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Keywords:

  • hepatitis B;
  • liver cirrhosis;
  • treatment;
  • nucleoside analogues;
  • hepatocellular carcinoma

Abstract

  1. Top of page
  2. Abstract
  3. The natural course of the development of cirrhosis in HBV
  4. Risk factors for the development of cirrhosis in HBV-infected individuals
  5. Treatment in HBV-related cirrhosis
  6. How to treat
  7. Influence of antiviral treatment on the risk of development HCC
  8. Summary
  9. Disclosure
  10. References

Until very recently, hepatitis B virus (HBV)-associated cirrhosis was often regarded as an irreversible condition. It is associated with strongly increased mortality and a high risk of the development of hepatocellular carcinoma (HCC). Indeed, the incidence of HCC per 100 person years was shown to be 2–3.7 in patients with cirrhosis compared with only 0.3–0.6 in patients with active hepatitis B without cirrhosis and 0.02–0.2 in asymptomatic carriers. Liver transplantation was considered to be the only medical intervention, which could resolve this condition and which could improve the general condition of these patients. However, it is now becoming increasingly evident that long-term suppression of viral replication allows the regenerative potential of the liver to reverse even high grade liver fibrosis. For the management of HBV-related cirrhosis, it is therefore important to provide effective treatment and to identify and avoid risk factors for the development of cirrhosis and hepatic decompensation.


Abbreviations
ADV

adefovir dipivoxil

ETV

entecavir

HBV

hepatitis B virus

HCC

hepatocellular carcinoma

IFN

interferon

LAM

lamivudine

LdT

telbivudine

NUC

nucleos(t)ide analogues

TDF

tenofovir disoproxil fumarate

The natural course of the development of cirrhosis in HBV

  1. Top of page
  2. Abstract
  3. The natural course of the development of cirrhosis in HBV
  4. Risk factors for the development of cirrhosis in HBV-infected individuals
  5. Treatment in HBV-related cirrhosis
  6. How to treat
  7. Influence of antiviral treatment on the risk of development HCC
  8. Summary
  9. Disclosure
  10. References

The development of cirrhosis is the most frequent complication of chronic hepatitis B virus (HBV) infection [1, 2]. In long term, 4–7% of patients with HBeAg-positive disease and 2–3% of patients with HBeAg-negative disease will develop cirrhosis per year if untreated [3]. The development of cirrhosis is mainly mediated by inflammatory activity in the liver, which represents an immune response to infection and which may not be reflected by elevated ALT levels, but also other factors may contribute. At the first diagnosis of compensated cirrhosis, about 30–70% of patients still have active HBV replication associated with continued progression of liver disease and decreased survival [4, 5]. Decompensation of cirrhosis can either develop unperceived over a long period or as a complication of an acute hepatitis flare, which was found to be the cause in 14% of decompensation in one study [6, 7]. Another study in 161 patients showed that the risk of hepatic decompensation was four times higher in HBV DNA-positive patients (13–18%) than in HBeAg-negative/HBV DNA-negative patients (4%, P = 0.04) during a median follow-up period of 6.6 years [8]. Without treatment, the cumulative probability of survival over 5 years in patients with HBV-related cirrhosis was shown to be 84% in two European studies [4, 5].

Risk factors for the development of cirrhosis in HBV-infected individuals

  1. Top of page
  2. Abstract
  3. The natural course of the development of cirrhosis in HBV
  4. Risk factors for the development of cirrhosis in HBV-infected individuals
  5. Treatment in HBV-related cirrhosis
  6. How to treat
  7. Influence of antiviral treatment on the risk of development HCC
  8. Summary
  9. Disclosure
  10. References

Alcohol consumption

In individuals with HBV infection and heavy alcohol use, the progression to cirrhosis and HCC is faster compared with those who consume alcohol without HBV infection and their survival is decreased [9, 10].

HBeAg status

Studies in European patients have shown that HBeAg positivity at first presentation of cirrhosis is associated with poorer survival, and HBeAg seroclearance or undetectable HBV DNA during follow-up is associated with better survival [4, 5].

Metabolic syndrome

Metabolic syndrome may lead to liver manifestations as non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD). Both represent risk factors for hepatic fibrosis and may lead to liver cirrhosis. Metabolic syndrome was strongly associated with increased risk of severe fibrosis and cirrhosis in patients with chronic HBV infection in a recent large-scale study [11]. Parameters associated with superimposed NASH in patients with chronic HBV infection are known components of the metabolic syndrome and include abdominal obesity, dyslipidaemia, hyperglycaemia and arterial hypertension [12].

HBV genotypes and variants

For HBV, eight genotypes (A–H) have been identified based on an intergroup divergence of > 8% of the whole HBV genome [13, 14]. Hepatitis B virus genotypes may play a role in the progression of disease to cirrhosis and HCC [15]. Thus, HBV genotype A is associated with a relatively low risk of development of cirrhosis. On the other hand, genotype C seems to be associated with a higher risk of HCC and cirrhosis than genotypes A, B or D [15-17]. However, because HBV genotypes have a typical geographical distribution, it has to be taken into account that epidemiological and environmental influences may contribute to the individual risk of developing cirrhosis as well as the mode of HBV transmission, the duration of HBV infection, exposure to liver-toxic agents and secondary diseases, which may have an impact on different dynamics of the development of cirrhosis in different parts of the world. Apart from HBV genotypes, other genetic variations of HBV such as pre-S mutations were also found to influence the development of cirrhosis. Thus, in a long-term follow-up study in 141 HBeAg-negative patients, a two-fold increase in the risk of developing cirrhosis was found in patients in whom pre-S mutations were detectable at baseline [15]. Also, mutations within the core promoter region, namely the mutations A1762T/G1764A and T1768A have been shown to be associated with an increased development of cirrhosis [18, 19].

The level of HBV replication

Numerous studies have shown that in individuals with HBV infection, the progression to cirrhosis correlates with the serum level of circulating virus, despite their different methodology and study designs [1, 20-22]. In the REVEAL study (Risk Evaluation of Viral Load Elevation and Associated Liver disease/cancer-HBV), which analysed 3653 mono-infected HBV carriers over 12.5 years of follow-up, elevated HBV DNA levels at baseline were significantly associated with HBeAg positivity, cirrhosis, younger age, male sex and elevated serum ALT levels [21]. In this study, the incidence of newly diagnosed cases of cirrhosis increased over time in proportion to serum HBV DNA levels at study entry, which were found to be the strongest independent predictors of the development of cirrhosis. A low incidence of the development of cirrhosis was found in patients with HBV DNA of less than 2000 IU/ml. Based on these results, a HBV DNA level of ≥ 2000 IU/ml was chosen as an indication of antiviral treatment for patients without cirrhosis by many recent treatment guidelines [23-25].

Treatment in HBV-related cirrhosis

  1. Top of page
  2. Abstract
  3. The natural course of the development of cirrhosis in HBV
  4. Risk factors for the development of cirrhosis in HBV-infected individuals
  5. Treatment in HBV-related cirrhosis
  6. How to treat
  7. Influence of antiviral treatment on the risk of development HCC
  8. Summary
  9. Disclosure
  10. References

The aim of antiviral therapy is to stop HBV-associated liver injury, to improve hepatic dysfunction and decrease the risk of mortality. The observation of a strong association between the development and decompensation of cirrhosis as well as between the development of HCC and the level of HBV replication suggests that suppression of HBV replication by long-term antiviral treatment may decrease the risk of complications in patients with HBV-related cirrhosis [23-25]. Antiviral therapy should therefore be begun as soon as the diagnosis is established to suppress HBV replication to undetectable levels as measured with a highly sensitive assay as recommended in recent treatment guidelines. The indication for antiviral treatment is given if any HBV DNA levels are detectable in the serum of HBV-infected patients with cirrhosis.

How to treat

  1. Top of page
  2. Abstract
  3. The natural course of the development of cirrhosis in HBV
  4. Risk factors for the development of cirrhosis in HBV-infected individuals
  5. Treatment in HBV-related cirrhosis
  6. How to treat
  7. Influence of antiviral treatment on the risk of development HCC
  8. Summary
  9. Disclosure
  10. References

In patients with HBV-related cirrhosis, the use of interferon (IFN) alpha can lead to decompensation and increase the risk of bacterial infections even in low doses. As well tolerable nucleos(t)ide analogues (NUCs) have become available, the use of IFN is contraindicated in these patients today [23-25]. To date, the NUCs lamivudine (LAM), adefovir dipivoxil (ADV), telbivudine (LdT), entecavir (ETV) and tenofovir disoproxil fumarate (TDF) have been approved for the treatment of HBV infections in patients with and without cirrhosis. All these substances inhibit HBV replication by competition with the incorporation of natural endogenous intracellular nucleotides in nascent HBV DNA. As a result, a decrease in inflammatory activity in the liver can be observed. Long-term treatment with NUCs can delay the progression of fibrosis, can reverse fibrosis and cirrhosis and can restore liver function in many patients [26-28]. Also, the rate of hepatic decompensation is significantly decreased in patients with HBV-related cirrhosis receiving NUC as it could be shown for treatment with LAM [29]. As a result of these effective treatments, the number of patients with HBV-related cirrhosis on the waiting list for liver transplantation has significantly decreased (Fig. 1) [30].

image

Figure 1. Number of patients on the waiting list for liver transplantation for hepatitis B-related indications in the United States [30].

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Lamivudine is the nucleoside analogue that has been in use for the longest time and for which the most clinical experience exists in patients with cirrhosis. In a study in patients with decompensated HBV-related cirrhosis, it became evident that by treatment with LAM ALT levels decreased, biochemical function of the liver could improve and survival could increase (Fig. 2) [31]. Also, the rate of re-infection after liver transplantation decreased and survival after transplantation increased in these patients [31].

image

Figure 2. Probability of survival in patients with hepatitis B virus (HBV)-related cirrhosis, HBV-related decompensated cirrhosis and in patients with HBV-related decompensated cirrhosis receiving treatment with lamivudine. Treatment with lamivudine seems to be associated with longer survival. Of note, the data are derived from three different studies and represent no head-to-head comparison trial [31, 32, 4].

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However, mortality in patients with decompensated cirrhosis remains significant. Importantly, the estimated chance of survival and the severity of liver dysfunction are obviously more important than response to LAM treatment. This was shown in a study in 154 patients with decompensated cirrhosis who were treated with LAM for a mean 16 months and 21% of whom died of liver failure [33]. Most of the deaths (78%) occurred within the first 6 months of treatment. A prediction of the 6-month mortality during LAM treatment could be obtained with baseline serum bilirubin and creatinine levels and detectable serum HBV DNA, but not from the changes in HBV DNA levels during treatment. In a randomized placebo-controlled study in 651 patients, LAM therapy for a median 32.4 months was shown to reduce decompensation in patients with advanced fibrosis or compensated cirrhosis. The Child-Turcotte-Pugh-Score (CTP) score increased in 3.4 per cent of the patients receiving lamivudine and 8.8 per cent of those receiving placebo (hazard ratio, 0.45; P = 0.02) [29].

Adefovir dipivoxil treatment can also improve CTP scores in patients with decompensated cirrhosis. This was shown in a study using ADV 10 mg daily in 128 patients on a wait list with decompensated cirrhosis who had previously failed LAM therapy. After 48 weeks of treatment, 81% of those on the wait list and 34% post-transplant patients achieved undetectable HBV DNA (<400 copies/ml) and normal ALT respectively. The CTP score improved in over 90% of patients and the 1-year survival was 84% [34]. Although ADV was generally well tolerated, it is no longer recommended as first-line treatment today because of possible renal side effects and a high rate of resistance [22, 23].

Treatment with Entecavir can lead to improvement in liver histology and Ishak fibrosis score. This was shown in sequential liver biopsies in 10 patients with fibrosis or cirrhosis at baseline (Ishak fibrosis score, ≥ 4) [38]. After approximately 6 years of cumulative Entecavir therapy (range, 267\x96297 weeks), a mean change in the baseline Ishak fibrosis and Knodell necroinflammatory scores were found to be 2.2 and 7.6 respectively. In the four patients who had cirrhosis at baseline, a reduction in the Ishak fibrosis score to 4 or less was observed.

It remains unclear whether treatment with a NUC with a low antiviral activity such as ADV or with a NUC with higher antiviral activity would result in a different rate of survival in patients with decompensated HBV-related cirrhosis. In a randomized, open-label, multicentre trial in 191 patients with a CTP score ≥ 7 comparing the safety and efficacy of ADV 10 mg/day with ETC 1.0 mg/day over 96 weeks, resulted in equally significant improvements in hepatic function, HCC occurrence and mortality in both groups, although the suppression of HBV replication was significantly higher in ETV-treated patients (P < 0.0001) [35]. In this study, lactic acidosis was reported as an adverse event of ETV in 1/99 patients. This patient had a baseline MELD score of 21 points after 1293 days of ETV treatment and the complication resolved with continued ETV treatment. However, another small study reported lactic acidosis in 5/16 patients with decompensated cirrhosis treated with ETV, all of whom had a MELD score > 22 points when treatment was initiated [34]. Lactic acidosis was not reported in any of 70 Korean patients with decompensated cirrhosis treated with ETV over 2 years [37].

Telbivudine at the dose of 600 mg/day was given to 114 patients with HBV-related cirrhosis in a multicentre, double-blind, randomized trial and compared with the efficacy and safety of LAM 100 mg/day in another 114 patients [39]. Even though there was a greater decrease in HBV DNA levels in LdT-treated patients, the benefit of treatment was similar in both groups. The cumulative HCC and death rates were 15 and 16% for LdT, and 16 and 22% for LAM, respectively, which was not different. Also the rate of adverse events was not different in the groups; HBV resistance occurred in both arms.

The efficacy and tolerability of tenofovir at a dose of 300 mg/day as monotherapy (N = 45) or as fixed-dose combination therapy with emtricitabine (FTC) 200 mg/day (N = 45) was compared to ETV at a dose of 0.5 or 1 mg/day (n = 22) in a randomized multicentre study for 168 weeks in patients with present or a past history of cirrhotic decompensation, a median MELD score of 10 points (range, 7–12) and median CTP scores of 7 (range, 7–12) [40]. The proportions of patients achieving suppression of HBV DNA to levels < 400 copies/ml were comparable in the three groups with 70.5, 87.8 and 72.7%, respectively, as well as the proportions of patients with ALT normalization; which was 57, 76 and 55% respectively. The median reduction in the MELD score from baseline was 2 points, resulting in a median MELD score of 8 at week 48 in all three groups. There were two deaths in each group owing to disease progression. Grade 3 or 4 adverse events were less common in the TDF arms (20% vs. 53%).

Also during TDF treatment, most patients show improvement in liver histology. Recently, pared biopsies from 331 patients who were obtained at baseline and week 240 of treatment with TDF 300 mg/day as monotherapy showed that liver histology had improved in 292 patients (88%) defined as an improvement of at least two points in the Knodell necroinflammatory score with no worsening in the Knodell fibrosis score [39]. Cirrhosis regressed in 69/94 patients (73%) with cirrhosis at baseline (Ishak fibrosis score ≥ 5 and 68 (72%) had at least a two-point reduction in Ishak fibrosis score.

Influence of antiviral treatment on the risk of development HCC

  1. Top of page
  2. Abstract
  3. The natural course of the development of cirrhosis in HBV
  4. Risk factors for the development of cirrhosis in HBV-infected individuals
  5. Treatment in HBV-related cirrhosis
  6. How to treat
  7. Influence of antiviral treatment on the risk of development HCC
  8. Summary
  9. Disclosure
  10. References

The incidence of HCC is increasing slowly in patients with HBV-related cirrhosis and to date, only a few long-term studies of patients undergoing antiviral treatment are available. A randomized placebo-controlled study in 651 patients showed that LAM therapy for a median of 32.4 months could reduce the incidence of HCC in patients with advanced fibrosis or compensated cirrhosis (hazard ratio 0.49, P = 0.047) [29]. However, no protective effect was found in patients whose CTP was greater than 7 at the start of LAM treatment. Consistently, in a recent retrospective Greek study in 818 patients (517 with chronic hepatitis B only, 160 with compensated and 56 with decompensated cirrhosis, 85 with unclassified disease) who were retrospectively analysed for a mean of 4.7 years of successful NUC treatment, the incidence of HCC in Child B and Child C patients was not decreased (Fig. 3) [42]. The probability of developing HCC was also strongly associated with an age>60 years. In patients with a longer duration of disease and more significant fibrosis, the conditions for the development of HCC may already exist regardless of the beneficial effects of an antiviral treatment.

image

Figure 3. Rate of the development of hepatocellular carcinoma (HCC) in HBeAg-negative patients receiving different nucleos(t)ide analogue (NUC) treatments (initially with lamivudine). Even though all patients showed complete remission during NUC treatment, the risk of HCC was not eliminated and patients with cirrhosis or decompensated cirrhosis are especially at high risk. Other risk factors for the development of HCC in this study were older age and male gender [40].

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Summary

  1. Top of page
  2. Abstract
  3. The natural course of the development of cirrhosis in HBV
  4. Risk factors for the development of cirrhosis in HBV-infected individuals
  5. Treatment in HBV-related cirrhosis
  6. How to treat
  7. Influence of antiviral treatment on the risk of development HCC
  8. Summary
  9. Disclosure
  10. References

Antiviral treatment with NUCs can prevent the development of cirrhosis in patients with chronic HBV infection and hepatic decompensation in many patients with HBV-related cirrhosis. NUC treatment also results in better survival and improves recovery of liver function in patients with HBV-related decompensated cirrhosis as well as reverting fibrosis and cirrhosis in many patients. NUC treatment in patients with cirrhosis should be initiated as early as possible and should result in complete suppression of HBV replication. In the present studies, the antiviral potency of the different NUCs did not influence the survival rate. However, these studies were performed over a short period and the results in long-term studies in patients treated with NUCs with higher antiviral potency may be different.

Treatment with NUCs is generally safe and well tolerated in patients with decompensated cirrhosis, which was recently shown by the absence of severe changes in glomerular filtration rate in patients treated with either TDF, a combination of TDF and emtricitabine or ETV for 48 weeks [40]. However, as a decrease in renal function is more frequently observed in non-cirrhotic patients, the use of ADV should be avoided in patients with decompensated cirrhosis [43]. As LAM, ADV and LdT have a high rate of HBV resistance, treatment of patients with cirrhosis should be restricted to substances with a high genetic barrier against resistance such as ETV or TDF. Lactic acidosis is a general risk in patients with decompensated cirrhosis; therefore, lactate levels should be monitored in all patients with HBV-related cirrhosis undergoing antiviral treatment. Although NUC treatment can decrease the probability of the development of HCC in patients with cirrhosis, patients with a CPT score ≥ 7 remain at a high risk of developing HCC whatever the long-term response to antiviral treatment may be and thus require life-long screening for HCC.

References

  1. Top of page
  2. Abstract
  3. The natural course of the development of cirrhosis in HBV
  4. Risk factors for the development of cirrhosis in HBV-infected individuals
  5. Treatment in HBV-related cirrhosis
  6. How to treat
  7. Influence of antiviral treatment on the risk of development HCC
  8. Summary
  9. Disclosure
  10. References