Download Benefits and risks of combination therapy for hepatitis B

Benefits and Risks of Combination Therapy for
Hepatitis B
Norah A. Terrault
In successful antiviral therapy of hepatitis B, drug combinations, particularly combinations
without cross-resistance, can delay or prevent the emergence of drug-resistant mutants. Because
drug-resistant mutants are archived and may limit future therapeutic options, prevention is
important for long-term therapeutic efficacy. Additionally, combining drugs may achieve synergistic or additive antiviral effects compared with single drug therapy. Undesirable aspects of
combination therapy include higher treatment costs and possibly lower adherence rates (due to
pill number or complexity of regimen). Potentially harmful effects of combination therapy
include higher rates of side effects, reduced efficacy due to drug competition, and the risk of
multidrug-resistant hepatitis B virus (HBV) if combination therapy is insufficient to prevent
resistance. Combination therapy has been shown to reduce the rate of drug resistance in chronic
hepatitis B, but only when drugs with a low barrier to resistance are used (lamivudine, adefovir).
Combination therapies may achieve greater degrees of HBV DNA suppression, but this has not
been associated with higher rates of seroconversion (hepatitis B e antigen or hepatitis B surface
antigen) compared to single drug therapy. The benefit of combination therapy has yet to be
demonstrated with agents that are associated with a high barrier to resistance (tenofovir, entecavir). The use of combination therapy is recommended in specific patient groups: those with
decompensated cirrhosis, those coinfected with human immunodeficiency virus and HBV who
are on antiretroviral therapy, those who have undergone liver transplantation, and those with
drug-resistant HBV infection. There is insufficient evidence to recommend combination therapy
as first-line therapy for all patients with chronic hepatitis B. (HEPATOLOGY 2009;49:S122-S128.)
Rationale of Combination Therapy of
Hepatitis B
Current therapies for chronic hepatitis B virus (HBV)
infection are approved for use as monotherapies; however,
combination therapy offers several advantages over single
drug therapy and has been found to be necessary in many
chronic infectious diseases. Combining drugs may achieve
synergistic or additive antiviral effects compared with single
drug therapy. For example, more rapid achievement of an
undetectable HBV DNA level may increase the rates of se-
Abbrevations: HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen;
HBeAg, hepatitis B e antigen; HIV, human immunodeficiency virus.
From the Departments of Medicine and Surgery, University of California San
Francisco, San Francisco, CA.
Received January 21, 2009; accepted February 11, 2009.
Address reprint requests to: Norah Terrault, M.D., S357, 513 Parnassus Avenue, San Francisco, CA 94143-0538. E-mail: [email protected]; fax:
415-476-0659.
Copyright © 2009 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.22921
Potential conflict of interest: Dr. Terrault has done consulting for Bristol-MeyersSquibb and Roche Pharmaceuticals, and has received grant support from Roche
Pharmaceuticals and Gilead Sciences.
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roconversion of hepatitis B e antigen (HBeAg) or hepatitis B
surface antigen (HBsAg) or improvement in liver tests or
liver histology. Additionally, combinations of drugs without
cross-resistance can delay or prevent the emergence of drugresistant mutants, a paradigm well established in other
chronic viral infections. Because emergence of these drugresistant viral variants can limit future therapeutic options, minimizing this complication is critical for a
successful regimen.
The ideal combination therapy would target different aspects of HBV replication using agents that have no crossresistance. Interferon (nonpegylated and pegylated forms)
has both antiviral and immune-modulating effects. Currently, all of the approved oral drugs for hepatitis B target the
HBV polymerase, though there are reported differences in
the aspects of polymerase function affected by each drug
(Table 1). Combining drugs with the same mechanism of
action may lead to drug interference rather than synergy, or
to other adverse effects. All of the nucleoside analogs inhibit
elongation of the viral minus-strand DNA. Adefovir dipivoxil and entecavir, and to a weaker extent clevudine, inhibit
the priming of reverse transcription, and clevudine and entecavir inhibit plus-strand DNA synthesis.1-5 In general,
HEPATOLOGY, Vol. 49, No. 5, Suppl., 2009
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Table 1. Nucleoside Analogs: Structural Groups and
Polymerase Inhibitory Activities
Polymerase Functions
Drug
Structural
Group
Priming
Elongation
Negative
Strand
⫹⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹⫹
Lamivudine
Telbivudine
Clevudine
Emtricitabine
L-Nucleosides
Entecavir
Deoxyguanosine
analogs
⫹⫹
⫹⫹⫹
Adefovir
Acyclic
nucleotide
phosphonates
⫹⫹
⫹⫹⫹
⫹
Plus Strand
Synthesis
⫹⫹
⫹⫹
⫹⫹⫹
Tenofovir
however, these nucleoside analogs have very similar mechanisms of action, and drugs with different targets and mechanisms of action are desirable for combination therapy.
Combined drugs should have complementary resistance profiles. There is no clinically-evident resistance to
peginterferon, whereas selection of drug-resistant mutants
occurs with all the nucleoside analogs to greater or lesser
extent. The nucleoside analogs approved for use in hepatitis
B fall into three groups in terms of structure and resistance
patterns. The L-nucleosides include lamivudine, emtricitabine, telbivudine, and clevudine; the acyclic nucleoside
phosphonates include tenofovir and adefovir; and the deoxyguanosine analogs include entecavir.6 Resistance to one
drug confers at least some resistance to others within the
group and may reduce sensitivity to nucleoside analogs from
other groups. Studies using combination L-nucleosides have
not shown success in terms of antiviral efficacy or prevention
of resistance.7,8
Current Indications for Combination
Antiviral Therapy of Hepatitis B
The American Association for the Study of Liver Diseases and other societal treatment guidelines recommend
the use of combination therapy in a limited number of
patient subgroups, including those with decompensated
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cirrhosis, those with human immunodeficiency virus
(HIV)/HBV coinfection on antiretroviral therapy, and
patients after liver transplantation.9-11 These recommendations are not based on results of randomized controlled,
prospective trials but rather upon anecdotal data, small
case series, and the recognized risk of rapid disease progression and life-threatening complications in the absence
of controlled HBV replication in these patient populations.12,13 Combination therapy is also recommended for
patients with evidence of drug resistance to minimize the
risk of multidrug-resistant HBV with sequential monotherapy.14,15 This latter use of combination therapy is
particularly important given the limited number of treatment options available for patients with drug-resistant
HBV infection. Combination therapy in this setting does
not represent “de novo” combination therapy because
these patients already have archived resistance mutations
from prior drug exposures. The combination therapy recommended for these select groups of patients is two or
more nucleoside analogs without cross-resistance.
Combination Therapy for Drug-Resistant
HBV Infection
In patients with lamivudine-resistant HBV infection,
the combination of adefovir with lamivudine is superior
to adefovir alone. Two randomized controlled studies
have addressed this issue (Table 2). While no differences
in rates of response or virological breakthrough were evident with treatment for 12 months,16 longer duration
treatment showed superiority of combination therapy
over adefovir monotherapy in preventing adefovir resistance.17 The largest study was based on a retrospectiveprospective cohort of 585 patients with lamivudineresistant chronic hepatitis B (86% HBeAg-negative)
treated with adefovir in addition to lamivudine (N ⫽
264) or adefovir alone (N ⫽ 273) for a median of 33
months.18 The 3-year cumulative risk of adefovir resistance was 16% in the adefovir monotherapy group versus
0% in the combination group (P ⬍ 0.001). Other cohortstudies have reported superior efficacy with the strategy of
adding adefovir to lamivudine rather than switching to
Table 2. Randomized Controlled Studies of Combination Therapy for Lamivudine-Resistant HBV Infection
Study Population (Reference
Number)
N
Treatment
Groups
LMV-resistant HBeAg-positive16
19
19
20
LMV
ADV
ADV & LMV
LMV-resistant HBeAg-negative17
14
28
ADV
ADV & LMV
LMV, lamivudine; ADV, adefovir; NA, not applicable.
Duration of
Treatment
% HBV DNA Levels
Undetectable (copies/mL)
HBeAg
Seroconverson
% with DrugResistance
12 months
0 (⬍1000)
26 (⬍1000)
35 (⬍1000)
0
11
6
100
0
0
30 months
40 months (median)
79 (⬍1000)
68 (⬍1000)
NA
NA
21
0
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HEPATOLOGY, May 2009
Table 3. Randomized Studies of Combination Therapy: Peginterferon and Lamivudine: 24 Weeks Posttreatment Results
Outcomes
Treatment Arms
N
HBV DNA ⬍400
copies/mL (%)
HBeAg
seroconversion
(%)
HBsAg loss (%)
LMV Resistance
(%)
Janssen et al.23
HBeAg-Positive
Lau et al.27
HBeAg-Positive
Chan et al.24
HBeAg-Positive
Marcellin et al.25
HBeAg-Negative
Peg-IFN 100
␮g/week for
32 weeks,
350 ␮g/
week for 12
weeks
155
7
Peg-IFN 100
␮g/week
and LMV
100 mg/day
for 52
weeks
152
9
Peg-IFN & LMV
100 mg/day for
48 weeks
Peg-IFN 180
␮g/week for
48 weeks
LMV 100 mg/day
for 48 weeks
LMV 100 mg/day
for 52 weeks
Peg-IFN 1.5 ␮g/kg
for 32 weeks &
LMV 100 mg/day
for 52 weeks*
LMV 100 mg/day
for 52 weeks
Peg-IFN 180
␮g/week for 48
weeks
Peg-IFN 180
␮g/week &
LMV 100
mg/day for
48 weeks
272
14
271
14
272
7
50
4
50
6
181
7
177
19
179
20
29
29
24
27
20
14
36
NA
NA
NA
7
0
7
11
0
4
3
0
0
18
0
40
2
21
0
18
4
0
3
1
LMV, lamivudine; Peg-IFN, peginterferon; NA, not available.
*LMV added 8 weeks after peg-IFN and continued 8 weeks beyond stop of peg-IFN. Maximum dose peg-IFN given 100 ␮g/week.
adefovir.19,20 The combination of lamivudine and adefovir significantly reduced but did not completely prevent
virological breakthrough due to resistance. Although data
are sparse, the factors that were associated with a higher
likelihood of virological breakthrough due to resistance
were higher baseline HBV DNA levels, persistence of detectable HBV DNA during therapy,20 and presence of
pre-existing drug-resistant variants.19
There have been no comparison studies of therapy of
chronic hepatitis B with adefovir-resistant, tenofovir-resistant, or entecavir-resistant HBV mutations, as rates of
resistance to these agents is less than with lamivudine, and
these drugs have been available for shorter periods of time.
Nonetheless, the lessons learned from the lamivudineresistance studies support use of combination therapy in
patients with drug-resistant HBV and lead to the recommendation that the drugs used should have high antiviral
potency and a high barrier to resistance. To optimize the
choices of drugs used in treating drug-resistant HBV infection, pretreatment resistance testing may be useful to
fully characterize the viral variants present.
Combination Therapy in Treatment-Naı̈ve
Patients
Combination therapy has been evaluated as first-line therapy
for patients with chronic HBV infection. Randomized studies
of combination therapy versus monotherapy have included
peginterferon with lamivudine (Table 3) and combinations of
nucleoside analogs (Table 4).7,21-27 These data are limited in
several ways. First, there are no or very limited data on
combination therapy with recently approved therapies
such as entecavir, telbivudine and tenofovir. Additionally, the studies of combination nucleoside analogs
were of small sample size, were of relatively short duration, and were underpowered to detect small-tomoderate treatment differences.7,21,22,26
Peginterferon and Nucleoside Analog
Combination Therapy
There have been four randomized controlled trials
evaluating combined peginterferon and lamivudine (Table 3) and one evaluating peginterferon and adefovir28
Table 4. Randomized Studies of Combination Nucleoside Analog Therapy: On Treatment Responses
Study Population
(Reference Number)
N
Treatment
Groups
HBeAg-positive21
57
54
LMV
LMV & ADV
HBeAg-positive21
14
16
HBeAg-positive, HIV/HBV
coinfection22
HBeAg-positive7
Duration of
Treatment
% HBV DNA Levels
(copies/mL)
% HBeAg Seroconversion
% Drug-Resistance
2 years
14 (⬍200)
26 (⬍200)
20
13
43
17**
ADV
ADV & EMT
96 wks
38 (⬍300)
79 (⬍300)
25
14
0
0
13
12
11
LMV
TDF
TDF & LMV
1 year
46 (⬍170)
75 (⬍170)
64 (⬍170)
11
17
43
15
0
0
19
44
41
LMV
TBV61
TBV & LMV
1 year
32 (⬍170)
(⬍170)
49 (⬍170)
22
31
15
16
5
12*
*Three M204I and one L180M ⫹ M204V mutations, 1 wild-type.
**One N236 and six M204V/I mutations.
LMV, lamivudine; ADV, adefovir; EMT, emtricitabine; TDF, tenofovir; TBV, telbivudine
HEPATOLOGY, Vol. 49, No. 5, Suppl., 2009
compared to one or the other agent alone. Four of the five
studies started and stopped both peginterferon and the
nucleoside analog at the same time; the fifth study used a
staggered approach.24 In all studies, patients were treated
for one year and evaluated at the end-of-treatment and 24
weeks after treatment for clinical, biochemical, and virological responses. Long-term follow-up data are available
in one study of HBeAg-negative patients29 and one study
of HBeAg-positive patients.30
The studies were consistent in their findings. Peginterferon (with or without lamivudine) was superior to lamivudine monotherapy, but there was no advantage of
combination therapy over use of peginterferon alone. Interestingly, the decline in HBV DNA levels during treatment was greater with combination therapy compared to
peginterferon alone or lamivudine alone, with a mean
⫺2.7 log10 copies/mL greater fall in HBV DNA with
combination therapy than with peginterferon monotherapy in HBeAg-positive patients and mean 0.9 log10
copies/mL greater decline in HBsAg-negative patients.25,27 However, these differences did not translate
into higher rates of HBeAg seroconversion or HBsAg
loss.23,25,27 Furthermore, sustained suppression of HBV
DNA at 4 years after treatment was not significantly different in HBeAg-negative patients receiving peginterferon than in those receiving both peginterferon and
lamivudine.25 Similar preliminary results were obtained
in a smaller randomized controlled trial of peginterferon
and adefovir versus peginterferon alone for 48 weeks in
HBeAg-negative chronic hepatitis B.28 Although greater
HBV DNA decline was seen during combination therapy, rates of sustained responses (virological and biochemical) 24 weeks after treatment were not significantly
different.
In terms of preventing lamivudine resistance, the combination of peginterferon and lamivudine was associated
with significantly lower rates of genotypic resistance at the
end of 48 weeks of treatment compared to lamivudine
alone24,25,27; nevertheless, lamivudine resistance was not
completely prevented (Table 3).
Whether specific subgroups may benefit from the combination of a nucleoside analog and peginterferon therapy
has yet to be determined. One post-hoc analysis of factors
associated with sustained responses in HBeAg-negative
chronic hepatitis B suggested that patients infected with
HBV genotype D had higher rates of responses with combination peginterferon and lamivudine than with peginterferon monotherapy.31 Uncontrolled studies of the
combination of peginterferon with a nucleoside analog
suggest that declines in intrahepatic HBV DNA and covalently closed circular DNA levels are greater than those
historically achieved with monotherapy using a nucleo-
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side analog,32-34 but whether intrahepatic HBV DNA and
covalently closed circular DNA levels are reduced more
with the combination of peginterferon and a nucleoside
analog compared to peginterferon alone is unknown.
There is a lack of controlled trials evaluating current
first-line therapies (entecavir, tenofovir, peginterferon)
alone and in combination. Additionally one treatment
strategy has predominated, namely combination therapy
starting and ending at the same time. Few studies have
examined alternative combination approaches. Of note,
the one study that started peginterferon 8 weeks before
adding lamivudine reported the highest rate of HBeAg
seroconversion among the combination studies of a nucleoside analog and peginterferon.24
Combination Nucleotide Analog Therapy
Published controlled trials comparing combinations of
nucleoside analogs versus nucleoside analog monotherapy
with one or the other for treatment-naı̈ve patients are few
in number and predominantly studied drugs that are no
longer considered first-line treatment for chronic hepatitis B.21,22,26 Nonetheless, these studies revealed little additive or synergistic antiviral effects of combination
nucleoside analog therapy over monotherapy. The decline in HBV DNA levels and rate of HBeAg and HBsAg
seroconversion were comparable between groups (Table
4). However, a greater proportion of patients on combination therapy achieved long-term HBV suppression
seemingly related to a lower rate of virological breakthrough compared to single drug therapy. For example, in
a study of patients with HBeAg-positive chronic hepatitis
B, only 17% of patients treated with the combination of
adefovir and lamivudine developed genotypic resistance
after 2 years compared to 43% of those on lamivudine
monotherapy.21 In a small study of patients coinfected
with HIV/HBV who were randomized to receive lamivudine, tenofovir, or the combination of the two, genotypic
resistance was not seen after 1 year in the tenofovir or
combination group but was found in 15% of patients
treated with lamivudine monotherapy.22 In contrast, the
combination of lamivudine and telbivudine was not effective in reducing the risk of genotypic resistance,7 highlighting the importance of combining drugs with
different drug resistance patterns.
In general, antiviral efficacy appears to be driven primarily by the most potent of the nucleoside analogs in the
combination, and synergistic or additive effects are not
apparent. For example, in a small study of 40 HBV/HIV
coinfected patients who had not previously received antiretroviral therapy, treatment with the combination of tenofovir and lamivudine (n ⫽ 11) or tenofovir alone (n ⫽
12) was superior to lamivudine alone (n ⫽ 13) for reduc-
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tion in HBV DNA levels and proportion of patients with
HBV DNA levels below 1000 copies/mL. There were no
significant differences in the viral outcomes between the
tenofovir monotherapy and the combination tenofovirlamivudine arms.22 This study, like others that have evaluated combination nucleoside analogs in treatment-naı̈ve
patients, was of small sample size. Thus, the overall benefit of combination nucleoside analogs therapy compared
to single agents with potent activity against HBV (such as
entecavir or tenofovir) has yet to be shown.
While the available data indicate that combination
therapy reduces the risk of genotype resistance, this benefit is evident only in studies that used drugs with a high
rate of resistance. In studies using drugs with a low rate of
resistance, such as entecavir and tenofovir, the benefits of
combination therapy versus monotherapy have not been
established. Indeed, given the low reported rates of resistance with these drugs, large-scale studies of prolonged
duration will be necessary to establish such a benefit.
Adding Versus Switching Nucleoside
Analogs in Therapy for Patients with a
Suboptimal Antiviral Response
A related, but separate issue relates to the role of “add
on” combination therapy in current treatment algorithms. For patients treated with nucleoside analogs, it is
recommended that antiviral response to treatment be
evaluated at specific intervals and changes in therapy
made in those with a “suboptimal” virological response.9,35 The guidelines indicate this change in drug
therapy can either be “add on” (i.e., adding the second
agent resulting in combination therapy) or a “switch”
(i.e., switching to alternative single drug). There are no
randomized studies that directly assess which strategy is
better.
Preliminary results from observational studies provide
some insights into the factors of potential importance in
making this decision. In a small study of 79 patients
(⬃60% LMV-experienced) with suboptimal responses to
adefovir therapy after a median treatment period of ⬃415
days, patients were randomized to receive tenofovir
(switch, N ⫽ 39) or tenofovir plus emtricitabine (add,
n ⫽ 40). After 24 weeks, those with HBV DNA ⱖ400
copies/mL were eligible to receive open-label combination therapy. At the end of 48 weeks treatment, the proportion of patients with undetectable HBV DNA levels
was the same in patients receiving combination versus
tenofovir monotherapy (81% in both groups).36 In another small study of 69 HBeAg-positive patients with suboptimal response to adefovir, defined as less than 3-log
decline in HBV DNA, after 24 weeks therapy, those who
switched to telbivudine had a ⫺2.1 log decline in the
HEPATOLOGY, May 2009
subsequent 28 weeks compared to only a ⫺0.8 log decline
in those continuing adefovir. None of the patients switching therapy developed virologic breakthrough during the
study period.37 Finally, in the registration trials for tenofovir, patients initially randomized to adefovir were
switched to tenofovir at week 48.38 Of the 125 patients
who were initially treated with adefovir but continued to
have HBV DNA levels above 400 copies/mL, suppression
of HBV DNA to undetectable levels was achieved in 75%
of 90 HBeAg-positive and 94% of 35 HBeAg-negative
patients 24 weeks after the change to tenofovir monotherapy.
Thus, based on current understanding of factors influencing treatment failure, the add-on strategy may be preferred if the initial drug has a low genetic barrier to
resistance and/or if the time from initiation of therapy to
change is prolonged, such that resistance mutations are
likely to have been selected. However, switching to an
agent with a higher genetic barrier to resistance may be
more effective than adding a second agent with a low
genetic barrier to resistance. Regardless of whether an
add-on or switch of therapy is undertaken, the subsequent
drug used should be one without cross-resistance to the
first drug.
Risks of Combination Therapy
Combination therapy may have undesirable or harmful effects. Undesirable aspects of combination therapy
include higher treatment costs and possibly lower adherence rates (because of pill number or complexity of regimen). Cost considerations are complex because a cheaper
drug with a higher rate of resistance has additional costs in
terms of managing drug-resistant disease. Cost-effectiveness models will be useful in assessing this issue in future,
but none are available at present. Indeed, the lack of clinical data on long-term outcomes of combination therapy
makes it challenging to develop cost-effectiveness models.
Adherence is influenced by the duration and complexity
of a regimen. Although the development of combination
pills may be important for improving adherence with
combination regimens, enhanced monitoring tools and
greater emphasis on education of patient and provider are
also important.
Potentially harmful effects of combination therapy include higher rates of side effects, reduced efficacy due to
drug competition, and the risk of multidrug-resistant
HBV if combination therapy is insufficient to prevent
resistance. In prospective control trials, the combination
of peginterferon and lamivudine had similar tolerability
to peginterferon alone, but was associated with more
symptoms than in patients who received lamivudinemonotherapy.24,25,27 Combinations of nucleoside analogs
HEPATOLOGY, Vol. 49, No. 5, Suppl., 2009
Table 5. Summary of Efficacy Outcomes with Combination
Therapy in Treatment-Naı̈ve Patients with Chronic Hepatitis B
Treatment Outcomes
HBV DNA suppression
Rapidity of achieving HBV DNA
suppression
HBeAg serconversion
HBsAg seroconversion
Rate of virologic resistance
Histological improvement
Combination Versus Monotherapy
Combinations of nucleoside
analogs do not yield increases
in HBV DNA suppression;
Combination of peginterferon
and lamivudine appears to have
additive effects
No advantage of combination
therapy
No difference between
combination therapy and
monotherapy
No difference between
combination therapy and
monotherapy
Rates are lower with combination
therapy, but resistance is not
completely prevented
No difference between
combination therapy and
monotherapy
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Needs for Future Research
1. Defining efficacy of add-on versus switching nucleoside analog therapy for patients with a suboptimal initial
virologic response.
2. Evaluation of monotherapy with a nucleoside analog with a high resistance barrier to combination nucleoside analog therapy.
3. Evaluation of the relative efficacy and safety of starting treatment with a combination of nucleoside analogs
versus adding a second agent only once antiviral resistance
has arisen.
4. Evaluation of the possible role of a limited course of
peginterferon in combination with long-term nucleoside
analog therapy compared to long-term therapy with the
nucleoside analog alone.
Fortunately, at least some of these questions will be
addressed by clinical trials that are currently planned or
underway (see the registry at www.clinicaltrials.gov).
References
appear to be well-tolerated in the short term, in studies to
date.21,22 Adherence has not been adequately evaluated
outside of clinical trial settings.
Conclusions
1. At present, combination therapy can be recommended only for patients who are at high risk of complications in the event of virological breakthrough (e.g.,
patients with advanced cirrhosis, liver transplant recipients, patients with HBV/HIV coinfection) and patients
who already have drug-resistant HBV.
2. For patients with drug-resistant HBV, combination
therapy of drugs without cross-resistance and preferably
with high genetic barrier to resistance is recommended to
prevent the subsequent development of multidrug-resistant HBV.
3. There is insufficient evidence to recommend combination therapy as first-line therapy for the typical patient with chronic hepatitis B requiring treatment (Table
5). This lack of evidence is particularly true with current
first-line agents that have no (peginterferon) or low (entecavir or tenofovir) rates of antiviral resistance.
4. There have been no studies addressing the issue of
whether add-on (combination) therapy versus switching
to an alternative monotherapy is preferable in patients
with a suboptimal initial virological response to a single
nucleoside analog. Add-on therapy may be advisable if the
initial drug used has a low genetic barrier to resistance or
if the duration of therapy has been prolonged because
these factors increase the likelihood of drug-resistant
HBV being present.
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