Book on hepatitis from page 156 to 167

Book on hepatitis from page 156 to 167

156  Hepatology 2012
Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil
for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology
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virus infection. J Hepatol 2011;55:1215-21. (Abstract)
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fumarate treatment for chronic hepatitis B. Gastroenterology 2011;140:132-43.
(Abstract)
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(Abstract)
Keeffe EB, Zeuzem S, Koff RS, Dieterich DT, et al. Report of an international workshop:
Roadmap for management of patients receiving oral therapy for chronic hepatitis B.
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Kumar M, Satapathy S, Monga R, et al. A randomized controlled trial of lamivudine to treat
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lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients.
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European Association for the Study of the Liver; April 14-18, 2010; Vienna, Austria.
Abstract 1009.
Lange CM, Bojunga J, Hofmann WP, et al. Severe lactic acidosis during treatment of chronic
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Hepatitis B Treatment  157
Leung NJ. Entecavir (ETV) therapy in chronic hepatitis B patients previously treated with
adefovir (ADV) with incomplete response on-treatment or relapse off-treatment.
Hepatology 2009;50:S334.
Leung N, Peng CY, Hann HW, et al. Early hepatitis B virus DNA reduction in hepatitis B e
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Suboptimal Response to Adefovir (ADV) or ADV/LAM Treatment: Results of the
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Liaw YF, Leung NW, Chang TT, et al. Effects of extended lamivudine therapy in Asian patients
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(Abstract)
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(Abstract)
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entecavir in patients with decompensated chronic hepatitis B liver disease.
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chronic hepatitis B. Gastroenterology 2000;119:172-80.
Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007 ;45:507-39. (Abstract)
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Manesis EK, Hadziyannis SJ. Interferon alpha treatment and retreatment of hepatitis B e
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Liver Diseases (AASLD 2009). Boston 2009b, Abstract 387.
Marcellin P, Buti M, Gane EJ, et al. Five,years of treatment with tenofovir DF (TDF) for chronic
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2011;54:1011A.
Marcellin P, Heathcote J, Buti M, et al. Characterization of HBsAg seroconversion in patients
with chronic hepatitis B (CHB) treated with tenofovir disoproxil fumarate (TDF).
Hepatology 2011;54:1036A.
Mauss S, Berger F, Filmann N, et al. Effect of HBV polymerase inhibitors on renal function in
patients with chronic hepatitis B. J Hepatol 2011;55:1235-40. (Abstract)
McMahon BJ, Alward WL, Hall DB, et al. Acute hepatitis B virus infection: relation of age to the
clinical expression of disease and subsequent development of the carrier state. J
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Mommeja-Marin H, Mondou E, Blum MR, Rousseau F. Serum HBV DNA as a marker of
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literature. Hepatology 2003;37:1309-19. (Abstract)
Moses SE, Lim ZY, Sudhanva M, et al. Lamivudine prophylaxis and treatment of hepatitis B
virus-exposed recipients receiving reduced intensity conditioning hematopoietic stem
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158  Hepatology 2012
Moucari R, Mackiewicz V, Lada O, et al. Early serum HBsAg drop: a strong predictor of
sustained virological response to pegylated interferon a-2a in HBeAg-negative
patients. Hepatology 2009;49:1151-7. (Abstract)
Moucari R, Korevaar A, Lada O, et al. High rates of HBsAg seroconversion in HBeAg-positive
chronic hepatitis B patients responding to interferon: a long-term follow-up study. J
Hepatol 2009;50:1084-92. (Abstract)
Ning Q, Han MF, Sun YT, et al. Patients with HBeAg-positive chronic hepatitis B with a
maintained virologic response to entecavirachieved HBsAg clearance when switched
to peginterferon alfa-2a (40KD) therapy (the OSST study). Hepatology
2011;54:1010A.
Papatheodoridis GV, Manolakopoulos S, Touloumi G, et al. Virological suppression does not
prevent the development of hepatocellular carcinoma in HBeAg-negative chronic
hepatitis B patients with cirrhosis receiving oral antiviral(s) starting with lamivudine
monotherapy: results of the nationwide HEPNET. Greece cohort study. Gut
2011;60:1109-16.
Park JW, Park KW, Cho SH, et al. Risk of hepatitis B exacerbation is low after transcatheter
arterial chemoembolization therapy for patients with HBV-related hepatocellular
carcinoma: report of a prospective study. Am J Gastroenterol 2005;100:2194-200.
(Abstract)
Perrillo RP, Lai CL, Liaw YF, et al. Predictors of HBeAg loss after lamivudine treatment for
chronic hepatitis B. Hepatology 2002;36:186-94. (Abstract)
Perrillo RP, Schiff ER, Davis GL, et al. A randomized, controlled trial of interferon alpha-2b
alone and after prednisone withdrawal for the treatment of chronic hepatitis B. N Engl
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Petersen J, Ratziu V, Buti M, et al. Entecavir plus tenofovir combination as rescue therapy in
pre-treated chronic hepatitis B patients: An international multicenter cohort study. J
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Rehermann B, Ferrari C, Pasquinelli C, Chisari FV. The hepatitis B virus persists for decades
after patients' recovery from acute viral hepatitis despite active maintenance of a
cytotoxic T-lymphocyte response. Nat Med 1996;2:1104-8. (Abstract)
Reijnders JG, Pas SD, Schutten M, et al. Entecavir shows limited efficacy in HBeAg-positive
hepatitis B patients with a partial virologic response to adefovir therapy. J Hepatol
2009;50:674-83. (Abstract)
Reijnders JG, de Vries-Sluijs T, Hansen BE, et al. Five years tenofovir therapy is associated
with maintained virologic response, but significant decline in renal function in
HIV/HBV coinfected patients. 60th Annual Meeting of the American Association for
the Study of Liver Diseases (AASLD 2009). Boston 2009a. Abstract 425.
Roche B, Samuel D. The difficulties of managing severe hepatitis B virus reactivation. Liver Int
2011;31:104-10. (Abstract)
Rutgeerts P, Vermeire S, Van Assche G. Biological therapies for inflammatory bowel diseases.
Gastroenterology. 2009;136:1182-97. (Abstract)
Schiff ER, Lee SS, Chao YC, et al. Long-term treatment with entecavir induces reversal of
advanced fibrosis or cirrhosis in patients with chronic hepatitis B. Clin Gastroenterol
Hepatol. 2011;9:274-6. (Abstract)
Sherman M, Yurdaydin C, Simsek H, et al. Entecavir therapy for lamivudine-refractory chronic
hepatitis B: improved virologic, biochemical, and serology outcomes through 96
weeks. Hepatology 2008;48:99-108.
Seto WK, Lai CL, Fung J, et al. Significance of HBV DNA levels at 12 weeks of telbivudine
treatment and the 3 years treatment outcome. J Hepatol 2011;55:522-8. (Abstract)
Snow-Lampart A, Chappell B, Curtis M, et al. No resistance to tenofovir disoproxil fumarate
detected after up to 144 weeks of therapy in patients monoinfected with chronic
hepatitis B virus. Hepatology 2011;53:763-73.
Sonneveld MJ, Rijckborst V, Boucher CA, et al. Prediction of sustained response to
peginterferon alfa-2b for hepatitis B e antigen-positive chronic hepatitis B using on-treatment hepatitis B surface antigen decline. Hepatology 2010;52:1251-7.
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for the treatment of HBeAg-positive chronic hepatitis B. J Hepatol 2008;48:728-35.
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159
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infection after delivery. J Viral Hepat 2008;15:37-41. (Abstract)
Tillmann HL, Hadem J, Leifeld L, et al. Safety and efficacy of lamivudine in patients with severe
acute or fulminant hepatitis B, a multicenter experience. J Viral Hepat 2006;13:256-63. (Abstract)
Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring shows hepatitis B virus
resistance to entecavir in nucleoside-naïve patients is rare through 5 years of
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the mortality and morbidity of active chronic hepatitis B. Hepatology 2009;50:743-751. (Abstract)
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infections resistant against adefovir. Hepatology 2007;46:664A.
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for hepatitis B virus-monoinfected patients after failure of nucleoside/nucleotide
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van Zonneveld M, van Nunen AB, Niesters HG, et al. Lamivudine treatment during pregnancy
to prevent perinatal transmission of hepatitis B virus infection. J Viral Hepat
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tenofovir: a first case report. Am J Kidney Dis 2002;40:1331-3. (Abstract)
Vassilopoulos D, Calabrese LH. Risks of immunosuppressive therapies including biologic
agents in patients with rheumatic diseases and co-existing chronic viral infections.
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history of chronic hepatitis B and decline during adefovir dipivoxil therapy.
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Wiegand J, Wedemeyer H, Finger A, et al. A decline in hepatitis B virus surface antigen
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160  Hepatology 2012
10. Management of Resistance in HBV
Therapy
Stefan Mauss and Heiner Wedemeyer
Introduction
Interferon monotherapy has been the standard of care for chronic hepatitis B since
the mid-1990s. Primary resistance to interferon presents as lack of HBe or HBs
antigen loss or seroconversion. Interferon-induced immune control of HBV is less
frequently reported for HBV genotypes B, C and D than for HBV genotype A
(Erhardt 2005, Flink 2006). However, the development of resistance mutations to
interferon while on therapy has not been reported to date. Recently, in patients with
chronic hepatitis C, a genetic polymorphism at locus IL28B has been identified as a
host factor associated with response to interferon-based therapy (Ge 2009). If
similar host factors exist for response to interferon therapy in chronic hepatitis B,
they are not known. However, a recent paper did demonstrate an association of the
natural history of hepatitis B infection and genetic variants in the HLA-DP locus
(Kamatami 2009).
Since the introduction of lamivudine, treatment of chronic hepatitis B has been
characterised by a rapid increase in the number of available antiviral drugs, all
belonging to the class of HBV polymerase inhibitors (Figure 1). Due to better
tolerance and more  convenient administration compared to interferon, HBV
polymerase inhibitors today account for the vast majority of prescribed therapies for
chronic hepatitis B in Western countries. However, due to the slow kinetics of
immune control, long-term suppression of HBV is needed, particularly in HBeAg-negative patients harbouring the precore mutant. This is due to the high relapse rate
after discontinuation of antiviral therapy in patients with precore mutants in the
absence of HBs antigen seroconversion. HBs antigen seroconversion is a rare event
in the first years of treatment.
For this reason, the understanding of resistance and cross-resistance of HBV
polymerase inhibitors is relevant in long-term treatment strategies. Suboptimal
antiviral therapy resulting in the development of early resistance will harm future
treatment options and lead to progressive liver disease, especially in those with
Management of Resistance in HBV Therapy  161
limited treatment options (Brunelle 2005, Kurashige 2009). In addition, some HBV
polymerase variants may interact with immunologically relevant epitopes of the
envelope resulting in immune escape mutants. These mutants may be able to
successfully infect vaccinated individuals. Although this finding is currently an in
vitro observation, any confirmation of this phenomenon in patients will result in a
serious public health concern, particularly in countries with a high prevalence of
hepatitis B.
Figure 1. Proportion of patients with undetectable HBV DNA after 48 or 52 weeks of
treatment. Data does not represent “head-to-head” trials (based on Heathcote 2007, Lai 2006,
Liaw 2009, Marcellin 2003, Marcellin 2007).
Antiviral HBV therapy – how to avoid resistance
Treatment of HBV is relatively safe and easy compared to hepatitis C treatment or
HIV therapy. But avoiding the induction of resistance is one of the critical efforts
that need to be made by physicians and patients. They need to choose the right
therapy and monitoring schedule, and pay close attention to good adherence.
Entecavir and tenofovir have proven efficacy and very little or no resistance in
treatment-naïve patients in the first years of therapy (Heathcote 2011,Yuen 2011).
In patients with limited HBV replication, telbivudine has also shown good results,
although in patients with high viral load treatment results can be compromised by
the development of resistance, also true for adefovir and lamivudine (Zeuzem
2009).
As previously stated, treating patients for longer periods with HBV polymerase
inhibitors can result in the development of viral resistance – particularly in patients
with less than optimal viral suppression (Lai 2006). In particular, lamivudine and
telbivudine are prone to developing resistance rapidly. Therapy with HBV
polymerase inhibitors needs to fully suppress viral replication (HBV DNA <300
copies/ml). HBV DNA should be monitored after the first 4-6 weeks of therapy to
assess adherence and then every 3-6 months while on therapy. If complete viral
162  Hepatology 2012
suppression determined by an ultrasensitive assay is not achieved on monotherapy
within the first 6 months on lamivudine, telbivudine or adefovir, treatment should
be switched to tenofovir or entecavir. In patients on either tenofovir or entecavir,
combination therapy with non-cross-resistant HBV polymerase inhibitors may be
considered after 12 months in case a plateau of viral replication is reached. There is
only one study to date showing a stronger efficacy of combination therapy in
patients with high viral load comparing entecavir monotherapy with entecavir plus
tenofovir (Lok 2011). For tenofovir the benefit of adding a second drug has not been
assessed prospectively.
Resistance to nucleoside polymerase inhibitors, i.e., lamivudine, telbivudine,
emtricitabine or entecavir, eliminates or markedly reduces antiviral efficacy of all
other nucleosides and may affect even nucleotide polymerase inhibitors due to
cross-resistance.
Resistance can also be associated with significant flares of hepatitis and has been
associated with a higher rate of clinical complications in one Asian study (Liaw
2004) and with a lower overall survival in an Italian cohort (DiMarco 2004).
Therefore, resistance needs to be avoided, particularly in patients with liver
cirrhosis. Based on these severe consequences of treatment failure, we would
recommend selecting a drug with a high genetic barrier for antiviral resistance in
cirrhotic individuals.
Treatment endpoints
In HBe antigen-positive patients infected with wild-type HBV strains HBeAg
seroconversion has been shown to be associated with a reduction in liver-associated
morbidity and increased survival (Niederau 1996). Thus, HBe antigen
seroconversion is considered a clinical endpoint in this patient population and
discontinuation of HBV polymerase inhibitors is recommended 6-12 months after
HBe antigen seroconversion in those who have not developed liver cirrhosis
(Cornberg 2007). HBe antigen loss is reported in up to 50% of patients treated with
HBV polymerase inhibitors after prolonged periods – several years - of therapy
(Hadziyannis 2006). Recent cohort data sheds some doubt on the durability of HBe
antigen seroconversion via therapy with polymerase inhibitors, with reported
relapse rates of about 50%, which is considerably higher than with interferon-induced HBe antigen seroconversion (Reijinders 2010).
Treatment with pegylated interferon alfa-2a for 48 weeks results in HBe antigen
seroconversion and a very low relapse rate in about a third of patients (Lau 2005).
Discontinuation of HBV polymerase inhibitor therapy in patients without HBe
antigen seroconversion usually results in relapse of chronic hepatitis B. With
interferon, the situation may become more complex and is at least partially
dependent on the HBV genotype in addition to the HBe antigen status (Erhardt
2005, Erhardt 2010).
HBV polymerase inhibitors treatment endpoints in HBe antigen-negative hepatitis
B in most cases are restricted to sustained normalisation of ALT levels, suppression
of HBV DNA and improvement in liver histology, as HBs antigen seroconversion is
rare with current treatment options. Consequently, treatment duration and endpoints
are more difficult to define in these patients. Reappearance of HBV DNA after
stopping HBV polymerase inhibitor treatment is observed in almost all patients,
Management of Resistance in HBV Therapy  163
even after fully suppressive treatment for multiple years (Marcellin 2004, Petersen
2011). Most guidelines therefore recommend indefinite treatment of HBe antigen-negative patients without HBs antigen seroconversion.
PEG-IFN α-2a has also been studied in HBe antigen-negative hepatitis B leading
to a 6-month off-treatment response (HBV DNA <400 copies/ml) in up to 20% of
patients (Marcellin 2004). HBs antigen seroconversion happens in about 5% of
patients after a year of treatment with PEG-IFN. In addition, about 20% of patients
reach a low replicative status of their chronic hepatitis B, at least temporarily, after
interferon discontinuation (Bonino 2007). After an observational period of five
years after one year of interferon-based therapy, the seroconversion rate increases to
12% (Marcellin 2009). For HBV polymerase inhibitors HBs antigen seroconversion
has been reported for HBe antigen negative patients in less than 5% of patients in
published prospective studies.
Resistance patterns of HBV polymerase inhibitors
Lamivudine was the first approved HBV polymerase inhibitor. It is characterized by
good clinical tolerability, moderate antiviral efficacy and rather quick development
of resistance in cases of not fully suppressive antiviral therapy (Figure 2). Within
the first year of therapy up to 20% of patients may develop mutations in the YMDD
motif associated with loss of activity against HBV. About 70-80% of patients
without HBe antigen seroconversion develop lamivudine-resistant variants after
four or more years of therapy (Figure 2).
Figure 2. Cumulative incidence of HBV polymerase inhibitor resistance. These numbers
are average estimates based on numerous studies. Resistance rates differ between trials
and cohorts. Overall, resistance rates have been higher in HBe antigen-positive patients than in
HBe antigen-negative patients. Long-term data for adefovir has only been reported for HBe
antigen-negative patients and thus resistance rates may be even higher for HBe antigen-positive individuals. Data for entecavir is biased since both patients with best responses (e.g.,
HBe antigen seroconversion) and patients with suboptimal virological responses (>700,000
copies/ml after one year of treatment) were withdrawn from the study.
164  Hepatology 2012
Lamivudine mutations confer cross-resistance to telbivudine, emtricitabine and
entecavir. Preliminary data indicate that the development of multiple lamivudine-associated mutations may even reduce the efficacy of tenofovir therapy (Lada
2008).
Emtricitabine has comparable antiviral properties and a similar resistance profile
to lamivudine (Lim 2006). However it is only approved as an antiretroviral
medication for HIV, not for treatment of chronic hepatitis B. In HBV, its use is
mainly limited as part of combination therapy with tenofovir in HIV-coinfected
patients with an indication for antiretroviral therapy.
Telbivudine has shown superior antiviral efficacy compared to lamivudine in HBe
antigen-positive and -negative patients. However, development of resistance is
considerable in naïve patients with highly replicative hepatitis B and the resistance
pattern is essentially the same as that of lamivudine, resulting in complete cross-resistance of the two compounds (Liaw 2009, Zeuzem 2009) (Table 1). Outcomes
are better and antiviral efficacy more sustained in patients with an HBV DNA of
less than 10
6
IU/ml (Zeuzem 2009). Combination therapy of telbivudine and
lamivudine does not improve the antiviral efficacy nor does it delay the
development of resistance compared to telbivudine monotherapy (Lai 2005).
Figure 3. Resistance patterns of different antiviral drugs used for the treatment of
chronic hepatitis B. The numbers indicate the respective amino acid position in the HBV
polymerase gene. For entecavir, resistance at positions 204/180 plus an additional mutation at
position 184, 202 or 250 is required to lead to clinically significant drug resistance. Most but not
all variants have been shown to be associated with drug resistance both in vitro and in vivo.
Adefovir was the second approved HBV polymerase inhibitor. It has full activity
in lamivudine-resistant patients. However, its antiviral potency is limited by its
nephrotoxicitiy. Due to tubular damage of the kidney, the approved dose is limited
to 10 mg/day, although 30 mg/day showed superior antiviral efficacy (Marcellin
2003). The reduced antiviral potency is counterbalanced, however, by a favourable
resistance profile. Development of resistance occurs later and to a lesser extent
compared to lamivudine or telbivudine (Figure 3), although resistance to adefovir
Management of Resistance in HBV Therapy  165
may occur more often in patients with pre-existing lamivudine resistance (Lee
2006). No association of response to treatment with HBV genotypes was evident in
the registrational trials (Westland 2003).
Table 1. Recommendations in secondary treatment failure of HBV polymerase
inhibitors.
Resistance against
nucleoside analogs
Recommended therapeutic option
Lamivudine  Tenofovir, adefovir*
Telbivudine  Tenofovir, adefovir*
Entecavir  Tenofovir, adefovir*
Resistance against
nucleotide analogs
Recommended therapeutic option
Adefovir (LAM-naïve)  Entecavir, tenofovir, (telbivudine), (lamivudine)
Adefovir (LAM-resistant)  tenofovir
Tenofovir (no in vivo data available)  Entecavir, (telbivudine), (lamivudine)
*in case tenofovir is not available
Adefovir-resistant or non-responding HBV strains seem to respond to tenofovir
with a slower viral decline, but without signs of true cross-resistance (Berg 2008,
Van Bömmel 2010). Adefovir resistant strains respond fully to entecavir therapy
(Reijinders 2010).
The combination of adefovir plus lamivudine in the presence of lamivudine
resistance delays the development of adefovir resistance considerably compared to
switching to adefovir monotherapy (Lampertico 2006, Lampertico 2007).
Entecavir is an HBV nucleoside polymerase inhibitor with good antiviral efficacy
and slow development of resistance in treatment-naïve patients (Chang 2006, Lai
2006, Lampertico 2009). This is due to the fact that more than one mutation in the
HBV polymerase gene is required to confer resistance to entecavir. However,
entecavir shares some resistance mutations with lamivudine and telbivudine. The
presence of lamivudine resistance mutations at L180M, M204I, L180M + M204V
facilitates the development of resistance to entecavir because only one additional
mutation is required for the development of full resistance. As a result, in contrast to
treatment of naïve patients where entecavir is clearly superior to lamivudine, its
antiviral potency is markedly reduced in patients with lamivudine resistance and up
to 40% of lamivudine-resistant patients develop full entecavir resistance after 3
years of treatment (Tenney 2007, Colonno 2007).
Patients with resistance only to adefovir have favourable treatment results with
entecavir, while patients with combined adefovir and lamivudine resistance do not
respond well to entecavir monotherapy (Reijnders 2007, Nguyen 2009, Chloe 2009,
Shim 2009).
Tenofovir is approved for the treatment of HIV and HBV. Early data from HBV/
HIV-coinfected patients showed a strong antiviral potency and slow development of
resistance (Núñez 2002, Nelson 2003, van Bommel 2004). In its registrational trials,
tenofovir was superior to adefovir resulting in substantially higher rates of full viral
suppression in HBe antigen-positive (tenofovir 69% vs. adefovir 9%, HBV DNA
<40 IU/ ml) and HBe antigen-negative patients (tenofovir 91% vs. adefovir 56%
HBV DNA <40 IU/ml) at 52 weeks of therapy (Heathcote 2009, Marcellin 2008). In
166  Hepatology 2012
HIV-positive patients, anecdotal cases of renotubular dysfunction were reported.
Otherwise tenofovir is well-tolerated. It is active in lamivudine-resistant patients
(Schmutz 2006, Manns 2009). So far, no obvious resistance patterns to tenofovir
associated with antiviral failure in trials and cohorts have been observed (Snow-Lampart 2010).
The acquisition of adefovir resistance mutations and multiple lamivudine
resistance mutations may impair the activity of tenofovir (Fung 2005, Lada 2008,
van Bömmel 2010), although even in these situations tenofovir retains activity
against HBV (Berg 2008, Petersen 2009).
Combination therapy of chronic hepatitis B to
delay development of resistance
Combination therapy is thought to be superior to monotherapy, particularly in
patients with highly replicative hepatitis B (HBV DNA >10
9
copies/ml). However,
so far the response rate in trials assessing the long-term efficacy of tenofovir and
entecavir show a long-acting antiviral effect even in patients with high viral load
and little to no development of resistance (Snow-Lampart 2011). Trials assessing de
novo combination therapy versus monotherapy are limited. The experience with
combining telbivudine and lamivudine suggests that combinations of two nucleoside
analogs with an overlapping resistance profile do not have an additive antiviral
effect (Lai 2005). In contrast, combining a nucleoside with a nucleotide polymerase
inhibitor with different resistance profiles may be of benefit (Sung 2008, Lok 2011).
Trials that will provide more evidence on how to best use the current antiviral
options are currently underway or are being designed. However, these trials may
require larger patient numbers than currently included and may need longer
observational periods due to  agents like entecavir and tenofovir having such
considerable efficacy as monotherapy. However, it should be remembered that – in
contrast to HIV – immune control of HBV is possible, limiting the duration of
therapy in particular in HBe antigen-positive patients. With the availability of HBV
polymerase inhibitors with high resistance barriers, even treatment-naïve patients
with high levels of HBV replication should be treated initially with one drug. In
patients with considerable viral replication despite good adherence a possible option
is to add a non-cross-resistant drug in order to maximise viral suppression and to
avoid development of resistance.
Management of drug resistance
Primary and secondary treatment failure has to be distinguished in the treatment of
hepatitis B. A clinically sufficient primary response after 6 months is defined by a
reduction of HBV DNA to at least <10
3
copies/ml (200 IU/ml) or by a continuous
drop of HBV DNA through month 12. In contrast, if a rise in HBV DNA by one log
or more is observed while on antiviral therapy, a secondary resistance or non-adherence is very likely to be present. HBV resistance usually arises several months
before biochemical relapse with elevation of transaminases, thus regular HBV DNA
monitoring is required during antiviral therapy (e.g., every 3 months) (Cornberg
2007). Testing for variants associated with resistance might be useful if HBV DNA
levels rise during treatment.
Management of Resistance in HBV Therapy  167
Most viral breakthroughs in treatment-naïve patients on entecavir or tenofovir are
the result of adherence issues. Therefore, patient adherence should be assessed
before genotypic resistance testing is done.
Additional compensatory mutations can develop if monotherapy is continued
despite HBV resistance, thereby broadening the possibilities of cross-resistance
(Locarnini 2004). Knowledge of the antiviral efficacy, the resistance barrier, and the
resistance profile of each available oral antiviral is a prerequisite for the rational use
of nucleos(t)ide analogs for hepatitis B. In the case of resistance to a nucleoside
analog  (lamivudine, telbivudine, emtricitabine, entecavir), early replacement by
tenofovir or add-on treatment with adefovir (if tenofovir is not available) is
recommended. In the opposite scenario, a nucleoside addition to current nucleotide
treatment should happen if adefovir or tenofovir treatment failure begins to occur
(Figure 4). In the case of adefovir, switching from adefovir to tenofovir should be
assessed as an additional measure.
Historically, most data generated has been from patients with lamivudine
resistance. In this setting the advantage of adding adefovir rather than switching to
adefovir is well-established (Lampertico 2005,  Lampertico 2007). Moreover,
adefovir should be added early at low HBV DNA levels, when a rise in HBV DNA
has been confirmed but before a biochemical relapse has occurred. Today, the most
appropriate strategy may be a switch to tenofovir with or without continuation of
lamivudine (Manns 2009).
Figure 4. Mutations in the HBV polymerase. Due to the overlapping reading frame between
HBV polymerase and envelope sequences, mutations in the HBV polymerase, in particular at
codons 173, 180 and 204, may lead to changes in the conformation of immunodominant
domains of the HBV envelope.