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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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Special Issue Featuring Highlights
from an Expert Panel Meeting
“Hepatitis B Virology and Clinical
Management: Key Issues and Current Perspectives”
Chaired by Jules L. Dienstag, MD and Emmet B. Keeffe, MD
MOLECULAR VIROLOGY OF HEPATITIS B VIRUS – Stephen
Locarnini, MD, PhD, FRCP
The outcome of hepatitis B virus
(HBV) infection is determined by the interplay between the virus, hepatocytes
and host immune responses. In chronic hepatitis B (CHB), liver damage occurs as
a result of host cellular immune responses to HBV-infected hepatocytes
associated with immune clearance. There are 8 HBV genotypes (A, B, C, D, E, F,
G, H) and 4 different recombinants (A/D, B/C, Ba, Bj); each of these genotypes
and recombinants are associated with a different geographical endemicity. HBV
is characterized by high virion production (1012-13 virions per day) and a high
mutational rate (1010-11 point mutations per day). Clinically significant HBV
mutants include basal core promoter and precore mutants (including A1762T,
G1762A, G1896A), envelope mutants (associated with HBV vaccine, HBIG and
diagnostic escape), and polymerase antiviral resistance mutants (such as
lamivudine-resistant rtM204I/V/S and adefovir-resistant rtN236T). Clinical and
laboratory manifestations of the emergence of drug-resistant virus include
increasing serum HBV DNA (>0.5 log), increasing serum ALT levels, clinical
deterioration, and identification of known genotypic markers of drug resistance
within the viral polymerase. Strategies to prevent resistance to antiviral
agents include: 1) maximizing antiviral activity, by using the maximum
tolerated dose and the most effective regimen, and 2) maximizing genetic
barriers to resistance, by avoiding sequential therapy or treatment
interruptions, and choosing drugs requiring multiple resistance mechanisms,
drugs to which the patient is naďve, or drug combinations that work around
phenotypic reversion.
HEPATITIS B VIRAL KINETICS AND MATHEMATICAL MODELING – Alan S.
Perelson, PhD
Mathematical models have proven
useful in the study of HIV and HCV, and have contributed to the understanding
of the dynamics of HBV infection. In these models, the basic biology of the
system is distilled into a set of mathematical equations that describe the
dynamics of the virus, host cells, and the immune system. Comparison of these
mathematical equations with data from clinical studies provides insights into
dynamic behaviors, such as viral replication, host cell death rate, and the
effects on the immune system. However, these models are based on a
simplification of the biology of HBV infection – they do not account for cell
proliferation, varying numbers of copies of cccDNA in
infected hepatocytes, the complex immune response, or the existence of
different types of HBV infectious and non-infectious particles. Second
generation models are being developed to address some of these deficiencies (Ribiero RM et al. Microbes and Infection 2002;4:829-35).
NATURAL HISTORY OF CHRONIC HEPATITIS B – Brian J.
McMahon, MD
The phases of CHB include: 1)
immune tolerant phase, 2) CHB, and 3) inactive HBsAg carrier (NIH Workshop on
Hepatitis B, Lok et al, Hepatology, 2000). The immune
tolerant phase is typically found in children or young adults who were infected
via perinatal transmission and is characterized by normal ALT levels, HBeAg+,
HBV DNA >105 copies/mL, and liver biopsy showing minimal hepatitis and no
fibrosis. CHB is characterized by HBeAg+ or HBeAg, elevated ALT levels,
HBV DNA >105 copies/mL, and liver biopsy showing active hepatitis with or
without fibrosis. Inactive HBsAg carriers are usually older adolescents or
adults who are HBeAg and anti-HBe+, and have normal ALT levels, HBV DNA
<105 copies/mL, and minimal hepatitis with no or only mild fibrosis on liver
biopsy. Morbidity and mortality due to HBV infection is due to the development
of CHB leading to cirrhosis and hepatocellular carcinoma (HCC). Core promoter
mutations are characterized by anti-HBe+, high levels of HBV DNA, and a greater
risk of hepatic decompensation and HCC. Natural clearance of HBeAg occurs in
4-12% of HBeAg+ carriers per year; 40-50% of carriers clear HBeAg in 5 years
and 70-80% in 10 years. This natural clearance occurs more frequently in older
carriers and those with elevated ALT levels. After HBeAg seroconversion, most
(~70%) have inactive hepatitis B; however, some (~20-30%) develop HBeAg
CHB, and some (~5-20%) have one or more reversions to HBeAg. Clearance of HBsAg
in persons chronically infected with HBV occurs in ~0.5% of HBsAg carriers per
year; however, 50% of these carriers have HBV DNA present in sera (1-2
logs). Clearance of HBsAg does not
eliminate the risk of HCC.
OVERVIEW OF TREATMENT OF HBV – KEY
APPROACHES AND CLINICAL CHALLENGES – Robert P. Perrillo,
MD.
Currently available treatment
options for HBV include interferon (IFN) alpha, and the nucleoside/nucleotide
analogues (NA) lamivudine (LAM) and adefovir dipivoxil (ADV). NAs under development include entecavir, emtricitabine,
tenofovir and telbivudine. The advantages of IFN are
its immunomodulatory properties and a relatively short course of therapy (16-32
weeks) that results in HBeAg loss in 30-35% and HBsAg clearance in 5-10% of
patients. Disadvantages include high cost, troublesome side effects and lack of
safety in decompensated cirrhotics. The advantages of NAs
include oral administration, minimal side effects, safety in decompensated
cirrhotics and post-OLT patients, and relatively low cost. However,
disadvantages include the need for a long duration of treatment (>1 year),
development of drug-resistant mutants, lack of effect on HBsAg loss and
post-withdrawal ALT flares (20-25%). Combination therapy with IFN and NAs or multiple NAs may provide
better treatment outcomes and are under investigation. Potential candidates for
combination IFN/NA therapy include patients failing monotherapy, as well as
those with high viremia, HIV co-infection, modestly
elevated ALT levels, and HBeAg (precore mutant) CHB.
LAMIVUDINE FOR HEPATITIS B – Teresa
L. Wright, MD
Lamivudine (LAM) therapy is
indicated in patients with chronic HBV infection (HBsAg+); compensated liver
disease; HBeAg+ or HBeAg– with elevated ALT levels (>2 x ULN) and HBV DNA
(>105 copies/mL); and in patients with significant liver disease by liver
biopsy (>stage 2 fibrosis) and active viral replication, even if ALT levels
are normal or near normal. After 52 weeks of therapy in HBeAg+ patients, LAM
(100 mg/d) has been shown to induce HBeAg seroconversion in 16-18%, produce
loss of HBeAg in 17-33%, and decrease Knodell HAI by >2 points in 55-56% of
patients. HBeAg seroconversion with LAM is associated with longer treatment
duration and higher baseline ALT levels. HBeAg loss persists in 81-86% of
patients at >12 months. The 52-week virological response to LAM in
HBeAg patients ranges from 65% to 74%, with approximately 90% of
patients having a biochemical response. LAM resistance develops in 10%
of patients at 12 months, 37% at 24 months, and 46% at 36 months. The clinical
consequences of LAM resistance include: 1) a decreased rate of HBeAg
seroconversion, 2) worsening liver histology, 3) increase in graft failure and
fulminant hepatitis in OLT patients, and 4) in rare cases, death due to
resistance.
TREATMENT OF PATIENTS WITH CHB WITH ADEFOVIR
DIPIVOXIL – Myron J. Tong, PhD, MD
Clinical studies of adefovir
dipivoxil (ADV) have been completed in HBeAg+ patients (Marcellin
P et al, NEJM 2003;348:808-16), HBeAg patients (Hadziyannis SJ et al,
NEJM 2003;348:800-7), and LAM-resistant HBV patients (Peters et al, 2003, in
press). In 2 pivotal studies, one in 338 treatment-naďve HBeAg+ patients with
CHB randomized to receive ADV 10 mg/d or placebo (PLA) for 48 weeks, and the
other in 184 treatment-naďve HBeAg patients with CHB randomized to
receive ADV 10 mg/d or PLA for 48 weeks, ADV resulted in statistically
significant improvement in: 1) liver histology, 2) serum HBV DNA reduction and
percent of patients <400 copies/mL, and 3) HBeAg loss and seroconversion. No
ADV resistance mutations were observed, and ADV was well tolerated with a
safety profile similar to PLA. In a third study among 58 YMDD mutant HBV
patients randomized to receive ADV 10 mg/d, ADV 10 mg/d + LAM 100 mg/d, or LAM
100 mg/d, switching to ADV monotherapy or adding ADV to ongoing LAM resulted in
significant reductions in serum HBV DNA (~4 log10 copies/mL at 48 weeks)
compared to continued LAM therapy. Additionally, a greater number of patients
receiving ADV monotherapy or ADV + LAM had ALT normalization. All regimens were
well tolerated. Recent data show that 1.7% of patients treated with ADV develop
a unique mutation (N236T) after 2 years of therapy.
TREATMENT WITH PEGINTERFERON ALFA-2A IN PATIENTS WITH
CHB – W. Graham E. Cooksley, MD
In a recently reported phase II
study (Cooksley WGE et al. J Viral Hepatitis
2003;10:296-305), 194 IFN-naďve CHB patients were randomized to receive weekly
peginterferon (PEG-IFN) alfa-2a 90, 180 or 270 µg, or standard IFN alfa-2a 4.5
MIU tiw for 24 weeks. At the end of the 24 week
treatment-free follow-up, HBeAg had cleared in 37%, 35% and 29% of patients
receiving PEG-IFN alfa-2a 90, 180 and 270 µg, respectively, compared with 25%
of patients on standard IFN alfa-2a. The combined response (HBeAg loss, HBV DNA
suppression, and ALT normalization) of all PEG-IFN alfa-2a doses combined was
twice that achieved with IFN alfa-2a (24% vs 12%; p=0.036). At the 180 µg dose,
there was a more rapid and greater HBeAg loss and a larger reduction in HBV DNA
levels compared with IFN alfa-2a. PEG-IFN alfa-2a monotherapy was well tolerated.
Low pre-treatment quantitative HBeAg and HBV DNA, and genotype B were
predictive of response to PEG-IFN alfa-2a. PEG-IFN alfa-2a was associated with
substantially greater efficacy vs IFN alfa-2a in patients with
“difficult-to-treat” disease – low pre-treatment ALT levels, high pre-treatment
HBV DNA levels and HBV genotype C. Large-scale phase III studies of PEG-IFN
alfa-2a are ongoing in HBeAg+ and HBeAg– patients.
MANAGEMENT OF HBV INFECTION IN LIVER TRANSPLANT
PATIENTS – Didier Samuel, MD
Historically, OLT for chronic HBV
infection has been associated with a high rate of reinfection, aggressive
recurrent hepatitis B and poor survival. However, major improvements have been
made in post-OLT prophylaxis of HBV infection with the use of hepatitis B immune
globulin (HBIG), LAM therapy and combination HBIG + LAM therapy. Prior to OLT,
patients with detectable HBV DNA should receive LAM and/or ADV, taking into
consideration the severity of liver disease and the expected waiting time for
OLT. There is no need for pre-OLT antiviral treatment in HBV DNAnegative patients. After OLT, HBV DNA-positive
patients should receive combination HBIG + LAM; HBV DNAnegative
cirrhotic patients should probably receive combination HBIG + LAM as well. In HBV DNAnegative
delta cirrhotic and fulminant HBV patients, HBIG alone is probably sufficient.
High doses of HBIG are necessary in the immediate post-OLT period to produce
immediate HBsAg negativity and to protect the graft from early reinfection. HBV
reinfection after OLT is often severe and requires anti-HBV treatment,
depending on previous antiviral treatment and possible resistance. LAM should
be used if HBIG alone had been administered for prophylaxis; ADV should be used
if HBIG + LAM had been employed post-OLT.
HBV INFECTION IN HEMODIALYSIS AND RENAL TRANSPLANT
PATIENTS – Paul Martin, MD
The incidence of HBV infection and
HBsAg positivity in hemodialysis (HD) units has declined dramatically among
both patients and staff from 1976 to 1997 following the adoption of CDC recommendations
in 1977. These recommendations include segregation of HBsAg+ patients,
provision of dedicated machines for infected patients, regular serological
screening, and disinfection of equipment. Vaccination with the higher 40 µg
dose with booster doses when anti-HBs falls below 10 IU/mL is advocated before
renal replacement therapy becomes necessary. However, as of 1997 only 47% of HD
patients (vs 87% of staff) received vaccination. A study reported by Fornairon and colleagues of HBV-infected renal transplant
(RT) recipients showed an association with reactivation of HBV and enhanced HBV
replication post-RT, as well as disease progression (Fornairon
S et al. Transplantation 1996;62:297-99). Noteworthy
was a high frequency of histologic deterioration (85%), accompanied by
cirrhosis in 28% and by HCC in 23% of cirrhotic patients. HCV co-infection was significantly associated with histologic
worsening. Chan and colleagues reported that
preemptive LAM therapy based on HBV DNA levels in HBsAg+ RT recipients
increased survival (Chan TM et al. Hepatology 2002;36:1041-5).
PRACTICAL MANAGEMENT OF CHRONIC HEPATITIS B –
The following patient groups
should be screened for HBV: persons born in endemic areas, men who have sex
with men, IV drug users, dialysis patients, HIV-infected patients, pregnant
women, and those with family/household and sexual contact. Initial patient evaluation
should include a thorough history and physical and diagnostic tests including
liver markers, viral markers, screening for HCC and liver biopsy if active
disease present. Regular monitoring of patients is necessary to assess
progression of liver disease, assess need for treatment, follow response to
treatment, and conduct HCC surveillance. Recommendations for treatment of CHB
are as follows: (Conjeevaram HS and Lok ASF. J Hepatol 2003;38:S90-S103)
|
HBeAg |
HBV DNA |
ALT |
Treatment Strategy |
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+ |
+ |
<2 x
ULN |
Observe; treat when ALT ↑ |
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+ |
+ |
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IFN, LAM or ADV; LAM or ADV for
IFN nonresponders or when IFN contraindicated; ADV for LAM resistance |
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- |
+ |
|
Same as above; long-term
treatment |
|
- |
- |
<2 x
ULN |
No treatment |
|
+/- |
+ |
Cirrhosis |
Compensated: IFN, LAM or ADV.
Decompensated: LAM or ADV; ADV for LAM resistance |
|
+/- |
- |
Cirrhosis |
Compensated: observe.
Decompensated: OLT |
NEW AGENTS UNDER DEVELOPMENT FOR THE TREATMENT OF CHB – Anna S.
F. Lok, MD
New agents under development for
the treatment of CHB include: entecavir, emtricitabine, clevudine, LdT (telbivudine), LdC (valtorcitabine),
B-L-Fd4C and tenofovir. Entecavir appears to be very promising; phase II trials
(48 weeks) have shown that entecavir at doses of 0.1 and 0.5 mg is superior to
LAM 100 mg in nucleoside-naďve patients, and demonstrates superior antiviral
activity compared to continued LAM in LAM-resistant
patients, including OLT recipients. No drug-resistant mutations have been
observed thus far. Phase II trials of emtricitabine (96 weeks) have demonstrated
an optimal dose of 200 mg with no significant adverse effects. The HBeAg
seroconversion rate in year 2 is similar to LAM, and drug-resistant rtM204 V/I
is slightly less frequent. Four weeks treatment with clevudine at a dose up to
200 mg/d was well tolerated and showed a significant reduction in HBV DNA at
week 4 in all dosage groups; however, the appropriate dosing interval needs to
be determined. LdT and LdC are HBV-specific small molecule inhibitors of HBV
polymerase that have shown marked reduction in HBV DNA (8-10 log10) in
woodchucks. A phase IIb trial of LdT
showed greater HBV suppression in the LdT arms vs the
LAM arm at week 52. However, the combination of LdT
and LAM was not superior to LdT alone. Preliminary
data showed rtM204I mutations detected at the end of 1 year. Tenofovir,
approved for HIV infection, has shown in vivo activity against LAM-resistant
and wild-type HBV. Tenofovir at a dose of 300 mg daily has been shown to
decrease HBV DNA by 3-4 log10 and normalize ALT levels in most patients. New
treatment approaches for HBV will likely involve combination therapy with more
potent antiviral agents in combination with PEG-IFN. Therapy will be tailored
according to genotype, viral load, HBeAg status, immune status and liver
disease.
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