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Hepatitis B – Recent Developments in Therapy
upper limits of normal (ULN).
13
In a study of 3,233 patients with CHB, Figure 1: Summary of Recommendations for
those with ALT levels 0.5–1 x ULN had a higher risk of complications
Treatment of HBeAg-positive Chronic Hepatitis B
than those with ALT levels <0.5 x ULN.
14
Indeed, individuals with
persistently normal ALT levels have been noted to have significant HBeAg-positive
inflammation or fibrosis on biopsy.
15,16
HBV DNA HBV DNA
Because higher HBV DNA levels are significantly correlated with both
<20,000IU/ml ≥20,000IU/ml
liver disease progression and HCC risk, they are another important
factor in deciding who to treat. The association between initial HBV
AASLD
monitor q3mo x
ALT <1 x ULN ALT 1–2 x ULN ALT ≥2 x ULN
DNA levels with cirrhosis and HCC has been demonstrated repeatedly 1 yr, then q6–12 mo
in a series of studies in Taiwan.
17–19
In these studies, a high HBV DNA
US panel
(Keefe et al.) AASLD AASLD AASLD
level remained an independent predictor of disease progression even monitor q3 mo x q3–6 mo ALT q3 mo ALT q1–3 mo ALT,
after controlling for other risk factors, including ALT levels. However,
1 yr then q5–12 q6–12 mo q6 mo HBeAg HBeAG
mo HBeAG consider biopsy treat if persistent
these findings may not be directly applicable to non-Asian
consider therapy
US panel
if persistent or treat immediately
if known
populations or those who did not acquire HBV infection peri-natally.
20
(Keefe et al.)
age >40 yrs if jaundice or
significant
q3–6 mo ALT US panel
decompensated
histological disease
consider biopsy, (Keefe et al.)
liver disease
especially if treat
biopsy optional
HBeAg-positive Patients age >35–40 yrs US panel
(Keefe et al.)
Figure 1 shows a treatment algorithm based on recommendations of
treat
the AASLD and 2008 US treatment guidelines. In the absence of
histological evidence of disease, patients with HBV DNA levels
AASLD = American Association for the Study of Liver Diseases; ALT = alanine
aminotransferase; HBeAg = hepatitis B e antigen; HBV = hepatitis B virus;
<20,000IU/ml are not recommended for treatment but should be ULN = upper limit of normal. Adapted from the recommendations of the American
2,7
monitored every three months for one year, followed by every six to 12
Association for the Study of Liver Diseases (AASLD) and a 2008 US Consensus Panel.
months. Treatment guidelines for those with HBV DNA levels
Figure 2: Summary of Recommendations for
≥20,000IU/ml are based on ALT levels and, when available, liver biopsy
Treatment of HBeAg-negative Chronic Hepatitis B
results. The AASLD recommends treatment if the ALT is persistently ≥2
x ULN and consideration of biopsy if ALT is 1–2 x ULN and the patient is
HBeAg-negative
40 years of age or over. Patients with moderate/severe inflammation or
significant fibrosis on biopsy should be considered for treatment.
2
Given the importance of HBV DNA level on disease progression and the
HBV DNA HBV DNA
<2,000IU/ml ≥2,000IU/ml
evidence of liver disease progression despite high normal ALT levels,
Keefe and the US consensus panel recommend treating patients with
AASLD
HBV DNA levels ≥20,000IU/ml and non-normal ALT levels and
monitor q3 mo
ALT <1 x ULN ALT 1–2 x ULN ALT ≥2 x ULN
ALT x 1 yr, then
considering liver biopsy in patients over 35 years of age with DNA
q6–12 mo
≥20,000IU/ml and normal ALT levels.
7 US panel US panel AASLD AASLD
(Keefe et al.) (Keefe et al.) 2,000–20,000: treat if persistent
monitor q6–12 monitor q3 mo ALT and biopsy optional
HBeAg-negative Patients
mo consider biopsy HBV DNA;
consider therapy
US panel
and treat if consider biopsy
The threshold of HBV DNA level at which to consider treatment in chronic
if known significant
(Keefe et al.)
significant if persistent amd
histological
treat
disease treat if significant
HBeAg-negative disease is lower, at 2000IU/ml (see disease diseaseFigure 2). The AASLD
recommends initiating treatment when HBV DNA level is ≥2000IU/ml and
US panel
(Keefe et al.)
ALT levels are ≥2 x ULN and considering liver biopsy if ALT levels are treat
persistently 1–2 x ULN. Keefe and the US consensus panel recommend
treatment in all patients with HBV DNA ≥2,000IU/ml and abnormal ALT
AASLD = American Association for the Study of Liver Diseases; ALT = alanine
aminotransferase; HBeAg = hepatitis B e antigen; HBV = hepatitis B virus;
and consideration of biopsy in those with HBV DNA ≥2,000IU/ml and ULN = upper limit of normal. Adapted from the recommendations of the American
2,7
normal ALT. In patients for whom treatment is not indicated, serial
Association for the Study of Liver Diseases (AASLD) and a 2008 US Consensus Panel.
monitoring of ALT and HBV DNA levels are critical; the reactivation phase • telbivudine; and
of CHB is characterised by fluctuating HBV DNA levels, and in the • tenofovir.
absence of HBeAg these patients can be misclassified as inactive carriers
based on a single low DNA value. In addition, the NUC emtricitabine, which is structurally similar to
lamivudine, is approved as part of combination therapy for the
Treatment Strategies for Chronic Hepatitis B treatment of HIV infection and is being tested in combination with
There are two classes of drug, comprising seven drugs in all, tenofovir for the treatment of CHB. The treatment decision for an
approved in the US and Europe for treating CHB: individual patient should be based on the potency of the medication
as well as its associated resistance rates and side effects, the
• the injectable interferons (IFNs): patient’s co-morbidities and patient preference (see Table 1).
• standard IFN alpha; and
• pegylated IFN alpha; and Interferon Alpha
• the oral nucleoside/nucleotide analogues (NUCs): Standard IFN for management of CHB has largely been replaced by
• lamivudine; peginterferon alpha due to the latter medication’s more favourable
• adefovir; dosing schedule and improved efficacy.
21
Advantages of peginterferon
• entecavir; over the NUCs include its pre-defined fixed duration of therapy and its
EUROPEAN GASTROENTEROLOGY & HEPATOLOGY REVIEW 39
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