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Keywords:

  • chronic hepatitis B;
  • nucleoside analogues;
  • nucleotide analogues;
  • resistance;
  • roadmap;
  • treatment

Abstract

  1. Top of page
  2. Abstract
  3. NAs are more potent than PEG-IFN for suppressing hepatitis B virus replication
  4. Prolonged NA therapy can achieve high HBeAg seroconversion
  5. NA therapy improves histological hepatic necroinflammation and fibrosis
  6. NA therapy improves clinical outcome in patients with advanced fibrosis, compensated or even decompensated cirrhosis
  7. NA resistance can be minimized by selecting highly potent agents, or by optimization with a roadmap approach
  8. NAs can be stopped after a certain period of consolidation
  9. Disclosure
  10. References

Chronic hepatitis B (CHB) is a worldwide public health problem which represents an enormous economic and social burden. Convincing evidence has shown that persistent active viral replication is an independent predictor of disease progression. Therefore, sustained suppression of HBV replication is the cornerstone for preventing the progression of disease and prolonging survival in patients with CHB. Pivotal clinical trials and real-world studies show that nucleos(t)ide analogues (NAs) are potent suppressors of HBV DNA replication with very good safety profiles. Although 1-year treatment with NAs only results in a modest rate of HBeAg seroconversion, extended treatment could increase this rate. Profound suppression of HBV DNA can result in histological improvement and a clinical benefit with a decrease in disease progression in patients with compensated or decompensated cirrhosis. Treatment must be begun with a highly potent and low resistant regimen to obtain long-term suppression of viral replication. An alternative solution may be a roadmap approach in which an inexpensive antiviral drug is started and another drug is added-on or switched-to if there is a suboptimal on-treatment decrease in HBV DNA. Clinical evidence has shown that once HBV DNA is suppressed and long-term HBeAg seroconversion is achieved, NAs can be stopped. In summary, high antiviral efficacy, excellent tolerance, extensive applicability, clearly proven histological improvement and long-term clinical benefit all make NAs the preferred choice for the management of CHB in most patients.

Abbreviations
CHB

chronic hepatitis B

CTP

Child-Turcotte-Pugh score

HBV

hepatitis B virus

NAs

nucleos(t)ide analogues

PEG-IFN

pegylated interferon

Chronic hepatitis B (CHB) is a worldwide public health problem that represents an enormous economic and social burden. This is especially true in the Asian-Pacific regions including China where the prevalence of HBsAg in the general population is around 7% [1]. Convincing evidence has shown that persistent active viral replication is an independent predictor of disease progression. Indeed, a large prospective cohort study has demonstrated that elevated HBV DNA (≥104 copies/ml) significantly increases the risk of cirrhosis, HCC and death over a 10-year follow-up period, regardless of HBeAg status or ALT levels at baseline [2, 3]. Therefore, sustained suppression of HBV replication is the cornerstone for preventing disease progression and prolonging survival in patients with CHB.

In the last decade, pegylated interferon (PEG-IFN) and nucleos(t)ide analogues (NAs) have been approved and recommended for the treatment of CHB [4-6]. Both PEG-IFN and NAs have advantages and disadvantages. The advantages of PEG-IFN therapy include the finite duration of therapy, relatively higher HBeAg seroconversion rate and durable efficacy [7]. However, PEG-IFN is administered by injection, is associated with possibly severe side effects and its efficacy is limited to a small proportion of highly selected patients. On the other hand, NAs possess potent antiviral activity, can be taken orally and are well tolerated in patients with or without cirrhosis [8]. However, the disadvantages of NAs include uncertain treatment duration, less durable efficacy and the emergence of resistance during long-term therapy.

The major international guidelines on the management of CHB suggest that either PEG-IFN or NAs can be used as first-line therapy, without specific recommendations on how to choose between these two treatments [4-6]. Therefore, choosing PEG-IFN or NAs becomes a decision-making process. The following points explain why I choose NAs in the treatment of CHB.

NAs are more potent than PEG-IFN for suppressing hepatitis B virus replication

  1. Top of page
  2. Abstract
  3. NAs are more potent than PEG-IFN for suppressing hepatitis B virus replication
  4. Prolonged NA therapy can achieve high HBeAg seroconversion
  5. NA therapy improves histological hepatic necroinflammation and fibrosis
  6. NA therapy improves clinical outcome in patients with advanced fibrosis, compensated or even decompensated cirrhosis
  7. NA resistance can be minimized by selecting highly potent agents, or by optimization with a roadmap approach
  8. NAs can be stopped after a certain period of consolidation
  9. Disclosure
  10. References

Pivotal clinical trials show that NAs are very potent for suppressing HBV DNA replication. Compared to PEG-IFN, NAs achieve a higher rate of HBV DNA undetectability or a lower threshold by quantitative PCR assay [9]. Real-world observational studies have also confirmed the efficacy and safety of NAs in clinical practice. For example, in a prospective cohort study [10], 2600 patients (who were NAs-naïve or -experienced) from 50 study sites in China received entecavir therapy (0.5 or 1.0 mg), and 1530/2398 (64%) patients with compensated liver disease, and 30/44 (68%) patients with decompensated liver disease achieved HBV DNA <50 IU/ml at week 48. This study demonstrates that in a ‘real-world’ setting, entecavir was effective and well tolerated for 48 weeks in a heterogeneous Chinese population with CHB [10].

Prolonged NA therapy can achieve high HBeAg seroconversion

  1. Top of page
  2. Abstract
  3. NAs are more potent than PEG-IFN for suppressing hepatitis B virus replication
  4. Prolonged NA therapy can achieve high HBeAg seroconversion
  5. NA therapy improves histological hepatic necroinflammation and fibrosis
  6. NA therapy improves clinical outcome in patients with advanced fibrosis, compensated or even decompensated cirrhosis
  7. NA resistance can be minimized by selecting highly potent agents, or by optimization with a roadmap approach
  8. NAs can be stopped after a certain period of consolidation
  9. Disclosure
  10. References

Although HBsAg loss or HBsAg seroconversion is an ideal endpoint, it can only be achieved in minority of patients with CHB. HBeAg seroconversion is also associated with a reduction in disease progression and can be achieved in a reasonable percentage of patients. Although the rate of HBeAg seroconversion after 1 year of treatment with NA is modest, extended treatment can increase this rate. Recently, Gane et al. reported that after 3 years of treatment with telbivudine, the cumulated HBeAg seroconversion rate reached 58% [11].

In a prospective cohort of 170 HBeAg-positive CHB who had been receiving NAs for at least 2 years, the host-induced ALT increases (characterized by a moderate increase in ALT and a slow decrease in HBV DNA occurring mainly in the first year of treatment) were associated with higher HBeAg seroconversion (82% vs. 7%), more frequent undetectable HBV DNA (82% vs. 0%), and histological improvement, compared to those with a virus-induced increase in ALT (characterized by a rapid increase in serum ALT and HBV DNA usually after 2 years of treatment) [12].

NA therapy improves histological hepatic necroinflammation and fibrosis

  1. Top of page
  2. Abstract
  3. NAs are more potent than PEG-IFN for suppressing hepatitis B virus replication
  4. Prolonged NA therapy can achieve high HBeAg seroconversion
  5. NA therapy improves histological hepatic necroinflammation and fibrosis
  6. NA therapy improves clinical outcome in patients with advanced fibrosis, compensated or even decompensated cirrhosis
  7. NA resistance can be minimized by selecting highly potent agents, or by optimization with a roadmap approach
  8. NAs can be stopped after a certain period of consolidation
  9. Disclosure
  10. References

Although histological improvement has been observed during treatment with lamivudine, adefovir and tenofovir, this benefit is compromised in those who develop resistance to NAs [13-15]. Not surprisingly, a recent report showed that sustained suppression of HBV DNA during long-term entecavir therapy (of up to 5 years) which has a very low rate of resistance, resulted in significant improvement in necroinflammation and the reversal of fibrosis, as well as the regression of cirrhosis [16]. Similar histological improvement has been reported in patients who received long-term NA therapy with telbivudine [17].

NA therapy improves clinical outcome in patients with advanced fibrosis, compensated or even decompensated cirrhosis

  1. Top of page
  2. Abstract
  3. NAs are more potent than PEG-IFN for suppressing hepatitis B virus replication
  4. Prolonged NA therapy can achieve high HBeAg seroconversion
  5. NA therapy improves histological hepatic necroinflammation and fibrosis
  6. NA therapy improves clinical outcome in patients with advanced fibrosis, compensated or even decompensated cirrhosis
  7. NA resistance can be minimized by selecting highly potent agents, or by optimization with a roadmap approach
  8. NAs can be stopped after a certain period of consolidation
  9. Disclosure
  10. References

Profound HBV DNA suppression can result in a clinical benefit including a decrease in disease progression in patients with cirrhosis. A landmark report of a randomized, placebo-controlled clinical trial in CHB patients with advanced fibrosis or cirrhosis showed that antiviral therapy improved disease progression, with the group receiving lamivudine having significantly less worsening of the Child-Turcotte-Pugh (CTP) score, decompensation, hepatocellular carcinoma (HCC) and death over 3 years compared with the placebo group (7.8% vs. 17.7%, P = 0.001) [18]. However, this reduction in disease progression was significantly limited by the emergence of lamivudine resistance. Thus, a sustained off-treatment virological response (SVR) or a maintained on-treatment response is necessary to improve long-term clinical outcomes.

An early report from a United States study on compassionate use of lamivudine for HBV-related decompensated cirrhosis shows that lamivudine can lead to profound HBV DNA suppression and more importantly, significant improvement in the severity of liver disease in terms of a reduction in the CTP score [19]. Recently, in a randomized, open-label comparative study of 191 subjects with CHB and liver decompensation, entecavir (1.0 mg/day) resulted in a higher proportion (57%) of HBV DNA <300 copies/ml at week 48 than adefovir (20%, P < 0.0001). Approximately, two-thirds of subjects in both groups had improvement/stabilization in the CTP score. The proportion of adverse events was similar in the two groups [20]. In phase 2, double-blind study of 112 patients with CHB and decompensated liver disease, at week 48 HBV DNA was <400 copies/ml (69 IU/ml) in 70.5% (TDF), 87.8% (FTC/TDF) and 72.7% (ETV) of patients. The CTP and MELD scores improved in all groups and all treatments were well tolerated [21].

NA resistance can be minimized by selecting highly potent agents, or by optimization with a roadmap approach

  1. Top of page
  2. Abstract
  3. NAs are more potent than PEG-IFN for suppressing hepatitis B virus replication
  4. Prolonged NA therapy can achieve high HBeAg seroconversion
  5. NA therapy improves histological hepatic necroinflammation and fibrosis
  6. NA therapy improves clinical outcome in patients with advanced fibrosis, compensated or even decompensated cirrhosis
  7. NA resistance can be minimized by selecting highly potent agents, or by optimization with a roadmap approach
  8. NAs can be stopped after a certain period of consolidation
  9. Disclosure
  10. References

Most patients who receive NA may require long-term therapy to prevent the progression of liver disease and to prolong survival. Thus, a major concern is the development of antiviral resistance. Clinical studies have demonstrated that antiviral drugs with a high barrier to resistance such as entecavir and tenofovir have significantly lower rates of resistance compared with those with a low barrier to resistance such as lamivudine, adefovir or telbivudine [9]. Therefore, it is essential to start therapy with a potent drug to achieve persistent long-term suppression of viral replication. Indeed, in American and European guidelines, entecavir and tenofovir are recommended as first-line oral antiviral agents because of their potent antiviral effect and very low risk of drug resistance [4, 5]. As shown in an expert review article, treatment with a potent drug that has a high barrier to resistance such as entecavir or tenofovir, will minimize the future development of resistance, preserve future treatment options, protect public health and maximize the chances of long-term treatment success [9].

However, in the Asia-Pacific consensus statement, no clear recommendations were made on the choice of antiviral agents [6], mainly owing to the highly heterogeneous economic situations in this region of the world. In countries with resource limitations where potent antiviral agents such as entecavir or tenofovir are not available, not reimbursed or not affordable [22], a roadmap approach may be an alternative solution in which an inexpensive antiviral drug (such as lamivudine or adefovir) is begun and another drug is added-on (such as adefovir) or switched-to (such as entecavir) if there is a suboptimal on-treatment HBV DNA response [23]. Indeed, an interim analysis of a prospective, randomized, controlled clinical study performed in China where telbivudine is extensively used [24], shows that the efficacy of HBV suppression by telbivudine is strengthened and resistance is reduced by add-on adefovir based on the roadmap concept [25]. Another interim analysis from Thailand also confirmed that beginning with telbivudine and adding-on tenofovir could reduce the overall resistance rate [26].

NAs can be stopped after a certain period of consolidation

  1. Top of page
  2. Abstract
  3. NAs are more potent than PEG-IFN for suppressing hepatitis B virus replication
  4. Prolonged NA therapy can achieve high HBeAg seroconversion
  5. NA therapy improves histological hepatic necroinflammation and fibrosis
  6. NA therapy improves clinical outcome in patients with advanced fibrosis, compensated or even decompensated cirrhosis
  7. NA resistance can be minimized by selecting highly potent agents, or by optimization with a roadmap approach
  8. NAs can be stopped after a certain period of consolidation
  9. Disclosure
  10. References

Clinical evidence shows that NAs can be safely stopped once HBV DNA is suppressed and long-term HBeAg seroconversion has been maintained. The HBeAg seroconversion rate and its durability are determined by host factors such as age, gender, route of HBV infection, immune status and liver disease activity, and virological profiles such as genotype, HBeAg positivity and gene mutations. In a long-term follow-up study of 125 Chinese patients with HBeAg-positive CHB, Wang et al. found that younger age (<30 years old) and longer consolidation after HBeAg seroconversion was predictive of a lower relapse rate once lamivudine was stopped [27]. Similarly, a Korean study in 178 patients who received lamivudine therapy also found that patients who were under 40 and who had more than 12 months consolidation of HBeAg seroconversion had a better chance of sustained remission [28]. Thus, clinicians should clearly understand all these baseline factors and carefully monitor the on-treatment HBV DNA profiles to optimize the therapeutic course and decision to stop therapy. Obviously, there are still challenges to define treatment cessation criteria and the best treatment endpoint in the future [29].

In conclusion, significant antiviral efficacy, good tolerance, wide applicability, clearly proven histological improvement and long-term clinical benefit all make NA the first choice in most patients for the management of CHB.

References

  1. Top of page
  2. Abstract
  3. NAs are more potent than PEG-IFN for suppressing hepatitis B virus replication
  4. Prolonged NA therapy can achieve high HBeAg seroconversion
  5. NA therapy improves histological hepatic necroinflammation and fibrosis
  6. NA therapy improves clinical outcome in patients with advanced fibrosis, compensated or even decompensated cirrhosis
  7. NA resistance can be minimized by selecting highly potent agents, or by optimization with a roadmap approach
  8. NAs can be stopped after a certain period of consolidation
  9. Disclosure
  10. References