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Editorial
Board:
Emmet B. Keeffe, MD (Chair); |
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HBV Watch™ |
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Timely Information for Practicing Physicians |
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HIGHLIGHTS FROM THE
AASLD HEPATITIS SINGLE TOPIC CONFERENCE
NEW DIRECTIONS IN THE
TREATMENT OF HEPATITIS B
TREATMENT OF HBV
Current therapeutic
options and promising new therapies in development. Approved first-generation (interferon) and second-generation
(lamivudine and adefovir) therapies can suppress hepatitis B virus (HBV)
replication by as much as 2-4 orders of magnitude and reduce HBV DNA in some
cases to levels undetectable by polymerase chain reaction. Profound HBV DNA suppression (≤104
copies/mL) is associated with hepatitis B e antigen (HBeAg) seroconversion,
which is durable in >80% of patients with HBeAg-positive chronic hepatitis B
and leads to improvement in the natural history of the disease. On the other hand, in HBeAg-negative
patients, sustained responses are uncommon and relapses frequently occur after
therapy is stopped. New antiviral agents
with early promise in this disease include the guanine analogue entecavir, the
cytosine analogue emtricitabine and the small molecule nucleosides telbivudine
and valtorcitabine. Preliminary results
of ongoing trials with peginterferon in patients with chronic hepatitis B
indicate a greater efficacy versus standard interferon and a higher sustained
virologic response versus lamivudine.
Next generation antiviral agents are anticipated to be even more potent
and orally active. (JL Dienstag)
Approaches to the
management of chronic hepatitis B in cirrhotic patients and liver transplant
recipients. Mortality is significant in
untreated patients with cirrhosis caused by HBV with 5-year mortality rates of
16% and 65-86% in compensated and decompensated patients, respectively. All of the three FDA-approved antiviral therapies
for HBV infection (ie, interferon, lamivudine and adefovir) have been studied
in cirrhotic patients. Control of HBV
replication with antiviral therapy in these patients has been associated with a
decreased risk of end-stage liver disease and its complications, clinical
stabilization, delayed need for liver transplantation and the potential for a
decreased recurrence of hepatocellular carcinoma following resection. In cirrhotic patients requiring liver
transplantation, long-term suppression of HBV replication is critical to
preventing histological progression and ensuring long-term graft survival. Treatment strategies that minimize the risk
of drug resistance and provide long-term suppression of HBV replication are
highly desirable. (NA Terrault)
Therapeutic strategies
for patients coinfected with HBV and the human immunodeficiency virus
(HIV). Coinfection of patients with HIV and
HBV is a common occurrence due to shared modes of transmission. Since infection with HBV accelerates the
progression of liver disease, any patient with active HBV replication (ie, the
presence of HBsAg and detectable HBV DNA levels) and liver disease should be
evaluated for therapy. The choice of
therapy should be based on a consideration of the stage of both the HIV and HBV
infection. In patients who are naïve to
lamivudine and in need of therapy for HIV infection, a combination of
lamivudine or emtricitabine and tenofovir in combination with a highly active
antiretroviral therapy regimen is recommended, whereas in coinfected patients
who do not need HIV therapy, the treatments of choice are peginterferon and
adefovir. In patients with
lamivudine-resistant HBV infection, the available options are peginterferon,
adefovir and tenofovir; discontinuing lamivudine in these cases risks rebound
hepatitis, whereas continuing it risks the emergence of additional
mutations. The optimal duration of
treatment of HBV infection has not yet been established for either the
HIV-infected or HIV-uninfected patients. (CL Thio)
TARGETS FOR THERAPY
Hepatitis B virus
regulatory mechanisms and targets for new antiviral strategies. HBV, a member of a group called hepadnaviruses, is a small
DNA virus 42 nm in diameter composed of an outer envelope and an internal core,
or nucleocapsid, which contains the hepatitis B core antigen (HBcAg), a DNA
polymerase/reverse transcriptase and the viral genome. The mechanism of replication of
hepadnaviruses is different from that of other known DNA viruses since it
replicates through reverse transcription of an RNA intermediate. There are at least 15 defined steps in the
reproductive cycle of HBV in hepatocytes that represent potential targets for
new antiviral drug development; major targets include viral replication and
gene expression and function, viral RNA encapsulation and the processing and
maturation of viral proteins. Nucleoside
and nucleotide analogs are currently the most promising group of HBV antiviral
agents, and the role of immunomodulatory drugs aimed at elimination of
HBV-infected cells is also being explored. New antiviral targets for HBV
therapy are expected to be identified when the mechanisms involved in the early
stages of HBV infection are further elucidated. (HE Blum)
Molecular epidemiology
and genotypes: HBV variation and antiviral response. There are currently 7 classes of HBV genotypes that are
derived from an 8% difference in nucleotides.
These genotypes are prevalent to various extents in different parts of
the world. Evidence indicates that HBV
genotypes play a role both in the natural history of HBV infection and in the
response to antiviral therapy, especially interferon therapy. For example, in
chronic HBeAg-positive patients receiving a one-year course of peginterferon
alfa-2b, there was a sustained suppression in HBV DNA six months after the end
of treatment in 47%, 44%, 28% and 25% of patients with genotypes A, B, C, and
D, respectively (H Janssen et al, Hepatology 2003; 38:1323). Although the relationship between genotype
and the response to nucleoside therapy needs further study, evidence supports
that the rate and pattern of lamivudine resistance may be different between HBV
genotypes A and D. Future trials should
be stratified according to HBV genotype so that the relationship between HBV
genotype and response can be more accurately established. (ASF Lok)
Assessment of disease
status and activity in chronic hepatitis B (CHB). The three major clinical forms of CHB (ie, HBeAg-positive,
HBeAg-negative and the inactive carrier state) differ in their optimal
approaches to therapy and clinical outcomes as well as their clinical and
virological characteristics. Testing for
serum HBsAg, HBeAg and HBV DNA and serial determinations of aminotransferase
levels are useful in defining these three forms, but are less reliable for
determining staging and grading and in providing a basis for initiation of
therapy. Currently recommended therapies
for CHB include either a defined course of interferon or peginterferon for 4-12
months, or long-term treatment of one year or more with an oral nucleoside
analogue alone or in combination therapy.
Until a standardized definition for response to therapy in patients with
HBV infection is developed, it is recommended that definition of a response
should be based on a combination of factors, including biochemical results
(decrease in aminotransferase levels), virological results (decrease in HBV
DNA, and loss of HBeAg and HBsAg) and liver histology (improvement in Histology
Activity Index). (JH Hoofnagle)
NEW AVENUES FOR
TREATMENT
Potent antiviral and
immunomodulatory effects of peginterferon alfa-2a in patients with chronic
hepatitis B. P Marcellin and colleagues reported the
virological and immunological responses to peginterferon alfa-2a in patients
with CHB in a randomized phase II proof-of-concept trial in 194 HBeAg-positive
patients and a randomized phase III, partially double-blinded trial in 537
HBeAg-negative patients. In the phase II
study, peginterferon alfa-2a 180 µg demonstrated potent antiviral activity as
shown by a 3.5 log10 reduction in HBV DNA at the end of 24 weeks. At the end of follow-up (week 48), a higher
percentage of patients treated with peginterferon alfa-2a compared to those
receiving conventional interferon alfa-2a achieved HBV DNA suppression to
<500,000 copies/mL, HBeAg loss, HBeAg seroconversion, and normalization of
ALT. In the phase III study, patients
were treated for 48 weeks; at the end of follow-up (72 weeks), HBV DNA
suppression to <20,000 copies/mL was achieved in a significantly higher
percentage of patients receiving peginterferon alfa-2a monotherapy (43%) and
peginterferon alfa-2a plus lamivudine (44%) compared with patients receiving
lamivudine alone (29%). These data
support the use of peginterferon afa-2a in both HBeAg-positive and
HBeAg-negative CHB patients. (P Marcellin et al)
Entecavir is a potent
and selective treatment for HBV infection. The safety and
efficacy of entecavir were analyzed in six phase II trials conducted in both
treatment-naïve and interferon/lamivudine-refractory patients infected with
HBV. Entecavir demonstrated potent
antiviral activity and normalized ALT levels in both of these populations. In one study both 1.0 and 0.5 mg daily doses
of entecavir produced superior reductions in HBV DNA (log10
decreases of 5.1 and 4.1, respectively compared with 1.4 log10 reduction
for lamivudine [p<0.0001]).
Normalization of ALT was superior in patients receiving 1.0 and 0.5 mg
entecavir (68% and 59%, respectively) compared to patients who continued to
receive lamivudine (6%; p<0.0001). In
another phase II study, entecavir was highly effective in reducing serum HBV
DNA regardless of baseline ALT levels, in contrast to lamivudine. Across these studies, viral resistance to
entecavir occurred infrequently; only two heavily pretreated patients developed
resistance. Entecavir was well tolerated
with a safety profile comparable to that of lamivudine; no dose-related
increase in adverse events was observed.
These promising results must be confirmed in the large ongoing phase III
trials of entecavir 0.5 mg daily for nucleoside-naïve and 1.0 mg daily for
lamivudine-refractory patients. (D Apelian)
Do appropriate
monotherapy or combination therapy paradigms exist for the treatment of chronic
hepatitis B? The efficacy and safety of several
new antiviral agents for the treatment of patients infected with HBV have been
demonstrated in clinical trials, but there is still an urgent need to develop
an overall strategy for the treatment of these patients. Monotherapy may provide sustained reductions
in viral load and sustained improvement in necroinflamation and fibrosis for
some patients, but there is a need to identify those patients with a high
probability of response. Several major
predictive factors (eg, baseline serum ALT and baseline HBV DNA levels) have
been identified, but standardized measures of response, including standard
measures of HBV DNA, are required for accurate prediction and assessment of
response. In principle, combination
therapy may lead to rapid maximal viral suppression, but synergy with
nucleoside/nucleotide combinations has not been observed, and the combination
of peginterferon plus lamivudine does not appear superior to peginterferon
alone. Variables such as viral
resistance, toxicity and cost benefit must be considered in the future
development of an appropriate treatment paradigm for CHB. (GM Dusheiko)
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