HBeAg positivity were found to harbour genotype D. mortality in Caucasian adults with chronic hepatitis It is, therefore, suggested that HBeAg-negative geno- B is strongly related to sustained disease activity and type A chronic HBV infection is either extremely rare ongoing high levels of HBV replication independent or non-existent [48]. Accordingly, HBeAg-negative of HBeAg status [25]. chronic HBV infection is most common in regions Approximately 50% of patients are seropositive for where genotype D infection dominates. The percent- HBeAg or for HBV DNA (measured by hybridization age of patients with chronic HBV infection who are assays) at the onset of cirrhosis [60,61], suggesting HBeAg-negative is 80–90% in genotype-D-dominant that disease progression might continue after cirrho- Mediterranean areas, 30–50% in Southeast Asia and sis develops [61]. The 5-year probability of hepatic <10% in the United States and Northwestern Europe, decompensation is 15–20%, being fourfold higher in where genotype A is prevalent and genotype D infec- patients with active HBV replication than in patients tion is relatively rare [49]. The higher incidence of without [62]. The estimated 5-year survival rate of HBeAg-negative hepatitis was well demonstrated in a patients with compensated and decompensated cir- Greek study involving 85 ‘inactive carriers’. During a rhosis is 80–85% and 30–50%, respectively [60]. mean follow-up period of 36 months (range 12–48), The risk of HCC correlates with underlying liver the cumulative incidence was 24% at the end of year disease and most cases of HCC develop in patients 4 [50]. This rate was much higher than the 9.7% at with cirrhosis; therefore, HCC and cirrhosis share year 5 and 21.6% at year 20 of follow-up reported in the same risk factors. Patients with a family history 1,965 inactive carriers from Taiwan [44]. of HCC are at increased risk [63]. Cohort studies showed that the incidence of HCC was <0.2% per year in inactive HBsAg carriers and <0.6% per year Long-term outcomes of infection in patients with chronic hepatitis B [64]. The annual Cirrhosis, HCC or both might develop during the incidence of HCC in patients with cirrhosis is 2–6% natural course of chronic HBV infection. Large [60,61,63]. Of the viral factors, HBV DNA level, geno- population-based studies involving primarily (85%) type and naturally occurring mutations, such as HBV HBeAg- negative HBsAg-positive patients over the pre-S and basal core promoter A1762T/G1764A dou- age of 30 years (67% of patients were >39 years) at ble mutations, are also associated with HCC develop- recruitment have shown that the risk of cirrhosis, ment [9,52,65,66]. A multivariate analysis involving HCC and mortality increases proportionally with 2,762 Taiwanese HBsAg carriers with 33,847 person- HBV DNA levels ≥10 copies/ml [51–53]. These find- years of follow-up showed that A1762T/G1764A and ings suggest that HBV replication, with subsequent genotype C were independent factors with an adjusted immune-mediated liver injuries, is the primary driving hazard ratio of 1.73 (P=0.013) and 1.76 (P=0.005), force of disease progression [54]. Other risk factors respectively [66]. Investigators noted that the associa- for the development of cirrhosis include male gender, tion between HBV mutations and HCC development increasing age [51–56], HBV genotype [7,16,20], per- was most profound in patients who had a pre-S dele- sistent HBeAg seropositivity or reversion [31,55,57], tion followed by basal core promoter mutations, and HBV reactivation [22,31,41,44], persistent HBV DNA that combination of these mutations had a synergistic seropositivity [58] and persistent ALT abnormality effect on the development of HCC [67]. Concurrent [59], as well as the severity (hepatic decompensation), infection with HCV, HDV or HIV also increased the extent (bridging hepatic necrosis) and frequency of risk of cirrhosis and HCC [68]. Other factors that hepatitis flares, and the duration of hepatic lobular contribute to HCC development include habitual 28 ©2010 International Medical Press AVT-10-SA-1003_Liaw.indd 28 28/7/10 11:25:43 Geographical variations in the natural history of chronic hepatitis B alcohol consumption, cigarette smoking and aflatoxin predictive of cirrhosis were similar between western exposure [68]. Studies in Africa and China showed and Asian countries, including older age, histological a significant association between urinary aflatoxin evidence of bridging hepatic necrosis and persistent levels and HCC, and a synergistic interaction with HBeAg and/or HBV DNA seropositivity [55,64]. In HBsAg carrier status [69]. addition, the incidence of cirrhosis varied among dif- ferent cohorts, being lowest in inactive HBsAg car- riers [24,25,31–35], lower in HBeAg-positive young Geographical differences patients with normal baseline ALT [14] and consider- In addition to the geographical differences in age at ably higher in patients with active hepatitis at entry the time of HBV infection and the incidence of the [17,55,57,58,64,70]. Even in patients with active major HBV genotypes, there are also geographical hepatitis, the incidence was different between HBeAg- differences in the natural history of chronic HBV positive and HBeAg-negative cohorts and also dif- infection (Table 1). Firstly, chronic HBV infection ferent between younger and older cohorts [64]. For acquired perinatally or in infancy usually has a pro- example, an Italian study showed that the cumulative longed uneventful immune tolerant phase, whereas probability of cirrhosis development after 5 and 10 HBV infections acquired later in life have no or a very years of follow-up was 5% and 46%, respectively, in short immune tolerant phase [4,5]. Secondly, patients patients younger than 36 years, but it was 28% and infected with genotypes A, B and D HBV undergo 93%, respectively, in those older than 36 years [58]. earlier HBeAg seroconversion [9,19,23], but patients Another Italian study showed that none of the 85 pae- infected with genotypes C and D have a higher inci- diatric patients developed cirrhosis during 15 years dence of HBeAg-negative hepatitis after spontaneous of follow-up [34]. Similarly, in a study from Taiwan, HBeAg seroconversion [22,29,50]. Accordingly, areas the incidence of cirrhosis in HBeAg-negative patients where genotypes C or D HBV are predominant have aged >50 years was 4.14%, but only 0.5% per year more HBeAg-negative hepatitis [17]. Thirdly, Euro- in those aged <30 years [44]. The calculated differ- pean patients predominantly (>90%) infected with ences might reflect differences in the study cohorts; genotype D seem to have a higher incidence of cir- therefore, age, gender and stage of fibrosis should be rhosis development despite early HBeAg seroconver- considered in such comparisons. sion. This finding suggests that genotype is a more HBV hepatocarcinogenesis is a multistage proc- crucial factor for the difference between geographical ess involving many factors and it usually takes dec- locations. As mentioned earlier, patients infected with ades for HCC to develop. Chronic HBV infection genotype D have a higher incidence of HBeAg-neg- acquired in adults has a much lower risk of HCC ative hepatitis [50], which is an important risk fac- development than infections resulting from maternal– tor for cirrhosis development. The calculated annual neonatal transmission, possibly reflecting differences incidence of cirrhosis in patients with HBeAg-positive in the duration of infection. The risk of HCC among hepatitis was 3.8% in western countries compared White asymptomatic carriers from North America with 1.6% in Asian countries. The corresponding and Europe is low, with an estimated annual risk of 0 figures in HBeAg-negative patients were 9.7% and and 13 per 100,000 individuals, respectively [70–72]. 2.8% per year, respectively [64]. Of note, the factors These figures are much lower than the annual risk of Table 1. Comparisons among representative studies from geographical areas of different HBsAg prevalences Southeast Asia Mediterranean Basin United States HBsAg prevalence High Intermediate Low Age of infection Perinatal or <2 years Childhood Adolescent/adult Major HBV genotype B and C D A, C and D Immune tolerant phase Long Short Short Age of HBeAg seroconversion, 30–35 <20 50th percentile <20 years (genotypes A and D) HBeAg-negative/chronic HBV infection, % 30 80–90 <10 (genotype A) Cirrhosis, % per year 0.07, 1.6, 2.8 0.01, 3.8, 9.7 – c d d e HCC, % per year 0.2, 0.6, 3.7 0.02, 0.3, 2.2 0.01, 0.9, 3.3 a b Abstracted from [2] and [3]. Data expressed in the sequence of inactive hepatitis B surface antigen (HBsAg) carriers, hepatitis B e antigen (HBeAg)-positive and c d HBeAg-negative chronic HBV infection [64]. Data expressed in the sequence of inactive HBsAg carriers, chronic HBV infection and compensated cirrhosis. Data from [64]. Data from [70]. Antiviral Therapy 15 Suppl 3 29 AVT-10-SA-1003_Liaw.indd 29 28/7/10 11:25:43 Y-F Liaw et al. 494 [55] and 324–1,169 [73] per 100,000 reported in the long-term outcomes of chronic HBV infection. two Taiwanese studies, 240 per 100,000 reported in Geographical differences in the age of acquisition of Japan [74] and 256 per 100,000 reported in Alaska HBV infection and in major HBV genotypes might [75]. The overall annual incidence of HCC in seven be responsible for the geographical differences in the studies involving 732 patients with chronic hepatitis natural history of chronic HBV infection. However, from Europe and the United States was calculated to some of the observed geographical differences might be 300 per 100,000. By contrast, the annual incidence actually result from comparisons between cohorts calculated from nine studies involving 5,661 patients with different distribution in age, gender or fibrosis from Taiwan, China, Korea and Japan was 600 per stage – all of which also affect outcome. Finally, there 100,000 [64]. The risk of HCC increases further in is one other variable that must be considered: namely, patients with cirrhosis: in a European study involv- the progressive change in the way we have looked at ing 161 patients (89% male) with a median age of 48 HBeAg-negative and anti-HBe-positive carriers over years (range 17–78) who remained untreated during a the years. Prior to the 1980s, all such patients were follow-up period of 6.4 years, the 5-year risk of HCC considered to be healthy; however, more recently, was 9% and the annual incidence was 2.2% [62]. The approximately 25% of patients in the Mediterra- overall annual incidence of HCC in seven studies from nean area were found to be viraemic (based on an Europe and the United States involving 540 patients HBV DNA cutoff of 10 copies/ml – the limit of assay followed for 6 years was calculated to be 2.2% (95% sensitivity at the time) and have a distinct form of CI 1.71–2.71) [64]. These figures are lower than a cal- HBeAg-negative/anti-HBe-positive chronic hepatitis. culated annual rate of 3.7% (95% CI 3.2–4.14) [64], In the 1990s, improvements in the sensitivity of diag- based on reports from Taiwan, Japan and Asia where nostic tools (for example, PCR for HBV DNA detec- genotypes B and C HBV are predominant [52,76–78]. tion) lowered the HBV DNA threshold to 10 copies/ A recent study has shown that the intracellular expres- ml to confirm HBV-replication-associated liver dis- sion of HBV DNA, HBcAg and cellular stress proteins ease in these patients and, more recently, population- are highest for genotypes B and C followed by geno- based studies have identified 10 copies/ml as the type D and lowest in genotype A HBV [79]. Intracellu- new threshold for HBeAg-negative/anti-HBe-positive lar accumulation of HBV DNA, of HBV antigens and chronic HBV infection. increased cellular stress might promote hepatocyte International studies comparing cohorts that are damage and inflammation, which could contribute well matched in terms of these factors are warranted to hepatocarcinogenesis [80]. In South Africa, HCC to elucidate the actual role of age of infection and of occurs in younger men who are anti-HBe-positive and HBV genotypes in the observed geographical differ- non-cirrhotic. Aflatoxin exposure could also be a fac- ences in the natural history of chronic HBV infection. tor in increasing the risk of HCC [69] as could infec- tion with genotype A , which is associated with a 4.5- Acknowledgements fold increased risk of HCC [81]. Y-FL thanks Chang Gung Medical Research Fund and the Prosperous Foundation (Taipei, Taiwan) for Summary and perspectives the long-term grant support and Su-Chiung Chu for It is clear that chronic HBV infection is a global health secretarial administration. Editorial support was pro- issue, although there are geographical differences in the vided by Liesje Thomas at Elements Communications mode of transmission, prevalence and HBV genotype and was funded by F Hoffmann–La Roche (Basel, distribution. Typically, the natural history of chronic Switzerland). HBV infection starts with an immune tolerant phase followed by an immune clearance phase and finally by Disclosure statement an inactive phase. The duration of the immune toler- ant phase varies and is usually long in chronic HBV Y-FL has been involved with clinical trials or has infection acquired perinatally or in infancy, but very served as a global advisory board member for Roche, short in infections acquired in later life. Bristol–Myers Squibb, Novartis and Gilead Sci- During the inactive phase, HBV reactivation fol- ences. MRB is a member of the speakers’ bureaus lowed by immune-mediated hepatocytolysis or by for F Hoffmann– La Roche, Gilead Sciences, Bristol– active hepatitis might occur in one-quarter to one- Myers Squibb, Novartis and Abbott Laboratories. SH third of HBsAg-seropositive patients. Immune clear- has received research grants from Gilead Sciences and ance of reactivated HBV occurs more frequently in F Hoffmann–La Roche, has participated in clinical tri- genotype D- and C-infected patients. Clinical stud- als and has been in global advisory boards of Roche, ies suggest that there are geographical differences in Gilead Sciences, Bristol– Myers Squibb and Novartis. 30 ©2010 International Medical Press AVT-10-SA-1003_Liaw.indd 30 28/7/10 11:25:43 Geographical variations in the natural history of chronic hepatitis B 21. Yuen MF, Sablon E, Tanaka Y, et al. 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Antiviral Therapy – SAGE

Published: Apr 1, 2010

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