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Does chemotherapy prevent HBV-related hepatocellular carcinoma? Pros
Digestive and Liver Disease 42S (2010) S293–S297
Does chemotherapy prevent HBV-related hepatocellular carcinoma? Pros Yun-Fan Liaw * Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
Abstract Studies have shown that hepatitis B virus (HBV) replication is the key driver of disease progression, including development of cirrhosis and hepatocellular carcinoma (HCC), in patients with chronic HBV infection. Among the currently available anti-HBV drugs, the most extensive and longest experience has been gained with conventional interferon α (IFN) and lamivudine. Both controlled studies and meta-analyses have shown that a finite course of IFN therapy has long-term benefit in achieving cumulative response and corresponding reduction of cirrhosis and/or HCC. Maintained virological response to lamivudine therapy has similar long-term benefits in reducing disease progression. Although emergence of lamivudine drug resistance may negate therapeutic effect, rescue drugs are now available to overcome the adverse effect of drug resistance. Pegylated IFN and newer nucleos(t)ide analogs may have even better long-term outcomes because of better therapeutic efficacy and/or much lower risk of drug resistances. However, the treatment outcomes are still far from satisfactory. The development of safe and affordable anti-HBV agents/strategies is needed to further improve outcomes. © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Cirrhosis; Drug resistance; Hepatocellular carcinoma; Interferon α; Nucleos(t)ide analogs; Pegylated interferon
1. Introduction Chronic hepatitis B virus (HBV) infection is a serious clinical problem because of its worldwide distribution and potential adverse sequelae. People with chronic HBV infection are at risk of developing hepatic decompensation, liver cirrhosis or hepatocellular carcinoma (HCC) [1]. The advent of effective anti-HBV agents with different mechanisms of action, and the accumulation of substantial experience in the use of these drugs have led to better therapeutic strategies for chronic HBV infection. Evidence has shown that the long-term outcomes of chronic HBV infection may improve under therapy.
* Correspondence to: Prof. Yun-Fan Liaw, Liver Research Unit, Chang Gung University and Memorial Hospital, 199, Tung Hwa North Road, Taipei, Taiwan. Tel.: 886-3-3281200 ext. 8120, fax: 886-3-3282824. E-mail address: liveryfl@gmail.com
2. Natural history and disease progression in chronic HBV infection Chronic HBV infection is a dynamic state of interactions between the virus (HBV), the hepatocytes and the immune system of the patient. Accordingly, the natural course of chronic HBV infection can be divided into different phases [1]. Patients in the immune tolerant phase and those in the inactive phase following HBeAg seroconversion have no or minimal disease progression as long as serum alanine aminotransferase (ALT) remains normal [2,3]. HBeAg-positive patients who enter the immune clearance phase encounter ALT elevations and develop hepatitis activity. Episodes of ALT elevation or hepatitis flares with ALT increases over 5 times the upper limit of normal (ULN) may occur, sometimes complicated by hepatic decompensation. These events may lead to a decline of serum HBV-DNA level and eventually HBeAg loss with appearance of its antibody (anti-HBe), defined as HBeAg seroconversion. On the other hand, these episodes of hepatitis activity and liver injuries may lead to fibrosis and in some patients cirrhosis development at an estimated annual incidence of 2.4% [4], and an even higher incidence
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of up to 3.9% per year in patients with persistent HBeAg seropositivity [5]. Age and the frequency of flares, the extent, the severity and the duration of hepatic lobular alterations were found to be factors connected to disease progression and outcomes [4]. Following HBeAg seroconversion, patients enter an inactive residual phase with sustained remission and low HBV-DNA level (<104–5 copies/ml). During this inactive phase, incidence of cirrhosis and HCC development is very low (0.9% and 0.2% per year respectively) [6,7]. Studies in asymptomatic “inactive carriers” of mainly adult-acquired chronic HBV infection also showed that the risk of liver cirrhosis was very low [8]. However, HBeAg-negative hepatitis may develop in up to 25–30% of patients following HBeAg seroconversion [6]. The incidence of cirrhosis and HCC development was much higher (cumulative incidence of 32.1% and 8.8% respectively during 1–27 [mean 11.7, median 11.5] years follow up) in those who developed HBeAg-negative hepatitis [7]. The incidences were even higher in European patients with HBeAg-negative hepatitis [9]. HBsAg seroclearance may occur at an annual incidence of 1–2% [8–10] after a long period of sustained remission, and confers excellent prognosis [11]. About 50% of the patients are still seropositive for HBeAg and/or HBV-DNA at the onset of cirrhosis. Therefore, further disease progression after the development of cirrhosis may continue to occur in these patients [12,13]. HCC develops at an annual incidence of 2–6% in patients with cirrhosis and far less frequently in non-cirrhotic patients [6,7,12,13]. Conceivably, factors for cirrhosis development are also factors for the development of HCC. Large community-based studies have confirmed that age, sex, HBeAg serostatus and ALT levels are factors for the development of liver cirrhosis and HCC. These studies further indicate that serum HBV-DNA level is associated with cirrhosis and HCC development in a dose-dependent manner starting from serum HBV-DNA level >2000 IU/ml [14,15]. These findings suggest that HBV replication, with subsequent immune-mediated liver injuries, is the primary driving force for liver disease progression [16]. Several studies in Asian patients have shown that genotype B HBV infection, compared to genotype C, is associated with spontaneous HBeAg seroconversion at a younger age, less active liver disease, slower progression to cirrhosis, and less frequent development of HCC. Patients with genotype C HBV infection have a higher HBV-DNA level, higher frequency of pre-S deletions, higher prevalence of A1762T/G1764A double mutations than patients infected with genotype B HBV, and have a significantly higher chance of developing HCC [15,17]. A study in patients with genotype D HBV infection showed that 32.7% had A1762T/G1764A double mutations, which was associated with more aggressive liver disease including HCC [18]. In general, genotype D is associated with less favorable prognosis than genotype A [19]. HBV hepatocarcinogenesis is not only a multistage process but also involves multiple factors. Besides viral factors (viral load, genotype, genomic mutations) and host factors (age, sex, immune status), other factors may also contribute to the progression of liver disease. These include habitual alcohol
Fig. 1. Hepatitis B virus (HBV) hepatocarcinogenesis is a multi-stage process involving multiple factors. Note the association of hepatic necroinflammation, liver disease progression and genetic alterations during the course of chronic HBV infection. Host factors and environmental factors also contribute to the disease progression and hepatocarcinogenesis. HCV: hepatitis C virus; HDV: hepatitis delta virus; HIV: human immunodeficiency virus.
consumption, cigarette smoking, exposure to aflatoxin and other viral superinfections [20]. Of note is that the risk of developing HCC increases along with increasing disease stage, being 200–400/100,000 per year in asymptomatic HBsAg carriers, 600–800/100,000 per year in chronic hepatitis B [5–7] and 2700–5700 in cirrhosis [12,13]. More importantly, the HBV driven hepatic necroinflammation is associated with liver disease progression and genetic alterations (Fig. 1). Obviously, it is important to intervene as early as possible to achieve the goal of reducing HCC. Other than life style changes (alcohol, cigarette, risk behavior, metabolic), antiviral therapy is the most practical intervention.
3. Antiviral therapy for chronic HBV infection The observations on the natural history of chronic HBV infection suggest that active HBV replication is the key driving force for the subsequent HBV-related immune clearance events that determine the clinical outcomes [16]. HBV elimination or permanent HBV suppression, spontaneously or by antiviral therapy, should theoretically be able to reduce the risk of or slow the progression of liver disease. Accordingly, cirrhotic or non-cirrhotic patients with HBV replication and active liver disease, whether HBeAg positive or negative, require active therapy [19]. A critical review of 26 therapeutic trials involving 3428 patients did show that treatment-induced HBV DNA reduction correlated significantly and consistently with histologic, biochemical, and serologic responses, especially in studies using direct antiviral agents and in HBeAg-positive patients [21]. Currently, conventional interferon α (IFN), pegylated interferon-α2a (Peg IFN), and nucleos(t)ide analogues (NUC) including lamivudine, adefovir, entecavir, telbivudine and tenofovir have been approved for the treatment of chronic
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HBV infection. The most extensive and longest experience with the use of these agents in controlling disease progression has been gained with IFN and lamivudine. 3.1. Long-term outcomes after IFN-based therapy Long-term follow-up studies after a 4- to 6-month course of IFN therapy in HBeAg-positive patients showed cumulative HBeAg seroconversion, reduction in fibrosis progression and reduced development of cirrhosis and its complications in patients with HBeAg seroconversion, as compared with patients who remained persistently HBeAg seropositive. These studies also showed that sustained elimination of HBeAg was associated with a significant reduction in the occurrence of severe cirrhotic complications, the need for liver transplantation and an increase in survival [5,22,23]. However, these studies failed to show significant reduction of cirrhosis as compared with untreated patients, probably because of a small sample size or the small increase in HBeAg seroconversion rate in the IFN-treated patients [23]. To overcome the limitation of small sample size, a recent large multicenter study comparing 233 IFN-treated HBeAg-positive patients with 233 well matched (age, sex, ALT, HBeAg status, histology, and length of follow-up) untreated patients in Taiwan did show a reduced cumulative incidence of cirrhosis (17.8% vs. 33.7% in the controls; P = 0.041) and HCC (2.7% vs. 12.5% in the controls; P = 0.011) during a median follow-up period of 6.8 (1.1 to 15.5) years [5]. Another large study from Honk Kong (207 vs. 203 untreated controls) failed to show the benefit of IFN therapy in reducing cirrhosis or HCC [24]. Compared with the study from Taiwan, the control group in the Hong Kong study was not well comparable to the IFN treated group as there were significantly more female patients in the untreated control group [24]. In addition, the majority of the patients in Hong Kong study had a normal ALT level (63.8% of IFN group and 84.3% of control group) and 89 were children. Compared with the Taiwan study [5], they had a much lower baseline ALT level (46 vs. 175 U/L), lower response rate (15 vs. 30%) and younger age (27 vs. 32 years), indicating that the majority of their patients were in the immune tolerant phase. This may explain the finding that only 1% of the control group had long-term HBV related complications and no mortality occurred. This strongly suggests that the conclusion drawn from that study is misleading or only applicable to subjects who are not meeting the indication of anti-HBV therapy according to currently available Asian–Pacific guidelines [19]. In HBeAg-negative European patients treated with IFN for 6 to 24 months, sustained responders also showed decreased progression of Ishak fibrosis score [25,26] or decreased risk of cirrhosis [27]. Sustained responders also had significantly improved long-term outcomes, including less severe cirrhosis-related complications, reduced incidence of HCC (1.8% vs. 10.5% in relapsers; P = 0.027 and 7.7% in untreated; P = 0.048), less need for liver transplantation, and lower mortality. But the sustained response rate in HBeAg-negative patients was usually lower than 30% [25–27]. Long-term follow-up in
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IFN treated European patients showed that initial responders had a HBsAg seroclearance rate up to 52% (vs. 9% of nonresponders; P < 0.001) during a mean follow-up period of 10.6 (0.8–19.5) years [23,25]. HBsAg seroconversion also occurred more frequently in IFN-treated cirrhotic patients with sustained response [23,25,26,28]. A recent meta-analysis involving 12 trials (1292 IFN treated and 1450 untreated patients) showed that the risk of HCC was significantly reduced by 34% (RR: 0.66, 95% CI: 0.48–0.89; P = 0.006) after treatment with IFN [29]. Another meta-analysis involving 11 trials also showed that IFN therapy had a beneficial effect in reducing cirrhosis and HCC [30]. In patients with cirrhosis, a retrospective cohort study of European patients (82 IFN-treated vs. 196 untreated) showed that the treated patients had a higher likelihood of HBsAg loss (5-year probability, 16% vs. 4%; P = 0.0021), which was associated with a lower rate of decompensation, lower incidence of HCC and longer survival [28]. An earlier meta-analysis of 7 nonrandomized controlled trials in cirrhosis patients (1505 patients with 122 observed HCC cases) suggested that IFN-α therapy decreased the incidence of HCC, but the difference was significant in only 3 Asian trials; the pooled estimate, however, was significantly in favor of the preventive effect of IFN-α therapy. The inconsistency among the trials was a major problem in reaching a firm conclusion [31]. However, a subgroup meta-analysis of six studies recruiting patients with compensated cirrhosis (241 treated vs. 475 untreated) reported a 47% reduction of HCC (RR: 0.53; 95% CI: 0.36–0.78; P = 0.001) after IFN therapy [29]. Recently, it has been shown that IFN therapy in compensated cirrhotic patients is safe and even more effective than in noncirrhotic patients [12]. This finding suggests that the benefit of reducing HCC in IFN-treated cirrhotic patients might be evident upon longer follow-up. A subgroup analysis in a recent long-term follow-up study did show that HCC incidence was reduced significantly in IFN-treated cirrhotic patients [5]. Since peg IFN is more effective than conventional IFN in the treatment of chronic hepatitis B and may result in complete response with HBsAg seroconversion [32,33], long-term follow-up studies will likely prove that peg IFNs have similar or even better long-term effects. 3.2. Long-term outcomes of NUC therapy Long-term data on the effect of direct antiviral agents in reducing the risk of cirrhosis and further disease progression are limited. Long-term (>3 years) lamivudine, adefovir or entecavir therapy all showed reversal of advanced fibrosis [34–36]. Furthermore, a long-term lamivudine (median 89.9 months; range 26.5–128.3 months) therapy involving 142 HBeAg-positive, non-cirrhotic patients from Hong Kong demonstrated a significantly lower cumulative rate of cirrhosis and/or HCC development (P = 0.005) as compared with 124 HBeAg-positive untreated control [37]. A double blind, randomized controlled trial demonstrated that maintenance lamivudine therapy for a median of 32.4 months in 436 patients with cirrhosis or advanced fibrosis (Ishak fibrosis
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score ≥4) significantly reduced overall disease progression, as compared with 215 untreated controls [38]. Long-term lamivudine therapy in 303 HBeAg-negative patients with cirrhosis also showed that patients who maintained virologic response were less likely than those with viral breakthrough to have worsening of liver disease [39]. The incidence of HCC was also significantly reduced (3.9%, vs. 7.4% in the placebo group, P = 0.048) in the lamivudine treated patients with advanced fibrosis or cirrhosis [38]. A study of 377 patients (51% HBeAg-negative, 17% with cirrhosis) treated with lamivudine for up to 96 months (23.1 ± 19.0 months) in Japan also showed a marked reduction in the incidence of HCC as compared with a historical control group matched for age, sex, hepatic fibrosis score, albumin level, and platelet count (0.4% vs. 2.5% per year; P < 0.001) [40]. A retrospective multicenter study involving 656 HBeAgnegative patients (353 with chronic hepatitis, 303 with liver cirrhosis) treated with lamivudine for 1 to 66 months (median, 22 months) also showed that HBV suppression reduced HCC development, even in patients with liver cirrhosis [39]. However, long-term lamivudine therapy was associated with a high rate of drug-resistant mutations [37–39]. These patients were more likely to experience disease progression and to die for reasons related to the worsening of liver function [38]. In HBeAg negative patients, the chance of developing HCC was significantly greater in patients experiencing virologic breakthrough than those who maintained viral suppression [39]. A meta-analysis involving 1267 NUC treated and 1022 untreated patients showed that HCC was reduced by 78% (RR: 0.22, 95% CI: 0.10–0.50; P = 0.0003) on maintained NUC therapy and more benefit was observed in cirrhotic patients (RR: 0.17 vs. 0.21) and HBeAg-positive patients (RR: 0.21 vs. 0.25) [29]. These results have proven the concept that suppression of HBV reduces the risk of or slows the progression of liver disease, and that resumption of HBV replication may restore the potential for disease progression. The adverse effect of drug resistant mutations can now be overcome by the timely use of rescue therapy [41]. This was well demonstrated in a trial of long-term therapy started with lamivudine and rescued by adefovir [42]. It is anticipated that long-term therapy using NUC with high genetic barrier to drug resistance would have similar or even better long-term outcomes.
4. Summary and perspectives Clinical and epidemiological studies have shown that HBV is the key driver of hepatitis activity and subsequent disease progression in patients with chronic HBV infection. Overall long-term data show that IFN-α therapy in HBeAg-positive patients results in cumulative HBeAg seroconversion, increasing HBsAg seroclearance and reducing cirrhosis and/or HCC development, especially in those demonstrating a sustained response. However, such long-term efficacy is less conclusive in HBeAg negative chronic hepatitis B patients. More significant benefits were demonstrated in those with cirrhosis.
Data also suggest that maintained suppression of HBV replication using NUC may reduce the worsening of liver fibrosis, reverse advanced fibrosis, reduce cirrhosis development, and prevent further disease progression including HCC in patients with advanced fibrosis or cirrhosis. The main problem of drug resistance can now be overcome by the timely use of rescue drug(s). Long-term studies will undoubtedly confirm that the effects of entecavir or tenofovir in reducing disease progression are similar to or better than those of lamivudine because of a much lower risk of drug resistance. However, current therapy can only reduce the risk of or slow the disease progression, not prevent all adverse sequelae. Surveillance of HCC using ultrasongraphy supplemented with alphafetoprotein assay is required to improve outcomes by increasing the rate of early detection and thus the opportunity of curative treatment [43]. The development of safe and affordable agents and the establishment of management strategies capable of producing a better sustained or maintained HBV suppression without inducing drug resistance would be the ultimate goal in the management of chronic HBV infection.
Acknowledgment The author thanks the long-term grant support provided by Chang Gung Medical Research Fund (SMRPG1005) and the Prosperous Foundation, Taipei, Taiwan and the excellent assistance of Ms Su-Chiung Chu.
Conflict of interest Y.-F. Liaw has served as consultant for BMS, Novartis and Roche; and received grant/research support from BMS, Novartis, Roche and Gilead. The author has received a fee from Bayer HealthCare for his contribution to this supplement. Bayer HealthCare played no role in the preparation, review, or approval of the manuscript.
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Does chemotherapy prevent HBV-related hepatocellular carcinoma? Pros Yun-Fan Liaw * Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
Abstract Studies have shown that hepatitis B virus (HBV) replication is the key driver of disease progression, including development of cirrhosis and hepatocellular carcinoma (HCC), in patients with chronic HBV infection. Among the currently available anti-HBV drugs, the most extensive and longest experience has been gained with conventional interferon α (IFN) and lamivudine. Both controlled studies and meta-analyses have shown that a finite course of IFN therapy has long-term benefit in achieving cumulative response and corresponding reduction of cirrhosis and/or HCC. Maintained virological response to lamivudine therapy has similar long-term benefits in reducing disease progression. Although emergence of lamivudine drug resistance may negate therapeutic effect, rescue drugs are now available to overcome the adverse effect of drug resistance. Pegylated IFN and newer nucleos(t)ide analogs may have even better long-term outcomes because of better therapeutic efficacy and/or much lower risk of drug resistances. However, the treatment outcomes are still far from satisfactory. The development of safe and affordable anti-HBV agents/strategies is needed to further improve outcomes. © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Cirrhosis; Drug resistance; Hepatocellular carcinoma; Interferon α; Nucleos(t)ide analogs; Pegylated interferon
1. Introduction Chronic hepatitis B virus (HBV) infection is a serious clinical problem because of its worldwide distribution and potential adverse sequelae. People with chronic HBV infection are at risk of developing hepatic decompensation, liver cirrhosis or hepatocellular carcinoma (HCC) [1]. The advent of effective anti-HBV agents with different mechanisms of action, and the accumulation of substantial experience in the use of these drugs have led to better therapeutic strategies for chronic HBV infection. Evidence has shown that the long-term outcomes of chronic HBV infection may improve under therapy.
* Correspondence to: Prof. Yun-Fan Liaw, Liver Research Unit, Chang Gung University and Memorial Hospital, 199, Tung Hwa North Road, Taipei, Taiwan. Tel.: 886-3-3281200 ext. 8120, fax: 886-3-3282824. E-mail address: liveryfl@gmail.com
2. Natural history and disease progression in chronic HBV infection Chronic HBV infection is a dynamic state of interactions between the virus (HBV), the hepatocytes and the immune system of the patient. Accordingly, the natural course of chronic HBV infection can be divided into different phases [1]. Patients in the immune tolerant phase and those in the inactive phase following HBeAg seroconversion have no or minimal disease progression as long as serum alanine aminotransferase (ALT) remains normal [2,3]. HBeAg-positive patients who enter the immune clearance phase encounter ALT elevations and develop hepatitis activity. Episodes of ALT elevation or hepatitis flares with ALT increases over 5 times the upper limit of normal (ULN) may occur, sometimes complicated by hepatic decompensation. These events may lead to a decline of serum HBV-DNA level and eventually HBeAg loss with appearance of its antibody (anti-HBe), defined as HBeAg seroconversion. On the other hand, these episodes of hepatitis activity and liver injuries may lead to fibrosis and in some patients cirrhosis development at an estimated annual incidence of 2.4% [4], and an even higher incidence
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of up to 3.9% per year in patients with persistent HBeAg seropositivity [5]. Age and the frequency of flares, the extent, the severity and the duration of hepatic lobular alterations were found to be factors connected to disease progression and outcomes [4]. Following HBeAg seroconversion, patients enter an inactive residual phase with sustained remission and low HBV-DNA level (<104–5 copies/ml). During this inactive phase, incidence of cirrhosis and HCC development is very low (0.9% and 0.2% per year respectively) [6,7]. Studies in asymptomatic “inactive carriers” of mainly adult-acquired chronic HBV infection also showed that the risk of liver cirrhosis was very low [8]. However, HBeAg-negative hepatitis may develop in up to 25–30% of patients following HBeAg seroconversion [6]. The incidence of cirrhosis and HCC development was much higher (cumulative incidence of 32.1% and 8.8% respectively during 1–27 [mean 11.7, median 11.5] years follow up) in those who developed HBeAg-negative hepatitis [7]. The incidences were even higher in European patients with HBeAg-negative hepatitis [9]. HBsAg seroclearance may occur at an annual incidence of 1–2% [8–10] after a long period of sustained remission, and confers excellent prognosis [11]. About 50% of the patients are still seropositive for HBeAg and/or HBV-DNA at the onset of cirrhosis. Therefore, further disease progression after the development of cirrhosis may continue to occur in these patients [12,13]. HCC develops at an annual incidence of 2–6% in patients with cirrhosis and far less frequently in non-cirrhotic patients [6,7,12,13]. Conceivably, factors for cirrhosis development are also factors for the development of HCC. Large community-based studies have confirmed that age, sex, HBeAg serostatus and ALT levels are factors for the development of liver cirrhosis and HCC. These studies further indicate that serum HBV-DNA level is associated with cirrhosis and HCC development in a dose-dependent manner starting from serum HBV-DNA level >2000 IU/ml [14,15]. These findings suggest that HBV replication, with subsequent immune-mediated liver injuries, is the primary driving force for liver disease progression [16]. Several studies in Asian patients have shown that genotype B HBV infection, compared to genotype C, is associated with spontaneous HBeAg seroconversion at a younger age, less active liver disease, slower progression to cirrhosis, and less frequent development of HCC. Patients with genotype C HBV infection have a higher HBV-DNA level, higher frequency of pre-S deletions, higher prevalence of A1762T/G1764A double mutations than patients infected with genotype B HBV, and have a significantly higher chance of developing HCC [15,17]. A study in patients with genotype D HBV infection showed that 32.7% had A1762T/G1764A double mutations, which was associated with more aggressive liver disease including HCC [18]. In general, genotype D is associated with less favorable prognosis than genotype A [19]. HBV hepatocarcinogenesis is not only a multistage process but also involves multiple factors. Besides viral factors (viral load, genotype, genomic mutations) and host factors (age, sex, immune status), other factors may also contribute to the progression of liver disease. These include habitual alcohol
Fig. 1. Hepatitis B virus (HBV) hepatocarcinogenesis is a multi-stage process involving multiple factors. Note the association of hepatic necroinflammation, liver disease progression and genetic alterations during the course of chronic HBV infection. Host factors and environmental factors also contribute to the disease progression and hepatocarcinogenesis. HCV: hepatitis C virus; HDV: hepatitis delta virus; HIV: human immunodeficiency virus.
consumption, cigarette smoking, exposure to aflatoxin and other viral superinfections [20]. Of note is that the risk of developing HCC increases along with increasing disease stage, being 200–400/100,000 per year in asymptomatic HBsAg carriers, 600–800/100,000 per year in chronic hepatitis B [5–7] and 2700–5700 in cirrhosis [12,13]. More importantly, the HBV driven hepatic necroinflammation is associated with liver disease progression and genetic alterations (Fig. 1). Obviously, it is important to intervene as early as possible to achieve the goal of reducing HCC. Other than life style changes (alcohol, cigarette, risk behavior, metabolic), antiviral therapy is the most practical intervention.
3. Antiviral therapy for chronic HBV infection The observations on the natural history of chronic HBV infection suggest that active HBV replication is the key driving force for the subsequent HBV-related immune clearance events that determine the clinical outcomes [16]. HBV elimination or permanent HBV suppression, spontaneously or by antiviral therapy, should theoretically be able to reduce the risk of or slow the progression of liver disease. Accordingly, cirrhotic or non-cirrhotic patients with HBV replication and active liver disease, whether HBeAg positive or negative, require active therapy [19]. A critical review of 26 therapeutic trials involving 3428 patients did show that treatment-induced HBV DNA reduction correlated significantly and consistently with histologic, biochemical, and serologic responses, especially in studies using direct antiviral agents and in HBeAg-positive patients [21]. Currently, conventional interferon α (IFN), pegylated interferon-α2a (Peg IFN), and nucleos(t)ide analogues (NUC) including lamivudine, adefovir, entecavir, telbivudine and tenofovir have been approved for the treatment of chronic
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HBV infection. The most extensive and longest experience with the use of these agents in controlling disease progression has been gained with IFN and lamivudine. 3.1. Long-term outcomes after IFN-based therapy Long-term follow-up studies after a 4- to 6-month course of IFN therapy in HBeAg-positive patients showed cumulative HBeAg seroconversion, reduction in fibrosis progression and reduced development of cirrhosis and its complications in patients with HBeAg seroconversion, as compared with patients who remained persistently HBeAg seropositive. These studies also showed that sustained elimination of HBeAg was associated with a significant reduction in the occurrence of severe cirrhotic complications, the need for liver transplantation and an increase in survival [5,22,23]. However, these studies failed to show significant reduction of cirrhosis as compared with untreated patients, probably because of a small sample size or the small increase in HBeAg seroconversion rate in the IFN-treated patients [23]. To overcome the limitation of small sample size, a recent large multicenter study comparing 233 IFN-treated HBeAg-positive patients with 233 well matched (age, sex, ALT, HBeAg status, histology, and length of follow-up) untreated patients in Taiwan did show a reduced cumulative incidence of cirrhosis (17.8% vs. 33.7% in the controls; P = 0.041) and HCC (2.7% vs. 12.5% in the controls; P = 0.011) during a median follow-up period of 6.8 (1.1 to 15.5) years [5]. Another large study from Honk Kong (207 vs. 203 untreated controls) failed to show the benefit of IFN therapy in reducing cirrhosis or HCC [24]. Compared with the study from Taiwan, the control group in the Hong Kong study was not well comparable to the IFN treated group as there were significantly more female patients in the untreated control group [24]. In addition, the majority of the patients in Hong Kong study had a normal ALT level (63.8% of IFN group and 84.3% of control group) and 89 were children. Compared with the Taiwan study [5], they had a much lower baseline ALT level (46 vs. 175 U/L), lower response rate (15 vs. 30%) and younger age (27 vs. 32 years), indicating that the majority of their patients were in the immune tolerant phase. This may explain the finding that only 1% of the control group had long-term HBV related complications and no mortality occurred. This strongly suggests that the conclusion drawn from that study is misleading or only applicable to subjects who are not meeting the indication of anti-HBV therapy according to currently available Asian–Pacific guidelines [19]. In HBeAg-negative European patients treated with IFN for 6 to 24 months, sustained responders also showed decreased progression of Ishak fibrosis score [25,26] or decreased risk of cirrhosis [27]. Sustained responders also had significantly improved long-term outcomes, including less severe cirrhosis-related complications, reduced incidence of HCC (1.8% vs. 10.5% in relapsers; P = 0.027 and 7.7% in untreated; P = 0.048), less need for liver transplantation, and lower mortality. But the sustained response rate in HBeAg-negative patients was usually lower than 30% [25–27]. Long-term follow-up in
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IFN treated European patients showed that initial responders had a HBsAg seroclearance rate up to 52% (vs. 9% of nonresponders; P < 0.001) during a mean follow-up period of 10.6 (0.8–19.5) years [23,25]. HBsAg seroconversion also occurred more frequently in IFN-treated cirrhotic patients with sustained response [23,25,26,28]. A recent meta-analysis involving 12 trials (1292 IFN treated and 1450 untreated patients) showed that the risk of HCC was significantly reduced by 34% (RR: 0.66, 95% CI: 0.48–0.89; P = 0.006) after treatment with IFN [29]. Another meta-analysis involving 11 trials also showed that IFN therapy had a beneficial effect in reducing cirrhosis and HCC [30]. In patients with cirrhosis, a retrospective cohort study of European patients (82 IFN-treated vs. 196 untreated) showed that the treated patients had a higher likelihood of HBsAg loss (5-year probability, 16% vs. 4%; P = 0.0021), which was associated with a lower rate of decompensation, lower incidence of HCC and longer survival [28]. An earlier meta-analysis of 7 nonrandomized controlled trials in cirrhosis patients (1505 patients with 122 observed HCC cases) suggested that IFN-α therapy decreased the incidence of HCC, but the difference was significant in only 3 Asian trials; the pooled estimate, however, was significantly in favor of the preventive effect of IFN-α therapy. The inconsistency among the trials was a major problem in reaching a firm conclusion [31]. However, a subgroup meta-analysis of six studies recruiting patients with compensated cirrhosis (241 treated vs. 475 untreated) reported a 47% reduction of HCC (RR: 0.53; 95% CI: 0.36–0.78; P = 0.001) after IFN therapy [29]. Recently, it has been shown that IFN therapy in compensated cirrhotic patients is safe and even more effective than in noncirrhotic patients [12]. This finding suggests that the benefit of reducing HCC in IFN-treated cirrhotic patients might be evident upon longer follow-up. A subgroup analysis in a recent long-term follow-up study did show that HCC incidence was reduced significantly in IFN-treated cirrhotic patients [5]. Since peg IFN is more effective than conventional IFN in the treatment of chronic hepatitis B and may result in complete response with HBsAg seroconversion [32,33], long-term follow-up studies will likely prove that peg IFNs have similar or even better long-term effects. 3.2. Long-term outcomes of NUC therapy Long-term data on the effect of direct antiviral agents in reducing the risk of cirrhosis and further disease progression are limited. Long-term (>3 years) lamivudine, adefovir or entecavir therapy all showed reversal of advanced fibrosis [34–36]. Furthermore, a long-term lamivudine (median 89.9 months; range 26.5–128.3 months) therapy involving 142 HBeAg-positive, non-cirrhotic patients from Hong Kong demonstrated a significantly lower cumulative rate of cirrhosis and/or HCC development (P = 0.005) as compared with 124 HBeAg-positive untreated control [37]. A double blind, randomized controlled trial demonstrated that maintenance lamivudine therapy for a median of 32.4 months in 436 patients with cirrhosis or advanced fibrosis (Ishak fibrosis
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score ≥4) significantly reduced overall disease progression, as compared with 215 untreated controls [38]. Long-term lamivudine therapy in 303 HBeAg-negative patients with cirrhosis also showed that patients who maintained virologic response were less likely than those with viral breakthrough to have worsening of liver disease [39]. The incidence of HCC was also significantly reduced (3.9%, vs. 7.4% in the placebo group, P = 0.048) in the lamivudine treated patients with advanced fibrosis or cirrhosis [38]. A study of 377 patients (51% HBeAg-negative, 17% with cirrhosis) treated with lamivudine for up to 96 months (23.1 ± 19.0 months) in Japan also showed a marked reduction in the incidence of HCC as compared with a historical control group matched for age, sex, hepatic fibrosis score, albumin level, and platelet count (0.4% vs. 2.5% per year; P < 0.001) [40]. A retrospective multicenter study involving 656 HBeAgnegative patients (353 with chronic hepatitis, 303 with liver cirrhosis) treated with lamivudine for 1 to 66 months (median, 22 months) also showed that HBV suppression reduced HCC development, even in patients with liver cirrhosis [39]. However, long-term lamivudine therapy was associated with a high rate of drug-resistant mutations [37–39]. These patients were more likely to experience disease progression and to die for reasons related to the worsening of liver function [38]. In HBeAg negative patients, the chance of developing HCC was significantly greater in patients experiencing virologic breakthrough than those who maintained viral suppression [39]. A meta-analysis involving 1267 NUC treated and 1022 untreated patients showed that HCC was reduced by 78% (RR: 0.22, 95% CI: 0.10–0.50; P = 0.0003) on maintained NUC therapy and more benefit was observed in cirrhotic patients (RR: 0.17 vs. 0.21) and HBeAg-positive patients (RR: 0.21 vs. 0.25) [29]. These results have proven the concept that suppression of HBV reduces the risk of or slows the progression of liver disease, and that resumption of HBV replication may restore the potential for disease progression. The adverse effect of drug resistant mutations can now be overcome by the timely use of rescue therapy [41]. This was well demonstrated in a trial of long-term therapy started with lamivudine and rescued by adefovir [42]. It is anticipated that long-term therapy using NUC with high genetic barrier to drug resistance would have similar or even better long-term outcomes.
4. Summary and perspectives Clinical and epidemiological studies have shown that HBV is the key driver of hepatitis activity and subsequent disease progression in patients with chronic HBV infection. Overall long-term data show that IFN-α therapy in HBeAg-positive patients results in cumulative HBeAg seroconversion, increasing HBsAg seroclearance and reducing cirrhosis and/or HCC development, especially in those demonstrating a sustained response. However, such long-term efficacy is less conclusive in HBeAg negative chronic hepatitis B patients. More significant benefits were demonstrated in those with cirrhosis.
Data also suggest that maintained suppression of HBV replication using NUC may reduce the worsening of liver fibrosis, reverse advanced fibrosis, reduce cirrhosis development, and prevent further disease progression including HCC in patients with advanced fibrosis or cirrhosis. The main problem of drug resistance can now be overcome by the timely use of rescue drug(s). Long-term studies will undoubtedly confirm that the effects of entecavir or tenofovir in reducing disease progression are similar to or better than those of lamivudine because of a much lower risk of drug resistance. However, current therapy can only reduce the risk of or slow the disease progression, not prevent all adverse sequelae. Surveillance of HCC using ultrasongraphy supplemented with alphafetoprotein assay is required to improve outcomes by increasing the rate of early detection and thus the opportunity of curative treatment [43]. The development of safe and affordable agents and the establishment of management strategies capable of producing a better sustained or maintained HBV suppression without inducing drug resistance would be the ultimate goal in the management of chronic HBV infection.
Acknowledgment The author thanks the long-term grant support provided by Chang Gung Medical Research Fund (SMRPG1005) and the Prosperous Foundation, Taipei, Taiwan and the excellent assistance of Ms Su-Chiung Chu.
Conflict of interest Y.-F. Liaw has served as consultant for BMS, Novartis and Roche; and received grant/research support from BMS, Novartis, Roche and Gilead. The author has received a fee from Bayer HealthCare for his contribution to this supplement. Bayer HealthCare played no role in the preparation, review, or approval of the manuscript.
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