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.
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