Book on hepatitis from page 146 to 155

Book on hepatitis from page 146 to 155

146  Hepatology 2012
with LAM and ADV to LAM monotherapy in untreated patients (Sung 2008). In
this study, there was no difference in the virologic and biochemical response
between both groups. The rate of LAM resistance was much lower in the
combination group. However, the development of resistance could not be
completely avoided even with the use of an additional dose of ADV. Another study
analyzing the combination of LAM with LdT also showed no benefit for
combination therapy (Lai 2005).
Especially in patients with liver cirrhosis, a fast and complete suppression of
HBV replication is desirable. A monotherapy with ETV was found to be as safe and
effective as monotherapy with TDF, and an addition of emtricitabine to TDF
showed no improvement in response. Therefore, in these patients as well,
combination treatment is currently not recommended (Liaw 2011).
Combination treatment with LdT and PEG-INF α should not happen. In a recent
study, peripheral neuropathy was described in 9 of 48 (18.8%) patients who
received combination therapy of PEG-INF α and LdT and only in 10 of 3,500
(0.28%) patients who received LdT monotherapy (Goncalves 2009). Although
combination of LAM plus PEG-IFN α failed to demonstrate benefit when evaluated
at the end of follow-up in most studies, a more pronounced on-treatment virologic
response (week 48) was observed with combination therapy as compared to LAM or
PEG-IFN α alone. This more profound HBV DNA suppression induced by the
combination regimen was associated with a lower incidence of LAM resistance
(presence of resistance mutations in 1% vs. 18% at the end of therapy).
However, combination therapies between PEG-IFN  α  and more potent
nucleos(t)ide analogs may be attractive. Recently, a combination treatment of ETV
and PEG-IFN α  after 4 years of complete response to ETV was superior to
continuation of ETV treatment by HBeAg and HBsAg loss and seroconversion rates
(Ning 2011). Similar studies are currently being undertaken investigating
combination treatment of PEG-IFN α and TDF. However due to the preliminary
character of the results a combination treatment of nucleos(t)ide analogs plus PEG-INF α is still not recommended.
Choosing the right treatment option
One can choose either to treat with PEG-IFN α in order to induce a long-term
control by finite treatment or with nucleos(t)ide analogs to inhibit HBV replication
in the long-term (Figure 5).
At first, interferon therapy should be evaluated. However, if a patient does not
fulfil the criteria for PEG-IFN α, has contraindications, or is intolerant, long-term
therapy with nucleos(t)ide analogs is recommended. If a nucleos(t)ide analog is
chosen several parameters have to be considered prior to therapy: the antiviral
efficacy of the drug, the durability of response, the resistance barrier, and the stage
of liver disease.
If the initial viral load is low and liver cirrhosis has been excluded, any approved
drug may be used. The use of LAM, however, should be restricted to patients with
mild fibrosis and HBV DNA levels <2,000 IU/mL (or <105
copies/mL). For patients
with high-level HBV replication (>2 x 10
8
IU/mL or >10
9
copies/mL) only drugs
with a high genetic barrier should be used (i.e., ETV or TDF)  (Table 3).
Hepatitis B Treatment  147
Prognostic factors for treatment response
Several factors are positively associated with long-term remission and may help to
guide treatment decisions. Pretreatment factors predictive of HBeAg seroconversion
are low  viral load, high ALT levels (above 2-5 x ULN) and high histological
grading (Flink 2006, Hadziyannis 2006a, Lai 2007, Perrillo 1990, Perrillo 2002,
Wong 1993, Yuen 2007, Zoulim 2008). These general baseline predictors are
relevant especially for treatment regimens with PEG-IFN α but may in part be
relevant also for nucleos(t)ide analogs (Table 4).
A pooled analysis from the two largest trials using PEG-IFN α-2a or -2b in
chronic hepatitis B tried to calculate a score predicting successful interferon therapy
based on an individual patient’s characteristics (viral load, ALT level, HBV
genotype, age, gender). However, this approach may only be feasible in HBeAg-positive patients (Buster 2009).
Table 4. Predictors of response to antiviral therapy.
Nucleos(t)ide analogs  Peg-interferon α
Before treatment   Low viral load (HBV DNA ≤10
7
IU/mL), high serum ALT levels (above 3
times ULN), high activity scores on liver biopsy (at least A2)
During treatment  Undetectable HBV DNA in a
real-time PCR assay at 24 or 48
weeks is associated with HBeAg
seroconversion in HBeAg-positive patients and lower
incidence of resistance
HBV DNA decrease <20,000 IU/ml
at 12 weeks is associated with 50%
chance of HBeAg seroconversion
in HBeAg-positive patients and with
a 50% chance of sustained
response in HBeAg-negative
patients
HBeAg decrease     HBeAg decrease at week 24 may
predict HBeAg seroconversion
HBV genotype  HBV genotype shows no
influence on suppression of HBV
DNA levels.
HBsAg seroconversions only
observed for genotypes A and D
Association with HBV genotype A
and B and response to IFN α is
higher than with genotypes C and
D, however the association is weak
and HBV genotype should not be
the only argument for treatment
decision
HBV genotypes and treatment response. HBV genotypes have been shown to
be associated with IFN α  treatment  success. Patients with HBV genotype A,
prevalent in northern Europe and the US, show a much higher rate of HBeAg and
HBsAg seroconversion than patients with HBV genotype D, prevalent in the south
of Europe, or the HBV genotypes B or C originating from Asia (Keeffe 2007,
Wiegand 2008). During treatment with nucleos(t)ide analogs, suppression of HBV
replication and induction of HBeAg loss can be achieved regardless of the present
genotype. However, HBsAg loss was almost exclusively observed in patients with
genotypes A or D.
HBV DNA levels and treatment response.  During antiviral therapy, the
decrease of HBV DNA levels from baseline is the most important tool in monitoring
treatment efficacy. Complete response to antiviral therapy is defined as suppression
of HBV DNA to below the limit of detection as measured by a sensitive real time
PCR assay (Figure 9). Incomplete suppression is characterized by persistent HBV
148  Hepatology 2012
replication despite antiviral therapy. Ongoing HBV replication should be avoided to
prevent the selection of resistant HBV strains by replication of the virus in the
presence of drug in the so-called “plateau phases”. An HBV DNA breakthrough
despite continuous antiviral therapy is often caused by viral resistance. Measuring
of HBV DNA kinetics early during therapy will help to guide antiviral treatment
and to establish early stopping rules or add-on strategies to avoid antiviral failure
(Figure 9).
Figure 9. Possible courses of HBV DNA levels during treatment with nucleoside or
nucleotide analogs. Incomplete suppression of HBV DNA results in either a “plateau phase” or
in a continuous slow decline. A plateau phase represents a high risk for selection of resistant
HBV variants, therefore treatment should be changed to a more effective agent or combination
therapy. A continuous slow decline should induce a treatment change after 6 months if drugs
with a low genetic barrier like LAM or LdT are used. If drugs with a high genetic barrier like ETV
or TDF are applied, a continuous slow decline can be monitored for at least 12 months without
increased risk of consecutive HBV resistance.
Incomplete or partial virologic response to oral nucleoside or nucleotide analogs
is defined as a decrease of HBV DNA >1 log10  but remaining measurable
(Lavanchy 2004) (Figure 9). The definition of partial response depends on the type
of treatment; thus, for agents with a high genetic barrier against resistance like ETV
or TDF partial response is defined after 12 months and for substances with a low
genetic barrier like LAM or LdT, after 6 months of monotherapy. In case of partial
response to a drug with a low genetic barrier, an appropriate rescue therapy should
be initiated. By current guidelines, a combination treatment with a nucleotide analog
is recommended for these patients. However, it was recently shown that patients
with partial response to LAM or to ADV have a high probability of responding to
TDF monotherapy, without risking the development of resistance (Heathcote 2011,
Marcellin 2011b, van Bömmel 2010, Berg 2010). Patients with a partial response to
ADV were also shown to have a high probability of responding to a subsequent
Hepatitis B Treatment  149
monotherapy with ETV, irrespective of the presence of mutations associated with
HBV resistance to ADV (Leung 2009, Leung 2009a).
For patients with partial response to a drug with a high genetic barrier as ETV or
TDF, current guidelines also recommend the initiation of a combination treatment.
Recently published long-term studies have shown that the continuation of a new
monotherapy in these patients does increase the percentage of patients with
undetectable HBV DNA without increasing the risk of development of resistance
(Chang 2010, Marcellin 2011b, Snow-Lampert 2011) (Figure 7, Figure 8). Thus,
during monotherapy with TDF in HBeAg-positive and HBeAg-negative patients, an
increase of patients with complete suppression of HBV DNA between the end of the
first and the end of the fifth year of treatment from 81% and 90% to 100% was
shown.
For monotherapy with ETV at 1 mg/day, an increase from 55% to 91% and 94%
after the fourth and fifth years was demonstrated (Chang 2010). In case of
incomplete viral suppression at week 48, a continuation of monotherapy with TDF
or ETV 1 mg is advisable as long as HBV DNA levels decrease continuously.
However, the debate on whether switching or adding a second drug as optimal
management is still unanswered.
Even though prolongation of monotherapy with ETV or TDF will probably lead
to undetectable HBV DNA in the long term in most patients, a fast suppression of
HBV replication is mandatory in some patients (e.g., those with liver cirrhosis) to
stop the progression of liver disease. For these patients, no definite therapeutic
strategies have been evaluated yet. Preliminary results of a study assessing the
efficacy of a rescue combination therapy with ETV and TDF have recently been
able to induce suppression to undetectable levels in most patients with partial
response; however, data on long-term efficacy and safety are not available (Petersen
2011).
In any case of treatment failure, adherence to therapy should be evaluated prior to
treatment modification. Elimination of HBV DNA during TDF-based therapeutic
regimes can drop from 87% to 71% of cases if adherence is not ensured, which is
also important in preventing drug resistance (Berg 2010).
Since only 30-35% of all patients treated with PEG-IFN  α  reach HBeAg
seroconversion after 48 weeks, studies have been conducted recently to predict the
probability of seroconversion in relation to viral kinetics. In one retrospective
analysis early prediction of stable seroconversion was possible by week 12 of
therapy if HBV DNA had reached levels below 5 log10 UI/mL within this short
treatment period (Fried 2005). In 53% of these patients, HBeAg seroconversion was
observed while patients with HBV DNA levels of 5 to 9 log10 copies/ml or levels
above 9 log10  IU/mL achieved HBeAg seroconversion in only 17% and 14%,
respectively.
Timepoint of HBeAg loss. In one study with 172 patients who were treated with
PEG-IFN α-2b as monotherapy or in combination with LAM, the loss of HBeAg
within the first 32 weeks of treatment was shown to be an on-treatment predictor for
HBsAg loss during a mean period of 3.5 years after the end of treatment. HBsAg
loss was found in 36% of the patients with early HBeAg loss and only in 4% of the
patients with HBeAg loss after 32 weeks of treatment (Buster 2009).
150  Hepatology 2012
HBsAg levels and treatment response.  Response of HBeAg-positive and
HBeAg-negative patients to PEG-IFN treatment can be predicted by measuring
HBsAg levels before and changes of HBsAg levels during treatment (Figure 10).
Figure 10. On-treatment prediction of treatment response by HBsAg levels. In different
trials, an association of the decline in HBsAg levels within the first 12 weeks of PEG-IFN α
treatment and treatment response defined as HBV DNA levels <2,000 copies/mL six months
after treatment was found (Zonneveld 2010, Piratvis-uth 2011, Lau 2009, Gane 2011,
Rijckborst 2010, Moucari 2009). Patients showing no decline in HBsAg levels at week 12 had
only a very small chance of long-term response.
During PEG-IFN treatment for HBeAg-positive chronic HBV infection, an
absence of a decline in HBsAg levels at week 12 of treatment reduces the
probability of response to <5% in one study (Sonnefeld 2010). In the NEPTUNE
trial investigating the predictive value of HBsAg levels in 114 HBeAg-positive
patients receiving PEG-IFN α2a over 48 weeks, it was shown that in patients
achieving suppression of HBsAg to levels <1,500 IU/mL after 12 weeks of
treatment, the chance of reaching HBeAg seroconversion, suppression of HBV
DNA to levels <2000 IU/mL and HBsAg loss 6 months after treatment was 58%,
52% and 10%, compared to 42%, 31% and 0% in patients with HBsAg levels
between 1500-20,000. In this study, patients still showing HBsAg levels >20,000
IU/mL after 12 weeks of treatment achieved none of the endpoints (Gane 2011).
Beyond that, the probability of HBeAg loss rose to 68% in patients with elevation of
ALT levels >2 x the upper limit of normal at treatment initiation (Figure 11).
Hepatitis B Treatment  151
Figure 11. The level of HBsAg levels after 12 weeks of treatment with PEG-IFN α-2a is
predictive for HBeAg seroconversion six months after treatment. A combination of ALT
levels and HBsAg decline improves positive predictive value in these patients (Gane 2011).
Also in HBeAg-negative patients the decrease of HBsAg after 12 weeks of PEG-IFN α treatment can predict long-term response. This prediction can be made even
more precise regarding the kinetics of both HBsAg and HBV DNA. In another
study comprising 48 patients who were treated with PEG-IFN α-2a, a decrease in
serum HBsAg levels of 0.5 and 1 log10 IU/mL at weeks 12 and 24 of therapy was
associated with a positive predictive value for HBsAg loss of 90% and 97% at week
96 after treatment, respectively (Moucari 2009).
Monitoring before and during antiviral therapy
Before therapy, HBV DNA levels should be measured with a highly sensitive assay.
These results should be confirmed 1-2 months after initiation of therapy. In
addition, ALT levels reflecting the inflammatory activity as well as creatinine levels
should be determined. HBV genotyping is only recommended in patients who are
considered candidates for treatment with interferon. HBV resistance testing can be
useful in patients with prior failure to more than one nucleoside/nucleotide analog,
but this is not yet a standard diagnostic approach. HBV resistance has to be
expected when an increase of HBV DNA of >1 log10 during antiviral treatment is
observed. In cases of primary treatment failure an appropriate second line treatment
can be chosen without resistance testing.
During therapy, HBV DNA, ALT and creatinine levels should be measured
initially, after 4 to 6 weeks and then every 3 months. The early identification of viral
resistance and an early adjustment of therapy are crucial. Patients with suppression
of HBV replication to <300 copies/ml (60 IU/ml) for at least 2 years may perhaps
152  Hepatology 2012
be scheduled at 6 month intervals (Table 5). However, no studies have been
performed that support this procedure.
In HBeAg-positive patients, HBeAg and anti-HBe as well as HBsAg and anti-HBs should be also measured if HBV DNA levels become undetectable to identify
seroconversion as an endpoint of HBV therapy (Table 5).
Because the risk for HCC development remains increased even in patients with
complete suppression during long-term treatment with nucleos(t)ide analogs, these
patients should still regularly receive ultrasound examinations (Figure 12)
(Papatheodoridis 2011).
Table 5. Recommendation for laboratory tests for monitoring antiviral therapy.
Tests before antiviral treatment   Interval
HBV DNA quantitative  
HBeAg, anti-HBe  
HBsAg quantitative  If IFN-based treatment is planned
HBV genotype  If IFN-based treatment is planned
ALT level  
Creatinine level  
Other chemistry tests  
Tests during antiviral treatment   Interval
HBV DNA quantitative  After 4-6 weeks, after 12 weeks, then every 3-6
months
HBeAg, anti-HBe  3-6 months, if HBV DNA is undetectable
HBsAg, anti-HBs
HBV
3-6 months, in HBeAg-positive patients after HBeAg
seroconversion in and HBeAg-negative patients if
DNA is undetectable
HBV resistance test  If HBV DNA increases >1 log during antiviral
treatment and pretreatment history is not tractable,
but first check for treatment adherence!
ALT level  Initially every month, than every 3-6 months
Creatinine level*  Every 3-6 months
Other chemistry tests  Every 3-6 months
* Patients treated with TDF should initially be monitored every 4 weeks to watch for decrease of
kidney function
Treatment duration and stopping rules
In HBeAg-positive patients continuous treatment with nucleos(t)ide  analogs is
necessary as long as HBeAg seroconversion is not achieved. Even after
seroconversion antiviral therapy should be continued for at least another 12 months
to avoid the risk of “seroreversion” upon stopping the nucleos(t)ide analog therapy.
Criteria for optimal treatment duration with nucleos(t)ide analogs are still lacking
in patients with HBeAg-negative chronic hepatitis B, therefore currently unlimited
treatment with nucleos(t)ide analogs is recommended.
PEG-IFN α  should be administered for 48 weeks in HBeAg-positive and -negative patients.
Recently, the effect of stopping therapy after a long-term ADV treatment of 4 to 5
years with complete viral suppression was recently evaluated (Hadziyannis 2008).
Despite the fact that all patients suffered a slight virologic relapse within 3 months
of stopping therapy, most patients went below detection over the following 4 years
Hepatitis B Treatment  153
without any therapy. Moreover, 28% of the patients lost HBsAg. But final
recommendations about the treatment period with defined stopping rules do not
exist for HBeAg negative patients.
In patients with liver cirrhosis oral antiviral treatment should not be discontinued
at any time point because of the risk of liver decompensation during a virologic
rebound.
Figure 12. Cumulative incidence of hepatocellular carcinoma (HCC) in 818 patients with
HBeAg-negative chronic hepatitis B (CHB) treated with nucleos(t)ide analogs. Virological
remission defined as durable suppression of HBV DNA to levels <200 IU/mL did not
significantly affect the HCC incidence in the long term (p=0.38) (Papatheodoridis 2011).
Treatment of HBV infection in special populations
Pregnancy. For a neonate born to a mother with high levels of HBV DNA (>8
log10 copies/mL) the risk of perinatal transmission is elevated. Therefore, antiviral
treatment is principally recommended in these women. PEG-IFN α is not indicated
in pregnant women, but most nucleos(t)ide  analogs can be used. The  risk of
teratogenicity of nucleos(t)ide analogs is assessed by a classification based on data
gathered in clinical trials as well as through the FDA Pregnancy Registry. TDF and
LdT are listed as pregnancy category B drugs and LAM, whereas ADV and ETV as
category C drugs.
In pregnant women with high levels of HBV DNA, LAM treatment during the last
trimester of pregnancy was reported to reduce the risk of intrauterine and perinatal
transmission of HBV if given in addition to passive and active vaccination by HBIg
and HBV (van Zonneveld 2003). During treatment with TDF, the birth defect
prevalence was recently shown to be as high as during treatment with LAM (Brown
2009). Finally, LdT  administered for an average of 15 weeks at the end of
pregnancy plus active-passive immunization to  neonates reduced vertical
transmission rates from 23% to 4% over immunization alone (Han 2011). However,
154  Hepatology 2012
treatment with nucleos(t)ide  analogs during pregnancy should be carefully
monitored and limited to the second and third trimester. As exacerbations of chronic
hepatitis B may occur, women with HBV should be monitored closely after delivery
(ter Borg 2008).
Immunosuppression. During immunosuppressive treatment, a reactivation of an
asymptomatic or inactive HBV infection can occur in 20% to 50% of patients (Lok
2009). Reactivations can occur in HBsAg carriers, but also in HBsAg-negative but
anti–hepatitis B core antibody (HBc)–positive patients. These reactivations are
characterised by increase in HBV replication followed by increase in liver
inflammation during immune reconstitution resulting in liver damage or even liver
failure in some patients (Feld 2010, Roche 2011).
HBV reactivation was especially frequently observed during treatment with
corticosteroids and antitumor necrosis factor therapies (i.e., infliximab, etanercept,
adalimumab), anti-CD20 therapies (i.e, rituximab-containing chemotherapeutics),
intra-arterial chemoembolisation for HCC (Vassilopoulos 2007, Moses 2006, Park
2005, Rutgeerts 2009). Reactivations during chemotherapy tend to appear
predominantly in men as well as in those undergoing treatments for breast cancer or
lymphoma.
Prior to initiating immunosuppressive therapies, screening for HBV infection is
recommended (Lok 2009, EASL 2009). Patients with baseline HBV DNA levels
<2,000 IU/mL should continue antiviral therapy for 6-12 months after the
discontinuation of chemotherapy/immunosuppression, while patients with baseline
HBV DNA levels >2,000 IU/mL should continue HBV therapy until they reach a
treatment endpoint.
References
Akarca US. Chronic hepatitis B. A guideline to diagnosis, approach, management, and follow-up 2007. Turkish Association for the Study of Liver. Turk J Gastroenterol
2008;19:207-30. (Abstract)
Beasley RP. Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer
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Berg T, Marcellin P, Zoulim F, et al. Tenofovir is effective alone or with emtricitabine in adefovir-treated patients with chronic-hepatitis B virus infection. Gastroenterology
2010;139:1207-17. (Abstract)
Brown R, Goodwin D, Peschell K, et al. Tenofovir Disoproxil Fumarate-Containing Regimens in
Pregnancy: Report From the Antiretroviral Pregnancy Registry. 60th Annual Meeting
of the American Association for the Study of Liver Diseases, October 30 - November
3, 2009 Boston, USA. Abstract 407.
Brunetto MR, Oliveri F, Colombatto P, et al. Treatment of HBeAg-negative chronic hepatitis B
with interferon or pegylated interferon. J Hepatol 2003;39:S164-7. (Abstract)
Brunetto MR, Oliveri F, Colombatto P, et al. Hepatitis B surface antigen serum levels help to
distinguish active from inactive hepatitis B virus genotype D carriers.
Gastroenterology 2010;139:483-90. (Abstract)
Buster EH, Flink HJ, Simsek H, et al. Early HBeAg loss during peginterferon alpha-2b therapy
predicts HBsAg loss: results of a long-term follow-up study in chronic hepatitis B
patients. Am J Gastroenterol 2009;104:2449-57. (Abstract)
Buster EH, van Erpecum KJ, Schalm SW, et al. Treatment of chronic hepatitis B virus infection
- Dutch national guidelines. Neth J Med 2008;66:292-306. (Abstract)
Carosi G, Rizzetto M. Treatment of chronic hepatitis B: recommendations from an Italian
workshop. Dig Liver Dis 2008;40:603-17. (Abstract)
Chan HL, Leung NW, Hui AY, et al. A randomized, controlled trial of combination therapy for
chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with
lamivudine alone. Ann Intern Med 2005;142:240-50. (Abstract)
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Chang TT, Lai CL, Kew Yoon S, et al. Entecavir treatment for up to 5 years in patients with
hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2010;51:422-30.
(Abstract)
Chang TT, Liaw YF, Wu SS, et al. Long-term entecavir therapy results in the reversal of
fibrosis/cirrhosis and continued histological improvement in patients with chronic
hepatitis B. Hepatology 2010;52:886-93. (Abstract)
Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of
serum hepatitis B virus DNA level. JAMA 2006;295:65-73. (Abstract)
Chen YC, Chu CM, Liaw YF. Age-specific prognosis following spontaneous hepatitis B e
antigen seroconversion in chronic hepatitis B. Hepatology 2010;51:435-44. (Abstract)
Cho SW, Koh KH, Cheong JY, et al. Low efficacy of entecavir therapy in adefovir-refractory
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HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype.
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tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis 2005;40:1194-8. (Abstract)
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(Abstract)
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HBeAg-positive chronic hepatitis B. Gastroenterology 2007;133:1437-44. (Abstract)
Gish RG, Chang TT, Lai CL, et al. Loss of HBsAg antigen during treatment with entecavir or
lamivudine in nucleoside-naïve HBeAg-positive patients with chronic hepatitis B. J
Viral Hepat 2010;17:16-22. (Abstract)
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(Abstract)

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Book on hepatitis from page 135 to 145

134  Hepatology 2012
Long-term observations reveal, however, that HBeAg seroconversion cannot
always be taken as a guarantee of long-term remission. A reactivation of the disease
with “seroreversion” (HBeAg becoming detectable again) as well as a transition to
HBeAg-negative chronic hepatitis B with increased, often fluctuating, HBV DNA
levels, can occur in up to 30% of patients (Hadziyannis 1995, Hadziyannis 2001,
Hadziyannis 2006). Therefore, HBeAg seroconversion should be regarded as a
stable treatment endpoint only in conjunction with durable and complete
suppression of HBV replication.
In the natural course of HBV infection, the time point of HBeAg seroconversion
is important regarding the probability of long-term complications. In a recent long-term observational study in 483 HBeAg-positive patients achieving spontaneous
HBeAg seroconversion, it was shown that for 15 years after HBeAg seroconversion
the incidence of cirrhosis and HCC was lower for patients who had achieved
HBeAg seroconversion at an age <30 years old compared to patients achieving
seroconversion at an age >40 years old (Chen 2010). This observation raises the
question of whether HBeAg seroconversions during antiviral treatment in patients
older than 40 years are also associated with a higher risk of complications compared
to patients who achieve HBeAg seroconversion at a younger age.
Sustained response and “immune control”. The endpoint of therapy for patients
with HBeAg-negative disease is more difficult to assess. Long-term suppression of
HBV replication and ALT normalization are the only practical parameters of
response to therapy. Once antiviral therapy is stopped, durability of response is not
guaranteed due to the fluctuating course of HBeAg-negative chronic hepatitis B.
For treatment with PEG-IFN α in both, HBeAg-positive and -negative patients,
the inducing of a so-called ‘immune control’ status, characterized by persistent
suppression of viral replication with HBV DNA levels <2,000 IU/ml and
normalisation of ALT levels was recently defined as another, combined treatment
endpoint (Marcellin 2009). If this condition is maintained over time, it increases the
probability of HBsAg loss and reduces the development of liver fibrosis and HCC.
Late relapse beyond 6 months post-treatment has been described, but a sustained
response at 1 year post-treatment appears to be durable through long-term follow-up (EASL 2009, Marcellin 2009). However, the immune control status needs to be
regularly monitored, and treatment needs to be re-introduced in case of increase of
HBV replication. For patients presenting any signs of liver fibrosis or family
history of HCC, immune control should not be regarded as the treatment endpoint
but rather the complete suppression of HBV replication.
Induction of HBsAg loss. The ultimate goal of antiviral treatment is HBsAg loss
or even seroconversion to anti-HBs. Because HBsAg loss or seroconversion is
associated with a complete and definitive remission of the activity of chronic
hepatitis B and an improved long-term outcome, it is regarded as a cure from
chronic hepatitis B. However, HBsAg loss or seroconversion can be induced in
only a limited number of patients after short-term treatment (<5%). Interestingly, in
recent follow-up studies in PEG-INF α as well as nucleoside/nucleotide analog
treated patients an increase of the rates of HBsAg loss during long-term studies was
shown (Marcellin 2009, Marcellin 2011). However, as the probability of HBsAg
seroclearance during therapy with nucleoside or nucleotide analogs is linked to the
decrease of HBsAg levels during the early treatment period, it seems questionable
Hepatitis B Treatment  135
if after a treatment duration of 4-5 years significantly higher rates of HBsAg loss
can be expected (Marcellin 2011).
Reversion of liver fibrosis. With long-term treatment with different nucleoside
and nucleotide analogs it has been demonstrated that liver fibrosis and even
cirrhosis can be reverted in the majority of patients. This was recently impressively
shown in a subgroup of 59 patients from a rollover study including two Phase III
trials of the efficacy of ETV in treatment-naïve patients. Liver biopsies from
baseline and after a median treatment duration of 6 years (range, 3-7 years) found
an histologic improvement, defined as a decrease of 2 points or greater in the
Knodell necroinflammatory score in absence of worsening of the Knodell fibrosis
score, in 96% of patients. In addition, an improvement of more than 1 point in the
Ishak fibrosis score was seen in 88%, including all 10 patients who had advanced
fibrosis or cirrhosis when they entered the Phase 3 studies (Chang 2010a). More
recently, in a subanalysis of the tenofovir Trials 102 and 103 evaluating 348
patients who underwent biopsies before and after five years of therapy, 88%
experienced an improvement in overall liver histology as measured by an
improvement of at least two points in the Knodell score of HAI (histologic activity
index) (Figure 4). Of the 94 patients who had cirrhosis at the start of therapy, 73%
experienced regression of cirrhosis, and 72% had at least a two-point reduction in
fibrosis scoring (Marcellin 2011).
Figure 4. Changes in liver histology after five years of TDF treatment. In a study looking at
348 patients with paired liver biopsies, regression of liver fibrosis and even liver cirrhosis (Ishak
score 5 and 6) was found in the majority of patients.
136  Hepatology 2012
Criteria for treatment response
Virologic response
–  sustained decrease of HBV DNA, to at least <2,000 IU/mL (corresponding to
<10,000 copies/mL), ideally to <60 IU/mL (<300 copies/mL).
–  sustained HBe seroconversion in HBeAg positive patients
–  ideally, loss of HBsAg
Biochemical response
–  sustained ALT normalization
Histologic response
–  reduction of fibrosis (histological staging)
–  reduction of inflammatory activity (histological grading)
Potential long-term effects
–  avoidance of cirrhosis, hepatocellular carcinoma (HCC), transplantation, and
death
How to treat
Therapy of chronic hepatitis B is possible with PEG-INF α in order to induce an
immunologic long-term control by finite treatment or with nucleos(t)ide analogs by
long-term inhibition of HBV replication (Figure 5) (Table 2).
At first, the option of interferon therapy should be evaluated. However, if a
patient does not fulfil the criteria for a higher likelihood for treatment success with
PEG-INF  α, has contraindications, or is intolerant, long-term therapy with
nucleos(t)ide analogs is recommended (Figure 5). If a nucleos(t)ide analog  is
chosen, several parameters have to be considered prior to therapy: the antiviral
efficacy of the drug, the durability of response, the resistance barrier, and the stage
of liver disease.
If the initial viral load is low and liver cirrhosis has been excluded, any approved
drug may be used. The use of LAM, however, should be restricted to patients with
mild fibrosis and HBV DNA levels <105
copies/ml. For patients with high-level
HBV replication (>10
9
copies/ml) only drugs with a high genetic barrier should be
used (i.e., ETV or TDF) (Table 3).
Treatment options
Because of a limited tolerability due to adverse events, duration with PEG-IFN α is
limited for a period of 6-12 months (maximum 24 months). Nucleoside and
nucleotide analogs have a good tolerability and are used in long-term treatment.
However, the efficacy of these oral agents can be hampered by emergence of
resistance. Two interferons and five oral HBV polymerase inhibitors are currently
approved for the treatment of chronic HBV infections: standard IFN α-2b and PEG-IFN  α-2a, lamivudine (LAM), adefovir dipivoxil (ADV), telbivudine (LdT),
entecavir (ETV) and tenofovir disoproxil fumarate (TDF) (Table 2). The efficacy of
the available drugs after one year of treatment, assessed by the proportion of
individuals with HBV DNA below the limit of detection, normalised transaminases
and HBeAg seroconversion is shown in Figure 6.
Hepatitis B Treatment  137
Figure 5. Treatment algorithm for chronic HBV infection according to the German
Guidelines (Cornberg 2011). The indication for interferon therapy should always be
considered. For treatment with nucleoside or nucleotide analogs, agents with high genetic
barrier against resistance such as entecavir or tenofovir should be preferred.
Table 2. Overview of interferons and oral antiviral drugs currently approved for the
treatment of HBV infection.
Drug  Name  Dose  Duration
Interferon α
Standard Interferon α-2a Roferon
®
2.5-5 mio. U/m
2
body surface
3x/week
4-6 months
Standard Interferon α-2b  Intron A
®
5-10 mio. IU 3x/week  4-6 months
Pegylated Interferon α-2a  Pegasys
®
180 µg/week  48 weeks
Nucleoside analogs
Lamivudine Zeffix
®
100 mg/day long-term*
Telbivudine  Sebivo
®
600 mg/day  long-term*
Entecavir  Baraclude
®
0.5 mg/day  long-term*
1 mg/day for patients with
lamivudine resistance
long-term*
Nucleotide analogs        
Adefovir dipivoxil  Hepsera
®
10 mg/day  long-term*
Tenofovir disoproxil fumarate  Viread
®
300 mg/day  long-term*
* see Figure 6
138  Hepatology 2012
Table 3. Recommendations for the use of nucleos(t)ide analogs in clinical practice.
Drug  Advantage  Disadvantage  Recommendation
Lamivudine
(LAM)
•  Low treatment costs
•  Oral solution
available for children
or individual dosage
in case of renal
impairment
•  High risk of
resistance in long-term monotherapy
•  Cross-resistance to
ETV and LdT
•  Use as first-line
therapy only in
selected patients with
low viral load
•  Prevention of
exacerbation in
HBsAg+, HBV DNA-patients with
immunosuppression
•  Preemptive therapy in
case of HBsAg-negative, anti-HBc
positive patients with
immunosuppression
•  Use in pregnancy
possible
Adefovir
dipivoxil
(ADV)
•  Experience in
combination with LAM
•  No cross-resistance
to LAM
•  Moderate antiviral
activity
•  Primary non-response in 10-20%
of cases
•  Slow viral kinetics
during therapy
•  Risk of viral
resistance in long-term monotherapy
•  Nephrotoxicity
•  Not to be used as
first-line therapy
Telbivudine
(LdT)
•  High antiviral efficacy
•  Potentially no cross-resistance to
entecavir
•  Moderate risk for viral
resistance in long-term monotherapy
•  Neuropathy and
myopathy
•  First-line therapy
•  Can be combined
with TDF
Entecavir
(ETV)
•  High antiviral efficacy
•  Low risk for viral
resistance in long-term monotherapy in
lamivudine-naïve
patients
•  Combination therapy
with TDF as rescue
therapy
•  Oral solution
available for
individual dosage in
case of renal
impairment
•  In LAM-experienced
patients high risk for
the development of
viral resistance and
virologic failure in
long-term
monotherapy
•  First-line therapy
•  Can be combined
with TDF
Tenofovir
disoproxil
fumarate
(TDF)
•  High antiviral efficacy
•  Low risk for viral
resistance in long-term monotherapy
•  Nephrotoxicity
•  Decrease in bone
mineral density
•  First line therapy
•  Can be combined
with ETV, LdT or LAM
if needed
* in HBV-monoinfected patients no renal toxicity was observed in 5 years of TDF treatment
Hepatitis B Treatment  139
Interferons
INF α is a natural occurring cytokine with immunomodulatory, antiproliferative and
antiviral activity. During treatment, the therapeutic efficacy of INF α can often be
clinically recognised by an increase of ALT levels to at least twice the baseline
levels. These ALT flares often precede virologic response.
The main aim of INF α treatment is to induce a long-term remission by finite
treatment duration. Overall a long-term response defined by either HBeAg
seroconversion or durable suppression of HBV DNA to low or undetectable levels
can be achieved in approximately 30% of treated patients. In these responders the
chance for HBsAg loss in the long-term is relatively high.
Figure 6. One-year efficacy of medications currently approved for the treatment of
chronic HBV infection (Lok 2009). Treatment efficacy is expressed as suppression of HBV
DNA below the limit of detection, ALT normalisation and rates of HBeAg seroconversion. As no
head-to-head trials comparing the substances have been undertaken, differences in antiviral
efficacy have to be interpreted with caution.
Standard INF α. Standard IFN α was approved for treatment of chronic hepatitis
B in 1992. IFN α is applied in dosages ranging from 5 million units (MU) to 10 MU
every other day or thrice weekly. In a meta-analysis, a significant improvement in
endpoints was shown in patients with HBeAg-positive chronic hepatitis B being
treated with standard IFN compared to untreated patients (Craxí 2003). Complete
remission of fibrotic changes was observed in some patients and the loss of HBsAg
occurred comparatively often. Furthermore, there was a trend towards reduction of
hepatic decompensation (treated 8.9% vs. untreated 13.3%), hepatocellular
carcinoma (1.9 vs. 3.2%), and liver associated deaths (4.9 vs. 8.7%) (Craxí 2003).
A significant decrease in ALT and in HBV DNA serum levels was also shown for
standard IFN α in the treatment of HBeAg-negative chronic hepatitis B (Brunetto
2003). However, a high percentage (25-89%) of these patients relapses after the end
of treatment showing elevation of ALT levels and a return of HBV DNA levels. The
relapse rate seems to be higher when treatment duration is short (16 to 24 weeks)
140  Hepatology 2012
compared to longer treatment (12 to 24 months). A retrospective comparison of IFN
therapies lasting from 5 to 12 months showed that with longer treatment the chance
of a long-term response was 1.6 times higher (normalization of ALT, HBV DNA
<1x10
6
copies/ml 1-7 years after end of therapy). The overall response rates were
54% at the end of therapy, 24% at 1 year after therapy, and 18% 7 years after
therapy (Manesis 2001).
Patients with long-term response to treatment have a more favourable course than
patients who were untreated, unresponsive, or who had a relapse interferon α
therapy with respect to progression to liver cirrhosis, liver associated deaths, and
development of hepatocellular carcinoma (Brunetto 2003, Lampertico 2003).
However, due to higher antiviral efficacy PEG-IFN α  should be preferred to
standard IFN α.
PEG-INF α. The addition of a polyethylene glycol molecule to the IFN resulted
in a significant increase in half-life, thereby allowing administration once weekly.
Two types of subcutaneously administered PEG-IFN α were developed: PEG-IFN
α-2a and PEG-IFN α-2b, of which PEG-IFN α-2a was licensed for the treatment of
chronic HBV infections in a weekly dose of 180 µg for 48 weeks in both HBeAg-positive and HBeAg-negative patients. However, PEG-IFN α-2b shows similar
efficacy. After one year on treatment with PEG-IFN α-2a and α-2b, 22% to 27% of
patients were reported to achieve HBeAg seroconversion (Janssen 2005, Lau 2005).
The safety profiles of standard IFN α and PEG-IFN α are similar. Following
therapy termination a relatively high relapse rate is to be expected (>50%). The dose
of 180 µg per week applied for 48 weeks was recently shown to exert a stronger
antiviral efficacy compared to administration for 24 weeks or to administration of
90 µg per week (Liaw 2011). In a small Italian study it was shown that prolongation
of 48 weeks of treatment with 180 µg PEG-IFN α per week by another 48 weeks of
135 µg PEG-IFN α-2a may enhance antiviral efficacy and increase the rate of
patients achieving HBsAg loss, at least in HBeAg-negative patients with HBV
genotype D (Lampertico 2010). However, the optimal treatment duration for PEG-IFN α has not been defined yet and treatment beyond 48 weeks is not recommended
by current guidelines.
PEG-IFN α in HBeAg-positive patients. Four randomized, controlled studies
investigating the efficacy of PEG-IFN α in HBeAg-positive patients have been
conducted (Crespo 1994, Chan 2005, Janssen 2005, Lau 2005). These studies
compared 180 µg PEG-INF  α  per week to standard IFN, LAM, and/or a
combination treatment with PEG-INF α + LAM for 48 weeks. Sustained HBeAg
seroconversion at the end of follow-up (week 72) was significantly higher in
patients treated with PEG-IFN α-2a alone or in combination with LAM than in
patients treated with LAM alone (32% and 27% versus 19%) (Marcellin 2004).
Importantly, it was recently shown that PEG-IFN  α  can induce
immunomodulatory effects which persist beyond the end of therapy leading to high
HBsAg clearance rates in the follow-up period. In a recent study, 97 patients with
chronic HBV infection who had received treatment with standard IFN α were
retrospectively analyzed for a median period of 14 (range, 5-20) years. During the
observation period, 28 patients (29%) of this cohort lost HBsAg (Moucari 2009).
PEG-IFN α in HBeAg-negative patients. The efficacy and safety of 48 weeks
treatment with 180 µg PEG-IFN α-2a once weekly + placebo, + 100 mg LAM daily,
or LAM alone was compared in 177, 179, and 181 HBeAg-negative patients,
Hepatitis B Treatment  141
respectively. After 24 weeks of follow-up, the percentage of patients with
normalisation of ALT levels or HBV DNA levels below 20,000 copies/ml was
significantly higher with PEG-IFN α-2a monotherapy (59% and 43%, respectively)
and PEG-IFN α-2a plus LAM (60% and 44%) than with LAM monotherapy (44%
and 29%); the rates of sustained suppression of HBV DNA below 400 copies/ml
were 19% with PEG-IFN α-2a monotherapy, 20% with combination therapy, and
7% with LAM alone.
Also in HBeAg-negative patients HBsAg loss can be induced in some patients by
PEG-IFN α treatment. In a study in 315 patients who were treated with either PEG-IFN α-2a, LAM 100 mg or a combination of both drugs for 48 weeks, three years
after the end of treatment, the rate of HBsAg loss was 8.7% in those who had been
treated with PEG-IFN α-2a alone or in combination with LAM while no patient
treated with LAM as monotherapy cleared HBsAg (Marcellin 2009a). Of the pa-tients who had received a PEG-IFN α-2a and who still had undetectable HBV DNA
three years after treatment, 44% had lost HBsAg.
Prolongation of PEG-IFN α treatment beyond 48 weeks may increase sustained
response rates. This was found in an Italian study in 128 mainly genotype D–
infected HBeAg-negative patients who were randomized to either treatment with
180 µg/week PEG-IFN α-2a for 48 weeks or a continuing treatment with PEG-IFN
α-2a at 135µg/week. Additionally, in a third arm patients received combination
treatment with PEG-IFN α-2a 180µg/week and LAM 100 mg/day, followed by 48
weeks of PEG-IFN α-2a in the dosage of 135 µg/week. As a result, 48 weeks after
the end of treatment 26% of patients who had received 96 weeks of PEG-IFN
treatment showed HBV DNA levels <2,000 IU/mL compared to only 12% of the
patients who had received PEG-IFN for 48 weeks. Combination with LAM showed
no additional effect (Lampertico 2010a).
Nucleoside and nucleotide analogs
Nucleoside and nucleotide analogs inhibit HBV replication by competing with the
natural substrate deoxyadenosine triphosphate (dATP) and causing terminating of
the HBV DNA chain prolongation. They represent two different subclasses of re-verse transcriptase inhibitors: while both are based on purines or pyrimidines,
acyclic nucleotide analogs have an open (acyclic) ribose ring that confers greater
binding capacity to resistant HBV polymerase strains.
Treatment duration for nucleos(t)ide analogs is not well-defined but a short-term
application of these agents for 48 weeks is associated with prompt relapse in
viremia and they should be administered for longer periods. Treatment efficacy of
nucleoside and nucleotide analogs implies complete suppression of HBV DNA
levels in serum. This should be achieved within six months if agents with high risk
for resistance development as LAM, ADV, and LdT are used.
Effective long-term control of HBV replication with nucleoside or nucleotide ana-logs is associated with a reduction of long-term complications such as HCC and
development of liver cirrhosis (Toy 2009). Studies with different nucleoside and
nucleotide analogs have demonstrated that suppression of HBV replication is
associated with a significant decrease in histologic inflammatory activity and fibro-sis, including partial reversion of liver cirrhosis (Chen 2006, Iloeje 2006, Mom-meja-Marin 2003, Chen 2010, Marcellin 2011, Schiff 2011). With increasing treat-ment duration HBeAg seroconversion rates increase (Liaw 2000, Lok 2000). Most
142  Hepatology 2012
importantly, there is also evidence that effective inhibition of HBV replication can
reduce HBV cccDNA, possibly running parallel to the decline in serum HBsAg
levels (Werle-Lapostolle 2004, Wursthorn 2006). These findings may indicate that
long-term antiviral therapy may lead to a complete response in a significant number
of patients.
A central aspect of HBV polymerase inhibitor treatment is the prevention and
management of HBV resistance to these drugs (see Chapter 10). Resistance against
nucleoside or nucleotide analogs can occur during suboptimal treatment and often
leads to aggravation of liver disease. Because of cross resistance between several
nucleoside and nucleotide analogs, nucleoside-naïve and nucleoside-experienced
patients have to be distinguished and prior nucleoside experience should be taken
into account when choosing a second line therapy. However, highly potent sub-stances such as ETV and TDF show minimal or even no resistance development in
treatment-naïve patients over 5-6 years (Snow-Lampert 2011).
Lamivudine (LAM). LAM, a (-) enantiomer of 2’ -3’ dideoxy-3’-thiacytidine, is
a nucleoside analog that was approved for the treatment of chronic HBV infection in
1988 with a daily dose of 100 mg. This dose was chosen based on a preliminary trial
that randomly assigned 32 patients to receive 25, 100, or 300 mg of LAM daily for a
total of 12 weeks (Dienstag 1995). In this study the dose of 100 mg was more
effective than 25 mg and was similar to 300 mg in reducing HBV DNA levels.
LAM exerts its therapeutic action in its phosphorylated form. By inhibiting both the
RNA- and DNA-dependent DNA polymerase activities, the synthesis of both the
first strand and the second strand of HBV DNA are interrupted.
Long-term LAM treatment is associated with an increasing rate of antiviral drug
resistance reaching approximately 70% after 5 years in patients with HBeAg-positive HBV infections. Therefore, in many guidelines LAM is not considered a
first-line agent in the treatment of chronic HBV infection any more. However, LAM
still may play a role in combination regimens or in patients with mild chronic
hepatitis B expressing low levels of HBV DNA (<10
5
copies/ml). An early and
complete virologic response to LAM within 6 months of therapy (<400 copies/mL)
constitutes a prerequisite for long-term control of HBV infection without the risk of
developing resistance.
Adefovir dipivoxil (ADV). Adefovir dipivoxil was approved for treatment of
chronic hepatitis B in the US in 2002 and in Europe in 2003. It is an oral diester
prodrug of adefovir, an acyclic nucleotide adenosine analog that is active in its
diphosphate form. Because the acyclic nucleotide already contains a phosphate-mimetic group, it needs only two, instead of three, phosphorylation steps to reach
the active metabolite stage. ADV was the first substance with simultaneous activity
against wild type, pre-core, and LAM-resistant HBV variants. It is active in vitro
against a number of DNA viruses other than HBV and retroviruses (i.e., HIV). The
dose of 10 mg per day was derived from a study comparing 10 mg versus 30 mg/d.
The higher dosage leads to stronger suppression of HBV DNA levels but also to
renal toxicity with an increase of creatinine levels (Hadziyannis 2003).
ADV was the first acyclic nucleotide that was widely used in the treatment of
LAM-resistant HBV infections. However, the antiviral effect of ADV in the
licensed dosage of 10 mg/day is rather low as compared to other available antivirals
(Figure 4); this disadvantage makes ADV vulnerable to  HBV resistance
Hepatitis B Treatment  143
(Hadziyannis 2006a). Now that TDF is approved, ADV should not be used as first-line monotherapy.
Telbivudine (LdT). Telbivudine is a thymidine analog which is active against
HBV but at least in vitro not active against other viruses, including HIV and
hepatitis C virus (HCV). LdT at 600 mg/day expresses higher antiviral activity
compared to either LAM at 100 mg/day or ADV at 10 mg/day (Figure 4). More
patients achieved HBeAg loss within 48 weeks as compared to other nucleos(t)ides.
LdT was reported to be non-mutagenic, non-carcinogenic, non-teratogenic, and to
cause no mitochondrial toxicity. A favourable safety profile at a daily dose of 600
mg was demonstrated (Hou 2008, Lai 2007). However, CK elevations were
observed more often as compared to the group treated with LAM and neurotoxicity
may be an issue when LdT is administered in combination with PEG-INF α
(Fleischer 2009). Thus, in the GLOBE trial, during a period of 104 weeks grades 3/4
elevations in CK levels were observed in 88 of 680 (12.9%) patients who received
LdT and in 28 of 687 (4.1%) patients who received LAM (p<0.001) (Liaw 2009).
However, rhabdomyolysis was not observed. Peripheral neuropathy was described
in 9 of 48 (18.75%) patients who received combination therapy of PEG-INF αnd
LdT and only in 10 of 3500 (0.28%) patients who received LdT monotherapy
(Goncalves 2009).
Resistance to LdT has been found to occur in up to 21% after 2 years of treatment
(Tenney 2009), predominantly in patients who did not achieve undetectable HBV
DNA level after 24 weeks of treatment (Zeuzem 2009). LdT shows cross-resistance
to LAM and ETV. As a consequence LdT should not be used in LAM or ETV
refractory patients.
Entecavir (ETV). Entecavir, a cyclopentyl guanosine nucleoside analog, is a
selective inhibitor of HBV replication and was licensed in 2006. Entecavir blocks
all three polymerase steps involved in the replication process of the hepatitis B
virus: first, base priming; second, reverse transcription of the negative strand from
the pregenomic messenger RNA; third, synthesis of the positive strand of HBV
DNA. In comparison to all other nucleoside and nucleotide analogs, ETV is more
efficiently phosphorylated to its active triphosphate compound by cellular kinases. It
is a potent inhibitor of wild-type HBV but is less effective against LAM-resistant
HBV mutants. Therefore, ETV was approved at a dose of 0.5 mg per day for
treating naïve HBeAg-positive and -negative patients at the dose of 1 mg per day for
patients with prior treatment with LAM (Lai 2005, Sherman 2008). ETV and LAM
are the only nucleoside analogs available as a tablet and an oral solution.
Treatment-naïve HBeAg-positive patients achieved undetectable HBV DNA
levels in 67% and 74% after one and two years of ETV treatment, reaching 94%
after five years, respectively (Figure 4, Figure 7) (Chang 2010). Long-term studies
in ETV responder patients demonstrated that response can be maintained in nearly
all patients over an observation period of up to six years. So far, the rate of
resistance at six years of treatment is estimated to be approximately 1.2% for
treatment-naïve patients (Tenney 2009). Loss of HBsAg occurs in 5% of treatment-naïve individuals after two years of ETV therapy (Gish 2010). A non-randomised
Italian study in a mixed population of predominantly HBeAg-negative patients
could demonstrate undetectable HBV DNA levels in 91% and 97% of patients at 1
and 2 years of ETV treatment, respectively (Lampertico 2010).
144  Hepatology 2012
In LAM-resistant patients ETV is less potent. Only 19% and 40% of these
patients achieved undetectable HBV DNA after one and two years, respectively,
despite an increased dose of 1 mg/day (Gish 2007, Sherman 2008). Due to cross-resistance up to 45% of patients with LAM resistance develop resistance against
ETV after 5 years of treatment (Tenney 2009).
ETV has a favourable tolerability profile and can be easily adjusted to renal
function. However, ETV may cause severe lactic acidosis in patients with impaired
liver function and a MELD score of >20 points (Lange 2009).
Figure 7. Percentage of patients achieving HBV DNA levels <400 copies/ml during long-term treatment with 1 mg ETV per day (Chang 2010). The long-term cohort ETV-901
consists of HBeAg-positive patients initially treated in the study ETV-022 (ETV 0.5 mg/day),
which was designed for a duration of one year.
Tenofovir  (TDF). Tenofovir disoproxil fumarate, an ester prodrug form of
tenofovir (PMPA; (R)-9-(2-phosphonylmethoxypropyl)), is an acyclic nucleoside
phosphonate, or nucleotide  analog  closely related to ADV. TDF has selective
activity against retroviruses and hepadnaviruses and is currently approved for the
treatment of HIV infection and of chronic hepatitis B. TDF showed marked antiviral
efficacy over five years with complete virologic response rates (HBV DNA <400
copies/ml) reaching nearly 100% in treatment-naïve HBeAg-negative and -positive
patients (Figure 8). In HBeAg-positive patients, 11% of patients experienced
HBsAg loss (Marcellin 2011). Other clinical studies showing a high efficacy of
TDF in LAM-resistant HBV infections irrespective of the mutation mediating LAM
resistance (van Bömmel 2010, Levrero 2010). Due to possibly existing cross-
Hepatitis B Treatment  145
resistance to ADV, the efficacy of TDF might be hampered by the presence of ADV
resistance in patients with high HBV viremia; however, a breakthrough of HBV
DNA during TDF treatment in patients with previous ADV failure or in treatment-naïve patients has not been observed (van Bömmel 2010, Levrero 2010, Snow-Lampert 2011).
Figure 8. Percentage of patients achieving HBV DNA levels <400 copies/mL during long-term treatment with 300 mg TDF per day (Marcellin 2010). Patients were originally
randomised to treatment with 300 mg TDF or 10 mg ADV per day. After one year, patients
receiving ADV were switched to TDF. Please note that the on-treatment analysis excluding the
missing patients showed undetectable HBV DNA in 96% of the TDF-TDF group and in 100% of
the ADV-TDF group.
TDF is generally well-tolerated and not associated with severe side effects. For
HBV-monoinfected, treatment-naïve patients, renal safety during TDF monotherapy
was investigated in three studies. In a randomized study comprising HBeAg-negative patients, none of 212 patients treated with TDF for three years and none of
112 patients who were treated with ADV for one year and then switched to TDF for
two years had a decrease in GFR to levels of <50 ml/min or an increase of serum
creatinine levels to >0.5 mg/dl (Marcellin 2009). In a similar study in HBeAg-positive patients, of 130 patients treated with TDF for 3 years and of 76 patients
treated with ADV for one year and consecutively with TDF for 2 years, only one
patients showed an increase in serum creatinine levels >0.5 mg/dl starting at year
two (Heathcote 2011). In a sub-analysis of both studies in 152 HBeAg-positive and
-negative Asian patients, no increase of serum creatinine >0.5 mg/dl or of eGFR
<50 ml/min was found in up to 3 years of TDF treatment (Liaw 2009a). In contrast,
in a recent study a benefit in renal function could be found in treated patients when
compared to untreated patients with HBV infection, which might reflect a lower
incidence of glomerulonephritis caused by HBsAg-induced immune complexes in
treated patients (Mauss 2011).
The use of tenofovir in HIV-coinfected patients is discussed in detail in Chapter
17.
Combination therapy as first-line treatment. As of now, first-line combination
treatments with nucleoside and nucleotide analogs or PEG-IFN α + nucleos(t)ide
analogs are not indicated. There is only one study comparing a combination therapy

Book on hepatitis from page 118 to 134

Book on hepatitis from page 118 to 134

Prophylaxis and Vaccination  117
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Hepatitis B: Diagnostic Tests  119
8.  Hepatitis B: Diagnostic Tests
Jörg Petersen
Introduction
The diagnosis of hepatitis B virus (HBV) infection was initiated by the discovery of
Australia antigen (hepatitis B surface antigen, HBsAg). During the following
decades, serologic assays were established for HBsAg and other HBV antigens and
antibodies. Advances in molecular biology techniques led to the development of
polymerase chain reaction (PCR) assays for direct determination of hepatitis B virus
DNA (HBV DNA).
Diagnosis of Hepatitis B Virus (HBV) infection tests for a series of serological
markers of HBV and excludes alternative etiological agents such as hepatitis A, C,
and D viruses. Serological tests are used to distinguish acute, self-limited infections
from chronic HBV infections and to monitor vaccine-induced immunity. These tests
are also performed to determine if the patient should be considered for antiviral
therapy. Nucleic acid testing for HBV DNA is used as the standard to quantify HBV
viral load and measure the effectiveness of therapeutic agents.
Other causes of chronic liver disease should be systematically looked for
including coinfection with HCV, HDV or HIV.  Cytomegalovirus, Epstein-Barr
virus, enteroviruses, other hepatotoxic drugs, and even herbal medicines should be
considered when appropriate. Moreover, co-morbidities, including alcoholic,
autoimmune, metabolic liver disease with steatosis or steatohepatitis should be
assessed. Finally, vaccination status and previous tests results should be used to
guide appropriate testing.
Serological tests for HBV
Collection and transport
Serological tests for viral antigens can be performed on either serum or plasma
(Yang 2002). The World Health Organization (WHO) has defined an international
standard for normalisation of expression of HBV DNA concentrations (Quint 1990).
Serum HBV DNA levels should be expressed in IU/ml to ensure comparability; the
same assay should be used in the same patient to evaluate antiviral efficacy. Both
HBV antigens and antibody are stable at room temperature for days, at 4°C for
months, and frozen at -20°C to -70°C for many years. Because current testing
120  Hepatology 2012
involves automated enzyme immunoassays that depend on colourimetric or
chemiluminescence signal measurement, care should be taken to avoid hemolysis of
the sample because it may interfere with the ability of the assay to accurately detect
these markers. Care must be taken to avoid the degradation of the viral nucleic acid
in the specimen, which can result in falsely low or no measurable viral load. Serum
should therefore be removed from clotted blood within 4 hrs of collection and stored
at -20°C to -70°C (Krayden 1998). Alternatively, the presence of EDTA in plasma
is known to stabilize viral nucleic acids. EDTA blood can be stored for up to five
days at 4°C without affecting the viral load. Polymerase chain reaction-based tests
that are routinely used as standard can use either serum or plasma. The diagnosis of
HBV infection can also be made by the detection of HBsAg or hepatitis B core
antigen (HBcAg) in liver tissues by immunohistochemical staining and of HBV
DNA by Southern hybridization, in situ hybridisation, or PCR.
Hepatitis B surface antigen and antibody
Hepatitis B surface antigen (HBsAg) is the serologic hallmark of HBV infection. It
can be detected by radioimmunoassays (RIA) or enzyme immunoassays (EIA).
HBsAg appears in serum 1 to 10 weeks after acute exposure to HBV, prior to the
onset of hepatitis and elevation of serum alanine aminotransferase. HBsAg usually
becomes undetectable after four to six months in patients who recover from
hepatitis B. Persistence of HBsAg for more than six months implies chronic
infection. It is estimated that about 5 percent of immunocompetent adult patients
with genuine acute hepatitis B progress to chronic infection (Chu 1989). Among
patients with chronic HBV infection, the rate of clearance of HBsAg is
approximately 0.5 to 1 percent per year (Liaw 1991). The disappearance of HBsAg
is followed by the appearance of hepatitis B surface antibody (anti-HBs). In most
patients, anti-HBs persists for life, thereby conferring long-term immunity.
Coexistence of HBsAg and anti-HBs has been reported in HBsAg positive
individuals (Tsang 1986, Dufour 2000). In most instances, the antibodies are unable
to neutralize the circulating virions. These individuals should therefore be regarded
as carriers of the hepatitis B virus.
In recent years the quantification of HBsAg levels (qHBsAg) has been used to
determine threshold levels to distinguish between patients with active hepatitis B
and inactive carrier state (Brunetto 2010). Furthermore, a continuous decline of
qHBsAg during IFN α therapy has been used as a response marker of therapy
(Marcellin 2009). In contrast, in patients with nucleos(t)ide therapy the
measurement of qHBsAg levels over time have not yielded definite answers yet in
helping to distinguish patients that will clinically resolve chronic hepatitis B
infection with HBsAg loss or seroconversion.
Hepatitis B core antigen and antibody
Hepatitis B core antigen (HBcAg) is an intracellular antigen that is expressed in
infected hepatocytes. It is  not  detectable in serum. Anti-HBc can be detected
throughout the course of HBV infection in the serum.
During acute infection, anti-HBc is predominantly of IgM class. IgM anti-HBc is
the important marker of HBV infection during the window period between the
disappearance of HBsAg and the appearance of anti-HBs. IgM anti-HBc may
remain detectable up to two years after acute infection. Furthermore, the titer of IgM
Hepatitis B: Diagnostic Tests  121
anti-HBc may increase to detectable levels during exacerbations of chronic hepatitis
B (Maruyama 1994). This can present a diagnostic problem, incorrectly suggesting
acute hepatitis B. Other common causes of acute exacerbation of chronic hepatitis B
are superinfection with hepatitis D virus (delta virus) or hepatitis C virus. IgG anti-HBc persists along with anti-HBs in patients who recover from acute hepatitis B. It
also persists in association with HBsAg in those who progress to chronic HBV
infection.
Isolated detection of anti-HBc can occur in three settings: during the window
period of acute hepatitis B when the anti-HBc is predominantly IgM; many years
after recovery from acute hepatitis B when anti-HBs has fallen to undetectable
levels; and after many years of chronic HBV infection when the HBsAg titer has
decreased to below the level of detection. HBV DNA can be detected in the liver of
most persons with isolated anti-HBc. Transmission of HBV infection has been
reported from blood and organ donors with isolated anti-HBc. There are, in a small
percentage of cases, false-positive isolated anti-HBc test results.
The evaluation of individuals with isolated anti-HBc should include repeat testing
for anti-HBc, HBsAg, anti-HBe, and anti-HBs. Those who remain isolated anti-HBc
positive should be tested for the presence of IgM anti-HBc to rule out recent HBV
infection. Individuals with evidence of chronic liver disease should be tested for
HBV DNA to exclude low-level chronic HBV infection.
Hepatitis B e antigen and antibody
Hepatitis B e antigen (HBeAg) is a secretory protein processed from the precore
protein. It is generally considered to be a marker of HBV replication and infectivity.
The presence of HBeAg is usually associated with high levels of HBV DNA in
serum and higher rates of transmission of HBV infection. HBeAg to anti-HBe
seroconversion occurs early in patients with acute infection, prior to HBsAg to anti-HBs seroconversion. However, HBeAg seroconversion may be delayed for years to
decades in patients with chronic HBV infection. In such patients, the presence of
HBeAg is usually associated with the detection of high levels of HBV DNA in
serum and active liver disease. However, HBeAg-positive patients with perinatally
acquired HBV infection may have normal serum ALT concentrations and minimal
inflammation in the liver (Chang 1988).
Seroconversion from HBeAg to anti-HBe is usually associated with a decrease in
serum HBV DNA and remission of liver disease. However, some patients continue
to have active liver disease after HBeAg seroconversion. Such individuals may have
low levels of wild type HBV or HBV variants with a stop codon in the precore or
dual nucleotide substitutions in the core promoter region that prevent or decrease
the production of HBeAg (Carman 1989).
Serum HBV DNA assays
Qualitative and quantitative tests for HBV DNA in serum have been developed to
assess HBV replication. Currently, most HBV DNA assays use real-time PCR
techniques, report results in IU/mL, have a lower limit of detection of around 20
IU/mL and a range of linearity up to 8 log10
IU/mL.
Recovery from acute hepatitis B is usually accompanied by the disappearance of
HBV DNA in serum. However, HBV DNA may remain detectable in serum for
122  Hepatology 2012
many years if tested by PCR assays (Cornberg 2011) suggesting that the virus
persists but is controlled by the immune system.
In patients with spontaneous or treatment-induced HBeAg seroconversion in
chronic hepatitis B, PCR assays usually remain positive except in patients with
HBsAg seroconversion. By contrast, most patients who develop HBeAg
seroconversion during nucleos(t)ide analog therapy have undetectable serum HBV
DNA. In fact, many patients receiving nucleos(t)ide analog therapy remain HBeAg
positive despite having undetectable serum HBV DNA for months or years. The
explanation for this phenomenon is unclear but is likely related to the lack of direct
effect of nucleos(t)ide analogs on covalently closed circular HBV DNA (ccc DNA)
and viral RNA transcription and viral protein expression.
HBV DNA levels are also detectable in patients with HBeAg negative chronic
hepatitis, although levels are generally lower than in patients with HBeAg positive
chronic hepatitis. Because of the fluctuations in HBV DNA levels there is no
absolute cutoff level that is reliable for differentiating patients in the inactive carrier
state from those with HBeAg negative chronic hepatitis B (Chu 2002).
HBV genotypes
HBV can be classified into eight genotypes and four major serotypes. There have
been reports about differing therapeutic responses with nucleos(t)ide analogs and
interferon α with respect to different genotypes. Furthermore, some genotypes, such
as B and C, may have a greater risk for the development of hepatocellular
carcinomas. Nevertheless, in the clinical setting in contrast to hepatitis C, the
diagnosis of HBV genotypes is not part of clinical routine (Thursz 2011).
Antiviral resistance testing
Drug-resistant hepatitis B virus (HBV) mutants frequently arise, leading sometimes
to treatment failure and progression to liver disease. There has been much research
time invested into the mechanisms of resistance to nucleos(t)ides and the selection
of mutants. The genes that encode the polymerase and envelope proteins of HBV
overlap, so resistance mutations in the polymerase usually affect the hepatitis B
surface antigen; these alterations affect infectivity, vaccine efficacy, pathogenesis of
liver disease, and transmission throughout the population (see  Chapter 2).
Associations between HBV genotype and resistance phenotype have allowed cross-resistance  profiles to be determined for many commonly detected mutants, so
genotyping assays can be used to adapt therapy. In vitro phenotyping procedures are
established in a rather small number of HBV laboratories and are not commercially
available. Known mutations can be detected by commercially available tests with a
threshold of about 5% (line probe assays, Inno-Lipa
®
) whereas determination of
novel mutations remain to be detected by research oriented laboratories with full
length sequencing methods. Novel ultra-deep pyrosequencing techniques are much
more sensitive in order to detect many more viral variants but are a tool only for
specialised research laboratories and not part of clinical routine (Zoulim 2009,
Margeridon-Thermet 2009).
Hepatitis B: Diagnostic Tests  123
Assessment of liver disease
As a first step, the causal relationship between HBV infection and liver disease has
to be established and an assessment of the severity of liver disease needs to be
performed. Not all patients with chronic hepatitis B virus infection have persistently
elevated aminotransferases. Patients in the immune tolerant phase have persistently
normal ALT levels and a proportion of patients with HBeAg-negative chronic
hepatitis B may have intermittently normal ALT levels. Therefore appropriate,
longitudinal long-term follow-up is crucial.
The assessment of the severity of liver disease should include: biochemical
markers, including aspartate aminotransferase (AST) and ALT, gammaglutamyl
transpeptidase (GGT), alkaline phosphatase, prothrombin time and serum albumin;
blood counts; and hepatic ultrasound. Usually, ALT levels are higher than AST.
However, when the disease progresses to cirrhosis, the ratio may be reversed. A
progressive decline in serum albumin concentrations and prolongation of the
prothrombin time, often accompanied by a drop in  platelet counts, are
characteristically observed once cirrhosis has developed (EASL 2009).
Acute HBV infection
The diagnosis of acute hepatitis B is based upon the detection of HBsAg and IgM
anti-HBc. During the initial phase of infection, markers of HBV replication, HBeAg
and HBV DNA, are also present. Recovery is accompanied by the disappearance of
HBV DNA, HBeAg to anti-HBe seroconversion, and subsequently HBsAg to anti-HBs seroconversion.
The differential diagnosis of HBsAg-positive acute hepatitis includes acute
hepatitis B, exacerbations of chronic hepatitis B, reactivation of chronic hepatitis B,
superinfection of a hepatitis B carrier with hepatitis C or D virus (Tassopoulos
1987), and acute hepatitis due to drugs or other toxins in a hepatitis B carrier.
Past HBV infection
Previous HBV infection is characterized by the presence of anti-HBs and IgG anti-HBc. Immunity to HBV infection after vaccination is indicated by the presence of
anti-HBs only.
HBsAg
−  If negative, acute HBV infection is ruled out (Dufour 2000).
−  If positive, the patient is infected with HBV. A repeat test six months later will
determine if the infection has resolved or is chronic.
Anti-HBs
−  If negative, the patient has no apparent immunity to HBV
−  If positive, the patient is considered immune to HBV (either because of
resolved infection or vaccination).
Anti-HBc-immunoglobulin M
In rare cases, anti-HBc immunoglobulin (Ig) M may be the only HBV marker
detected during the early convalescence or 'window period' when the HBsAg and
anti-HBs tests are negative. Because current tests for HBsAg are very sensitive, an
anti-HBc IgM that is typically positive with acute HBV infection is not generally
124  Hepatology 2012
required to diagnose active infection. Because some chronic HBV carriers remain
anti-HBc IgM positive for years, epidemiological information is necessary to
confirm that the infection is indeed acute. A negative anti-HBc IgM in the presence
of a positive HBsAg suggests that the infection is likely chronic. For these reasons,
routine testing for anti-HBc IgM is not generally recommended to screen for acutely
infected patients.
Chronic HBV infection
Chronic HBV infection is defined by the continued presence of HBsAg in the blood
for longer than six months. Additional tests for HBV replication, HBeAg and serum
HBV DNA, should be performed to determine if the patient should be considered
for antiviral therapy. All patients with chronic HBV infection should be regularly
monitored because HBV DNA and ALT levels vary during the course of infection
to monitor for progression of liver disease. In addition, patients who are not
candidates for treatment at the time of presentation may become candidates for
treatment during follow-up.
HBeAg-negative patients who have normal serum ALT and low (<2000 IU/mL)
or undetectable HBV DNA are considered to be in an inactive carrier state. These
patients generally have a good prognosis and antiviral treatment is not indicated.
However, serial tests are necessary to accurately differentiate them from patients
with HBeAg-negative chronic hepatitis who have fluctuating ALT and/or HBV
DNA levels (Lok 2007). Patients who are truly inactive carriers should continue to
be monitored but at less frequent intervals. HBeAg-negative patients with elevated
serum ALT concentrations should be tested for serum HBV DNA to determine if
the liver disease is related to persistent HBV replication.
HBsAg
−  If negative, chronic HBV infection is typically ruled out.
−  If positive,  the patient is considered HBV-infected. Chronic infection is
diagnosed when the HBsAg remains detectable for longer than six months.
Antibody to hepatitis B core protein
−  If negative, past infection with HBV is typically ruled out.
−  If positive, the patient has been infected with HBV. Infection may be resolved
(HBsAg-negative) or ongoing (HBsAg-positive). If the infection is resolved,
the person is considered naturally immune to HBV infection.
Antibody to hepatitis B surface protein
−  If negative, the patient has no apparent immunity to HBV
−  If positive, the patient is considered immune to HBV (either because of
resolved infection or as the result of prior vaccination). Very rarely (less than
1%) chronic carriers can be positive for HBsAg and antibody to hepatitis B
surface protein (anti-HBs) at the same time (Tsang 1986, Dufour 2000). In
such cases, the patient is considered infectious.
Serum transaminases
Once an individual has been diagnosed with chronic HBV infection, follow-up
testing must be performed for alanine aminotransferase (ALT), a marker of liver cell
Hepatitis B: Diagnostic Tests  125
inflammation. Repeat periodic testing is indicated because the ALT levels can
fluctuate (e.g., from less than the upper limit of normal to intermittently or
consistently elevated). Sustained and intermittent elevations in ALT beyond the
upper limit of normal are indicative of hepatic inflammation and correlate with an
increased risk of progressive liver disease. It must be noted that the normal ALT
ranges are both age and sex dependent and, occasionally, individuals with severe
liver disease may not manifest elevated ALT (Cornberg 2011, EASL 2009).
Occult HBV infection
This is defined as the presence of detectable HBV DNA by PCR in patients who are
negative for HBsAg. Most of these patients have very low or undetectable serum
HBV DNA levels accounting for the failure to detect HBsAg. Infections with HBV
variants that decrease HBsAg production or have mutations in the S gene with
altered S epitopes that evade detection in serology assays for HBsAg are
uncommon. HBV DNA is often detected in the liver and transplantation of livers
from these persons can result in de novo HBV infection (Margeridon-Thermet
2009).
Assessment of HBV immunity
Immunity to HBV is acquired from a resolved infection or from vaccination. The
HBV vaccine has been shown to induce protective immunity in 90% to 95% of
vaccinees. Most vaccinees will have protective levels of anti-HBs for 5-10 years
after vaccination, although the exact duration of immunity remains undefined.
Anti-HBs
−  If the anti-HBs level is less than 10 mIU/mL, this implies that the person is
nonimmune to HBV. In individuals who have received a complete course of
HBV vaccine, the level of anti-HBs may drop to less than 10 mIU/mL after
five to 10 years, but these individuals are generally considered to be immune
based on their vaccination history (Maruyama 1994).
−  If the anti-HBs result is greater than 10 mIU/mL, the person is considered to be
immune. Immunity may be due to immunization or resolved natural infection.
These two states can be distinguished by testing for antibody to hepatitis B
core protein (anti-HBc), which is present in subjects that have had HBV
infection but absent in vaccinees (see below).
Anti-HBc
−  If the anti-HBc total test is positive, this is compatible with current or resolved
HBV infection. A negative HBsAg confirms a resolved infection. HBV
vaccination does not induce anti-HBc total.
Liver biopsy and noninvasive liver transient elastography
A liver biopsy is recommended for determining the degree of necroinflammation
and fibrosis in patients with either increased ALT or HBV DNA levels >2000 IU/ml
(or both) since hepatic morphology can assist the decision to start treatment. Biopsy
is also useful for evaluating other possible causes of liver disease such as steatosis
or steatohepatitis. Although liver biopsy is an invasive procedure, the risk of severe
complications is low. It is important that the size of the needle biopsy specimen be
126  Hepatology 2012
large enough to precisely analyse the degree of liver injury and fibrosis. A liver
biopsy is usually not required in patients with clinical evidence of cirrhosis or in
those in whom treatment is indicated irrespective of the grade of activity or the
stage of fibrosis.
There is growing interest in the use of noninvasive methods, including serum
markers and transient elastography, to assess hepatic fibrosis to complement or
avoid a liver biopsy (Cornberg 2011, EASL 2009).
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128  Hepatology 2012
9.  Hepatitis B Treatment
Florian van Bömmel, Johannes Wiegand, Thomas Berg
Introduction
Individuals with HBV infection carry a significantly increased risk of life-threatening complications such as hepatic decompensation, liver cirrhosis and hepa-tocellular carcinoma (HCC) (Beasley 1988). Recent studies have shown that the
level of serum HBV DNA correlates higher with the risk of developing cirrhosis and
HCC as compared to other baseline or virologic parameters (Chen 2006, Iloeje
2006) (Figure 1). Thus, suppressing the replication of HBV to undetectable levels is
now a major goal in HBV treatment (Liaw 2008, Lok 2007, EASL 2009, Cornberg
2011). Moreover, it has now become clear that continuous suppression of HBV
replication can revert liver fibrosis or even cirrhosis in most patients (Marcellin
2011, Schiff 2011). HBeAg seroconversion is another endpoint, provided that HBV
replication remains durably suppressed to low levels. The ultimate treatment goal,
however, the loss of HBsAg or HBsAg seroconversion, remains difficult to achieve.
The level of hepatitis B surface antigen (HBsAg) before and during interferon-based
treatment is becoming a marker for response to interferon based treatment.
There are two drug classes available for the treatment of chronic HBV infection:
the immune modulator interferon  α  (standard or pegylated (PEG)-INF α) and
nucleoside or nucleotide analogs, which act as reverse transcriptase inhibitors of the
HBV polymerase. Currently, the nucleoside analogs lamivudine (LAM), telbivudine
(LdT), entecavir (ETV) and the acyclic nucleotide analogs adefovir dipivoxil
(ADV) and tenofovir disoproxil fumarate (TDF) are available. Due to this broad
spectrum of therapeutic options disease progression and complications can be
prevented if the infection is diagnosed early and treated effectively. The early
diagnosis of chronic hepatitis B by HBsAg screening in high-risk groups and in
patients with elevated transaminases plays a crucial role in the management of HBV
infection.
Indication for antiviral therapy
Acute hepatitis B
Acute hepatitis resolves spontaneously in 95-99% of cases (McMahon 1985, Liaw
2009). Therefore, treatment with the currently available drugs is generally not
Hepatitis B Treatment  129
indicated. However, in a recent trial comparing treatment with LAM 100 mg/day
versus no treatment in 80 Chinese patients with fulminant hepatitis B, a reduced
mortality of 7.5% was found in patients receiving LAM treatment compared to 25%
in the control group (p=0.03) (Yu 2010). These observations are supported by a
placebo-controlled trial investigating the use of LAM in 71 patients with fulminant
hepatitis B in India (Kumar 2007). Several case reports from Europe also revealed
that patients with severe and fulminate hepatitis B may benefit from early antiviral
therapy with LAM or other nucleos(t)ide analogs by reducing the need for high-urgency liver transplantation (Tillmann 2006). As a result, treatment for fulminant
hepatitis B with LAM is recommended by EASL and with LAM or LdT by AASLD
(EASL 2009, Lok 2009). Interferon therapy is contraindicated in patients with acute
HBV infection because of risk of increasing hepatitis. The endpoint of treatment of
acute HBV infections is HBsAg clearance (EASL 2009, Lok 2007).
Figure 1. Cumulative incidence of liver cirrhosis in untreated HBV-infected individuals
within a mean observation period of 11.4 years (REVEAL Study). The incidence of liver
cirrhosis increases over time depending on baseline HBV DNA levels (Iloeje 2006). The relative
risk for developing HCC was 1.4 in patients with HBV DNA levels of 300 to 1,000 and increased
to 2.4 in patients with 1,000-10,000 to 5.4 in patients with 10,000 to 100,000 and to 6.7 in
patients with HBV DNA levels >1 million copies/ml. A similar association between HBV DNA
levels and the risk of HCC development was shown (Chen 2006).
Chronic hepatitis B
All patients with HBsAg positive chronic hepatitis should be considered as possible
candidates for antiviral therapy especially in situations when there is a significant
level of HBV replication (Chen 2006, Iloeje 2006). Differentiation between
HBeAg-positive and HBeAg-negative chronic hepatitis B is not necessary anymore
for treatment indication, although with respect to the choice of the appropriate
antiviral drug these criteria may be still useful.
130  Hepatology 2012
Table 1. Key guideline recommendations for indication for antiviral treatment of
HBV infection.
AASLD
(Lok 2007, Lok
2009)
Consider treatment:
•  HBeAg(+): HBV DNA >20,000 IU/ml + ALT ≤2x ULN + biopsy shows
moderate/severe inflammation or significant fibrosis
•  HBeAg(+): HBV DNA >20,000 IU/ml + ALT >2x ULN. Observe for 3-6
months and treat if no spontaneous HBeAg loss
•  HBeAg(-): HBV DNA >20,000 IU/ml + ALT >2x ULN
Consider biopsy:
•  HBeAg(+): HBV DNA >20,000 IU/ml + ALT >2x ULN + compensated
•  HBeAg(+): HBV DNA >20,000 IU/ml + ALT 1-2x ULN + age >40 years
or family history of HCC
•  HBeAg(-): HBV DNA >2,000-20,000 IU/ml + ALT 1-2x ULN
APASL
(Liaw 2008)
Consider treatment:
•  All patients: HBV DNA detectable + advanced fibrosis/cirrhosis
•  HBeAg(+): HBV DNA >20,000 IU/ml + ALT >2x ULN + impending/
overt decompensation
•  HBeAg(-): HBV DNA > 2,000 + ALT >2x ULN + impending/ overt
decompensation
EASL
(EASL 2009)
Consider treatment:
•  HBV DNA >20,000 IU/ml + ALT >2x ULN + moderate to severe
necroinflammation
Belgian
(Colle 2007)
Consider treatment:
•  HBeAg(+): HBV DNA >20,000 IU/ml + ALT >2x ULN (or
moderate/severe hepatitis on biopsy)
•  HBeAg(-): HBV DNA ≥2,000 IU/ml and elevated ALT
Consider biopsy:
•  Fluctuating or minimally elevated ALT (especially in those older than
35-40 years)
Dutch
(Buster 2008)
Consider treatment:
•  HBeAg(+) and HBeAg(-): HBV DNA ≥20,000 IU/ml and ALT ≥2x ULN
or active necrotic inflammation
•  HBeAg(-): HBV DNA ≥2,000–20,000 IU/ml and ALT ≥2x ULN (and
absence of any other cause of hepatitis)
German
(Cornberg 2011)
Consider treatment:
•  HBV DNA >2,000 IU/ml + minimal inflammation/low fibrosis or ALT
elevation
Italian
(Carosi 2008)
Consider treatment:
•  HBeAg(+): HBV DNA >20,000 IU/ml + ALT >2x ULN
•  HBeAg(-): HBV DNA >2,000 IU/ml + abnormal ALT and or fibrosis
(Ishak ≥S2)
Consider biopsy:
•  HBeAg(-): HBV DNA >2,000 IU/ml + borderline ALT, or if DNA 2,000–
20,000 IU/ml + high ALT
Turkish TASL
(Akarca 2008)
Consider treatment:
•  HBV DNA >2,000 IU/ml + histological fibrosis >2
•  HBV DNA >20,000 IU/ml + any histological finding + ALT >2x ULN
Current recommendations of the different national and international societies are
shown in Table 1 (Akarca 2008, Carosi 2008, Colle 2007, Cornberg 2011, EASL
2009, Janssen 2008, Juszczyk 2008, Keeffe 2007, Liaw 2008, Lok 2009, Waked
2008). In most of these guidelines, the most relevant factor for a decision to initiate
treatment has shifted from histological proven disease activity to the level of HBV
Hepatitis B Treatment  131
DNA. Thus, most of the recently published guidelines now recommend antiviral
treatment for patients with HBV DNA levels >2,000 IU/mL (corresponding to
>10,000 copies/mL) in association with a sign of ongoing hepatitis which can either
be ALT levels greater than 2 times the upper limit of normal or significant fibrosis
demonstrated by liver histology greater than A1/F1. The recently updated German
treatment guidelines emphasise the importance of suppression of HBV replication
by recommending treatment in patients with HBV DNA levels >2,000 IU/mL and
any elevation of ALT levels or signs of fibrosis (Cornberg 2011).
All patients with liver cirrhosis or high-grade liver fibrosis and any measurable
HBV DNA should be considered for antiviral therapy (EASL 2009, Lok 2007,
Cornberg  2011). The indication for antiviral treatment according to the recent
German guidelines is depicted in Figure 2 (Cornberg 2011). In patients with
decompensated cirrhosis Child-Pugh score B or C, INF α is contraindicated.
Figure 2. Indication for antiviral treatment according to the German guidelines for the
treatment of chronic HBV infection. Treatment should be considered if HBV DNA levels
exceed 10
4
copies/ml and if ALT are elevated or if liver histology is abnormal. Of note,
asymptomatic carriers with family history of HCC should receive treatment even if signs of
hepatitis are absent (Cornberg 2011).
Inactive chronic HBsAg carriers, characterised by negative HBeAg and positive
anti-HBeAg, low HBV DNA levels (<2,000 IU/ml) and serum aminotransferases
within normal levels do not have an indication for antiviral therapy (Cornberg 2011,
Brunettto 2011). However, differentiation between inactive HBsAg carriers and
patients with chronic HBeAg-negative hepatitis may be difficult in some cases.
Elevated transaminases are no reliable parameter for assessing the stage of liver
fibrosis and long-term prognosis of HBV-infected patients. Even in patients with
normal or slightly elevated aminotransferases there can be a significant risk for the
development of HBV-associated complications (Chen 2006, Iloeje 2006, Kumar
2008). It is reasonable to perform a liver biopsy in these individuals and to control
132  Hepatology 2012
the level of HBV DNA at three-month intervals. However, a liver biopsy is not
mandatory to initiate treatment for the majority of patients (Table 1).
HBV immunotolerant patients are mostly under 30 years old and can be recog-nised by their high HBV DNA levels, positive HBeAg, normal ALT levels and
minimal or absence of significant histological changes. According to most practice
guidelines immediate therapy is not required (Akarca 2007, Balik 2008, Carosi
2008, Colle 2007, Cornberg 2011, EASL 2009, Buster 2008, Juszczyk 2008, Keeffe
2007, Liaw 2008, Lok 2009, Waked 2008). However, patients with elevated risk for
HCC development, such as those with a positive family history, and patients from
high endemic areas like Asia or Africa may perhaps benefit from early antiviral
therapy (Cornberg 2011). Studies are under way  to further clarify this issue,
especially to answer the question whether early intervention with antiviral therapy
will positively influence the long-term risk for HCC.
Summary of treatment indications in the German Guidelines of 2011
–  All patients with chronic hepatitis B should be evaluated for treatment.
Indication for treatment initiation depends on the level of viral replication
(HBV DNA ≥2,000IU/mL, corresponding to ml ≥10,000 copies/mL), any
elevation of serum aminotransferases and the histological  grading and
staging.
–  Patients with advanced fibrosis or cirrhosis and detectable viremia need
consistent antiviral therapy.
–  Reactivation of HBV replication due to immunosuppression should be
avoided by preventive therapy.
–  Alcohol and drug consumption are not a contraindication for treatment with
nucleos(t)ide analogs.
–  Therapy with nucleos(t)ide analogs during pregnancy may be considered if
the benefit outweighs the risk. A running treatment with LAM or TDF can be
continued during pregnancy.
–  Occupational and social aspects and extrahepatic complications may justify
therapy in individual cases.
Endpoints of antiviral treatment
Due to persistence of episomal covalently closed circular DNA (cccDNA), a
template of the HBV genome located in the nucleus of infected hepatocytes, a
complete eradication of HBV infection is currently impossible (Rehermann 1996).
Reactivation of an HBV infection can occur in certain circumstances from these
nuclear reservoirs even decades after HBsAg loss, for instance during
immunosuppressive therapy. The aim of treatment of chronic hepatitis B is to
reduce complications such as liver failure and HCC and to increase survival (EASL
2009, Lok 2009, Cornberg 2011). To determine the success of antiviral therapy
surrogate markers are used during and after treatment. These parameters include
virologic (HBeAg and HBsAg status, HBsAg levels, HBV DNA level) and patient-related parameters (aminotransferases, liver histology).
Suppression of HBV replication. In two recent studies a close correlation be-tween baseline HBV DNA levels and progression of the disease was demonstrated.
In the REVEAL study, 3774 untreated HBV-infected individuals were followed
Hepatitis B Treatment  133
over a mean time period of 11.4 years in Taiwan (Chen 2006, Iloeje 2006). HBV
DNA levels at baseline were the strongest predictors of cirrhosis and HCC devel-opment (Figure 1). In multivariate models, the relative risk of cirrhosis increased
when HBV DNA reached levels greater than 300 copies/mL, independent of
whether patients were negative or positive for HBeAg. In addition, individuals with
HBV DNA levels ≥10
4
copies/mL (or ≥2,000 IU/mL) were found to have a 3-15
fold greater incidence of HCC as compared to those with a viral load <10
4
copies/mL. According to these results, a meta-analysis covering 26 prospective
studies revealed a statistically significant and consistent correlation between viral
load levels and histologic, biochemical, or serologic surrogate markers (Mommeja-Marin 2003). It can therefore be concluded that the complete and persistent
suppression of HBV replication is a reliable endpoint for the treatment of chronic
HBV infection.
Induction of HBeAg seroconversion.  In HBeAg-positive patients,
seroconversion from HBeAg to anti-HBe was found to be a reliable surrogate
marker for prognosis of chronic HBV infection leading in many cases to an inactive
HBsAg carrier state (Figure 3). In these patients, HBsAg remains detectable but
HBV replication continues at low or even undetectable levels and transaminases are
generally within normal ranges.
Figure 3. Possible endpoints of treatment of chronic HBV infection. After achieving
HBeAg or HBsAg seroconversion, antiviral treatment can be stopped. However, it is
recommended to maintain treatment for a period of 6-12 months after HBeAg or HBsAg
seroconversion.