Download Effectiveness of Hepatitis B Treatment in Clinical Practice

GASTROENTEROLOGY 2012;142:1360 –1368
Effectiveness of Hepatitis B Treatment in Clinical Practice
Steven J. Scaglione
Anna S. F. Lok
CLINICAL LIVER
Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan
It is important to examine the effectiveness of current
therapies for chronic hepatitis B in clinical practice,
given the therapeutic advances over the past 15 years. A
2010 Institute of Medicine report on hepatitis and liver
cancer stated that the public and health care providers
have a lack of knowledge and awareness about viral
hepatitis, and that there is a gap between medical innovation and community care. We review the efficacy of
hepatitis B treatment, based on results from clinical
trials, and discuss the effectiveness of these treatments in
clinical practice. We also discuss why having efficacious
treatments alone would have a small impact on the
global health burden of hepatitis B, and highlight the
importance of educating the public and the medical
community and coordination of care.
Keywords: Antiviral Therapy; Efficacy; Interferon; Nucleos(t)ide Analogues; Screening.
S
even drugs have been approved for the treatment of
chronic hepatitis B (CHB). These drugs can suppress
hepatitis B virus (HBV) replication and prevent disease
progression, but their efficacy in clinical trials does not
always correspond to their effectiveness in practice; approval of efficacious treatments alone will not necessarily
reduce the global burden of this disease. Clinical trials
involve highly selected, motivated patients with few comorbidities, and treatment is supervised by experienced
physicians and research staff who follow strict protocols.
Furthermore, costs of medications and monitoring usually are covered by the trial sponsor. On the other hand, in
clinical practice, physicians have to care for all patients,
could be less experienced, and have less support in monitoring their patients (Table 1). In addition, although the
cost of HBV treatment is covered by national health systems in some countries, patients in many countries, including the United States, often have to bear part or all of
the costs of treatment. Of even greater importance, realization of treatment benefits requires proper diagnosis,
referral to care, initiation of treatment, tolerance and
adherence to treatment, and ability to pay for the medications and monitoring.
A chasm between efficacy in clinical trials and effectiveness in the community was described in the 2010 Institute
of Medicine (IOM) report Hepatitis and Liver Cancer,1 and a
Hepatitis Summit Report, The State of Hepatitis B and C in
Europe.2 We review the efficacy of hepatitis B treatment, as
evaluated in clinical trials, and discuss the effectiveness of
these treatments in practice, the barriers between efficacy
and effectiveness, and strategies to remove these barriers.
Burden of Hepatitis B
Despite advances in prevention and treatment,
HBV infection remains a global public health concern.
Worldwide, approximately 2 billion people have been exposed and 350 million people are chronically infected
with HBV, which is estimated to be responsible for
620,000 deaths per year.3 HBV infection is a major burden
in resource-limited countries, accounting for 30% of cases
of cirrhosis and 53% of cases of hepatocellular carcinoma
(HCC).4 Even in developed countries with universal vaccination programs and availability of efficacious treatment, the burden of HBV-related disease remains high.
The prevalence of chronic HBV infection in the US
population is estimated to be 0.27%,5 but many screening
programs conducted in Asian American communities
have shown prevalence rates of 10%–15%.6 Furthermore,
the IOM committee estimated that of the 0.8 –1.4 million
persons in the United States with chronic HBV infection,
65% are not aware of their infection.1 The prevalence of
HBV infection in Europe varies from 0.2% in Ireland to 7%
in Turkey. It has been estimated that 14 million EuropeAbbreviations used in this paper: ALT, alanine aminotransferase;
CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen; HBsAg, hepatitis
B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HIV, human immunodeficiency virus; IFN, interferon; IOM, Institute of Medicine; PCR, polymerase chain reaction; PEG-IFN, pegylated
interferon; ULN, upper limit of normal.
© 2012 by the AGA Institute
0016-5085/$36.00
doi:10.1053/j.gastro.2012.01.044
HBV TREATMENT EFFECTIVENESS
Table 1. Efficacy of CHB Treatment in Clinical Trials vs
Effectiveness in Clinical Practice
Efficacy
Utility of a medical treatment
evaluated under optimal
conditions
Highly selected, motivated
patients
Experienced physicians and
support staff
Standardized algorithm for
monitoring of response and
management of suboptimal
response/breakthrough
Frequent visits and laboratory
tests
Free medications, evaluations,
and tests
Effectiveness
Utility of medical treatment in
routine clinical settings (ie,
real life)
All patients
All physicians with varying
knowledge and experience,
limited or no support staff
Monitoring of response and
management of suboptimal
response/breakthrough at
discretion of physician
Less frequent office visits and
laboratory tests
Costs borne by health insurance
and/or patient
ans are chronically infected with HBV, resulting in 36,000
deaths each year, but accurate data are lacking in most
European countries; as many as 90% of HBV-infected
Europeans are not aware of their infection.2
Efficacy of Treatments for CHB
Goals and End Points
The ultimate goal of CHB treatment is to prevent the
development of cirrhosis, liver failure, and HCC. Clinical
trials have relied on surrogate end points that correlate with
clinical end points. Surrogate end points are biochemical (a
normalized level of alanine aminotransferase [ALT]), virologic (suppression of HBV DNA to undetectable levels by
polymerase chain reaction [PCR] assays), serologic (loss of
hepatitis B e antigen [HBeAg], with or without seroconversion to hepatitis B e antibody, in HBeAg-positive patients
and loss of hepatitis B surface antigen [HBsAg], with or
without seroconversion to hepatitis B surface antibody), as
well as histologic (decrease in necrosis and inflammation
score by ⱖ2 points with no worsening of fibrosis). PCR
assays with lower limits of detection of 300 –1000 copies/
mL, or roughly 60 –200 IU/mL, were used in phase 3 trials,
but real-time PCR assays with improved sensitivity (a lower
limit of detection of 10 –20 IU/mL) are available and should
be used to monitor virologic response.
Eligibility Criteria
Phase 3 trials of therapies for CHB have focused on
enrolling patients with high levels of HBV DNA, abnormal levels of ALT, and compensated liver disease. Phase 3
trials of pegylated-interferon (PEG-IFN), with or without
lamivudine, compared with lamivudine monotherapy, enrolled adult HBeAg-positive patients with serum levels of
HBV DNA greater than 500,000 copies/mL (⬃100,000
IU/mL) and HBeAg-negative patients with levels of HBV
DNA greater than 100,000 copies/mL (⬃20,000 IU/mL),
along with abnormal levels of ALT (1–10 times the upper
limit of normal [⫻ULN]) and evidence of chronic hepa-
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titis from liver biopsy specimens.7–10 Phase 3 trials of
nucleos(t)ide analogues generally have enrolled HBeAgpositive patients with levels of HBV DNA greater than
1,000,000 copies/mL (⬃200,000 IU/mL) and HBeAg-negative patients with levels of HBV DNA greater than
100,000 copies/mL (⬃20,000 IU/mL), along with levels of
ALT 1.3–10 ⫻ULN and evidence of chronic hepatitis from
liver biopsy specimens.11–17 These trials excluded patients
with decompensated liver disease; other causes of liver disease; co-infection with human immunodeficiency virus
(HIV), hepatitis C virus, or hepatitis D virus; severe or unstable medical comorbidities; or medical conditions that
require chronic immunosuppressive therapies, along with
women who were pregnant or of child-bearing potential but
were unwilling to practice contraception.
Responses
Published reports from phase 3 trials have focused
on responses at the end of 1 year of treatment. Although
responses up to year 5 had been reported from some trials,
these follow-up studies did not include all patients in the
original trial, and some studies had modifications to the
original treatment after the first year. Tables 2 and 3
summarize responses to the approved drugs in HBeAgpositive and in HBeAg-negative patients with CHB.
PEG-IFN. A large, phase 3 trial of PEG-IFN with or
without lamivudine, compared with lamivudine monotherapy, in HBeAg-positive patients showed that PEGIFN, with or without lamivudine, was superior to lamivudine monotherapy—the addition of lamivudine to PEGIFN did not provide any benefit.7 Similar responses were
observed in other trials of PEG-IFN (Table 2).9,10 Follow-up evaluation of patients from one trial in Europe
and Asia (of mixed HBV genotypes) showed that 19% had
undetectable levels of HBV DNA, 37% had lost HBeAg,
and 11% had lost HBsAg after a mean of 3.5 years from
completion of PEG-IFN treatment. Patients with genotype A infection had a significantly higher rate of HBsAg
loss than those with non-A genotype infection (28% vs
3%). Among the initial responders, 81% had durable loss
of HBeAg and 30% lost HBsAg.18 By contrast, follow-up
evaluation of patients in a trial in Hong Kong (only
genotypes B and C) found that only 2.4% of patients lost
HBsAg at 5 years, despite similarly high rates (82%) of
durable seroconversion of HBeAg.19
A large, phase 3 trial of a 48-week course of PEG-IFN, with
or without lamivudine, compared with lamivudine monotherapy, in patients with HBeAg-negative CHB showed that
patients who received PEG-IFN had a significantly higher
rate of sustained, off-treatment response (Table 3).8 This
difference was maintained when patients were re-evaluated 3
years after treatment was discontinued.20
Nucleos(t)ide analogues. Phase 3 clinical trials
of nucleos(t)ide analogues in patients with HBeAgpositive CHB showed that after 1 year of treatment,
21%–76% had an undetectable level of HBV DNA and
41%–77% had a normalized level of ALT, but only 12%–
22% achieved HBeAg seroconversion and 0%–3% lost
CLINICAL LIVER
May 2012
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SCAGLIONE AND LOK
GASTROENTEROLOGY Vol. 142, No. 6
Table 2. Response Rates to Approved Therapies for HBeAg-Positive CHB
Treatment response parameters
CLINICAL LIVER
Telbivudine
Tenofovir
disoproxil
fumarate
PEG-IFNa
PEG-IFN plus
lamivudinea
6.9
67
68
22
21
2
72
0
6.5
60
77
26
22
⬍1
65
4.4
6.2
76
77
21
21
3
74
0
2–4.5
25
34–39
⬃30
27
3
38
0
5–7.2
69
46–51
27–44
24
3–7
41
4–11
94 (5)
41 (5)
5 (5)
1.2 (6)
79 (4)
42 (4)
1.3 (2)
21 (2)
65 (5)
31 (4)
10 (5)
0 (5)
19 (3.5)d
37 (3.5)d
11 (3.5)d
0
26 (3)d
25 (3)d
15 (3)d
N/A
Lamivudine
Adefovir
dipivoxil
Entecavir
5.5
36–44
41–75
17–32
16–21
⬍1
49–56
27
3.5
13–21
48–61
24
12–18
0
53
0
39 (5)
48 (5)
2 (5)
42 (5)
Responses at weeks 48–52
Log reduction in HBV DNA, copies/mL
Undetectable HBV DNA, %
ALT normalization, %
Loss of HBeAg, %
HBeAg seroconversion, %
Loss of HBsAg, %
Histologic improvement, %b
Genotypic resistance
Responses during extended treatmentc
Undetectable HBV DNA, %
HBeAg seroconversion, %
Loss of HBsAg, %
Genotypic resistance
39 (2)
47 (3)
0–3 (2–3)
65 (5)
NOTE. The percentage of patients in the original cohort included in extended response reports was as follows: lamivudine, 17%–72%; adefovir,
38%; entecavir, 49% (entecavir 1.0 mg was used beginning in year 3 instead of approved 0.5 mg); tenofovir, 76% (34 of 39 patients with
detectable HBV-DNA levels at week 72 opted to add emtricitabine); PEG-IFN, 65%. Data are from references 10 –13, 14 –20, 21, 24, 25–29.
N/A, not available.
aLiver biopsy performed at weeks 72 or 78, 24 weeks after stopping treatment.
bHistologic improvement defined as a ⱖ2-point decrease in necroinflammatory score and no worsening of fibrosis score.
cThe time point at which response was assessed in years from start of treatment is shown in parentheses.
dAssessment performed off treatment.
HBsAg (Table 2).11,12,14,16,17,21 Extension of the duration
of nucleos(t)ide analogue treatment to 4 –5 years was
associated with a progressive increase in the rate of
HBeAg seroconversion, to 31%– 48%, but the rate of
HBsAg loss remained low (0%–10%) (Table 2). In some
studies, treatment in later years differed from that of
standard clinical practice; the dose was increased (1
mg/d instead of the approved dose, 0.5 mg/d) from year
3 onward in the entecavir study, and 34 of 39 patients
who had detectable levels of HBV DNA at week 72
opted to receive additional emtricitabine treatment in
the tenofovir study.22–25
The durability of HBeAg seroconversion after treatment
with nucleos(t)ide analogues has been reported to be less
than 50% in some studies and more than 80% in others.
Nucleos(t)ide analogues were found to induce only temporary HBeAg seroconversion in one study of 9 patients.26
However, a study of 178 patients reported the durability
of HBeAg seroconversion to be 78% in the overall cohort
and 91% among 117 patients who completed at least 12
months of consolidation therapy (the duration of continued treatment after HBeAg seroconversion).27
A 1-year course of treatment with nucleos(t)ide analogues produced high rates of undetectable levels of
Table 3. Response Rates to Approved Therapies for HBeAg-Negative CHB
Treatment response parameters
Responses: weeks 48–52
Histologic improvement, %b
Undetectable HBV DNA, %
HBsAg loss, %
Genotypic resistance, %
Responses: extended treatmentc
Undetectable HBV DNA, %
HBsAg loss, %
Genotypic resistance, %
Telbivudine
Tenofovir
disoproxil
fumarate
PEG-IFNa
PEG-IFN plus
lamivudinea
70
90
⬍1
0.2
67
88
⬍1
2.7
72
93
0
0
48
63
4
0
38
87
3
1
NA
NA
NA
84 (4)
⬍1 (2)
8.6 (2)
83 (5)
0.3 (5)
0 (5)
18 (3)d
8 (3)d
0
13 (3)d
8 (3)d
N/A
Lamivudine
Adefovir
dipivoxil
Entecavir
60–66
60–73
⬍1
23
64–69
51
0
0
6 (4)
⬍1 (4)
70–80 (5)
67 (5)
5 (5)
29 (5)
NOTE. The percentage of patients in the original cohort included in the extended response reports was as follows: lamivudine, 17%–72%;
adefovir, 47%; entecavir, 50%; telbivudine, 100%; tenofovir, 76% (34 of 39 patients with detectable HBV-DNA levels at week 72 opted to receive
additional emtricitabine); PEG-IFN, 58%. Data are from references 11, 17, 18, 20, 23, 26, 32, 33.
N/A, not available.
aLiver biopsy performed at week 72, 24 weeks after stopping treatment.
bHistologic improvement defined as a ⱖ2-point decrease in necroinflammatory score and no worsening of fibrosis score.
cThe time point at which response was assessed in years from the start of treatment is shown in parentheses.
dAssessment performed off treatment.
May 2012
Clinical Outcomes
Because of the slow course of chronic HBV infection, it is a challenge to implement randomized, controlled trials of antiviral agents with liver failure or HCC
(clinical outcomes) as end points. Evidence to support the
ability of antiviral therapy to prevent clinical outcomes
has been obtained mainly from retrospective or prospective cohort studies and meta-analyses. However, fewer
patients have been listed for liver transplantation for
HBV-related end-stage liver disease since 1999 (after the
approval of the first nucleos[t]ide analogue), indicating
that these drugs reduce clinical outcomes.31
Interferon. Most of the studies that reported that
interferon (IFN) treatment prevented clinical outcomes
used conventional IFN. Several studies found that IFNtreated patients had a reduced incidence of cirrhosis,
decompensation, liver-related death, and HCC, compared
with untreated patients, and that there was a greater
benefit among the responders.32,33 Meta-analyses confirmed that IFN therapy prevented complications of cirrhosis and HCC, although the studies analyzed had a high
degree of heterogeneity.34,35
Nucleos(t)ide analogues. A randomized, controlled trial of lamivudine therapy in 651 patients with
advanced fibrosis or cirrhosis, who were HBeAg-positive
or had serum levels of HBV DNA greater than 0.7
MEq/mL (⬃⬎140,000 IU/mL), reported that nucleos(t)ide analogues prevented clinical outcomes. After a median of 32 months, 7.8% of lamivudine-treated and 17.7%
of patients who received placebo (controls) reached the
combined end point (an increase in Child–Turcotte–Pugh
score by ⱖ2 points or development of clinical complications of cirrhosis, HCC, or liver-related death); HCC developed in 3.9% of the patients who received lamivudine
and 7.4% of controls.36 Fewer patients who maintained
viral suppression reached the combined end point than
those who developed resistance to lamivudine. Nucleos(t)ide analogues that have a higher genetic barrier to
resistance, such as entecavir or tenofovir, are therefore
more likely to reduce clinical outcomes.
A systematic review and a meta-analysis found a reduction in the incidence of HCC among patients who received nucleos(t)ide analogue therapy.35,37 Long-term
treatment with nucleos(t)ide analogues also was associ-
1363
ated with a decrease in liver fibrosis and reversal of cirrhosis.29,38,39 These data indicate that long-term viral suppression not only prevents further liver damage but also
might reverse previous damage.
Predictors of Response
PEG-IFN. Pretreatment factors that have been
shown to predict the response of HBeAg-positive patients
to IFN therapy include a high level of ALT, a low level of
HBV DNA, and infection with HBV genotype A.7,9
Younger age, female sex, a high level of ALT, a low level of
HBV DNA, and infection with HBV genotypes B or C were
associated with a higher rate of sustained response in a
phase 3 trial in HBeAg-negative patients.40 Recently, it was
suggested that a decreased titer of HBsAg at weeks 12 or
24 of PEG-IFN treatment predicted a sustained response
in HBeAg-positive and in HBeAg-negative patients, and
that this factor could be used to decide whether treatment
should be continued.41 However, these algorithms have
not been validated in prospective studies.
Nucleos(t)ide analogues. A high pretreatment
level of ALT is the best predictor of the response of
HBeAg-positive patients to nucleos(t)ide analogues,16,42
but there is no consistent predictor of response for
HBeAg-negative patients. All major genotypes of HBV
have similar levels of response to nucleos(t)ide analogues.
Adverse Events
Interferon. IFN therapy produces a wide range of
side effects, including fatigue, flu-like symptoms, mood
changes, bone marrow suppression, and development or
exacerbation of autoimmune illnesses. As many as 40% of
patients have an increase in ALT level during IFN therapy,
which generally is associated with response, but also could
precipitate liver failure in patients with cirrhosis.
Nucleos(t)ide analogues. All 5 nucleos(t)ide analogues that have been approved for treatment of CHB are
well tolerated, but produce several adverse reactions. Telbivudine has been associated with myopathy and peripheral neuropathy.14,43 Tenofovir and adefovir have been
associated with nephrotoxicity and renal tubular dysfunction; tenofovir also has been associated with decreased
bone mineral density. Entecavir was associated with lactic
acidosis in a case series of patients with decompensated
liver disease,44 but this finding was not reported in larger
studies.45,46
Effectiveness of CHB Treatment
Efficacy is the ability of a drug or intervention to
produce an effect under optimal conditions, whereas effectiveness is its usefulness in routine practice. Clinical
trials differ in many ways from clinical practice (Table 1),
so efficacy does not always result in effectiveness. For
example, clinical trials have stringent eligibility criteria.
Many physicians in clinical practice treat patients that fall
outside these criteria, assuming that efficacy and safety
observed in clinical trials can be extrapolated to their
patients.
CLINICAL LIVER
HBV DNA (51%–93%) and normalization of ALT levels
(62%–78%), but low rates of HBsAg loss (⬍1%) in nucleoside-naive patients with HBeAg-negative CHB (Table 3).14,15,17,28 Viral relapse occurred in almost all patients
when treatment was discontinued. Extending treatment
with adefovir or tenofovir to 4 –5 years maintained viral
suppression in 67%– 83% of patients, but the rate of
HBsAg loss remained low (0%–5%).24,29
Virus resistance to nucleos(t)ide analogues limits their
long-term success. The reported incidence of viral resistance to the 5 approved drugs ranged from 0% to 27%
after 1 year of therapy to 0%– 80% after 5 years of therapy
(Tables 2 and 3).12,14 –17,23,28,30
HBV TREATMENT EFFECTIVENESS
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SCAGLIONE AND LOK
Patients With Normal Levels of ALT
CLINICAL LIVER
Traditionally, treatment for CHB is recommended
only for patients with increased levels of ALT. A threshold
level of ALT that is 2⫻ ULN has been recommended in
guidelines from the American Association for the Study of
Liver Diseases and the Asian Pacific Association for the
Study of the Liver, based on the assumption that ALT level
is a reliable marker of liver injury.47,48 Furthermore, increased levels of ALT predict HBeAg seroconversion during
treatment with IFN or nucleos(t)ide analogues. Guidelines
from the European Association for the Study of the Liver do
not require increased levels of ALT for patients to receive
therapy, but rather histologic evidence of moderate to severe
necroinflammation and/or fibrosis.49
Several large, population-based studies have associated
high levels of HBV DNA with increased risk for cirrhosis,
HCC, and liver-related mortality,50–52 so many experts
advocate treatment of patients with CHB based only on
level of HBV DNA. The Risk Evaluation of Viral Load
Elevation and Associated Liver Disease study found that
participants with a high baseline level of HBV DNA that
decreased during follow-up evaluation had a lower risk of
HCC than those with persistently high levels of HBV
DNA. Participants with persistently abnormal levels of
ALT had an 8-fold higher risk of HCC than those with
persistently low to normal levels of ALT.53 These findings
indicate that an HBsAg-positive patient with persistently
normal levels of ALT and a single measurement of a high
level of HBV DNA might not need treatment.
Clinicians also might initiate antiviral treatment for
patients with normal levels of ALT based on reports that
they can develop histologically significant liver disease.
However, most of these studies included small numbers of
patients, and the normal level of ALT was determined
based on only 1 or 2 values. Studies that focused on
HBeAg-positive patients in the immune-tolerant phase
have shown that hepatic inflammation and fibrosis were
negligible to mild in most patients with normal levels of
ALT,54,55 and studies of HBeAg-negative patients who had
persistently normal levels of ALT (based on ⱖ3 values
over a period of ⱖ12 months) found that less than 10%
had significant amounts of inflammation or fibrosis.56,57
Patients with normal levels of ALT (particularly those
with persistently normal levels), therefore have a lower
risk of clinical outcomes and histologically advanced liver
disease, so the benefits of antiviral treatment might be less
than for those with abnormal levels of ALT. Furthermore,
the effects of antiviral agents in clinical trials, which only
include patients with abnormal levels of ALT, cannot be
extrapolated to patients with normal levels of ALT.
Data from 2 large, global trials of PEG-IFN showed that
HBeAg-positive patients (infected with genotypes A–D)
with pretreatment levels of ALT ⱕ2⫻ ULN had lower
rates of sustained response, defined as loss of HBeAg and
level of HBV DNA less than 2000 IU/mL, 6 months after
stopping treatment than those with pretreatment levels of
ALT ⱖ2⫻ ULN.58 There was a more than 7-fold difference
GASTROENTEROLOGY Vol. 142, No. 6
in the percentage of patients with sustained response
between the least responsive group (HBV genotype D,
HBV DNA ⱖ9 log copies/mL and ALT level ⬍2⫻ ULN;
7% response) and the most responsive group (HBV genotype A, HBV DNA ⬍9 log copies/mL and ALT ⱖ2⫻ ULN;
54% response). A phase 3 trial of entecavir in HBeAgpositive nucleoside-naive patients showed that patients
with pretreatment levels of ALT 1.3–2⫻ ULN had lower
rates of response than patients with pretreatment levels of
ALT ⬎2⫻ ULN; the responses in these groups at 1 year
were 62% and 75% for histologic improvement, 48% and
73% for level of HBV DNA ⬍300 copies/mL, 55% and 73%
for normal levels of ALT, and 8% and 26% for HBeAg
seroconversion.59 Therefore, there is a wide range in responses, even among patients who meet the stringent
criteria for inclusion in phase 3 trials (which do not
include normal levels of ALT). Responses to IFN and
nucleos(t)ide analogue therapy are lower in patients with
pretreatment level of ALT 1–2⫻ ULN in clinical trials, so
responses of patients with normal pretreatment levels of
ALT, seen in clinical practice, are likely to be even lower.
Patients With Low Levels of HBV DNA
Phase 3 clinical trials of PEG-IFN and nucleos(t)ide
analogues enrolled HBeAg-positive patients with serum levels of HBV DNA greater than 100,000 IU/mL and HBeAgnegative patients with levels greater than 20,000 IU/mL.
Based on data from the Risk Evaluation of Viral Load Elevation and Associated Liver Disease study, it was proposed
that the threshold for initiation of treatment should be
reduced to 2000 IU/mL.49 Virologic response rates (suppression of HBV DNA to undetectable levels) are likely to be
higher in patients with lower pretreatment levels of HBV
DNA; but the benefits of preventing clinical outcomes and
the cost effectiveness of many years of nucleos(t)ide analogue therapy are likely to be lower for patients with levels of
HBV DNA between 2000 and 20,000 IU/mL.
Extending Duration of Treatment
Practice guidelines recommend that treatment for
HBeAg-positive patients should be continued for at least
6 months after HBeAg seroconversion.47,49 However, a
longer duration of consolidation treatment, 12 months, is
preferred.27 Long-term follow-up data from phase 3 trials
showed that approximately 50% of HBeAg-positive patients achieved HBeAg seroconversion after 4 –5 years of
continuous treatment, so half of the patients will require
more than 5– 6 years of nucleos(t)ide analogue treatment.
There are no published data on the safety and efficacy of
nucleos(t)ide analogues beyond 5 years, yet in clinical
practice most physicians recommend continuing treatment beyond 5 years for patients who have not achieved
HBeAg seroconversion.
This recommendation is based on the assumption that
the treatment is safe and that incremental responses will
be observed with time. In fact, many experts have argued
that treatment should be continued indefinitely, even for
patients who have achieved HBeAg seroconversion, be-
cause of the low durability of nucleos(t)ide-related HBeAg
seroconversion and because HBV replication can persist
even in patients with durable HBeAg seroconversion.26,60
For HBeAg-negative patients, none of the guidelines provide clear-cut recommendations on when nucleos(t)ide
analogues can be stopped, although it has been suggested
that treatment could be discontinued for patients who
have cleared HBsAg. HBsAg loss, however, is a rare event,
occurring in 0%–5% of patients after 4 –5 years of continuous treatment. Therefore, most HBeAg-negative patients
in clinical practice are treated indefinitely.
In clinical practice, rates of response and of drug resistance during extended treatment with approved doses of
entecavir or tenofovir monotherapy might be lower than
those reported from clinical trials. Studies of treatment of
CHB in the community showed a wide range of responses
because of variations in inclusion and exclusion criteria, and
definitions of response. Reports from larger studies found
similar rates of response as those reported in phase 3 clinical
trials, indicating that efficacy in clinical trials can be replicated in the community, if the criteria for treatment are
similar and treatment is monitored by experienced physicians. A study of 63 HBeAg-positive patients treated with
PEG-IFN for 48 weeks found that 32% achieved HBeAg
seroconversion at the end of treatment and only 6.5% discontinued therapy owing to adverse reactions.61 Another
study compared the effects of telbivudine and entecavir in
195 HBeAg-positive patients and found that after 1 year of
treatment, serum levels of HBV DNA were undetectable in
82% and 94.9% of patients, respectively, and drug resistance
developed in 6.7% and none, respectively.62
Although nucleos(t)ide analogues are well tolerated and
generally very safe, adverse events have been reported, albeit
rarely in clinical trials, which include highly selected patients
who are treated only for up to 5 years. Patients who receive
adefovir or tenofovir and have other medical conditions,
such as diabetes or hypertension, which increase the risk of
renal failure, and those who receive concomitant medications that are potentially nephrotoxic, have increased risks of
renal impairment. These situations are more likely to arise in
clinical practice. In long-term carcinogenicity studies, doses
of entecavir that are 35– 42 times higher than those used in
clinical practice were associated with tumor development in
rodents. There is no evidence for an association between
entecavir and cancer risk in human beings. Although data
from an ongoing long-term safety study are not yet available,
many patients worldwide have been receiving entecavir continuously for more than 5 years.
Adherence
Treatment can be effective only if patients take
their medications as prescribed. In phase 3 trials of PEGIFN, approximately half of the patients required dose
reduction and 2%–7% had early discontinuation.7,8 Similar
to PEG-IFN and ribavirin treatment of chronic hepatitis
C, the rate of sustained response could be lower in patients with CHB who receive lower doses or have a shorter
duration of therapy.
HBV TREATMENT EFFECTIVENESS
1365
Adherence to nucleos(t)ide analogues is a bigger concern because of the need for long durations of treatment
and the increased risk of drug resistance among patients
with poor adherence. In phase 3 clinical trials of entecavir
and tenofovir, 2% of patients experienced virologic breakthrough during the first year, but none were found to
have drug-resistance variants, indicating that the breakthrough resulted from poor adherence. Adherence to
nucleos(t)ide analogues in clinical practice could be lower
than in clinical trials because patients are less motivated,
less frequently monitored, and often have to pay for part
of the costs of the medications. In a study of a pharmacy
claims database with more than 11,000 adult patients
who received nucleos(t)ide analogues for CHB in the
United States between 2007 and 2009, the mean persistence rate (defined as continued refill of medication over
a 12-month period) was 81% and the mean adherence rate
(defined as the percentage of days during which a patient
had medications in his/her possession during the period in
which the medication was prescribed) was 88%.63 Another
study found that 26% of patients who received nucleos(t)ide
analogue treatment at an academic liver center in the United
States reported having missed 1 or more doses during the
past 30 days,24 and patients with lower adherence had a
trend toward a higher rate of virologic breakthrough. A third
study found that the 5-year cumulative probability of virologic breakthrough was 46% among patients who received
nucleos(t)ide analogue therapy in clinical practice, but 40%
of the breakthroughs were not related to viral resistance.64
These findings confirm the effects of adherence on the effectiveness of CHB treatment.
Reducing the Burden of Hepatitis B
Despite the proven efficacy of CHB treatments,
numerous barriers keep these advances from reducing the
global burden of HBV infection. Identifying and removing
these barriers require coordinated efforts from policy
makers and health care providers (Table 4).
Diagnosis and Access to Care
Most people with CHB are asymptomatic until
they reach advanced stages of liver disease. Early diagnosis
requires recognition of persons with risk factors (by themselves or by a health care provider) and screening.
The IOM committee estimated that 65% of individuals
chronically infected with HBV in the United States are not
aware of their infection. Self-awareness of risks of HBV
infection among high risk populations in the United
States is low, varying from 26% to 70%.65,66 Among AsianPacific Islanders, only 30%– 40% are aware of their HBV
status, and as few as 8%– 65% of foreign-born Asian-Pacific
Islanders have been screened for HBV.66,67 Even among
those who are diagnosed, only 40%– 66% had been referred
to appropriate care.68,69 Many factors contribute to the
low rate of referral, including lack of health care insurance, language and cultural barriers, and failure (by individuals or health care providers) to recognize that absence
CLINICAL LIVER
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GASTROENTEROLOGY Vol. 142, No. 6
Table 4. Barriers Between Efficacy of CHB Treatment in Clinical Trials and Effectiveness in Clinical Practice and Solutions to
Bridge the Gap Between Efficacy and Effectiveness
Barriers
Diagnosis
Lack of awareness of risk
Fear of stigmatization
Lack of infrastructure in
primary care clinics to flag
at-risk patients and to
implement screening
Lack of access to care
Access to care
Language and cultural barrier
Lack of health care insurance
CLINICAL LIVER
Evaluation of disease and
indications for treatment
Lack of referral to appropriate
physicians
Failure to perform appropriate
evaluation and to
recommend treatment when
indicated
Initiation of treatment with
appropriate drugs
Lack of knowledge
Costs and availability of drugs
Adherence to treatment
Lack of knowledge about
importance of medication
adherence
Lack of tools to remind
patients
High costs or co-pay
Solutions to bridge the gap between efficacy and effectiveness
Education of public (particularly high-risk groups) and providers
Education of public (particularly high-risk groups)
Re-engineered care processes such as use of electronic medical records to
prompt screening of at-risk patients
Incorporate HBV screening in clinics with a high percentage of at-risk
patients (eg, HIV and sexually transmitted disease clinics)
Financial incentives for providers to perform HBV screening and vaccination
Free HBV screening for persons with risk factors through public health
clinics and community screening programs
Community health centers with staff who understand the language and
culture serving as navigators, strategic location of these centers
Social workers to help eligible persons apply for health care insurance
through private or government programs
Affordable Care Act in the United States
Education of patients about outcomes of chronic HBV infection and
available treatments
Navigators to assist with access to appropriate providers
Education of providers on diagnostic evaluation, natural history, and
treatment options
Remote learning, consultation, and shared management via video
conference
Quality measures of care
Adaptation of guidelines for resource-limited countries
Education of providers
Coordinated efforts of policymakers, providers, and pharmaceutical
companies to ensure availability of approved drugs worldwide and to
provide generic or discounted drugs to resource-limited countries and
patients with limited resources
Education of patients and providers
Counseling and reminders at follow-up visits
Pill box, reminders from pharmacy
Alerts from pharmacy to providers
Patient assistance program
Affordable Care Act in the United States
of symptoms or normal levels of liver enzymes does not
preclude the presence of liver disease or risk of cirrhosis or
HCC. Studies have shown that primary care physicians in
the United States have significant deficits in their knowledge
of risk factors for HBV infection, use of HBV serology tests,
interpretation of test results, and available treatment options
and their efficacy.1,70,71 One study estimated that 20%–30%
of Americans with CHB have been diagnosed, fewer than
50% have been referred to care, and only 3% are receiving
treatment (Figure 1).72 Similar gaps in diagnosis and referral
to care also were identified by a European panel.2 It is likely
that these gaps are wider in resource-limited countries where
HBV infection is more prevalent.
Implementation of Treatment and Choice of
First-Line Medication
Implementation of treatment requires an understanding of the indications and options for treatment, the
logistics of patient evaluation, the availability and affordability of treatment, and the infrastructure for monitoring response, adverse events, and drug resistance. In resource-limited countries, HBV-DNA assays and the
capacity to perform liver biopsy are not readily available,
so treatment decisions are made based on clinical assessment, age, level of ALT, and HBeAg status.73 In many
countries, noninvasive methods, such as blood tests for
panels of fibrosis markers and tools to measure liver stiffness, are increasingly used in place of liver biopsies to assess
liver disease and need for antiviral therapy. These methods
are expensive and not available in resource-limited countries,
but indices derived from routinely available laboratory tests,
such as aspartate aminotransferase–platelet ratio index, are
available and can provide additional information on the
likelihood of advanced liver disease.74
Ideally, patients should be treated with the medication
that is most likely to produce the desired response and be
tolerated by the patient. Professional organization guidelines
recommend PEG-IFN, entecavir, and tenofovir as first-line
medications, based on their efficacy and low risk for resistance in clinical trials. The decision whether to give PEG-IFN
or a nucleos(t)ide analogue usually is based on patient preference, although it also is based on physician bias, medical or
psychiatric comorbidities, the severity of liver disease, and
level of commitment to long durations of treatment. In
general, patients who are more likely to respond to PEG-IFN
May 2012
HBV TREATMENT EFFECTIVENESS
1367
but are not sufficient to reduce the global burden of HBV;
barriers to diagnosis, care, and treatment must be overcome. Advances in diagnostic tests and approval of new
drugs must be coupled with education programs for the
public and health care providers, and innovative strategies
are needed to improve access to care and affordability.
Only then can the efficacy of HBV treatment in clinical
trials be translated into effectiveness in the real world.
Given the need for long durations of anti-HBV therapy,
the most effective method to decrease the global burden
of HBV infection would be to implement universal vaccination of newborns worldwide.
Figure 1. HBV treatment, from efficacy to effectiveness. Of the estimated 1.4 –2 million persons in the United States with chronic HBV
infection, only approximately 33% are aware of the infection. Among the
estimated 350,000 –500,000 persons eligible for HBV treatment, approximately 50% are in care and 12.5% are receiving treatment. Rx,
treatment.
(high pretreatment levels of ALT and low pretreatment levels
of HBV DNA) are also more likely to respond to nucleos(t)ide analogues. The only exception is HBeAg-positive patients with genotype A infections who are predicted to have
a high rate of HBeAg and HBsAg loss with PEG-IFN treatment, but not with nucleos(t)ide analogue treatment. In
clinical practice, costs of medications (to the patients or the
health care system) are also important determinants. Therefore, despite a high rate of viral resistance, lamivudine is the
preferred first-line medication in some countries because of
its low cost.
The availability of the medications is another important determinant of care. Although tenofovir was approved for treatment of CHB in the United States and
Europe in 2008, it is still not available in many Asian
countries where hepatitis B is endemic and a large proportion of treated patients have received lamivudine. In
some resource-limited countries, various organizations
have developed comprehensive programs to screen at-risk
persons for HIV and provide care to those who are infected; these organizations have succeeded in collaborating with pharmaceutical companies in securing antiretroviral drugs at low cost. An expert panel convened by the
World Health Organization proposed that the infrastructure established for HIV care in these countries could be
used for HBV screening and treatment.73 However, this
proposal might not be applicable in many Asian countries, where similar programs are not available and where
the stigmatization of HIV infection could discourage persons with HBV from seeking care.
Conclusions
Approved therapies for CHB suppress HBV replication and prevent disease progression in clinical trials,
Note: The first 50 references associated with this
article are available below in print. The remaining references
accompanying this article are available online only with the
electronic version of this article. To access the supplementary
material accompanying this article, visit the online version of
Gastroenterology at www.gastrojournal.org, and at doi:10.10.
1053/j.gastro.2012.01.044.
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Received October 28, 2011. Accepted January 23, 2012.
Reprint requests
Address requests for reprints to: Anna S. F. Lok, MD, Division of
Gastroenterology and Hepatology, University of Michigan Health
System, 1500 E Medical Center Drive, 3912 Taubman Center, SPC
5362, Ann Arbor, Michigan 48109. e-mail: [email protected]; fax:
(734) 936-7392.
Conflicts of interest
This author discloses the following: Anna Lok has served on the
advisory board of Bristol-Myers Squibb, Gilead, GlaxoSmithKline, and
Roche. The remaining author discloses no conflicts.
Funding
Anna Lok has received research grants from Bristol-Myers Squibb,
Gilead, GlaxoSmithKline, Merck, and Roche.
May 2012
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