Hepatology - 2007 - Hoofnagle - Management of Hepatitis B Summary of A Clinical Research Workshop

REVIEW
Management of Hepatitis B: Summary of a Clinical

Research Workshop
Jay H. Hoofnagle,1 Edward Doo,1 T. Jake Liang,2 Russell Fleischer,3 and Anna S.F. Lok4
Chronic hepatitis B is caused by persistent infection with the hepatitis B virus (HBV), a unique
DNA virus that replicates through an RNA intermediate produced from a stable covalently closed
circular DNA molecule. Viral persistence appears to be due to inadequate innate and adaptive
immune responses. Chronic infection has a variable course after several decades resulting in
cirrhosis in up to one-third of patients and liver cancer in a proportion of those with cirrhosis.
Sensitive assays for HBV DNA levels in serum have been developed that provide important
insights into pathogenesis and natural history. Therapy of hepatitis B is evolving. Peginterferon
induces long-term remissions in disease in one-third of patients with typical hepatitis B e antigen
(HBeAg) positive chronic hepatitis B, but a lesser proportion of those without HBeAg. Several
oral nucleoside analogues with activity against HBV have been shown to be effective in suppress-
ing viral levels and improving biochemical and histological features of disease in a high propor-
tion of patients with and without HBeAg, at least in the short term. What is uncertain is which
agent or combination of agents is most effective, how long therapy should last, and which criteria
should be used to start, continue, switch or stop therapy. Long-term therapy with nucleoside
analogues may be the most appropriate approach to treatment, but the expense and lack of data
on long-term safety and efficacy make recommendations difficult. Clearly, many basic and
clinical research challenges remain in defining optimal means of management of chronic hepa-
titis B. (HEPATOLOGY 2007;45:1056-1075.)
I
n the last decade, important advances have been made have provided the basis for developing therapies, and
in the understanding of the hepatitis B virus (HBV), knowledge of the natural history has provided the basis for
the disease that it causes, and its treatment. Insights indications for treatment. Six therapies are now licensed
from the viral life cycle and pathogenesis of hepatitis B for chronic hepatitis B and several more are likely to be
available in the near future. Despite these advances, the
optimal approach to management of hepatitis B remains
Abbreviations: HBV, hepatitis B virus; NIH, National Institutes of Health; unclear. What are the important elements in evaluation of
FDA, Food and Drug Administration; AASLD, American Association for the Study
of Liver Disease; HBsAg, hepatitis B surface antigen; anti-HBs, antibody to HBsAg; patients? Which patients should be treated? With which
HBcAg, hepatitis B core antigen; anti-HBc, antibody to HBcAg; HBeAg, hepatitis agent or combination of agents? For how long? Using
B e antigen; anti-HBe, antibody to HBeAg; ccc DNA, covalently closed circular what factors to decide whether to continue, discontinue,
DNA; DHBV, duck hepatitis B virus; TNF␣, tumor necrosis factor alpha; HCC,
hepatocellular carcinoma; ALT, alanine aminotransferase; HR, hazards ratio;
or switch antiviral therapy? These questions provided the
HAI, histology activity index; PCR, polymerase chain reaction; basis for a clinical research workshop sponsored by the
From the 1Liver Disease Research Branch and 2Liver Diseases Branch, National Liver Disease Research Branch of the National Institutes
Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of
Health, Bethesda, MD; 3Division of Antiviral Products, Food and Drug Adminis-
of Health (NIH) with support and collaboration from the
tration, Silver Spring, MD; and 4Division of Gastroenterology, University of Mich- Food and Drug Administration (FDA), the American As-
igan Medical Center, Ann Arbor, MI. sociation for the Study of Liver Diseases (AASLD), the
Received December 15, 2006; accepted January 2, 2007.
Supported in part by the Intramural Division of the National Institute of Diabetes
Hepatitis B Foundation, the Hepatitis Foundation Inter-
and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health. national, and the American Liver Foundation. The meet-
Address reprint requests to: J.H. Hoofnagle, Bldg 31, Room 9A27, 31 Center ing included 436 participants and 42 speakers and
Drive, NIH, Bethesda, MD 20892. E-mail: [email protected]; fax:
moderators who met for 3 days to survey the current
301-480-7926.
Copyright © 2007 by the American Association for the Study of Liver Diseases. understanding of the pathogenesis, natural history, com-
Published online in Wiley InterScience (www.interscience.wiley.com). plications, virological and histological manifestations,
DOI 10.1002/hep.21627
and means of treatment of hepatitis B. This manuscript
Potential conflict of interest: Dr. Lok is a consultant and received grants from
GlaxoSmithKline, Bristol-Myers Squibb, Idenix, Gilead, Roche, and Innoge- summarizes the presentations and final recommendations
netics. from that meeting.
1056
15273350, 2007, 4, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.21627 by Karadeniz Technical University, Wiley Online Library on [25/04/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
HEPATOLOGY, Vol. 45, No. 4, 2007 HOOFNAGLE ET AL. 1057
Fig. 1. HBV Life Cycle: HBV enters the hepatocyte medi-

ated by receptor binding, followed by internalization, uncoat-
ing of virion DNA and delivery to the nucleus. The virion DNA
is repaired and converted to circular covalently closed (ccc)
HBV DNA from which HBV RNA is transcribed in several forms
for translation of HBV antigens (HBcAg, HBsAg and polymer-
ase [pol]) and for viral replication through encapsidation of
the RNA pregenome (pg RNA) mediated by the encapsidation
signal (⑀). Within core particles, negative followed by positive
strand viral DNA is synthesized directed by the HBV polymer-
ase while pregenome RNA is degraded by the polymerase
RNase H activity. The core particle with doubled stranded HBV
DNA is transferred to the endoplasmic reticulum (ER) where
it is coated with glycosylated and myristoylated HBsAg pro-
ducing intact virions that exit the cell by budding and vesic-
ular transport. (Reprinted from Gastroenterology, Volume
120, Doo E and Liang TJ, Molecular anatomy and pathophys-
iologic implications of drug resistance in hepatitis B virus
infection, pages 1000-1008, Copyright 2001, with permis-
sion from the American Gastroenterological Association.)
Hepatitis B Virus positive DNA strand from the newly synthesized negative
strand. The nucleocapsid then assembles with HBsAg
HBV is a member of the family hepadnaviridae, viruses molecules in the endoplasmic reticulum to form the
with a double-stranded circular DNA genome that repli-
virion and is secreted from the cell, probably by vesicular
cates through an RNA intermediate.1 HBV infects only
transport and budding from the plasma membrane.
humans and higher apes, but other similar hepadnaviruses
HBV is non-cytopathic, and the cellular injury of hep-
are endemic in rodent and bird species. The virus is de-
atitis B appears immune-mediated.5 Most persons ex-
tectable in serum in high levels and on electron micros-
posed to HBV have a transient infection which may or
copy is a 50 nm double-shelled particle with an outer
may not be accompanied by symptoms and jaundice. In a
envelop (HBsAg) and an inner nucleocapsid (HBcAg)
proportion, however, chronic infection ensues as a result
protein.2 Within the nucleocapsid is a partially double-
of failure of the host immune response to eliminate virus.
stranded, circular molecule of HBV DNA. The HBV
genome is ⬇3.2 kb in length and replicates in a unique Viral clearance is mediated by both cytopathic and non-
manner through an RNA intermediate. The genome en- cytopathic mechanisms, the existence of both pathways
codes four open reading frames for surface, core, polymer- being supported by extensive evidence in cell culture and
ase, and X genes. The core gene can also produce a soluble animal models.5 Cytopathic clearance is based on direct
small molecular weight protein called hepatitis B e anti- killing of virus-harboring hepatocytes by virus-specific T
gen (HBeAg) by an alternate start codon and post-trans- cells, followed by compensatory proliferation of hepato-
lational modification. The virus gains entry into cytes. This proliferation may also result in gradual loss of
hepatocytes, the primary site of infection, through yet cccDNA. Uninfected hepatocytes are protected from re-
undefined pathways and receptors (Fig. 1).3 After entry, infection through induction of neutralizing antibodies
HBV DNA is transported to the nucleus and converted to and innate immune mechanisms. Studies in the duck
covalently closed circular DNA (cccDNA), which serves hepatitis B virus (DHBV) model support a cytopathic
as the stable template for transcription of both messenger mechanism for viral clearance, as shown by the turn-over
RNA (for translation of viral proteins) and pre-genomic of large number of hepatocytes during viral clearance.6
RNA (for reverse transcription into genomic DNA). Studies in the HBV chimpanzee model and in transgenic
HBV cccDNA is present in the range of 5-50 copies per animals, on the other hand, support the importance of
hepatocyte and is the stable form of viral DNA that is the non-cytopathic clearance as mediated by antiviral cyto-
most resistant to antiviral therapy and host immunologi- kines such as type I interferon and tumor necrosis factor
cal response.4 alpha (TNF␣).7-9 Substantial reduction in viral replica-
Viral replication occurs in the cytoplasm where the tion during transient infection precedes infiltration of the
pre-genomic RNA associates with HBcAg and the HBV liver by virus-specific T cells and elevation of serum ami-
polymerase to form nucleocapsid core particles.3 HBV notransferase levels.7 The early decrease in virus correlates
DNA is produced within the core particle by synthesis of with the appearance of antiviral cytokines such as inter-
the negative DNA strand from HBV RNA and then the feron and TNF␣ which have direct inhibitory effects on
1058 HOOFNAGLE ET AL. HEPATOLOGY, April 2007
Table 1. Phases in Natural History of Chronic Hepatitis B

Phase ALT Liver Histology HBV DNA HBeAg HBsAg
Immune Tolerance Normal or minimally Minimal Activity, Scant Fibrosis High levels (108 to 1011 copies/ml) Present Present
elevated
HBeAg ⫹ve Chronic Elevated usually Active with variable amounts High levels (106 to 1010 copies/ml) Present Present
Hepatitis B persistently of fibrosis
HBeAg ⫺ve Chronic Elevated, often Active with variable amounts Moderate levels, often fluctuating Absent Present
Hepatitis B fluctuating of fibrosis (103 to 108 copies/ml)
Inactive Carrier Normal Inactive with variable, usually Low or no detectable levels Absent Present
State minimal amounts of fibrosis (⬍104 copies/ml)
Recovery Normal Inactive with scant amounts of No detectable levels in serum (low Absent Absent
fibrosis levels may be present in liver)
Abbreviations: ALT, alanine aminotransferase; HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen.
HBV replication.10 Thus, both cytopathic and non-cyto- HBV infection, only one-third of adults experience symp-
pathic mechanisms are important in clearance of HBV toms of acute hepatitis, while the majority (⬇65%) have
during transient infection. subclinical disease.22 Importantly, about 5% of adults (⬇
In addition to the humoral response, cell-mediated im- 2% of women and ⬇7% of men) develop chronic hepa-
munity is crucial for the control of HBV infection.5 Vig- titis B. Rates of chronicity are higher in newborns
orous virus-specific CD4⫹ and CD8⫹ T cell responses (⬇90%) and children (⬇30%) and in immune deficient
which target multiple viral antigens with broad specificity individuals. Some of the variation in outcome of HBV
are induced during transient infection, and these reinfection may relate to the genetic heterogeneity of the
sponses can persist for decades after viral clearance.11 The virus. Eight genotypes of HBV have been described, ge-
continued presence of T cell responses suggest that HBV notype A being most common in the United States and
persists at low levels despite absence of detectable HBV Northern Europe, B and C in Asia, and D in Mediterra-
DNA in serum and presence of antibodies to HBsAg nean counties and the Middle East.23,24 Chronic infection
(anti-HBs).12 The presence of low-levels of virus in the with HBV genotype C appears to have a poorer prognosis
liver after apparent recovery has been demonstrated by and greater likelihood of cirrhosis and hepatocellular car-
transmission studies in chimpanzees and results of organ cinoma (HCC) than genotype B.25
transplantation in humans.13,14 Reactivation of hepatitis The transition from acute to chronic infection appears
B in previously recovered people during immunosuppres- to represent a failure of immune clearance of virus-in-
sive therapy has been amply documented.15,16 Thus, re- fected cells and is marked by persistence of high levels of
covery from hepatitis B may not indicate virus eradication HBV DNA and HBeAg in serum.5 The accompanying
so much as firm immunological control. acute hepatitis is typically mild and subclinical with only
Acute evolves into chronic infection if T cell responses modest serum alanine aminotransferase (ALT) elevations
to HBV are not induced or are not capable of controlling and no jaundice. Importantly, the subsequent course of
the virus.17 T cell responses to HBV antigens disappear chronic hepatitis B is highly variable.
gradually with the onset of chronic infection, probably The variability in chronic hepatitis B has led to its
because of exhaustion and/or tolerance induction. Most classification into phases of disease based upon ALT ele-
patients with chronic hepatitis B have no or few HBV- vations, the presence of HBeAg, HBV DNA levels, and
specific T cells in the circulation. An increase in the HBV- suspected immune status (Table 1).21,26,27 Typical
specific T cell response can occur during acute chronic hepatitis B is marked by the presence of HBeAg
exacerbations of chronic hepatitis B or during seroconver- and high levels of HBV DNA with variable elevations in
sion from HBeAg to anti-HBe.18 Nucleoside analogue- ALT and histological activity. A proportion of HBeAg-
induced treatment responses have been shown to result in positive persons, however, have no ALT elevations and
a transient restoration of the T cell response.19,20 With scant histological activity and are referred to as “immune
long-term therapy, however, these T cell responses appear tolerant.”26,27 The immune tolerant phase of hepatitis B is
to be lost. most common in children, adolescents, and young adults
with perinatally acquired infection and may represent the
Clinical Features and Natural History earliest phase of chronic infection. The prognosis and
The natural history of hepatitis B is variable, complex natural history of the immune tolerant phase of chronic
and still not completely well defined.21 At the onset of hepatitis B are not well defined, although most studies
suggest that very little liver injury occurs during this [HR] ⫽ 3.0), more advanced age (HR ⫽ 3.6 to 8.3),
phase. Transition to typical chronic hepatitis B with acti- cigarette smoking (HR ⫽ 1.7) and alcohol consumption
vation of disease can be abrupt and resemble acute hepa- (HR ⫽ 2.6). Viral and disease factors predictive of HCC
titis.28 development included elevations in serum ALT levels
The duration of typical HBeAg-positive chronic hep- (HR ⫽ 4.1), presence of HBeAg (HR ⫽ 4.2) and higher
atitis B can be prolonged and severe and may result in levels of HBV DNA. Importantly, levels of HBV DNA at
cirrhosis, but for many persons it does not cause clinical the time of initial evaluation were most closely linked
symptoms and eventually transitions to an inactive phase with eventual development of HCC, levels above 105 cop-
with loss of HBeAg, seroconversion to antibody (anti- ies per ml being strongly linked (HR ⫽ 8.9 to 10.7) and
HBe) and fall of HBV DNA to low or undetectable lev- above 104 significantly linked (HR ⫽ 2.7). These rela-
els.29-31 This transition is referred to as HBeAg tionships between HBV DNA levels and HCC held true,
seroconversion and often results in the disappearance of even for patients with normal ALT levels at the time of
disease activity despite persistence of HBsAg and low lev- initial evaluation.
els of HBV DNA in serum, a phase of disease referred to
as the “inactive carrier state.”32 This transition can be Therapy of Hepatitis B: Background and
preceded by a transient flare of disease with marked ele- Definitions
vations in serum ALT levels, decreasing concentrations of The course of chronic hepatitis B is typically silent and
HBV DNA in serum and appearance of HBcAg-specific associated with few signs or symptoms of disease until
CD4⫹ and CD8⫹ T cells in the circulation.18 cirrhosis and/or HCC arise. As a consequence, the major
The inactive carrier state generally has a benign course, goals of therapy are not immediate amelioration of symp-
but can be reactivated either spontaneously or by immune toms, but rather long-term prevention of progression, de-
suppression.32-34 Indeed, up to one-third of patients un- velopment of cirrhosis and HCC.21 Because these
dergo another transition, with increases in HBV DNA endpoints arise only after decades of infection, studies of
and ALT elevations and disease activity without reappear- therapy (other than in patients with cirrhosis) have used
ance of HBeAg.35 This phase is referred to as HBeAg- short-term, surrogate outcomes to assess benefit, many of
negative chronic hepatitis B and its consequences can be which have yet to be shown to be durable or reliably
as severe (if not more so) than HBeAg-positive disease.36 predict lack of further progression.
The molecular basis for this form of disease appears to be Standardization of terminology and definitions for
the development of a variant HBV which is incapable or endpoints of therapy of hepatitis B are important in as-
only poorly able to produce HBeAg.36-38 The HBeAg- sessing antiviral agents and in guiding management.21,44
negative form of disease is more frequent with specific Therapeutic endpoints can be categorized as biochemical,
HBV genotypes B, C and D than with genotype A38 and virological and histological, and as initial, maintained (on-
is characterized by marked fluctuations in serum HBV treatment) or sustained (off-treatment).
DNA and ALT levels.27,36,37 The underlying pathogenesis Biochemical responses are defined by changes in se-
for the transition from one phase of disease to another is rum ALT levels; a biochemical response by a decrease into
not known, and some patients clearly do not progress or the normal range. There are shortcomings in using bio-
may transition backwards (reactivation) either spontane- chemical response as an end-point for successful therapy.
ously or due to change or manipulation of the immune This endpoint requires that patients have elevated ALT
system.15,16,39 levels initially. Furthermore, minor ALT elevations may
Large, long-term natural history studies of HBsAg- persist after successful therapy due to presence of another
positive persons have been conducted in Asia40-42 and liver disease or injury. Finally, there is no widely accepted
Europe.33,34,43 While these studies provided excellent data definition for the normal range of ALT values, average
on outcome, most lacked information on results of regu- values being lower in women than men, in children than
lar testing for molecular HBV markers, immunological adults, and in normal-weight than overweight or obese
assays and liver histology. Nevertheless, these studies persons.45
showed that development of cirrhosis and HCC was fre- Histological responses are usually defined based upon
quent and correlated with several pre-existing host and scoring systems for the grade and stage of chronic hepati-
viral factors. In the largest and most thorough evaluation, tis.46-48 In most trials, histological improvement has been
HCC developed in 4.5% of 3,653 HBsAg-positive per- defined as a two-point decrease in the histological activity
sons identified in a population-based survey who were index (HAI: which ranges from 0 to 18) with no worsen-
followed for an average of 11.4 years (0.4% per year).42 ing of fibrosis between pre-treatment and end-of-treat-
Risk factors for HCC included male sex (hazard ratio ment liver biopsies. The clinical significance of this degree
greater dynamic range of quantification (from 101 to 109

IU per ml).52 Nevertheless, viral responses usually have
been defined by results of PCR-based assays, with a viro-
logical response defined as the lack of detectable HBV
DNA in serum using an assay that is sensitive to 20 to 100
IU/ml, which is roughly equivalent to 100 to 500 copies/
ml. The major difficulty with this endpoint is its durabil-
ity, in that it can be rapidly lost once therapy is stopped.
Loss of HBeAg or seroconversion to anti-HBe has of-
ten been used as a virological endpoint in assessing ther-
apy of hepatitis B and has the advantage of being more
sustained than suppressed HBV DNA levels. This end-
point, however, is not always durable and relapse rates of
Fig. 2. Relative sensitivity and range of quantification of commercial 10% to 30% have been reported after interferon53-56 and
tests for HBV DNA. Assays from the Digene Corporation (Gaithersburg,
Maryland) and Bayer Heathcare LLC (Tarrytown, NJ) are hybridization as high as 60% after nucleoside analogue therapy, partic-
based; those from Roche Molecular Systems (Pleasanton, CA) & Artus ularly if treatment is stopped soon after HBeAg becomes
(Artus GMbH, Hamburg, Germany) are PCR-based; Cobas Taqman™and undetectable.57 Furthermore, some patients do not im-
Real Art HBV™ being real-time PCR assays. (Figure courtesy of Dr.
Jean-Michel Pawlotsky).
prove clinically despite loss of HBeAg, evolving into
HBeAg-negative hepatitis B.35 Finally, loss of HBeAg
cannot be used as an endpoint in HBeAg-negative
of histological improvement has never been shown; fur- chronic hepatitis B.
thermore, the variation in scores due to sampling error Loss of HBsAg and seroconversion to anti-HBs is
can be great, particularly with small liver biopsy sam- clearly the most desired endpoint and can be considered a
ples.49 Thus, while a two-point improvement in HAI complete response indicating resolution of hepatitis B and
scores may be useful in assessing histological responses in recovery. Loss of HBsAg is durable in all but rare in-
clinical trials where large cohorts of patients are com- stances. The difficulty is that loss of HBsAg is not fre-
pared, it is not reliable for assessing benefits to individual quent after antiviral therapy of hepatitis B, occurring in
patients. A more appropriate histological endpoint would 3% to 8% of patients receiving interferon or peginter-
be resolution of the chronic hepatitis with minimal or feron58-62 and less than 2% of patients receiving a one-
mild HAI scores (⬍3 points). Because liver biopsy is in- year course of nucleoside analogue therapy.63-71
vasive, potentially harmful and expensive, histological Nevertheless, in studies of long-term therapy, loss of HB-
endpoints cannot be applied repeatedly and are of limited sAg becomes increasingly common and should be the ul-
use in clinical practice. Nevertheless, histological response timate endpoint sought in long-term treatment trials.
has been the gold standard against which other surrogate Responses to therapy can also be categorized as initial,
endpoints are measured. maintained, and sustained. An initial response can be mea-
Virological responses based upon testing for levels of sured at 6 or 12 months and these responses have been
HBV DNA in serum are probably the most appropriate used in most clinical trials of antiviral therapy. More ap-
criteria of assessing beneficial outcome of antiviral ther- propriate for trials of long-term therapy, however, would
apy. Commercial assays for HBV DNA have been evolv- be a maintained response, indicating that the response was
ing. Currently most assays are based on polymerase chain still present when the patient was last seen on therapy. In
reaction (PCR), and there is an increasing shift toward a similar manner, a sustained response is defined as being
real-time PCR assays (Fig. 2).50 An important issue is the present 6 months after stopping therapy. Importantly,
ability of these assays to quantify HBV DNA levels over a sustained responses in hepatitis B still need to be assessed
wide range of concentrations with acceptable accuracy for durability during long-term follow-up and shown to
and reproducibility. Most hybridization assays provide be present when the patient was last seen more than 6
excellent and reliable quantification but are restricted by months after stopping therapy.
lack of sensitivity below 104 to 105 IU per ml. Polymerase Definitions are also needed to describe and assess viral
chain reaction based assays51 are more sensitive and detect resistance and breakthrough. Resistance is typically cate-
HBV DNA to levels of 102 to 103 IU per ml, but are not gorized as genotypic, viral, and clinical. Genotypic resis-
as reliable in quantification, particularly when viral levels tance is based upon detection of HBV mutations that are
are high (above 106 IU per ml). The recently described associated with in vitro and in vivo resistance to antiviral
real-time PCR assays provide increased sensitivity and a agents.3,72-74 Thus, during treatment with nucleoside an-
alogues, mutations in the polymerase gene of HBV often Table 2. Location and Terminology of Antiviral Resistant
can be detected before there is a rise in HBV DNA or ALT Mutations
levels.75,76 The difficulty with this definition is that it Domains Within Polymerase Region of HBV P gene and
Their Amino Acid Locations
requires molecular testing which is expensive and may not
be warranted clinically if there are no other signs of anti- Agent A B C D
viral resistance. Viral resistance or virological breakthrough Lamivudine and rtL80V/I* rtA181T, rtM204V/I/S
indicates that HBV DNA levels have increased, the usual Emtricitabine rtV173L*,
rtL180M*
criteria being greater than a one log10 increase from a
previous nadir in a patient who is compliant and still on Telbivudine rtM204I
treatment. A difficulty with this definition is that it re- Entecavir rtI169T rtT184S/A/I/L/F/G, rtS202G/I, rtM250V
rtL180M** rtM204V/I**
quires frequent determinations of HBV DNA levels to
Adefovir rtA181V/T rtN236T
detect the rise. Clinical resistance or biochemical break-
through is defined by a rise in serum ALT levels. For pa- *Secondary, compensatory mutation. ** Mutations selected during the first
tients whose serum ALT levels fall into the normal range steps toward entecavir resistance. Abbreviations: rt, reverse transcriptase.
during therapy, clinical resistance can be defined as a rise

to above twice the upper limit of the normal range in
conjunction with a rise in HBV DNA levels and/or geno- fective. However, rates of development and proportions
typic resistance. These criteria become difficult to apply in of various mutants may vary with different L-nucleosides.
the situation in which ALT levels never fall into the nor- Typical antiviral resistance mutations are shown in Table
mal range, or were normal before therapy, or fluctuate 2.74 These mutations that have been associated with a
spontaneously. decrease in activity of the antiviral agent are found in
domains A, B, C and D of the polymerase (rt) gene at the
Antiviral Resistance in Hepatitis B amino acid positions listed. A more thorough discussion
Treatment of chronic hepatitis B using nucleoside an- of antiviral resistance has been provided in recent re-
alogues can result in development of antiviral resistance, views.74,77
marked by appearance of circulating HBV with reduced Adefovir and tenofovir have potent activity against
sensitivity to the antiviral agent.3,72-74 The pattern of de- lamivudine-resistant strains in vitro and in vivo78,79
velopment of HBV resistant mutants varies by chemical whereas entecavir has reduced efficacy against rtM204V/I
class of nucleoside analogues which can be categorized as: mutants.80 The most common resistant mutations associ-
1. L-nucleosides, such as lamivudine, emtricitabine, ated with adefovir therapy have been rtA181V/T and
telbuvidine and clevudine. rtN236T, but several other single or multiple mutations
2. Acyclic phosphonates such as adefovir and tenofo- have been described.81-83 Resistance to entecavir has been
vir. encountered mainly in patients with pre-existing lamivu-
3. Cyclopente(a)nes such as entecavir. dine-resistance and include multiple changes, typically
Nomenclature in discussing HBV resistance uses an rtI169T, rtT184S/A/I/LG/C/M, rtS202G/C/I, or
abbreviation for the gene region in lower case (rt for re- rtM250I/V and one or more lamivudine-resistant muta-
verse transcriptase, c for HBcAg, s for HBsAg) followed tion sites, typically rtL180M and rtM204V.80,84 Detec-
by the wild-type amino acid symbol, its position in the tion of resistant mutations usually requires sequencing of
gene region, and finally the mutant or variant amino acid the polymerase gene, but various assays including reverse
symbol.77 The typical lamivudine resistant mutations in- hybridization and restriction fragment length polymor-
volve the conserved “YMDD” motif of the polymerase phism have been developed that detect the more common
gene, changing it to YVDD or YIDD, the standardized mutations.85
nomenclature being rtM204V and rtM204I. The
rtM204V/I mutation is usually accompanied by a com-
Monotherapy for Hepatitis B
pensatory mutation upstream of the YMDD motif at Six antiviral agents (standard interferon, peginter-
rtL180M and/or rtV173L. The rtM204V/I mutations are feron, lamivudine, telbivudine, adefovir dipivoxil, and
considered primary resistant mutations that lower the sus- entecavir) have been approved for use in chronic hepatitis
ceptibility of HBV to lamivudine, while the rtL180M and B in the United States and at least three others (emtricit-
rtV173L mutations are considered secondary or compen- abine, clevudine, tenofovir disoproxil fumarate) are being
satory, allowing for the resistant mutant to replicate at a evaluated and may be approved in the near future. Se-
higher rate. Generally, development of the lamivudine lected results of recently published randomized controlled
resistant HBV effectively makes other L-nucleosides inef- trials of one-year courses of monotherapy with these
Fig. 3. Results of one-year courses of therapy with single agents in treating HBeAg-positive chronic hepatitis B using different endpoints at 48
weeks: (A) loss of HBeAg and HBsAg; (B) lack of detectable HBV DNA by PCR based assays, (C) fall of alanine aminotransferase levels into the normal
range (among those with elevations before therapy), and (D) two point improvement in hepatic histology using the hepatic activity index. Data on
lamivudine from comparative arm in recent trials of peginterferon60 telbivudine65 and entecavir70 Data on placebo from control arms of studies of
adefovir67 and emtricitabine.66
agents are shown in Fig. 3 (HBeAg-positive) and Fig. 4 and side effects of peginterferon appear to be similar to
(HBeAg-negative). The relative rates of antiviral resis- standard interferon. In two large, randomized controlled
tance with each agent are shown in Fig. 5. trials, a one-year course of peginterferon yielded higher
All agents showed evidence of benefit using biochem- 6-month post-treatment sustained rates of loss of HBsAg,
ical, virological, and histological endpoints.58-71 Loss of HBeAg and HBV DNA and higher rates of improve-
HBeAg occurred in 14% to 30% of patients treated with ments in ALT and histology than did a one-year course of
antiviral agents compared to ⬃12% of placebo recipients. lamivudine.60,61 However, in clinical practice lamivudine
Loss of HBsAg occurred in 0.3% to 4% of treated patients therapy is not routinely discontinued after one year unless
but rarely in placebo recipients. Most strikingly, HBV there is loss of HBeAg or HBsAg. Indeed, in these trials
DNA became undetectable by PCR based assays after one withdrawal of lamivudine was associated with a transient
year of therapy in 21% to 67% of HBeAg-positive and exacerbation of disease in a proportion of patients which
51% to 90% of HBeAg-negative patients but in almost no was fatal in some instances. Thus, these studies evaluated
control patient. Finally, biochemical and histological im- an approach to therapy that cannot be recommended for
provements occurred more frequently with antiviral ther- nucleoside analogues.
apy than with placebo treatment, but a proportion of Basically, there are two approaches to therapy of
control subjects (averaging 25%) had improvements in hepatitis B: one using a defined, self-limited course of
these features. treatment and the other using long-term, continuous
Peginterferon alfa-2a (Pegasys™, Roche Pharmaceu- therapy. Interferon and peginterferon are typically
ticals, Nutley, NJ) has replaced use of standard interferon used in a limited course of 4 to 12 months, stopped and
in both hepatitis B and C, largely because it is more con- the outcome assessed 6 months afterwards. When eval-
venient to administer and is more effective.59 Tolerance uated in this manner, peginterferon appears to be su-
Fig. 4. Results of monotherapy in treating HBeAg-negative chronic hepatitis B using different endpoints: (A) loss of HBsAg; (B) lack of detectable
HBV DNA by PCR based assays, (C) fall of alanine aminotransferase levels into the normal range (among those with elevations before therapy), and
(D) two point improvement in hepatic histology using the hepatic activity index. Data on lamivudine from comparative arm in recent trials of
peginterferon,61 telbivudine,65 and entecavir.71 Data on placebo from control arms of studies of adefovir68 and emtricitabine.66
perior to current nucleoside analogues,59-62 largely but promises response rates that are ultimately higher,
because rates of loss of HBsAg and HBeAg after one although they may not be sustained when therapy is
year are more common. In contrast, continuous, long- stopped.
term therapy with nucleoside analogues yields rates of Post-hoc analyses of trials of peginterferon therapies
response somewhat lower than interferon at one year, have shown several pre-treatment factors that were pre-
dictive of loss of HBeAg, the major ones being higher
ALT levels, lower HBV DNA levels, and greater disease
activity on liver biopsy. These factors also predicted
responses to nucleoside analogue therapy as well as
spontaneous improvement in hepatitis B. The influ-
ence of genotype on outcome of antiviral therapy is
controversial.62,86,87 Among patients with typical
HBeAg-positive chronic hepatitis B, response rates to
peginterferon are higher among those infected with
genotype A and B than genotypes C and D, but the
differences have not been statistically significant in all
studies. Relapse after loss of HBeAg may also be less
common in patients with genotypes A and B than C
and D. Importantly, success of antiviral therapy and
Fig. 5. Rates of genotypic antiviral resistance for four therapies of degree of viral suppression by nucleoside analogues ap-
chronic hepatitis B.58-72 pears independent of HBV genotype.88
Lamivudine (3-thiacytidine: Epivir-HBV™, Glaxo- rtL180M were detected. Thus, telbivudine may have
SmithKline, Research Triangle Park, NC) was the first enhanced potency and lower rates of resistance than lami-
L-nucleoside analogue licensed for use in chronic hepati- vudine, but resistance rates are substantially higher than
tis B and has been considered the standard of therapy for with other approved therapies.
this disease. While initially evaluated as a 52-week course Adefovir dipivoxil (Hepsera™, Gilead Sciences, Fos-
of treatment,63,64 its major use has been as a continuous ter City, CA) is a pro-drug of adefovir and was the second
long-term therapy. Long-term therapy can be very effec- nucleoside analogue to be licensed for use in this disease.
tive and cases of resolution of disease and even loss of Rates of clearance of HBeAg and lack of detection of
HBsAg after long-term lamivudine have been report- HBV DNA were lower during adefovir than lamivudine
ed.89,90 Unfortunately, lamivudine has a high rate of an- therapy (Fig. 3), but biochemical and histological re-
tiviral resistance, averaging 15% to 20% per year, so that sponses were similar. Importantly, adefovir was associated
70% to 80% of patients have resistance after 4 to 5 years with a low rate of antiviral resistance, generally less than
of treatment (Fig. 5).74 Development of resistance is usu- 1% at one year although rising to 29% after 5 years (Fig.
ally followed by loss of the clinical response, rise of ALT 5).67-69,81,82 Adefovir is also associated with primary non-
levels and worsening of hepatic histology. Instances of response as shown by only a modest decrease of HBV
continued improvement despite lamivudine resistance DNA levels and little improvements in ALT in as many as
have been reported,90 but the long-term consequences of one-third of patients with HBeAg-positive hepatitis B,
viral resistance are generally poor.91 Indeed, severe exac- although a lower rate in HBeAg-negative hepatitis B. Pri-
erbation of disease and decompensation have been re- mary non-response correlates closely with high initial
ported at varying intervals after development of HBV DNA levels and may relate to an only moderate
resistance. For these reasons, long-term results of lamivu- antiviral activity of adefovir. The presence of HBV vari-
dine therapy are poor, particularly in HBeAg-positive ants with primary resistance to adefovir may also be im-
chronic hepatitis B. portant.94 Higher doses of adefovir have greater potency
Emtricitabine (5 Fluorocytidine: Emtriva™, Gilead against HBV, but are associated with an unacceptably
Sciences, Foster City, CA) is an L-nucleoside that has a high rate of renal toxicity. Long-term trials of adefovir are
level of potency and pattern of resistance similar to lami- ongoing and have demonstrated a high rate of maintained
vudine. In a randomized controlled trial, emtricitabine response particularly in HBeAg-negative chronic hepati-
given in a dose of 200 mg once daily for 52 weeks was tis B.69 Adefovir also has activity against lamivudine-re-
associated with suppression of HBV DNA to undetect- sistant HBV and significant improvements in
able levels in 39% of HBeAg-positive and 79% of biochemical, virological, and histological features of dis-
HBeAg-negative patients (compared to 2% in placebo ease occur in at least half of patients with lamivudine-
recipients).66 Rates of resistance were 17% among resistance treated with adefovir for one year.95-97
HBeAg-positive but only 3% of HBeAg-negative pa- Unfortunately, adefovir resistance may be more common
tients, the resistance patterns being the same as those with in patients with pre-existing lamivudine resistance, and
lamivudine. Thus, emtricitabine and lamivudine are sim- instances of combined resistance to both agents have now
ilar both in rates of response and patterns of resistance. been published.82,98,99
Telbivudine (L-deoxythymidine: Tyzeka™, Idenix Tenofovir disoproxil fumarate (Viread™, Gilead
Pharmaceuticals, Cambridge, MA) is an L-nucleoside Sciences, Foster City, CA) is an acyclic adenine nucleo-
with potent activity against HBV in cell culture and in tide with potent activity against both HBV and HIV in
animal models. In phase II trials, telbivudine resulted in vitro and in vivo.100 Tenofovir is licensed for use in HIV
5.8 to 6.5 log10 reduction in HBV DNA levels.92,93 In a infection and has been evaluated extensively in patients
large, ongoing multicenter trial, telbivudine therapy was with HIV/HBV co-infection.101-103 Tenofovir appears to
associated with similar rates of loss of HBeAg at one year be more potent than adefovir and is effective against lami-
(26%) compared to lamivudine (23%), but with higher vudine-resistant strains of HBV DNA. Small comparative
rates of loss of detectable HBV DNA (60% versus 40%) studies have been conducted in cohorts of patients with
(P ⬍ 0.05).65 At 2 years, rates of loss of HBeAg were still HBeAg-positive chronic hepatitis B and lamivudine-resis-
similar but virological breakthrough with confirmed ge- tance without HIV co-infection. In a study with greater
notypic resistance was found in 22% versus 35% of than 48 weeks of follow up, all 35 patients treated with
HBeAg-positive and 9% versus 22% of HBeAg-negative 300 mg of tenofovir daily were HBV DNA negative com-
patients receiving telbivudine versus lamivudine.65 Rates pared to only 44% (7 of 15 patients) treated with 10 mg of
of resistance with telbivudine were less than with lamivu- adefovir daily.104 Tenofovir could also rescue patients
dine and only rtM204I mutants without rtM204V/ with lamivudine resistance who had an inadequate re-
sponse to adefovir.105 Side effects and renal toxicity were vudine alone (in several doses) compared to lamivudine
comparable. These results suggest that tenofovir may be alone and the combination.93 Telbivudine alone was
the agent of choice for lamivudine-resistant HBV and found to be more potent in suppressing HBV DNA levels
may ultimately replace adefovir in treatment of typical than lamivudine alone (median reductions of 6.2 versus
hepatitis B. Phase III trials of tenofovir for chronic hepa- 4.7 log10) but the combination was no more potent than
titis B are now underway. telbivudine alone. These three studies suggest that the
Entecavir (Baraclude™ Bristol-Myers Squibb Com- combination of two nucleoside analogues is no more ef-
pany, Princeton, NJ) is an acyclic guanosine derivative fective than the more potent of the two agents alone.
with marked activity against HBV. In preliminary studies Combination therapy was associated with a lower rate of
and in randomized controlled trials, entecavir showed ex- antiviral resistance, but the duration of the studies did not
cellent potency, high rates of suppression of HBV DNA allow for meaningful analysis of long-term resistance
levels and improvements in biochemical and histological rates.
features of disease.70,71 Rates of clearance of HBeAg and Combination therapy has been more thoroughly eval-
HBsAg at one year were similar to those of other nucleo- uated in the treatment of lamivudine-resistant chronic
side analogues (Figs. 3 and 4). Importantly, antiviral re- hepatitis B. In a prospective, randomized controlled trial
sistance to entecavir occurred in less than 1% of in 59 patients with HBeAg-positive chronic hepatitis B
nucleoside-naı̈ve patients after 1 and 2-year courses of and lamivudine resistance, continuing lamivudine alone
therapy.84 In contrast, entecavir resistance and only mod- was associated with little change in HBV DNA levels and
est response rates were reported in cohorts of patients with no improvements in ALT levels.95 Switching to adefovir
pre-existing lamivudine-resistance.80 The entecavir-resis- (monotherapy) was associated with similar average de-
tant strains of HBV appear to be sensitive to adefovir. creases in HBV DNA levels compared to adding adefovir
Preliminary reports on patients receiving entecavir for 2 to lamivudine (combination therapy) (4.0 versus 3.5 log10
years indicate maintained suppression of HBV DNA to declines) and similar rates of normalization in ALT levels
undetectable levels in more than 85% of patients with (47% versus 53%). These results suggested that patients
both HBeAg-positive as well as HBeAg-negative disease. with lamivudine-resistance should be switched to adefovir
These results are extremely heartening, but the ultimate and lamivudine stopped. However, the possible effects of
long-term safety and efficacy of entecavir therapy remain continuing lamivudine in preventing adefovir-resistance
to be shown. could not be assessed, because adefovir resistance usually
arises only after one year of treatment.
Combination Therapy of Hepatitis B Support for combination therapy in treating lamivu-
The potential advantages of combination versus dine resistance in chronic hepatitis B has come from sev-
mono-therapy of hepatitis B include greater antiviral ac- eral more recent studies. In a retrospective analysis of a
tivity and lower rates of resistance to the individual agents large number of patients with chronic hepatitis B and
used. Unfortunately, there have been few properly con- lamivudine-resistance from Italy, 303 patients were
trolled trials comparing combination therapy with each of switched to adefovir (monotherapy) and 285 had adefovir
the agents alone. In the few studies that have been done, added (combination therapy).108 At 2 years, the rates of
combination therapy was no more effective than mono- suppression of HBV DNA to undetectable were similar in
therapy. the two groups (67% versus 69%) but rates of virological
In a pilot study in HBeAg-positive chronic hepatitis B, breakthrough (9% versus 2%) and adefovir-genotypic re-
115 patients were treated with either lamivudine alone or sistance (5% versus 0.8%) were higher with mono-
lamivudine and adefovir.106 At 52 weeks, the degree of therapy. Preliminary results from a prospective trial from
HBV DNA suppression (4.8 versus 5.4 logs10 ) and Greece among 46 patients with HBeAg-negative chronic
HBeAg loss (20% versus 19%) were similar, while nor- hepatitis B showed similar results of adefovir mono-
malization of ALT (70% versus 48%) was more frequent therapy to the combination of adefovir and lamivudine,
with monotherapy than combination therapy. A group with lack of detectable HBV DNA and normal ALT levels
receiving adefovir alone was not included. In another in 80% of patients in both groups at month 34.109 How-
multicenter study, 38 patients received either adefovir ever, adefovir resistance developed only among patients
alone or adefovir and emtricitabine.107 The combination treated with adefovir alone (22%), suggesting that the role
yielded a more rapid and more marked end-of-treatment of combination therapy is in prevention of resistance.
decrease in HBV DNA, but similar rates of loss of Neither of these studies, however, demonstrated whether
HBeAg. Importantly, a group receiving emtricitabine pre-emptive combination therapy was more effective than
alone was not included. A third study has evaluated telbi- adding lamivudine to adefovir once resistance appears.
Furthermore, adefovir therapy may be more effective in pensation, pregnancy, organ transplantation or co-infec-
suppressing HBV DNA levels if begun soon after emer- tion with human immunodeficiency virus (HIV).
gence of lamivudine resistance, before HBV DNA rises to Children. The few studies of antiviral therapy of
high levels or disease activity worsens, as shown by uncon- chronic hepatitis B in children suggest that response rates
trolled but sizeable studies in patients with advanced fi- are similar if not higher than in adults.112 Both standard
brosis and chronic hepatitis B.110,111 interferon alfa and lamivudine have been found to be
Theoretically, combinations of nucleoside analogues beneficial and are now approved for use in children above
to treat chronic hepatitis B may be limited because they the age of 2 years.112-114 The efficacies of peginterferon,
act upon the same viral target, the HBV polymerase, adefovir, tenofovir, telbivudine, entecavir and combina-
which may explain the lack of additive or synergistic ac- tion therapies await further study.115 While these drugs
tivity. In this regard, the combination of interferon or are likely to be as effective in children as they are in adults,
peginterferon with nucleoside analogues may be more ap- concerns about the long-term safety and consequences of
propriate as the antiviral effects of interferon are directed drug resistance are greater in the pediatric age groups.
more at viral RNA stability and virus assembly rather than Furthermore, the long-term efficacy of antiviral therapy
the HBV polymerase enzyme. The combination of pegin- of hepatitis B in children remains unclear, and many chil-
terferon and lamivudine has been assessed in three large, dren with this disease have benign outcomes without
multicenter trials.60-62 All three studies failed to show an therapy.116
increase in sustained response rate of the combination of Acute Hepatitis B. Most patients with symptomatic,
peginterferon and lamivudine over peginterferon alone acute hepatitis B recover, and antiviral therapy is usually
assessed 24 weeks after discontinuation of treatment. On neither recommended nor needed.21 Probably as a result
the other hand, the on-treatment suppression of HBV of wide-scale use of HBV vaccine and routine blood do-
DNA levels was superior in patients who received combi- nor screening, acute hepatitis B has been decreasing in
nation therapy: by the end-of-treatment, HBV DNA lev- frequency in the United States and is currently at a his-
els decreased by 5.2 logs10 in lamivudine-, 5.1 logs10 in toric low level, an estimated 20,000 to 25,000 cases oc-
peginterferon-, and 7.2 logs10 in combination-treated curring yearly, greatest decreases having occurred in
HBeAg-positive patients.60 These results suggest that children.117 Nevertheless, cases of acute hepatitis B still
combinations of agents that have different targets against occur in adult populations and can result in severe and
HBV may provide additive antiviral activity and higher even fatal outcomes.
potency. Use of standard interferon for typical acute hepatitis B
At present, however, medical evidence does not sup- was evaluated in a small controlled study and was without
port the use of combination therapy for chronic hepatitis benefit.118 There have been no prospective studies of nu-
B with the possible exception in lamivudine-resistant dis- cleoside analogues in typical acute hepatitis B, but case
ease where the combination of adefovir and lamivudine reports and small series in severe or prolonged acute hep-
appears preferable to adefovir alone. Because antiviral re- atitis and HBV-related liver failure suggest some benefit
sistance is slow to develop in chronic hepatitis B, longer of early therapy.119-122 The serious nature of acute liver
term studies are needed before one can assume that the failure and the safety of nucleoside analogue therapy sup-
prevention of resistance and maintenance of a response port its use in patients at the first sign of severe injury or
may be more common with combination therapy. Fi- impending liver failure (prolongation of prothrombin
nally, studies of combination of nucleoside analogues time or hepatic encephalopathy), particularly since a pro-
have used agents (lamivudine, emtricitabine, adefovir) portion of patients will be referred for emergency liver
with lower potency than more recently developed antivi- transplantation and require prophylaxis against recur-
rals (telbivudine, tenofovir, entecavir), and the advantages rence, which usually includes nucleoside analogue thera-
of combination versus monotherapy using the more po- py.123,124
tent agents awaits further study. Cirrhosis and Decompensated Liver Disease. Rec-
ommendations for therapy of patients with HBV-related
cirrhosis and decompensation are clearly supported by
Special Populations current medical evidence.125 Interferon and peginterferon
Most trials of therapy of hepatitis B have been in se- are contraindicated in patients with decompensated liver
lected patients without comorbidities or complications of disease, largely because of the high rate of serious, some-
chronic liver disease, frequently excluding special popula- times life-threatening adverse events.126,127 In contrast,
tions such as in children, or adult patients with acute the nucleoside analogues can be administered safely in
hepatitis B, chronic hepatitis B and cirrhosis, liver decom- patients with advanced cirrhosis, and recent studies indi-
cate that they are effective.128-130 In a landmark, random- tion possibly as a result of better use of anti-retroviral and
ized controlled trial from Asia, long-term lamivudine anti-HBV antiviral therapy.150
therapy was associated with improved survival and lower Prevention of Reactivation. An important but often
rates of HCC in patients with cirrhosis or advanced liver overlooked role of antiviral therapy is prevention of HBV
disease due to hepatitis B.131 The benefits were most clear reactivation during immune suppression. Patients who
among patients who maintained a virological response are inactive HBsAg carriers and a proportion of those who
and did not develop lamivudine resistance. These results have recovered from hepatitis B (who have anti-HBc
indicate that patients with advanced fibrosis and cirrhosis without HBsAg in serum) can suffer from reactivation in
and high levels of HBV DNA should receive nucleoside response to immune suppression either as a result of can-
analogue therapy. At issue is which agent to use and how cer chemotherapy,15,16,151-155 short courses of corticoste-
to avoid antiviral resistance with long-term therapy. HCC roids, immuno-modulatory agents (anti-cytokines),156-158
can develop despite successful suppression of HBV DNA, heart, kidney and liver transplantation159 and even as a
so that further studies are needed to identify the optimal result of advancing immune deficiency due to HIV infec-
long-term management of patients with advanced tion.160,161 Reactivation is reported to occur in 29% to
chronic hepatitis B. 56% of inactive HBsAg carriers treated with chemother-
Liver Transplant Recipients. With application of apy162 and can also occur in patients who have apparently
high doses of hepatitis B immune globulin usually in recovered from hepatitis B and have anti-HBc without
combination with nucleoside analogue therapy, hepatitis HBsAg in serum (regardless of anti-HBs status).15,163 This
B can be prevented in most patients after liver transplan- pattern of reactivation is particularly common in bone
tation for HBV-related end-stage liver disease or marrow transplant recipients.164-167 Reactivation of hep-
HCC.123,124 For these reasons, recurrence of hepatitis B atitis B in an immunosuppressed host can be severe result-
after liver transplantation is now uncommon.132-134 Nev- ing in acute liver failure or an unremitting and progressive
ertheless, breakthrough HBV infections do occur, usually chronic hepatitis. Several studies have shown that pre-
related to development of resistance to the antiviral agents treatment with lamivudine can prevent or at least amelio-
used to prevent re-infection.135-137 While such break- rate the course of reactivation.154,155,162,163,167 Delaying
through infections can be treated with other nucleoside therapy until HBV DNA levels rise is ineffective.16,163
analogues with different patterns of resistance, serial ther- Thus, patients who are to undergo chemotherapy for can-
apy with nucleoside analogues can lead to complex HBV cer, intensive immune suppression for autoimmune dis-
strains with resistance to multiple agents.82 Combination ease, or bone marrow transplantation should be screened
nucleoside analogue therapy is likely to be most beneficial for HBsAg and anti-HBc, and given prophylaxis with
in post-transplant patients, but the combination has to be lamivudine or another nucleoside analogue for the dura-
chosen based upon previous exposure and patterns of re- tion of immune suppressive therapy. Some patients will
sistance.123 experience a flare of hepatitis B when the antiviral therapy
HIV Co-infection. Patients with HBV/HIV co-infec- is stopped and require reinstitution of treatment.168 In-
tion present a particular challenge to management. Hep- terferon and peginterferon are ineffective and likely to be
atitis B can be severe in patients with HIV infection,138,139 poorly tolerated in this situation.
and, as therapies for HIV infection improve, an increasing
number of patients are dying from liver disease.140-142 Safety of Antiviral Therapy
Fortunately, many of the agents used to treat HIV infec- In contrast to interferon and peginterferon therapy,
tion have activity against HBV, in particular lamivudine, nucleoside analogue therapies for hepatitis B have had few
emtricitabine, and tenofovir. Lamivudine resistance is fre- and only minor side effects. Despite the concerns about
quent in patients with HIV/HBV infection who have pancreatitis, neuropathy, acute fatty liver and lactic aci-
been treated for prolonged periods.143 In patients with dosis associated with nucleoside analogue therapies, these
lamivudine-resistance, tenofovir has proven to have excel- side effects have been rarely reported and not definitely
lent activity.101-103,144-147 The combination of tenofovir linked with lamivudine, adefovir, and entecavir mono-
and emtricabine (Truvada™, Gilead Sciences, Foster therapy. In many clinical trials, common adverse events
City, CA) has been approved as therapy for HIV infection (headache, pharyngitis, diarrhea) have occurred as fre-
and is currently recommended by several expert interna- quently among placebo as lamivudine or adefovir recipi-
tional panels as the optimal therapy for patients with ents,64-68 and most cited serious side effects have not been
HIV/HBV co-infection who require treatment of both definitely linked to these therapies.
diseases.148,149 Indeed, recent findings indicate an im- An important exception is the occurrence of renal dys-
proved prognosis for patients with HIV-HBV co-infec- function with long-term adefovir and tenofovir thera-
py.169-172 Renal tubular acidosis, phosphate wasting and Table 3. Costs of Therapy for Chronic Hepatitis B
renal impairment occurred in as many as one-quarter of Cost per Cost per
patients treated with higher doses of adefovir (30 to 60 mg Agent Dose dose* year**
daily), appearing after 5 to 6 months of treatment and Lamivudine 100 mg daily $6.80 $2,482
resolving rapidly if identified and the medication stopped. Emtricitabine 200 mg daily $10.61 $3,872
Telbivudine 600 mg daily $16.23 $5,924
This side effect is rare in patients receiving 10 mg of Adefovir 10 mg daily $18.11 $6,647
adefovir and standard doses of tenofovir.173 Because of Tenofovir 300 mg daily $15.92 $5,811
this side effect, patients on adefovir or tenofovir are ad- Entecavir 0.5 mg daily $23.82 $8,694
Entecavir 1.0 mg daily* $23.82 $8,694
vised to be monitored for creatinine levels and the dose Peginterferon alfa-2a 180 ␮g weekly $385.00 $18,480
rapidly modified or discontinued if toxicity appears.125
*A 1.0 mg dose is recommended for treatment of patients with lamivudine
Prolonged tenofovir therapy may also be associated with
resistance. **Data from references 179 and 180 for average wholesale prices in
bone loss and decreases in bone density.174,175 All of the the United States, except for telbivudine for which the wholesale acquisition cost
nucleoside analogues have major renal excretion, so that is provided. Data from peginterferon are for 48 weeks; all others for 365 days.
dose adjustments are needed for renal insufficiency, and (Modified with permission from John Wong, Tufts University, New England Medical
Center, Boston, MA.)
adefovir and tenofovir should be used with caution in
patients with pre-existing kidney disease.
The side effects of interferon and peginterferon are well
described particularly in studies of therapy of hepatitis Entecavir and adefovir are classified as Category C, in that
C.176 Interestingly, the recommended doses of peginter- embryo and fetal toxicities have been observed in animals,
feron are similar in chronic hepatitis B than C, but side but these reproduction studies are not always predictive of
effects appear less.60,61 The better tolerance of interferon human response.
in hepatitis B may be due to the fact that patients with A central issue regarding safety of therapy during preg-
HBV infection are more likely to be younger and less nancy is whether nucleoside analogue therapy should be
affected by other medical co-morbidities than patients stopped in young women who are attempting pregnancy
with hepatitis C. or who become pregnant during treatment. Currently,
lamivudine and zidovudine are recommended for HIV-1
Pregnancy infected women during pregnancy. Thus, in women be-
ing treated for hepatitis B who become pregnant, switch-
The safety of antiviral therapy for hepatitis B during
ing to lamivudine for the duration of pregnancy is a
pregnancy and during breast feeding is not well de-
reasonable recommendation.125,149 The problem of anti-
fined.44,125 Interferon and peginterferon are contraindi-
viral resistance, however, makes use of lamivudine mono-
cated during pregnancy largely because of their known
therapy problematic, even for a period of 9 to 12 months.
anti-proliferative effects. In the event of pregnancy,
There have been two small trials of lamivudine therapy
peginterferon should be discontinued.
during pregnancy in women with chronic hepatitis B and
Medications are classified by the FDA in regard to
high levels of HBV DNA that focused the prevention of
safety during pregnancy into five categories: Category A
transmission of hepatitis B to the infant.177,178 HBV
(controlled studies show no risk and the possibility of fetal
transmission was less among women treated with lamivu-
harm appears remote); B (animal studies show no risk, but
dine, but none of these studies was adequately powered or
human studies have not been done or vice versa); C (ani-
controlled to prove the efficacy or advisability of this ap-
mal data show teratogenic effects but no controlled stud-
proach. Therapy appeared to be safe, at least to the infant.
ies done in humans); D (human fetal risk exists but
A potential complication for the mother is that flares of
benefit outweighs risks); or X (fetal risk outweighs bene-
hepatitis B can occur if nucleoside analogue therapy is
fit). Currently, lamivudine, telbivudine, emtricitabine,
stopped after childbirth.
and tenofovir are classified as category B, indicating that
they demonstrate no evidence of teratogenicity in animal
studies but have not been adequately evaluated in humans
Costs of Therapy
and ongoing registries include too few instances of preg- The costs of therapy of hepatitis B are considerable
nancy during therapy to provide reliable guidance. These (Table 3) and must be considered when initiating treat-
agents could be used if the potential benefit of treating ment. A one-year course of peginterferon costs $18,000 to
during pregnancy is believed to outweigh potential risks $20,000, considerably more than a one-year course of
to mother or fetus; although the possible effects of teno- nucleoside analogues.179,180 However, nucleoside ana-
fovir on bone density argue against its use during preg- logue therapy may be continued indefinitely, and cumu-
nancy and while mothers are breast feeding.174,175 lative costs rapidly can exceed those of peginterferon.
Furthermore, insurance coverage may be limited because death 1 (PD1) expression on T cells are alternative and
the majority of randomized controlled trials typically fo- attractive strategies for modulation of the immune re-
cused on the benefits of only a one-year course of treat- sponse.187,188 These have yet to be applied to patients with
ment. Additional costs of monitoring disease activity and chronic hepatitis B. Finally, therapeutic vaccination in-
HBV DNA levels must also be considered. In clinical cluding use of dendritic cell and T cell-based vaccines is
trials, a full panel of liver tests, blood counts and HBV being developed to target and induce HBV-specific T cell
DNA levels were done every 4 weeks during and after response, which has been shown to play a pivotal role in
therapy, a level of monitoring that is not necessary in viral clearance. Thus, an array of approaches to therapy
clinical practice. Serum testing at 3 to 6 month intervals are being pursued which ultimately may be beneficial ei-
may be adequate for routine treatment of compensated ther alone or in combination with peginterferon or nucle-
chronic hepatitis B using nucleoside analogues.125 oside analogue therapy of hepatitis B.
Future Therapy Recommendations for Future Research

Much of the effort on antiviral drug development in Despite more than 40 years of research, fundamental
hepatitis B has been focused on nucleoside analogues questions remain regarding HBV infection and its opti-
which target only a single step in the viral life cycle — mal management. The underlying reasons for the evolu-
DNA synthesis. While many of the new nucleoside ana- tion from acute to chronic HBV infection remain unclear.
logues have different resistance profiles and higher po- How does HBV evade immune clearance or induce toler-
tency which may limit the emergence of resistance, they ance to its protein antigens in the liver? What specific
also are likely to have interactions in terms of efficacy and defects or changes in the innate and/or adaptive immune
resistance when they are used sequentially or in combina- responses to HBV account for viral persistence? Can these
tion. Other steps of HBV replication deserve evaluation as processes be manipulated to promote recovery or response
targets for antiviral therapy (Fig. 1).3,181 Several classes of to antiviral therapy?
compounds have been developed that interfere with the Once chronic infection is established, clinical disease
encapsidation signal (attachment of polymerase to pre- and outcome vary greatly, yet the reasons for this variabil-
genomic RNA) during viral replication, including several ity are not clear. What factors determine the degree of
hetero-aryl-dihydropyrimidines and phenylpropen- hepatocellular injury during chronic hepatitis B? What
amides.182,183 These compounds had favorable efficacy factors control the level of viral replication? What under-
and toxicity profiles in pre-clinical testing but have yet to lying mechanisms account for spontaneous clearance of
be tested in humans. Other potential targets for small HBV that can occur during chronic infection? And what
molecule development are HBV receptors on the surface factors lead to resolution of disease activity in some pa-
of hepatocytes, the HBV assembly process, the interaction tients and evolution to progressive fibrosis, cirrhosis, and
of nucleocapsid and HBsAg, and the unique viral func- end-stage liver disease in others?
tions mediated by the HBV X protein.184,185 Gene thera- Six agents are now available for treating hepatitis B, all
pies using anti-sense, ribozyme and siRNA molecules of which are effective in the short-term. Nevertheless,
have been designed that target and breakdown HBV practical management is plagued by uncertainties. Which
RNA inside hepatocytes. Several of these approaches have patients should be treated? At what stage of infection or
shown promise in vitro and in animal models.186 The disease? With which agent or combination of agents? For
major obstacle with these approaches is delivery into the how long? Which criteria should be used to continue
hepatocyte and the appropriate site where HBV repli- therapy, or switch to other therapies, or stop altogether?
cates. Recent advances in delivery technology may render The two-and-a-half day workshop allowed for answer-
solutions to this critical issue. ing of some questions regarding management of hepatitis
Another potential future approach to therapy of B, but succeeded more in focusing questions of what
chronic hepatitis B is by modulation of the immune re- should to be addressed in future research. What are the
sponse that is detective in persons with chronic infection. most important clinical questions to be addressed and
Immunomodulatory agents that nonspecifically enhance how can research help resolve them within the next 5 to
host–immune responses include multiple cytokines with 10 years?
antiviral actions, such as interferon gamma, interleukin Studies of natural history of chronic hepatitis B need to
(IL)-2, IL-12, IL-18. Studies of these molecules in hu- be combined with prospective analyses of virological, ge-
mans have shown little effect on viral replication or dis- netic, and immunological factors using state-of-the-art
ease activity.181 Toll-like receptor ligands to activate methodology. Studies of viral genetic variation and diver-
innate immunity or inhibitors of IL-10 or programmed sity and changes in serum levels combined with analysis of
the state and levels of replicative forms of HBV in liver favorable predictive factors for a response, such as
should be combined with prospective studies of innate HBeAg-positivity, genotype A or B, or marked ALT ele-
and adaptive immune responses to HBV antigens using vations?
both peripheral blood and hepatic infiltrating mononu- ● What should be the criteria for judging success of
clear cells. Assessment of genetic factors, particularly of therapy? Should the goal be to maintain HBV DNA be-
genes that regulate the adaptive and innate immune re- low a certain level? Normalization of ALT levels? Or im-
sponse, should be combined with these studies, but most provement in liver histology?
important is to correlate these findings with careful clin- ● Similarly, what should be the criteria for switching
ical phenotypes of disease. therapy? From peginterferon to nucleoside analogues? Or
Four phases of chronic hepatitis B have been defined: from one nucleoside class (L-nucleosides, PMEA deriva-
two marked by immune control (immune tolerant phase tive, guanosine derivative) to another?
and inactive carrier state) and two by immunological in- ● Should therapy be stopped after HBV DNA has
jury (HBeAg-positive and -negative chronic hepatitis B). been undetectable for a certain period? Or only once
Therapy of hepatitis B has focused largely on the phases HBeAg becomes undetectable? Or only after seroconver-
without immune control with resulting liver injury and sion to anti-HBe? Or only if HBsAg becomes undetect-
high viral replication. Nevertheless, the role of treatment able?
during the immune tolerant phase and even the inactive At present these issues are only partially resolved and
carrier state deserves prospective analysis. Animal models recommendations for therapy must be based on imperfect
of chronic HBV infection do not adequately reflect these information and extrapolation of results.
four phases of infection and cannot help in defining
Acknowledgment: The authors would like to thank
pathogenesis, natural history or therapy. Few prospective the participants and moderators in the Symposium
studies in humans have adequately addressed the clinical, “Management of Hepatitis B: 2006”: William S. Mason,
viral, immunological and host genetic factors that accom- Stefan F. Wieland, Barbara Rehermann, Edward Doo,
pany and account for these four phases of infection. Jack R. Wands, Jia.-Horng Kao, Solko W. Schalm, Za-
Recommendations for therapy of hepatitis B are diffi- chary Goodman, Robert Fontana, Leonard B. Seeff, Anna
cult and are limited by the lack of reliable information on S.F. Lok, Jean-Michel Pawlotsky, Brent Korba, D. Lorne
the long-term safety and efficacy of therapies.125 The un- Tyrrell, Raymond Chung, Alfredo Alberti, Marc G.
certainty surrounding these recommendations indicates Ghany, Adrian M. Di Bisceglie, Stephanos J. Hadziyan-
that further studies of therapy of hepatitis B are needed — nis, Marion G. Peters, Eugene R. Schiff, Jules L. Dien-
not aimed at proving efficacy, but at placing therapies in stag, Stephen Locarnini, Fabien Zolium, Harry L.A.
Janssen, Daryl T.-Y. Lau, E. Jenny Heathcote, Robert P.
context of how they should be used, in which patients, at
Perrillo, Patrick Marcellin, Jean P. Molleston, Norah A.
what phase of infection, to what endpoint and using what Terrault, Chloe L. Thio, George K.K. Lau, Tony H.H.
factors to judge success or failure. Important current is- Chen, Brenda Ross, John Wong, John M. Vierling, Jay
sues include. H. Hoofnagle, Yun-Fan Liaw, T. Jake Liang, Russell
● Which patients with chronic hepatitis B should be Fleischer and Timothy M. Block.
treated? Should criteria for therapy be based upon ALT
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Management of Hepatitis B: Summary of a Clinical

Fig. 1. HBV Life Cycle: HBV enters the hepatocyte medi-

Table 1. Phases in Natural History of Chronic Hepatitis B

greater dynamic range of quantiﬁcation (from 101 to 109

during therapy, clinical resistance can be deﬁned as a rise

Future Therapy Recommendations for Future Research

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