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267
Comprehensive Analysis for the Impact of
on-Treatment Intermediate Endpoints on
Outcomes of Hbeag (+) Chronic Hepatitis B
Jonggi Choi1, Young-Suk Lim1, Seungbong Han2, Ju Hyun
Shim3, Kang Mo Kim3, Han Chu Lee1 and Yung Sang Lee1,
(1)Department of Gastroenterology, Liver Center, Asan
Medical Center, University of Ulsan College of Medicine,
(2)Department of Applied Statistics, Gachon University, (3)
Gastroenterology, Asan Medical Center, University of Ulsan
College of Medicine
Background: Alanine aminotransferase (ALT) normalization,
virologic response (VR), and HBeAg seroclearance are
intermediate endpoints to be achieved during antiviral
treatment for patients with HBeAg-positive chronic hepatitis
B (CHB) based on current international guidelines. However,
the impact of these intermediate endpoints on the longterm
clinical outcomes remains unanswered in the era of
high potency antiviral agents. Methods: A historical cohort
of 2,630 treatment-naïve HBeAg-positive CHB patients
who initiated treatment with entecavir or tenofovir disoproxil
fumarate at a tertiary referral hospital in Korea from 2007
through 2016 were included. The risk of HCC was analyzed
by landmark analysis, and time-dependent Cox model. ALT
normalization was defined as ALT ≤25 U/L for female and
≤35 for male. VR was defined as undetectable serum HBV
DNA levels (<60 IU/mL). Results: The mean age was 45.1
years and 1,712 (65.1%) were male. Cirrhosis was present
in 1,018 (38.7%) of patients. With the median follow-up of
5.1 years, ALT normalization, VR, and HBeAg seroclearance
were achieved in 2,318 (88.1%), 2,341 (89.0%), and 1,102
(41.9%), respectively. At 1-year landmark analysis, patients
with normal ALT was significantly associated with a lower
risk of HCC (p<0.001), whereas achieving VR was not a
significant predicting factor for HCC (p=0.10). At 2-year
landmark analysis, ALT normalization remained as a
significant factor for lower risk of HCC (p<0.001), whereas VR
and HBeAg seroclearance were not significantly associated
with a lower risk of HCC (p=0.97 and p=0.13, respectively). By
multivariable analysis using time-dependent Cox model, ontreatment
ALT normalization was independently associated
with a lower risk of HCC (adjusted hazard ratio [AHR]: 0.44,
95% CI: 0.32-0.60, p<0.001). while HBeAg seroclearance
(AHR: 1.30, 95% CI: 0.96-1.75, p=0.09) was not a significant
factor for predicting HCC development, as well as VR (HR:
1.24, 95% CI: 0.85-1.81, p=0.26). Among baseline factors,
older age (AHR: 1.05, 95% CI: 1.03-1.07, p<0.001), male sex
(AHR: 2.05, 95% CI: 1.49-2.84, p<0.001), high ALT levels, x5
upper limit of normal (AHR: 0.46, 95% CI: 0.30-0.72, p<0.001),
lower albumin (AHR: 0.77, 95% CI: 0.59-0.99), p=0.049), and
cirrhosis (AHR: 2.11, 95% CI: 1.40-3.18, p<0.001) were found
to be independent predictive factors for HCC development.
Conclusion: In a large historical cohort of HBeAg-positive
CHB patients undeter treatment with entecavir or tenofovir,
on-treatment ALT normalization was a sole independent
surrogate marker for predicting HCC development, whereas
VR and HBeAg seroclearance during treatment were not
significantly associated with the development of HCC. |
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