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Treatment of Chronic Hepatitis B—When to Start, When to Stop, and When to Alter Therapy
Table 1: Treatment Recommendations for Hepatitis ‘e’ Table 2: Treatment Recommendations for Hepatitis ‘e’
Antigen-positive Patients Antigen-negative Patients
HBV DNA
a
ALT
b
Treatment Strategy HBV DNA
a
ALT
b
Treatment Strategy
<20,000 Normal No treatment <2,000 Normal No treatment; majority inactive HBsAg carriers
Monitor every 6–12 months
c
Monitor every 6–12 months
c
Consider therapy in patients with known significant Consider therapy in patients with known significant
histological disease even if low-level replication histological disease even if low-level replication
≥20,000 Normal Low rate of HBeAg seroconversion for all treatments ≥2,000 Normal Consider biopsy; treat if disease present. In the absence
Younger patients often immune tolerant of biopsy, observe for rise in serum ALT levels.
Consider biopsy—particularly if older than age 35–40 If treated, adefovir, entecavir, peginterferon alfa-2a, or,
years—treat if disease. In the absence of biopsy, observe for possibly, telbivudine are preferred
d
rise in ALT levels ≥2,000 Elevated Adefovir, entecavir, peginterferon alfa-2ª, or, possibly,
If treated, adefovir, entecavir, peginterferon alfa-2a, or, telbivudine are preferred
d
possibly, telbivudine preferred
d,e
Long-term treatment required for oral agents
≥20,000 Elevated Adefovir, entecavir, peginterferon alfa-2a, or, possibly,
a. IU/mL (1IU/ml is equivalent to approximately 5.6 copies/ml).
telbivudine are preferred
d,e b. The upper limit of normal for serum alanine aminotransferase (ALT) concentrations for men and women are
If ‘high’ HBV DNA, adefovir, entecavir, or telbivudine
30IU/l and 19IU/l, respectively.
c. Upon initial diagnosis, every three months for one year to ensure stability.
preferred over peginterferon alfa-2a
d. Lamivudine is not considered a reasonable treatment option due to the high risk of resistance with long-term
therapy, and proven inferiority to peginterferon alfa-2a and entecavir in randomized clinical trials. Telbivudine has
a. IU/ml (1IU/ml is equivalent to approximately 5.6 copies/ml).
a moderate rate of resistance, which can be minimized if an undetectable HBV DNA is achieved after 24 weeks
b. The upper limit of normal for serum alanine aminotransferase (ALT) concentrations for men and women are
of therapy.
30IU/l and 19IU/l, respectively.
HBsAg = hepatitis B surface antigen. Updated from Keeffe et al., 2006.
2
c. Upon initial diagnosis, every three months for one year to ensure stability.
d. Genotyping may be useful to help decide between treating with peginterferon alfa-2a rather than with adefovir
or entecavir, i.e. peginterferon has been shown to be more effective in patients with genotype A versus D.
Table 3: Recommendations for Treatment—Cirrhotic Patients,
e. Peginterferon alfa-2a, entecavir, and telbivudine are preferred over lamivudine as they have been shown to be Hepatitis ‘e’ Antigen-positive or -negative
superior in randomized clinical trials, and lamivudine is limited by high rates of resistance. However, telbivudine
has a moderate rate of resistance, which can be minimized if an undetectable HBV DNA is achieved after 24
weeks of therapy.
HBV DNA
a
Cirrhosis Treatment Strategy
HBeAg = hepatitis ‘e’ antigen-positive. HBV = hepatitus B virus. Updated from Keeffe et al., 2006.
2
<2,000 Compensated May choose to treat or observe
Adefovir or entecavir preferred
b
Interferon alfa-2b has been replaced in practice by peginterferon alfa-2a,
≥2,000 Compensated Adefovir or entecavir are first-line options
and lamivudine is not an optimal choice because of high rates of resistance Long-term treatment required, and combination
(65–70% after four to five years of therapy).
2
Recent trends are to treat
therapy may be preferred
c
patients with compensated or decompensated cirrhosis associated with any
<200 or ≥200 Decompensated Combination with lamivudine, or, possibly,
elevation of HBV DNA levels. There are also increasing trends to use
entecavir plus adefovir preferred
c,d
combination nucleoside/nucleotide agents in cirrhotic patients, as well as
Long-term treatment required, and combination
therapy may be preferred
c
patients with HBV and HIV co-infection, and patients after liver
Wait list for liver transplantation
transplantation performed for HBV infection.
a. IU/ml (1IU/ml is equivalent to approximately 5.6 copies/ml).
b. Although there are no data available for peginterferon alfa-2a, it may be an option in patients with early well
When to Stop Therapy
compensated cirrhosis; no data are available for telbivudine.
c. Combination therapy with lamivudine, or possibly entecavir, plus adefovir has a theoretical advantage of a lower
Patients should be monitored at least every six months while receiving
likelihood of the development of resistance.
therapy with the oral agents, and more frequently when treated with
d.Limited data available for entecavir, and no data available for telbivudine; peginterferon alfa-2a contraindicated.
Updated from Keeffe et al., 2006.
2
peginterferon alfa-2a for the development of side effects and tolerance to
therapy. Patients treated with peginterferon alfa-2a are treated for a fixed
time period of one year. Therapy is stopped prematurely only if intolerable When to Alter Therapy
side effects develop, which occurs in less than 5% of patients. The time to alter therapy is treatment failure, either primary failure or in
association with an inadequate response while receiving treatment with oral
The traditional end-point of treatment for patients with HBeAg-positive agents. The definition of primary treatment failure is a serum HBV DNA decline
CHB treated with oral agents is HBeAg seroconversion to anti-HBe in of less than 1 log
10
IU/ml at week 12 of treatment, and the definition of an
association with very low or undetectable serum HBV DNA.
2–6
Treatment is inadequate virological response is a serum HBV DNA ≥2,000IU/ml at week 24
typically continued for an additional six to 12 months to reduce the of treatment).
12
For primary treatment failure, which is uncommon, the optimal
likelihood of relapse. Some clinicians favor treatment of patients with strategy is to switch to a more potent drug or possibly a combination of
cirrhosis long-term with oral agents, even after HBeAg seroconversion, to drugs.
12
For an inadequate virological response, the optimal approach is to add
avoid the risk of relapse with associated decompensation. The end-point of another drug—preferably one that is more efficacious; if such a drug is not
treatment for patients with HBeAg-negative CHB with oral agents is available, add one that is not cross-resistant—and repeat monitoring at three-
unknown, and current data favor long-term therapy, since relapse rates are month intervals. Monitoring after 48 weeks may be extended from three to six
high if treatment is stopped when serum HBV DNA becomes undetectable. months if the virological response becomes complete.
12
Another time to alter
Preliminary data suggest that the relapse rates are lower, although still therapy by switching or adding another drug is the development of HBV
substantial, if treatment is stopped after several years of undetectable antiviral drug resistance. Genotypic resistance with adefovir monotherapy is
serum HBV DNA when treated with lamivudine or adefovir.
10,11
29% after five years of therapy,
13
and the cumulative rate of resistance with
US INFECTIOUS DISEASE 2007 29