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Management of Chronic Hepatitis B - An Overview of Practice Guidelines For Primary Care Providers
Management of Chronic Hepatitis B - An Overview of Practice Guidelines For Primary Care Providers
Despite the introduction of hepatitis B virus (HBV) vaccination programs, chronic hepatitis B (CHB)
remains an important disease burden worldwide and in the United States. A number of clinical
practice guidelines are available to assist in the clinical management of CHB by providing recom-
mendations regarding screening and diagnosis, treatment indications, and the choice, duration,
and monitoring of treatment. Adherence to these guidelines has proven beneficial in terms of bet-
ter treatment compliance, improved clinical outcomes, and lower likelihoods of emergency admis-
sion. This review summarizes current recommendations from the major clinical CHB practice
guidelines and presents a simple algorithm for the treatment of patients with CHB to help primary
care providers make informed choices in clinical practice. In general, antiviral treatment should
be initiated in patients with CHB who have a high risk of liver-related morbidity and who are likely
to respond to treatment, that is, patients with persistently elevated serum HBV DNA and either in-
creased serum alanine aminotransferase concentrations or advanced liver disease. In patients who
are eligible for antiviral therapy, treatment should be initiated with one of the recommended first-
line therapies (pegylated interferon-␣, entecavir, or tenofovir), and treatment efficacy should be
monitored regularly for serum HBV DNA, alanine aminotransferase, and serologic responses. Patients who
are not immediately considered for treatment should be monitored and started on antiviral therapy in case of
disease progression. A number of issues in CHB management remain controversial or unresolved, such as
identifying treatment candidates, managing partial or nonresponders, and predicting treatment response; we
discuss some of the latest evidence around these topics. (J Am Board Fam Med 2015;28:822– 837.)
Keywords: Health Care Providers; Hepatitis B, Chronic; Practice Guideline; Primary Health Care
Despite vaccination programs, chronic hepatitis B (HBV),1 and 650,000 people die every year from
(CHB) remains an important disease burden world- HBV-related cirrhosis or hepatocellular carcinoma
wide and in the United States. Globally, 240 mil- (HCC).2 In the United States, 4.6% of the popu-
lion people are infected with the hepatitis B virus lation (⬃11 million people) have been exposed to
HBV, and 0.27% (⬃700,000 people) are affected
by CHB.3
This article was externally peer reviewed. Treatment of CHB has been shown to reduce
Submitted 2 December 2014; revised 2 April 2015; ac- the risk of HBV-related liver complications, in-
cepted 6 April 2015.
From the UCLA Medical Center, Pfleger Liver Institute, cluding decompensated cirrhosis and HCC.4 –9
Los Angeles, CA (S-HH); and the Liver Disease and Trans- CHB practice guidelines, such as those published
plant Center, Cedars-Sinai Medical Center, Los Angeles,
CA (TTT). by the American Association for the Study of
Funding: Editorial assistance was provided by Isabelle
Kaufmann of ArticulateScience UK, which was supported by
a grant from Bristol-Myers Squibb.
Conflict of interest: S-HH has received research grants for content of the review, that is, the data selection, drafting and
clinical studies from Bristol-Myers Squibb and Gilead Sci- reviewing of the manuscript, and the decision on any of the
ences. TTT has received research grants and personal fees conclusions, is entirely the product of the authors and rep-
from Bristol-Myers Squibb and Gilead Sciences, and per- resents their opinion.
sonal fees from Novartis. Corresponding author: Steven-Huy Han, MD, UCLA
Disclaimer: The sponsor had no role in the development Medical Center, Pfleger Liver Institute, 200 UCLA Medical
of the content of the manuscript. Bristol-Myers Squibb Plaza, Suite 214, Los Angeles, CA 90095 共E-mail:
reviewed the final article for scientific accuracy only. The steven.han@ucla.edu).
Vol. 28 No. 6
development or
progression
Inactive carrier ⬍2 ⫻ 103 ⫺ ⫹ 1.5–3.0 Normal Necroinflammation may WT ⬎ mutant ⬎35–40 Favorable prognosis,
disappear; halt of any (stable unless advanced
liver disease progression inactive fibrosis/cirrhosis has
carriers) developed during
Mutant ⬎ the HBeAg-positive
WT phase
(patients
who will
undergo
reactivation)
Reactivation Fluctuating, ⫺ ⫹ 2.5–4.0 Persistently or Advanced Mutant ⬎⬎ ⬎35–40 May lead to fibrosis
(HBeAg- ⬎2 ⫻ 103–4 intermittently WT progression or
negative elevated cirrhosis
disease)
Data compiled from Liaw et al,11 Liaw,22 and Kwon and Lok.23
*Alanine aminotransferase (ALT) upper limit of normal: 19 IU/mL in women, 30 IU/mL in men.
CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; ULN, upper limit of normal; WT, wild type.
http://www.jabfm.org
natally or during early childhood (which is usually CHB, a late stage of the infection generally associ-
the case in regions where HBV is endemic, such as ated with advanced liver disease.21–23 Annual re-
Asia), the immune-tolerant phase is long, typically lapse rates following HBeAg seroconversion are
lasting 2 or 3 decades; by contrast, it may be absent estimated to be 2% to 3% among Asians, with the
or very short in adult-acquired HBV. Thus, pa- highest rates in males, patients infected by geno-
tients in the immune-tolerant phase are generally type C, and those achieving HBeAg seroconversion
children or young adults from regions where HBV after the age of 40 years.22
is endemic.
If an immune response is mounted against the
virus, the disease progresses to the immune clear-
HBV Screening
ance phase. In this phase, called HBeAg-positive
CHB in the immune-tolerant or inactive carrier
CHB, the probability of achieving HBeAg sero-
phase is often asymptomatic; therefore, a consid-
clearance (ie, the loss of HBeAg and appearance
erable proportion of patients do not know they
of anti-HBeAb) is higher, with annual rates of
spontaneous HBeAg seroclearance ranging from are infected, thereby increasing the risk of devel-
2% to 20%. As a result of viral clearance, HBV oping severe liver complications and spreading
DNA levels decline, but because of the ongoing the virus to others. Among people affected by
liver injury associated with the immune response, CHB, an estimated 65% in the United States and
ALT concentrations are intermittently or persis- up to 90% in the European Union are not aware
tently elevated and may episodically reach up to of their infection.33,34 In Western countries, peo-
5 times the ULN (“ALT flares”). ple originating from a high or intermediate en-
Patients who achieve HBeAg seroconversion demic area (Asia, Africa, Australia, Central and
may enter the inactive carrier phase, character- South America, and the Mediterranean) account
ized by HBeAg negativity, anti-HBeAb positiv- for 50% to 95% of all patients with CHB35; thus,
ity, low or undetectable HBV DNA, and normal although in the United States the overall preva-
ALT. Unless advanced liver disease has devel- lence of HBV is ⬍1%, it is 10% or even higher
oped during the preceding immune clearance among Asian Americans.35,36 HBV screening al-
phase, the inactive carrier phase confers a favor- lows early diagnosis and treatment of infected
able prognosis, with improvements in liver his- individuals, as well as vaccination of their close
tology and a halt of disease progression.29 contacts, to reduce vertical and horizontal trans-
HBeAg seroconversion may also be followed by mission.36 CHB practice guidelines, and the re-
HBsAg seroclearance, which is considered to be a cently published guidelines from the US Preventive
state as close to remission as possible and is Services Task Force, recommend HBV screening
associated with a significant reduction (albeit not among high-risk populations, which include (1)
complete elimination) of HCC risk.30 If HBeAg
people born in high or intermediate endemic
seroconversion occurs late in life (after the age of
areas (for a complete list see ref. 37), (2) people
⬃40 years), however, the prolonged immune re-
who were not vaccinated as infants and whose
sponse may still allow liver disease to progress.31
parents were born in regions with high HBV
Importantly, HBV reactivation may occur, either
endemicity (Southeast Asia, China, sub-Saharan
as a result of HBeAg seroreversion (ie, restored
Africa), (3) people needing chemotherapy or im-
HBeAg positivity caused by reactivation of wild-
type HBV), or, more frequently, as a result of the munosuppressive therapy, (4) people with multi-
emergence of HBV mutants that no longer ex- ple sexual partners or a history of sexually trans-
press HBeAg (ie, precore or basal core promoter mitted disease, (5) people who have ever used
[PC/BCP] mutants); the latter event, which re- injecting drugs, (6) individuals infected with hu-
sults in HBeAg-negative CHB, is particularly man immunodeficiency virus or hepatitis C virus,
common among patients from Asia or the Med- and (7) household contacts or sexual partners of
iterranean, where the prevalence of PC/BCP mu- HBV-infected people.10,35 Testing should in-
tants is high.32 HBV reactivation can occur after clude a serologic assay for HBsAg, with chronic
years or decades of the inactive carrier state and HBV infection confirmed by the persistence of
represents, especially in the case of HBeAg-negative HBsAg for at least 6 months.35
Table 2. Summary of Anti–Hepatitis B Virus Treatment Indications as Recommended by Major Practice Guidelines
Practice Guidelines
10
AASLD APASL11 EASL12
HBeAg-positive • HBV DNA ⬎20,000 IU/mL • HBV DNA ⱖ20,000 IU/mL • HBV DNA ⬎20,000 IU/mL
• ALT ⬎2⫻ ULN • ALT ⱖ2⫻ ULN • ALT ⬎2⫻ ULN
• No spontaneous HBeAg
seroconversion after
3–6 months’ observation
• HBV DNA ⬎20,000 IU/mL • HBV DNA ⱖ20,000 IU/mL • HBV DNA ⬎2000 IU/mL
• ALT ⱕ2⫻ ULN • ALT ⱖ1 to ⬍2⫻ ULN • ALT ⬎1⫻ ULN
• Moderate or worse liver • Moderate or worse liver • Moderate or worse liver
inflammation or significant inflammation or fibrosis inflammation or moderate
fibrosis (on biopsy*) (on biopsy or noninvasive fibrosis (using a standardized
fibrosis assessment*) scoring system†)
• HBV DNA ⬎2000 IU/mL • HBV DNA ⱖ2000 IU/mL • Detectable HBV DNA
• Cirrhosis • Advanced fibrosis/cirrhosis • Cirrhosis
HBeAg-negative • HBV DNA ⬎20,000 IU/mL • HBV DNA ⱖ2000 IU/mL • HBV DNA ⬎20,000 IU/mL
• ALT ⬎2⫻ ULN • ALT ⬎2⫻ ULN • ALT ⬎2⫻ ULN
• HBV DNA ⬎2000 IU/mL • HBV DNA ⱖ2000 IU/mL • HBV DNA ⬎2000 IU/mL
• ALT ⱖ1–2⫻ ULN • ALT ⱖ1 to ⬍2⫻ ULN • ALT ⬎1⫻ ULN
• Moderate or worse liver • Moderate or worse liver • Moderate or worse liver
inflammation or significant inflammation or fibrosis inflammation or moderate
fibrosis (on biopsy) (on biopsy or noninvasive fibrosis
fibrosis assessment*)
• HBV DNA ⬎2000 IU/mL • HBV DNA ⱖ2000 IU/mL • Detectable HBV DNA
• Cirrhosis • Advanced fibrosis/cirrhosis • Cirrhosis
A
HBeAg-posive
HBV DNA
Treat if moderate or
severe liver inflammaon;
recommended agents:
ETV, TDF, or Peg-IFN-α
ommendations by AASLD, APASL, and EASL, For patients in whom antiviral therapy for CHB
and incorporating our experience and opinion. is indicated, the currently approved agents are in-
In real-life practice, patients with CHB may pres- terferons (IFNs) and NUCs (Table 4). IFNs
ent with coexisting morbidities such as advanced liver (IFN-␣ and pegylated IFN-␣), which historically
disease or coinfection with human immunodeficiency were the first available treatments for CHB, stim-
virus, hepatitis C virus, or hepatitis D virus, or they ulate immune-mediated suppression of HBV and
may have other special circumstances such as liver achieve higher HBeAg seroconversion rates than
transplantation, undergoing immune-suppressive NUCs after 1 year (⬃30%)12; however, they have
therapy, or pregnancy. In these cases, specific issues more adverse side effects than NUCs, are adminis-
need to be considered, and special management strat- tered by subcutaneous injection, and are effective in a
egies are required (Table 3). select minority (⬃30%) of all patients requiring therapy
B
HBeAg-negave
HBV DNA
Treat if moderate or
severe liver inflammaon;
recommended agents:
ETV, TDF, or Peg-IFN-α
(HBeAg-positive patients with high ALT and low term NUC therapy, however, drug resistance
HBV DNA at baseline).10,11 Furthermore, IFNs may develop.10 –12 Among the approved NUCs,
are contraindicated in patients with decompensated the nucleoside analog entecavir (ETV) and the nu-
cirrhosis, in whom there is increased risk of liver cleotide analog tenofovir (TDF) are currently the
failure and sepsis; in patients with autoimmune preferred first-line agents; both are potent com-
diseases, bone-marrow disorders, or uncontrolled pounds with high barriers to resistance (ⱕ1% dur-
psychiatric disorders; and during pregnancy.10 –12 ing long-term therapy).10 –12 Other approved
For these reasons, the use of IFNs in CHB treat- NUCs include the nucleoside analogs telbivudine
ment has declined with the availability of NUCs. and lamivudine (LVD), and the nucleotide analog
NUCs are oral agents and generally are better adefovir; however, these older NUCs have higher
tolerated than IFNs, allowing for prolonged use. rates of resistance and are no longer recommended
Compared with IFNs, NUCs are effective in for use as first-line monotherapy.10 –12 Nucleoside
most patients and achieve higher rates of HBV and nucleotide analogs generally have nonoverlap-
DNA suppression. Compared with IFNs, HBeAg ping resistance profiles, which is an important fac-
seroconversion rates with NUCs are lower after tor to consider when managing patients who de-
1 year (⬃20%)12 but may reach ⬃40% to 50% velop drug resistance (see Treatment Failure and
with continued NUC therapy.38,44 During long- HBV Resistance on NUC Therapy).
C
Liver cirrhosis
Cirrhosis status
Compensated Decompensated
Undetectable by Detectable
sensive PCR by sensive PCR
Special Considerations and Unresolved Issues HBsAg measurement is not routinely performed
in CHB Management in most US practices.
Treatment Eligibility Another difficulty relates to the variation in spe-
In real-life practice, the decision of whether to cific criteria for initiating antiviral therapy between
initiate HBV therapy may not always be straight- the different societal guidelines. For example, al-
forward. For example, among patients without de- though all 3 guidelines recommend treatment in
tectable HBeAg, it may be difficult to distinguish HBeAg-negative patients with ALT ⬎2 times the
true inactive carriers, who do not require treat- ULN and elevated HBV DNA, the HBV DNA
ment, from patients with HBeAg-negative CHB, threshold to start treatment is ⬎20,000 IU/mL in the
who require treatment. HBV DNA and ALT should US and European guidelines,10,12 but ⬎2000 IU/mL
be monitored regularly every 3 to 12 months for at in the Asian guidelines.11 Similarly, in HBeAg-
least 3 years10 –12 to detect any fluctuations indicative positive patients with minimally elevated ALT
of HBeAg-negative CHB.12 HBV genotyping can be (ALT ⬎1 but ⬍2 times the ULN), histologic
used to detect PC/BCP variants that are more prev- evaluation is recommended in patients with HBV
alent in HBeAg-negative CHB. DNA ⬎2000 IU/mL and age ⱖ30 years in the
Furthermore, quantitative HBsAg (qHBsAg) European guidelines,12 whereas it is HBV DNA
measurement, combined with HBV DNA, may ⬎20,000 IU/mL and age ⱖ40 years in the US
prove useful in the future, as qHBsAg levels have and Asian guidelines.10,11 These variations may
been found to be the lowest among inactive carriers be explained in part by geographic differences in
(see Table 1). In a study of patients with undetect- disease characteristics. For example, HCC risk is
able HBeAg and HBV genotype D, qHBsAg greater among Asian than among Western pa-
⬍1000 IU/mL and HBV DNA ⱕ2000 IU/mL tients, particularly those with HBeAg-negative
could accurately identify the inactive carrier state disease,46 and even in the absence of cirrhosis.47
in 90% of the patients45; however, quantitative The recommendations may also vary because of
Decompensated liver disease* • Higher risk of cirrhosis, HCC, and • Treatment is indicated irrespective of HBV DNA
mortality levels to improve clinical status
• Often associated with • Recommended agents: ETV and TDF (well
comorbidities such as renal tolerated and shown to improve liver status)
dysfunction, protein malnutrition, • Regular monitoring of renal function and lactic
or vitamin deficiencies acidosis recommended during ETV or TDF
therapy
• IFNs contraindicated; they may increase risk of
sepsis and decompensation
HCV, HDV, or HIV • Multiple viruses to be managed • Treatment should target the dominant virus
coinfection • Higher risk of cirrhosis, HCC, and • In HIV coinfection, LVD and TDF are active
mortality against both HBV and HIV; ETV is not
recommended unless the patient also receives
HAART
• Peg-IFN only drug effective against HDV
• Some reports of renal toxicity with TDF in
HBV/HIV-coinfected patients
LT recipients • Risk of HBV reactivation • Anti-HBV prophylaxis before and/or after LT
recommended
• HBIg with or without LVD historically is the
most common approach; however, there is no
consensus on HBIg dose and duration (that is,
long-term low dose vs. short-term high dose;
HBIg withdrawal; on-demand HBIg on NUC
maintenance)
• Alternative prophylactic regimens: ETV or TDF,
alone or combined with HBIg
Immune-suppressive or • Risk of HBV reactivation • In HBsAg-positive patients, preemptive NUC
chemotherapy therapy should be initiated at the onset of
immunesuppressive or chemotherapy to prevent
HBV reactivation
• In anti-HBc-positive patients receiving rituximab,
anti-HBV prophylaxis is recommended
Pregnancy • Risk of perinatal infection from • IFN-based therapy is contraindicated because of
highly viremic mothers its antiproliferative effect
• Risk of fetal damage • LdT and TDF are classified as category B (no
risk in animal studies but unknown in humans)
• LVD, ADV, and ETV are classified as category
C (teratogenic in animals, unknown in humans)
Pediatric patients • Infection at an early age is • Recommended to initiate treatment if ALT
associated with an increased risk of persistently ⬎2⫻ ULN
long-term complications • IFNs given parenterally and associated with
• Long-term safety and drug temporarily disrupted growth43
resistance are important concerns
geographic differences in the perceptions of phy- tients with HBV DNA ⬍2000 IU/mL but with
sicians as well as differences in publication dates. qHBsAg ⱖ1000 IU/mL have a 14 times higher
Another controversial issue concerning treat- HCC risk than those with qHBsAg ⬍1000 IU/mL.48
ment eligibility is whether the current criteria Another group of patients for whom treatment is
adequately identify all patients with CHB who not recommended are HBeAg-negative patients
are at risk of liver disease progression. For exam- with high HBV DNA and low/normal ALT;
ple, treatment is not recommended for patients however, persistently elevated HBV DNA has
with HBV DNA ⬍2000 IU/mL; however, it has been clearly established as an important HCC
recently been shown that HBeAg-negative pa- risk factor in these patients.24 –26 Family history
Interferons
Interferon ␣-2b Subcutaneous — 5 ⫻ 106 IU daily or 3 ⫻ 106 IU/m2, 3 times weekly, up HBeAg-positive: — Influenza-like symptoms,
(Intron A) 10 ⫻ 106 IU 3 times to a maximum of 10 ⫻ 106 IU 16⫺24 weeks fatigue, headache,
weekly weekly* HBeAg-negative: malaise, emotional
48 weeks lability (anxiety,
Pegylated-interferon Subcutaneous — 180 g weekly Not indicated in patients ⬍18 years 48 weeks — irritability)
␣-2a (Pegasys)† old
doi: 10.3122/jabfm.2015.06.140331
Nucleo(s)tide analogs
ETV (Baraclude)† Oral NUC 0.5 mg daily in NUC-naïve Indicated for patients aged ⱖ2 years ⱖ1 year 1% at year Negligible
patients‡ and weighing ⱖ10 kg HBeAg-positive: until 5
1.0 mg daily in LVD- Patients ⱕ30 kg: weight-based HBeAg
experienced patients‡ dosing of oral solution seroconversion* with
(ⱖ16 years old) LVD-naïve: 3–9 mL daily maintained
LVD-experienced: 6–18 mL daily undetectable HBV
Patients ⬎30 kg DNA (plus ⱖ6–12
LVD-naïve: 10 mL (0.5 mg) months’ consolidation
solution or one 0.5-mg tablet therapy)
daily HBeAg-negative: until
LVD-experienced: 20 mL (1 mg) maintained
solution or one 1-mg tablet undetectable HBV
daily DNA (plus ⱖ6–12
months’ consolidation
therapy)
TDF (Viread)† Oral NUC 300 mg daily‡ Not indicated for patients None up to Potential nephrotoxicity
(patients ⱖ12 years) ⬍12 years old year 5
LdT (Tyzeka; Oral NUC 600 mg daily‡ Not indicated for patients 17% at Negligible
Sebivo) (patients ⱖ16 years) ⬍16 years old year 2
ADV (Hepsera) Oral NUC 10 mg daily‡ Not indicated for patients 29% at Potential nephrotoxicity
(patients ⱖ12 years) ⬍12 years old year 5
LVD (Epivir, Zeffix) Oral NUC 100 mg daily‡ Patients aged 2–17 years: weight- 24% at Negligible
based dosing, oral solution or year 1
tablets; 3 mg/kg daily 70% at
(maximum 100 mg daily)* year 5
Data compiled from Lok and McMahon,10 European Association for the Study of the Liver clinical practice guidelines,12 US prescribing information for Baraclude (Bristol-Myers Squibb, 2014);
Viread (Gilead Biosciences, 2013); Tyzeka (Novartis, 2013); Hepsera (Gilead Biosciences, 2012); Epivir (ViiV Healthcare, 2013); Pegasys (Genentech/Roche, 2014); and Intron A (Merck, 2011).
*Use in pediatric patients approved in the United States but not in the European Union. Hepatitis B e antigen (HBeAg) loss and anti-HBe-positivity on 2 occasions 1–3 months apart.
†
831
of liver disease is another risk factor for HBV- rier-to-resistance NUCs such as ETV or TDF,
related liver complications and may also be taken there is also evidence showing that continued
into account when considering treatment.10 –12 monotherapy with the same agent often eventu-
Whether treatment indications should be ex- ally results in complete virologic suppression
tended to include these patients requires careful (with minimal resistance development), obviating
consideration of the benefit provided by treat- the need for treatment changes.52–54
ment, such as decreased risk of cirrhosis and
HCC, versus the risks of long-term treatment, Treatment Duration and Stopping Rules
such as side effects, resistance development, and For NUC-based antiviral therapy, the guidelines
increased cost. stipulate that treatment can be stopped after
achieving certain end points that reflect the pa-
Treatment Failure and HBV Resistance on NUC tient’s HBeAg status and degree of liver fibrosis. In
Therapy HBeAg-positive patients, the recommended end
An important point to consider with NUC-based points are HBeAg seroconversion following sus-
therapy is treatment failure (ie, partial virologic tained undetectable HBV DNA with ALT normal-
response [HBV DNA decrease ⬎1 log10 IU/mL ization; in HBeAg-negative patients or HBeAg-
after 6 or 12 months of treatment but still detect- positive patients who do not seroconvert, the
able], primary nonresponse [HBV DNA decrease recommended end points are sustained undetect-
⬍1–2 log10 IU/mL after 3 to 6 months of therapy], able HBV DNA with ALT normalization.10 –12
or virologic breakthrough [HBV DNA increase Consolidation therapy is recommended in patients
⬎1 log10 IU/mL above nadir after achieving a who achieve these end points, but there is no con-
virologic response10 –12). Treatment failure can sensus on its optimal duration (6 or 12 months or
be the result of drug resistance; however, com- longer).10 –12 Ultimately, HBsAg loss is the ideal
pliance should be ascertained, since with the cur- end point because it is associated with a signifi-
rent first-line agents ETV and TDF, develop- cantly reduced HCC risk, although not as low as
ment of resistance is rare. In compliant patients, that of a person who has never been infected with
HBV genotyping for identifying possible resis- HBV.30
tance mutations may guide further treatment de- However, achievement of these end points
cisions. In the case of resistance, the guidelines is rare with 4 to 5 years of treatment (40% to
recommend either switching to or adding a more 52% for HBeAg seroconversion,38,44 ⱕ10% for
potent agent with a nonoverlapping resistance HBsAg loss23), and there is also growing evidence
profile. Compared with sequential monotherapy, suggesting that it does not guarantee long-term
combination therapy may provide greater protec- remission. This is because of the presence of
tion against multidrug resistance; however, there covalently closed circular HBV DNA (cccDNA)
is no clear consensus regarding an optimal rescue inside the nuclei of infected hepatocytes, which is
strategy. For example, for patients with LVD the stable genetic component of HBV that may
resistance, which accounts for most cases of HBV persist even after HBsAg loss has occurred,
resistance, the US and Asian guidelines recom- thereby allowing HBV reactivation.21,55 Thus,
mend adding on TDF or adefovir,10,11 whereas even with consolidation therapy, HBV recur-
the European guidelines recommend either add- rence is frequent, with ⬃40% to 80% of patients
ing on or switching to TDF.12 ETV mono- experiencing virologic relapse after stopping
therapy is generally not suitable for patients with therapy.56 – 61 Therefore, in clinical practice, a
LVD resistance because the 2 agents have cross- considerable proportion of patients will require
resistance, with LVD resistance predisposing for long-term, if not indefinite, treatment with
ETV resistance.49 Other rescue strategies, NUCs to maintain these end points and prevent
such as adding on ETV50 or switching to ETV HBV reactivation.
plus TDF combination therapy,51 have also been IFN-based therapy is administered over a finite
shown to be effective in patients in whom prior duration (usually 48 weeks), irrespective of achieve-
NUC therapy has failed and therefore represent ment of these end points, since prolonged mainte-
alternative treatment options. For patients with a nance therapy to suppress HBV replication is not
partial virologic response when taking high-bar- feasible with these regimens.62