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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Natural history
  5. Prevention
  6. Treatment of chronic hepatitis B
  7. Approved therapies for treatment of chronic hepatitis B
  8. Management of resistance
  9. Roadmap for on-treatment management on hepatitis B
  10. Conclusions
  11. Acknowledgements
  12. References

Background  The long-term goals of therapy for chronic hepatitis B are to reduce serum HBV DNA to low or undetectable levels and ultimately reduce or prevent the development of cirrhosis and hepatocellular carcinoma.

Aim  To review the current treatment of chronic hepatitis B, with a focus on diagnosis and management of resistance and active management of suboptimal responses.

Methods  A systematic review of the literature, with a focus on recent guidelines, was undertaken.

Results  Among the six drugs licensed for the treatment of chronic hepatitis B in the US, the preferred agents in 2008 will include entecavir, peginterferon alfa-2a, possibly telbivudine, and tenofovir following licensure. When using an oral agent, a major focus of management is on the selection of a drug with high potency and low rate of resistance, and active on-treatment management to optimize therapy. Preventing the sequelae of antiviral drug resistance and appropriate management when resistance is initially detected are also the major focus of current management. The addition of an antiviral agent that is not cross-resistant is critical to restore suppression of viral replication.

Conclusions  Newer agents and modified treatment strategies, especially using combination therapy, hold promise to optimize the management of patients with chronic hepatitis B by achieving the high potency and the lowest rate of resistance.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Natural history
  5. Prevention
  6. Treatment of chronic hepatitis B
  7. Approved therapies for treatment of chronic hepatitis B
  8. Management of resistance
  9. Roadmap for on-treatment management on hepatitis B
  10. Conclusions
  11. Acknowledgements
  12. References

Chronic hepatitis B virus (HBV) infection is a major global cause of morbidity and mortality. Of 350 million people chronically infected with HBV worldwide, at least 1.25 million individuals live in the US.1, 2 The prevalence of chronic hepatitis B (CHB) in the US is under-reported, as epidemiological studies do not include the prison population or take into consideration the continuous influx of immigrants from endemic areas with a high prevalence rate of HBV infection. Individuals with CHB are at risk of premature death from cirrhosis with liver failure or hepatocellular carcinoma (HCC).2, 3 Recent studies have shown that the level of serum HBV DNA correlates over more than a decade with the risk of developing cirrhosis4 and HCC (Figure 1).5 For this reason, early diagnosis of chronic HBV infection and treatment to reduce serum HBV DNA to low or undetectable levels are important in preventing progression of HBV infection to advanced disease with these complications.

image

Figure 1.  Level of HBV DNA and progression to hepatocellular carcinoma (13-year follow-up).5

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The arsenal of medications to treat CHB continues to increase.3 Compared to two medications licensed by the US Food and Drug Administration (FDA) in the 1990s (interferon alfa-2b and lamivudine), four additional agents have now been licensed: adefovir dipivoxil, entecavir, peginterferon alfa-2a and telbivudine, with tenofovir likely to be licensed in the third quarter of 2008. The future management of CHB appears to be more promising than ever before, with many treatment options currently available, new drugs in development, and different on-treatment strategies for optimizing the use of current agents undergoing investigation.

Natural history

  1. Top of page
  2. Summary
  3. Introduction
  4. Natural history
  5. Prevention
  6. Treatment of chronic hepatitis B
  7. Approved therapies for treatment of chronic hepatitis B
  8. Management of resistance
  9. Roadmap for on-treatment management on hepatitis B
  10. Conclusions
  11. Acknowledgements
  12. References

An individual’s age and time of infection have a strong impact on the course of acute HBV infection.2, 6 Infection at birth or in early childhood results in the development of chronic HBV infection in more than 90% of individuals. In contrast, infection in adulthood is most often self-limited, with more than 95% of infected individuals clearing the virus.6 The hallmark of acute HBV infection is elevated alanine aminotransferase (ALT) levels and the presence of hepatitis B surface antigen (HBsAg), IgM antibody to hepatitis B core antigen (anti-HBc) and hepatitis B e antigen (HBeAg), although the latter serological test is not routinely used in practice.

Once chronicity is established, patients infected at birth or early in life typically enter into an initial immune tolerance phase, which is characterized by high levels of viral replication (elevated HBV DNA levels and presence of HBeAg), but normal ALT levels.6 This phase is usually short-lived or absent in adult infection, but long-lived when infection occurs in infancy or early childhood. Although a liver biopsy is not usually performed during the immune tolerance phase, studies have shown the presence of minimal or absent inflammation and fibrosis on histological examination.6–8

The immune clearance phase follows the immune tolerance phase and is characterized by clearance of infected hepatocytes, which results in elevated or fluctuating ALT levels and persistently high HBV DNA levels. Inflammation with varying degrees of fibrosis is characteristic of this stage on a liver biopsy specimen. Repetitive hepatitis flares and prolonged duration of this phase can lead to advanced fibrosis or cirrhosis. During this phase, patients may spontaneously seroconvert and develop antibodies to HBeAg (anti-HBe), which occurs at an annual rate of 5–15% without therapy, but this process can be accelerated by initiation of antiviral therapy.7, 8 A recent study of Alaska Native persons showed that individuals infected with HBV genotype C, compared to those with genotypes A, B, D and F, had an increased likelihood of having persistently detectable serum HBeAg and longer time to spontaneous HBeAg clearance.9 The age at which 50% of HBV genotype C-infected individuals cleared HBeAg was 47.8 years, while it was less than 20 years of age in those with genotypes A, B, D and F. In addition, after losing HBeAg, those with genotypes C and F were more likely to revert to the HBeAg-positive state. Thus, genotype may have a strong effect on the outcome of chronic HBV infection as patients with genotype C have a longer immune clearance phase, and genotype C may also be responsible for most perinatal transmission, given that seroconversion from HBeAg occurs decades later than in other genotypes.

Seroconversion from HBeAg to anti-HBe signals the transition to the nonreplicative phase of infection and patients in this stage are referred to as inactive HBsAg carriers, with normal ALT levels, undetectable or low levels of serum HBV DNA and the presence of anti-HBe.10 Liver biopsy at this stage may reveal either resolution or presence of minimal lingering inflammation, with variable amounts of fibrosis that may have developed during the immune clearance phase. Inactive carriers, particularly older subjects, may spontaneously lose HBsAg and seroconvert to antibody to HBsAg (anti-HBs). However, a small amount of serum HBV DNA can often be detected using sensitive polymerase chain reaction techniques.11

Reactivation of HBV infection may occur in a subgroup of patients despite HBeAg seroconversion. Reactivation usually occurs close to the time of HBeAg loss, but can also occur many years later, with high levels of serum HBV DNA and significant disease on liver biopsy.10, 12, 13 Emergence of the precore or core promoter mutants of HBV are responsible for such reactivation.11, 13 This phenomenon was first recognized in the Mediterranean area, but it is becoming more common in the US.11 Chu et al.14 reported a prevalence rate of 27% for precore and 44% for basal core promoter variants in a survey of patients with HBV infection in the US.

HBeAg-negative patients tend to have more severe liver disease than patients who are HBeAg-positive. Serum ALT levels may remain normal and serum HBV DNA undetectable for many years before later detection. Patients with HBeAg-negative CHB are often erroneously labelled as inactive carriers because of intermittently low or normal ALT levels and undetectable HBV DNA. However, frequent monitoring of HBV DNA and ALT can easily detect fluctuation in viraemia levels in this group of patients, leading to early detection and intervention prior to the development of progressive liver disease.15 Serum HBV DNA levels >2000 IU/mL should raise suspicion for HBeAg-negative CHB rather than an inactive carrier state.16 Therefore, it is not surprising that significant inflammatory changes and fibrosis are present in more than 50% of HBeAg-negative patients. A majority of these patients have a poor long-term prognosis, as the diagnosis of CHB is made late in the course of the disease, with 25–50% having cirrhosis at the time of diagnosis.10, 11, 17

Prevention

  1. Top of page
  2. Summary
  3. Introduction
  4. Natural history
  5. Prevention
  6. Treatment of chronic hepatitis B
  7. Approved therapies for treatment of chronic hepatitis B
  8. Management of resistance
  9. Roadmap for on-treatment management on hepatitis B
  10. Conclusions
  11. Acknowledgements
  12. References

Vaccination remains the best prevention against acquisition of HBV infection. There are three hepatitis B vaccines on the market in the US. Health policies have advocated hepatitis B vaccination since the 1980s and recommendations for vaccination were expanded in the 1990s, resulting in decreased incidence of acute and chronic HBV infection. During the period from 1990, 8 years after the first set of vaccination recommendations were issued from the Centers for Disease Control and Prevention, to 2005, the incidence of acute hepatitis B declined 78%.18 Currently, HBV vaccination for infants is nearly universal, and more than 90% of infants under the age of 3 years of age in the US have been vaccinated.18 Vaccination recommendations have also been expanded to include all adolescents up to 18 years of age. Furthermore, three additional strategies have been advocated to prevent dissemination of HBV: prevention of vertical transmission by screening all pregnant women and immunization of infants born of infected mothers, routine childhood vaccination and catch-up vaccination for adolescents, and vaccination of high-risk adults (Table 1).

Table 1.   Indications for hepatitis B virus vaccination18
  1. HBV, hepatitis B virus; STD, sexually transmitted disease; HIV, human immunodeficiency virus; HBsAg, hepatitis B surface antigen.

Universal
 All infants
 All children and adolescents not previously vaccinated
Exposure risk
 Partners and close contacts of HBV carriers
 Men who have sex with men
 Nonmonogamous sexually active persons   (more than one sex partner in the previous 6 months)
 History of STD or treatment in STD clinic
 Dialysis patients
 Health care workers in contact with blood or body fluids
 Recipients of blood derivatives
 Residents and staff of long-term correctional facilities   and developmentally disabled persons
 Patients with chronic liver disease
 Persons with HIV infection
 International travellers to regions with HBsAg   prevalence ≥2%

Treatment of chronic hepatitis B

  1. Top of page
  2. Summary
  3. Introduction
  4. Natural history
  5. Prevention
  6. Treatment of chronic hepatitis B
  7. Approved therapies for treatment of chronic hepatitis B
  8. Management of resistance
  9. Roadmap for on-treatment management on hepatitis B
  10. Conclusions
  11. Acknowledgements
  12. References

Achieving maximum viral suppression without the development of antiviral drug resistance, reducing progression to cirrhosis and decreasing the risk of developing HCC are the primary goals of treatment of CHB. Treatment is recommended for patients in the immune clearance and reactivation phases characterized by elevated serum ALT and HBV DNA levels. The aim of therapy in patients with HBeAg-positive CHB is loss of HBeAg and/or seroconversion to anti-HBe, normalization of ALT levels and maximum suppression of HBV DNA to low or undetectable levels. Accomplishing these goals will result in improvement in liver histology, reduction in disease progression and decreased incidence of HCC, as has been shown in patients with advanced hepatic fibrosis.19 Emerging evidence confirming the relationship between increased liver-related mortality and ALT levels >20 U/L for females and 30 U/L for males has led to the conclusion that a lower threshold for elevated serum ALT be used when considering candidates for treatment.10, 20

Indications for treatment differ in patients who are HBeAg-positive vs. HBeAg-negative.10, 21 A serum HBV DNA level of at least 20 000 IU/mL (∼100 000 copies/mL) and an ALT level that is elevated10 or two times the upper limits of normal (ULN)21 are indications for treatment in HBeAg-positive CHB. In the setting of an ALT level <2 × ULN and an elevated HBV DNA level, liver biopsy is usually recommended, as approximately 20% of individuals over the age of 35 will have significant hepatic fibrosis on biopsy.10 However, treatment is indicated regardless of the level of HBV DNA, if the liver biopsy reveals significant inflammatory activity and/or fibrosis. While therapy in patients with elevated ALT levels and HBV DNA levels can be deferred for 3 to 6 months to assess the development of HBeAg seroconversion, therapy should be promptly initiated in patients with elevated serum bilirubin levels or signs of hepatic decompensation.21

The two primary goals for the treatment of patients with HBeAg-negative CHB are viral suppression and normalization of ALT levels. Chu et al.16 have demonstrated the presence of significant inflammation on liver biopsy in HBeAg-negative patients with HBV DNA levels <100 000 copies/mL. Therefore, initiation of treatment is indicated in the setting of fluctuating ALT levels with serum HBV DNA levels >2000 IU/mL (∼10 000 copies/mL).10 Similar to HBeAg-positive patients, active hepatitis found in HBeAg-negative patients on liver biopsy dictates treatment for those with an elevated HBV DNA level, even if the setting is of normal ALT levels.

Regardless of HBeAg status, patients with low HBV DNA levels and normal ALT levels warrant surveillance. Serial monitoring with laboratory testing every 3 months for 1 year after initial diagnosis and again 6–12 months thereafter is usually recommended. Active inflammation found on liver biopsy indicates the need for treatment regardless of the low level of the viraemia.10, 21 Although antiviral therapy is continued for 6–12 months after seroconversion in HBeAg-positive CHB, it is usually continued indefinitely in HBeAg-negative CHB to prevent relapse.10, 21

Approved therapies for treatment of chronic hepatitis B

  1. Top of page
  2. Summary
  3. Introduction
  4. Natural history
  5. Prevention
  6. Treatment of chronic hepatitis B
  7. Approved therapies for treatment of chronic hepatitis B
  8. Management of resistance
  9. Roadmap for on-treatment management on hepatitis B
  10. Conclusions
  11. Acknowledgements
  12. References

Antiviral therapy for CHB includes immunomodulatory agents (interferon and peginterferon) and oral antiviral agents (the nucleoside and nucleotide analogues). Nucleoside analogues include lamivudine, telbivudine and entecavir, while nucleotide analogues include adefovir and tenofovir. While interferon has been limited by its poor tolerability and significant side effect profile, the efficacy of oral agents has been hampered by the necessity of prolonged use and emergence of resistance. Six drugs are currently approved by the FDA for the treatment of CHB: interferon alfa-2b, peginterferon alfa-2a, lamivudine, adefovir, entecavir and telbivudine.3, 10, 21

Initiation of therapy requires consideration not only of the potency of individual drugs, but also the resistance profile of each agent. Lamivudine is not used in most settings as a first-line agent secondary to a high rate of antiviral drug resistance (65–70% after 5 years of therapy).10, 21 Similarly, telbivudine is limited to patients who are able to achieve an undetectable serum HBV DNA by week 24 of therapy, which minimizes the rate of resistance. The overall rate of telbivudine resistance in pivotal trials was 22% in patients with HBeAg-positive CHB and 9% in those with HBeAg-negative CHB.21 Reaching the milestone of an undetectable serum HBV DNA by week 24 results in a very low rate of resistance and continued efficacy by week 96.22

Peginterferon alfa-2a

Peginterferon alfa-2a has replaced standard interferon alfa-2b due to its less demanding injection schedule and its comparable or improved efficacy.10, 21 Peginterferon alfa-2a used for 48 weeks results in a 27% rate of HBeAg seroconversion and 25% rate of loss of HBV DNA. HBeAg seroconversion is increased to 32% with longer duration of therapy at week 72. When compared to peginterferon alfa-2a alone, the addition of lamivudine to peginterferon alfa-2a therapy has no added benefit in HBeAg-positive and HBeAg-negative CHB.3, 23

In patients with HBeAg-negative CHB, 48 weeks of therapy with peginterferon alfa-2a, with or without lamivudine, resulted in a significantly greater percentage of patients with HBV DNA <400 copies/mL 24 weeks after the end of treatment compared with lamivudine monotherapy (19% and 20% vs. 7%).24 The combination of peginterferon alfa-2a plus lamivudine appeared to offer no advantages over treatment with peginterferon alfa-2a alone. HBsAg seroconversion was reported in 3% of patients treated with peginterferon alfa-2a, 2% of those treated with peginterferon alfa-2a plus lamivudine, and in no patients treated with lamivudine alone. In addition, the rate of emergence of lamivudine-resistant mutations was reduced markedly in the combination therapy arm. A recent 4-year follow-up study of patients with HBeAg-negative CHB treated with peginterferon alfa-2a ± lamivudine vs. lamivudine monotherapy reported significantly higher rates of ALT normalization (27% vs. 18%), HBV DNA <400 copies/mL (17% vs. 7%) and HBsAg loss (11% vs. 2%) in the peginterferon alfa-2a-treated patients.25 Among patients who either achieved or did not achieve an HBV DNA level <400 copies/mL by 48 weeks at the end of treatment, 43% and 0.5% respectively achieved HBsAg clearance.

Hepatitis B genotype predicts response to peginterferon therapy. Genotype A has a better response than genotype D, and genotype B has a better response than genotype C in most studies.3, 10 Patients with CHB infected with genotypes A and B are therefore the best candidates for treatment with peginterferon alfa-2a, especially if they are young, lack comorbidities, have HBV DNA levels <109 copies/mL and also have ALT levels at least two to three times the ULN.26

The fixed duration of therapy and the lack of antiviral drug resistance distinguish interferon-based therapy from treatment with available oral agents. However, administration by injection and the extensive side effect profile have hindered the broader use of peginterferon therapy in the US.

Lamivudine

The first breakthrough in oral anti-HBV therapy came with the FDA licensure of lamivudine in 1998. It has a lower durability of response than interferon in both HBeAg-positive patients (50–80%) and HBeAg-negative patients (20–25%).3, 10 In patients with HBeAg-positive disease, treatment is continued until HBeAg seroconversion occurs. Durability of response is further enhanced by extending treatment for an additional 6 months.10, 21 In addition, treatment of patients with advanced fibrosis is associated with a lower rate of disease progression as well as lower incidence of HCC.19 Patients who are HBeAg-negative are usually treated indefinitely, as relapse is invariable if treatment is stopped after a short duration of treatment even with an undetectable serum HBV DNA.

As with most of the oral agents, prolonged duration of therapy is associated with an increasing rate of antiviral drug resistance. Lamivudine leads to resistance at a rate of approximately 20% of patients per year and can reach 65–70% after 4–5 years of therapy. As a result, lamivudine is not considered a first-line agent in the treatment of CHB.10, 21

Patients who develop YMDD mutation with lamivudine therapy were initially switched to adefovir or entecavir.10, 21 However, recent data support the addition of a nucleotide agent such as adefovir, which avoids an increased rate of subsequent adefovir resistance.10, 21, 27 In addition, adefovir resistance can be successfully treated with the addition of lamivudine to continued adefovir, which is now the preferred approach.10, 21, 28

Adefovir dipivoxil

Adefovir dipivoxil is the second oral agent approved by the FDA in 2002 for the treatment of CHB, and is associated with a 12% rate of HBeAg seroconversion, 21% rate of undetectable serum HBV DNA and 53% rate of histological improvement in HBeAg-positive patients after 1 year of therapy.29 Similar to lamivudine, HBeAg seroconversion marks the end of therapy with adefovir in HBeAg-positive patients. Once seroconversion occurs, it is sustained in 91% of patients.10, 21

After 1 year of adefovir therapy in patients with HBeAg-CHB, serum HBV DNA is undetectable in 51% of patients, who are then treated long term.30 Histological improvement, ALT normalization, and viral suppression have been demonstrated for up to 5 years of administration of adefovir.31 However, resistance becomes a limiting factor with prolonged use. Resistance has been demonstrated at 1, 2, 4 and 5 years at a rate of 0%, 3%, 18% and 29% respectively.31 Furthermore, persistence of high level of HBV viraemia after 48 weeks of adefovir therapy predicts the emergence of resistance.31

Entecavir

Entecavir is a nucleoside analogue shown to have greater potency than other lamivudine. At a dose of 0.5 mg daily, therapy with entecavir results in a 6.98 log10 copies/mL decrease of HBV DNA levels in HBeAg-positive patients.32 When compared to lamivudine, entecavir achieves increased rates of histological improvement (72% vs. 62%), normalization of ALT (78% vs. 70%) and viral suppression of HBV DNA to <400 copies/mL (69% vs. 38% respectively).32 However, it has a comparable rate of HBeAg seroconversion when compared to lamivudine after 1 year of therapy. In addition, entecavir achieved greater histological improvement (70% vs. 61%) and viral suppression (91% vs. 73%) than lamivudine in HBeAg-negative CHB patients.33 The biochemical and virological response is further maintained up to 96 weeks on entecavir therapy.34

The rate of entecavir resistance is minimal (1.2%) in treatment-naïve patient after 5 years of therapy.35 However, in lamivudine-refractory patients, the cumulative probability of entecavir resistance at years 1 through 5 is 6%, 15%, 36%, 46% and 51% respectively.35

Telbivudine

Telbivudine is a nucleoside analogue and a potent inhibitor of HBV DNA polymerase. The GLOBE trial, a randomized phase III study, established the superiority of telbivudine to lamivudine in HBeAg-positive and HBeAg-negative patients after 1 and 2 years of therapy.36, 37 The rate of HBeAg seroconversion was 22% and viral suppression was limited to HBV DNA levels of <300 copies/mL after 1 year of therapy in 60% of HBeAg-positive patients.38

Resistance to telbivudine has been reported as 4.4% and 21.6% in HBeAg-positive patients and 2.7% and 8.6% in HBeAg-negative patients after 1 and 2 years of therapy.37 However, patients who achieved viral suppression of HBV DNA by week 24 of therapy had better rates of HBeAg seroconversion, ALT normalization and more importantly, a lower rate of antiviral drug resistance.22

Telbivudine also achieves improved early viral suppression compared to adefovir at week 24 in HBeAg-positive patients regardless of whether the patients were treated initially with telbivudine or switched from adefovir to telbivudine.39 The early virological suppression resulted in better rates of HBeAg seroconversion, ALT normalization and viral suppression.

Tenofovir

Tenofovir is structurally related to adefovir and is likely to be approved by the FDA for treatment of CHB in the third quarter of 2008. It is more potent than adefovir in achieving viral suppression defined as <400 copies/mL (76% vs. 13%), histological improvement (67% vs. 12%) and higher rates of HBsAg loss (3.2% vs. 0%) at 48 weeks in patients with HBeAg-positive CHB.40 In this study design, all eligible subjects were either continued on tenofovir or switched from adefovir to tenofovir for a planned additional 4 years. Recent 72-week data show that 89% of HBeAg-positive patients continued on tenofovir had serum HBV DNA <400 copies/mL, and 78% of patients who did not achieve complete viral suppression did so after 24 weeks of tenofovir therapy.41

In a second phase III study in patients with HBeAg-negative CHB, tenofovir was also superior to adefovir in achieving increased viral suppression (93% vs. 63%), improved inflammatory score and viral suppression (71% vs. 49%).42 Recent 72-week data show that 98% of patients continued on tenofovir had serum HBV DNA <400 copies/mL, and 94% of patients who did not achieve complete viral suppression did so after 24 weeks of tenofovir therapy.43 Both adefovir and tenofovir were well tolerated in all of the above studies, with no evidence of significant renal toxicity. No resistance to tenofovir has been detected to date.

Emtricitabine

Emtricitabine is a nucleoside analogue structurally similar to lamivudine that is currently approved for use with other antiretroviral drugs in the treatment of human immunodeficiency virus (HIV) infection. It demonstrates activity against HBV and shares the same drug resistance mutation as lamivudine (M204V/I ± L180M). A 48-week course of therapy with emtricitabine is associated with a 62% improvement in fibrosis and inflammation compared to 25% in the placebo group. Viral suppression to <400 copies/mL was achieved in 54% vs. 2% in the emtricitabine and placebo groups respectively. Resistance development occurred in 9% of patients after 1 year and 13% after 2 years of therapy.44, 45 The rate of emergence of resistance and cross-resistance with lamivudine limits use of emtricitabine as monotherapy in management of CHB. However, it is a good candidate for use with other antiviral agents and is currently being tested in combination with tenofovir in the management of CHB.

Management of resistance

  1. Top of page
  2. Summary
  3. Introduction
  4. Natural history
  5. Prevention
  6. Treatment of chronic hepatitis B
  7. Approved therapies for treatment of chronic hepatitis B
  8. Management of resistance
  9. Roadmap for on-treatment management on hepatitis B
  10. Conclusions
  11. Acknowledgements
  12. References

Recommendations regarding management of CHB once antiviral drug resistance has emerged have been addressed in guidelines of the American Association for the Study of Liver Diseases (AASLD) and the US treatment algorithm (Table 2).10, 21 The terminology that has been employed to define antiviral drug resistance has varied in different publications.46, 47 Genotypic resistance is universally defined by the detection of viral populations bearing amino acid substitutions in the reverse transcriptase region of the HBV genome that have been shown to confer resistance to antiviral drugs in in vitro phenotypic assays.46 These genotypic mutations usually are detected in patients who have developed virological breakthrough (also called secondary treatment failure), defined as a ≥1 log10 increase in serum HBV DNA above nadir on two or more occasions 1 month apart while receiving treatment, but genotypic mutations can also be present in patients with persistent viraemia and no virological breakthrough. Biochemical breakthrough is defined as a rise in ALT levels after achieving normalization while continuing to receive therapy. Typically, genotypic resistance is followed after some variable time interval with virological breakthrough, followed later by biochemical breakthrough and possible clinical symptoms, sometimes called clinical breakthrough. Others have used the terminology of phenotypic resistance to refer either to virological breakthrough (≥1 log10 increase in serum HBV DNA above nadir, as defined above) or to virological rebound (increase in serum HBV DNA to >20 000 IU/mL or to above pre-treatment HBV DNA level after achieving a virological response) during continued treatment.47 Some experts suggest limiting the use the term phenotypic resistance to a decreased susceptibility of an HBV polymerase to an antiviral treatment in vitro.46

Table 2.   Management of drug resistance adapted from the recommendations of the AASLD and US algorithm for management of patients with drug resistance10, 21
Drug resistanceAASLDKeeffe et al.
  1. AASLD, American Association for the Study of Liver Diseases; ADV, adefovir dipivoxil; ETV, entecavir; FTC, emtricitabine; LdT, telbivudine; LMV, lamivudine; TDF, tenofovir.

LMVAdd ADV or TDF Stop LMV and switch to FTC/TDF combination Stop LMV and switch to ETV (pre-existing LMV resistance mutations predispose to ETV resistance)Add ADV (may be preferred over switch to ADV) Switch to ETV (risk for subsequent ETV resistance) Potential future management: add TDF or switch to FTC/TDF combination
ADVAdd LMV Stop ADV and switch to FTC/TDF combination Switch to or add ETVAdd LMV (may be preferred over switch to LMV) Switch to ETV (if no prior LMV resistance) Potential future therapy: switch to FTC/TDF combination
ETVSwitch to or add ADV or TDFAdd or switch to ADV or TDF
LdTAdd ADV or TDF Stop LdT and switch to FTC/TDF combination Stop LdT and switch to ETV (pre-existing LdT resistance mutations predispose to ETV resistance) 

Experience derived from HIV drug development and observations from the current treatment of CHB has identified risk factors for emergence of viral resistance: monotherapy, long duration of therapy and inappropriate use of antiviral drugs when not indicated. Despite advances in HBV genotypic resistance testing, not all mutations can be detected at present. Therefore, genotypic testing cannot be recommended prior to initiation of therapy unless the patient is undergoing treatment for CHB.47 Instead, patients receiving monotherapy need frequent monitoring for emergence of resistance by checking serum HBV DNA with a sensitive assay on a regular basis. The AASLD guideline advocates monitoring HBV DNA levels in patients with CHB every 3–6 months while on treatment.21 Patients receiving lamivudine therapy should be tested every 3–6 months, whereas patients on adefovir or entecavir every 6 months after the first year of therapy.47 Patients with cirrhosis should be tested every 3 months.10

Once a patient develops virological breakthrough, resistance testing is paramount in identifying mutations and guiding the choice of a different agent.10, 21, 47 After mutation analysis results are available, a swift change in therapy will result in a more rapid virological response than delayed change in therapy. Lampertico et al.48 have demonstrated improved early virological suppression at 3 months (100% vs. 46%) and 2 years (100% vs. 78%), and normalization of ALT at 1 year (100% vs. 93%) when adefovir was added at the time of genotypic resistance (3–6 log10 copies/mL, normal ALT), compared to the addition at the time of phenotypic resistance (>6 log10 copies/mL, elevated ALT levels).

Patients with lamivudine resistance can be successfully treated by adding or switching to adefovir,49, 50 or by switching to entecavir,51 resulting in viral suppression, normalization of ALT levels and histological improvement. However, current guidelines recommend the adding rather than switching to a nucleotide agent to minimize the subsequent development of resistance to the new agent. The addition of adefovir to lamivudine in HBeAg-negative lamivudine-resistant CHB has been shown to result in effective viral suppression without the development of adefovir resistance.50

Tenofovir is an effective treatment for treatment-experienced patients, especially those with lamivudine resistance; however, patients with previous therapy with adefovir and the presence of adefovir resistance mutations have an inferior response to tenofovir.52 In a retrospective analysis of 131 patients from 16 centres in Germany and the Netherlands treated with tenofovir between 2002 and 2006, 85% of patients overall achieved HBV DNA <400 copies/mL at the end of follow-up. The rates of undetectable serum HBV DNA after 12 months of tenofovir were 100% in those with no mutations, 92% in those with YMDD mutations and only 30% in those with adefovir resistance mutations.52 Because of high rates of resistance, entecavir is not recommended as monotherapy in patients with YMMD mutations. In addition, telbivudine and lamivudine have cross-resistance at codon 204, making a change to telbivudine alone or in combination with other therapy less desirable.

It is clear from experience with lamivudine and adefovir that monotherapy can be associated with the development of resistance in the case of drugs with a low genetic barrier to resistance. A combination of a nucleoside and nucleotide analogues provides better viral suppression with a higher genetic barrier to the emergence of resistance. Tenofovir and entecavir are currently the only drugs that have demonstrated a very low rate of resistance and thus are preferred drugs for monotherapy. The combination of lamivudine with an immune modulator, peginterferon alfa-2a, results in a lower rate of resistance compared with lamivudine monotherapy in a 48-week active treatment trial (1% vs. 18% respectively).24 The combination of adefovir and peginterferon also results in improved 24-week viral suppression compared to peginterferon monotherapy (71% vs. 41%).53

Roadmap for on-treatment management on hepatitis B

  1. Top of page
  2. Summary
  3. Introduction
  4. Natural history
  5. Prevention
  6. Treatment of chronic hepatitis B
  7. Approved therapies for treatment of chronic hepatitis B
  8. Management of resistance
  9. Roadmap for on-treatment management on hepatitis B
  10. Conclusions
  11. Acknowledgements
  12. References

The implications of genotypic resistance in patients with CHB make on-treatment monitoring vital. The ‘roadmap’ approach, an on-treatment monitoring and management strategy for patients receiving oral therapy, advocates making treatment decisions based on the serum HBV DNA levels at 12 and 24 weeks of therapy (Figure 2).54 Treatment failure is defined as <1 log10 IU/mL decrease in serum HBV DNA from baseline at week 12, presuming that patient noncompliance has been excluded. When treatment fails, switching to a more potent alternative agent is recommended.

image

Figure 2.  The roadmap approach to on-treatment management of patients with chronic hepatitis B receiving oral antiviral therapy.54

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The most important aspect of the roadmap is to assess virological response at week 24, with categorization of patients receiving oral agents into three response groups: complete response (HBV DNA <60 IU/mL), partial response (HBV DNA 60 to <2000 IU/mL) or inadequate response (HBV DNA >2000 IU/mL).54 Frequent monitoring for virological breakthrough is recommended every 3–6 months. Patients who achieve only a partial virological response at week 24 may need to change to a different therapy. For some, a second drug can be added that is not cross-resistant with the first drug. However, if they are being treated with a drug with a high genetic barrier to resistance, such as entecavir, patients can continue treatment to and beyond 48 weeks. In this situation, patients should undergo viral level testing every 3–6 months. Some drugs, such as adefovir, have a delayed antiviral effect, and these patients can potentially continue therapy and be monitored every 3 months with further assessment at week 48. If their virological response remains partial or becomes inadequate at this time point, as defined by the roadmap (Figure 2), therapy should be changed. An exception might be a serum HBV DNA level that has been falling steadily and is nearly undetectable. If the response becomes complete at week 48, the therapy can be continued.

Patients with an inadequate virological response at week 24 need to switch to a different, more effective drug.54 Alternatively, a second drug without cross-resistance can be added to the first drug. The patient should then be monitored every 3 months up to week 48. If the serum HBV DNA level falls to undetectable levels at week 48, the HBV DNA testing can be decreased to every 6 months. However, patients with advanced disease should continue to be monitored every 3 months, regardless of their response to treatment.

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Natural history
  5. Prevention
  6. Treatment of chronic hepatitis B
  7. Approved therapies for treatment of chronic hepatitis B
  8. Management of resistance
  9. Roadmap for on-treatment management on hepatitis B
  10. Conclusions
  11. Acknowledgements
  12. References

Chronic hepatitis B (CHB) is a disease that is preventable with vaccination. The goal of therapy in patients with CHB is to prevent progression to cirrhosis, liver failure and HCC. This goal is best accomplished by achieving a rapid and long-lasting virological suppression. Combination therapy, especially with nucleoside/nucleotide analogues, may be the ultimate and ideal approach to achieve these goals. However, further clinical studies are needed for confirmation of pilot study results of combination therapy. The proposed roadmap approach will help clinicians make changes to therapy with the guidance of mutation analysis results before biochemical or clinical breakthrough occurs. With more drugs in development and the expected approval of tenofovir in 2008, the arsenal against HBV continues to expand. Tenofovir is a potent agent with a high genetic barrier, and will probably emerge along with entecavir as the most effective treatments for patients with CHB. Although tenofovir monotherapy has not yet been associated with the development of resistance, results after prolonged use remain to be determined.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Natural history
  5. Prevention
  6. Treatment of chronic hepatitis B
  7. Approved therapies for treatment of chronic hepatitis B
  8. Management of resistance
  9. Roadmap for on-treatment management on hepatitis B
  10. Conclusions
  11. Acknowledgements
  12. References

Declaration of personal and funding interests: W. S. Ayoub has nothing to declare. E. B. Keeffe is an employee of Romark Laboratories, L. C. and has served as a consultant and advisory board member for Bristol-Myers Squibb, Gilead, Idenix, Novartis and Roche.

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  2. Summary
  3. Introduction
  4. Natural history
  5. Prevention
  6. Treatment of chronic hepatitis B
  7. Approved therapies for treatment of chronic hepatitis B
  8. Management of resistance
  9. Roadmap for on-treatment management on hepatitis B
  10. Conclusions
  11. Acknowledgements
  12. References
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