for Hepatitis B: When to Start, What to Use, and When to Stop
the 13th International Symposium on Viral Hepatitis and Liver
Disease held in Washington March 20-24, 2009, invited experts
presented their views on a variety of important issues related
to the treatment and management of hepatitis
B and C.
Anna Lok of the University of Michigan at Ann Arbor summarized
her opinions on key aspects of therapy for chronic hepatitis
B. Following is a summary of her remarks.
for Hepatitis B
advances have been made in the treatment of hepatitis B. However,
current treatments suppress but [do] not eradicate hepatitis
B virus (HBV). Therefore, most patients will require long
durations if not life-long treatment to maintain virus suppression
and to derive continued clinical benefit.
to start treatment?
better understanding of the fluctuating nature of chronic
HBV infection, and improved treatment options, the question
is no longer whom to treat but when should treatment be initiated.
When deciding whether to start or to defer treatment, one
needs to have information on the HBV replication status, and
activity and stage of liver disease at the time of assessment
and the predicted risk of cirrhosis
and hepatocellular carcinoma
(HCC) for that particular patient.
treatment should be initiated in patients who have active
or advanced liver disease at presentation or who are predicted
to have a high risk of cirrhosis or HCC in the foreseeable
future. On the other hand, treatment can be deferred in patients
who have quiescent, early stage liver disease, and who are
predicted to have a low risk of cirrhosis and HCC. The latter
patients should continue to be monitored and treatment initiated
when the indications arise.
treatment recommendation is based on evidence of liver disease,
i.e. elevated aminotransferase (ALT), histological evidence
of inflammation or fibrosis, or clinical evidence of cirrhosis.
Recently, it has been suggested that treatment should be based
on virus level. Several cohort studies indicate that persistently
high virus level (lasting several decades) is associated with
increased risk of cirrhosis and HCC.
data indicate that the threshold HBV DNA and ALT levels for
initiating treatment should be lower in older patients who
may have been infected for a longer duration. Thus, decisions
regarding hepatitis B treatment should consider clinical features,
ALT, serum HBV DNA, and when available liver histology.
decisions are further modified by patients' age, hepatitis
B "e" antigen (HBeAg) status, plans to start a family
in women of reproductive age, occupational requirements, and
current HBV treatments suppress but do not eradicate the virus,
most patients require long durations and often life-long treatment
with associated risks of drug resistance, adverse events,
and costs. Therefore, the decision to initiate treatment should
also take into account the anticipated duration of treatment
and the likelihood of achieving sustained virus suppression
after a finite course of treatment.
are 7 [FDA-] approved therapies for hepatitis B: 2 formulations
of interferon (standard [Roferon A and Intron A] and pegylated
[Pegasys and PegIntron]) and 5 oral nucleoside/nucleotide
analogues: lamivudine [Epivir-HBV],
adefovir [Hepsera], entecavir
[Tyzeka], and tenofovir [Viread].
initial decision regarding which drug to use involves a choice
between interferon vs. nucleoside/nucleotide. Interferon has
the advantage that it is administered for a finite duration
and is not associated with specific drug-resistant mutations,
but it has to be administered parenterally [by injection],
is associated with many side effects, and is contraindicated
in patients with decompensated liver disease.
analogues have the advantage that they are administered orally
and have very little side effects, but they have to be administered
for many years which may lead to selection of drug-resistant
mutations. Among the nucleoside/nucleotide analogues, entecavir,
telbivudine, and tenofovir have more potent antiviral activity;
and entecavir and tenofovir have higher genetic barrier to
of the initial therapy is critical as resistance to the first
drug may diminish the response to other drugs due to cross-resistance.
to stop treatment?
general, treatment should continue until a patient achieves
therapeutic endpoint. Discontinuation of treatment may be
followed by virologic relapse, hepatitis flare, and hepatic
decompensation. Therefore, all patients must be closely monitored
after treatment is withdrawn.
is usually given for a finite duration regardless of response
because immunological effects of interferon may persist after
treatment is discontinued. With pegylated interferon, the
recommended duration is 12 months for both HBeAg positive
and HBeAg negative patients. Whether a shorter course of pegylated
interferon will suffice in HBeAg positive patients with favorable
HBV genotype and if a longer course will result in a higher
rate of sustained virus suppression in HBeAg negative patients
is being studied.
endpoint for oral nucleoside/nucleotide analogue therapies
is unclear. For HBeAg positive patients, the general recommendation
is to continue treatment until 6-12 months after HBeAg to
HBe antibody (anti-HBe) seroconversion. Some experts have
argued that HBeAg seroconversion is not an appropriate endpoint
because virus replication persists. However, many studies
have shown that 50%-70% of patients will remain in remission
(low or undetectable serum HBV DNA and normal ALT) for many
years if the above recommendation is followed.
HBeAg negative patients, treatment can be stopped in patients
who lose HBsAg, but that happens in roughly 5% of patients
after 5 years of treatment. For patients with underlying cirrhosis,
treatment is usually administered indefinitely.
Lok. Therapy of Hepatitis B. Invited Speaker Abstracts. 13th
International Symposium on Viral Hepatitis and Liver Disease
(ISVHLD). Washington, DC. March 20-24, 2009. Abstract SP-18.
JH Hoofnagle, E Doo, TJ Liang, and others. Management of hepatitis
B: summary of a clinical research workshop. Hepatology
45: 1056-1075. 2007.
AS Lok and BJ McMahon. Chronic hepatitis B. Hepatology
45: 507-539. 2007.
Association for the Study of the Liver. EASL clinical practice
guidelines: management of chronic hepatitis B. Journal
of Hepatology 50(2): 227-242. February 2009.
JL Dienstag. Hepatitis B virus infection. New England Journal
of Medicine 359: 1486-1500. 2008.