2015 Hepatol Long Term Antivirals in Decomp HBV Cirrhosis

8/17/2019 2015 Hepatol Long Term Antivirals in Decomp HBV Cirrhosis

1/38

Long-term effect of antiviral therapy on disease course after

decompensation in patients with hepatitis B virus-related

cirrhosis

Jeong Won Jang1,*, Jong Young Choi

*1,*

,†, Young Seok Kim

2,*, Hyun Young Woo

3,*, Sung

Kyu Choi4,

*, Chang Hyeong Lee5,

*, Tae Yeob Kim6,

*, Joo Hyun Sohn6,

*, Won Young

Tak 7,*, Kwang-Hyub Han

8,*

Departments of1 Internal Medicine,

1The Catholic University of Korea, College of Medicine,

2Soonchunhyang University College of Medicine,

3 Pusan National University Hospital,

4

Chonnam National University Medical School,

5

School of Medicine, Catholic University of Daegu,

6 Hanyang University Guri Hospital,

7 Kyungpook National University Hospital,

8Yonsei

University College of Medicine, * Liver Cirrhosis Clinical Research Center (LCCRC)

Running title: anti-HBV therapy for decompensated LC

E-mail address of the authors:

J W J d @ h li k J Y Ch i j h i@ h li k Y S k


2/38

Jang Page 2

CHB = chronic hepatitis B, CI = confidence intervals, HBeAg = hepatitis B e antigen, HBsAg =

hepatitis B surface antigen, HR = hazard ratios, PCR = polymerase chain reaction, IQR =

interquartile range.

This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry

of Health and Welfare, Republic of Korea (HI10C2020). The statistical consultation was

supported by Catholic Research Coordinating Center of the Korea Health 21 R&D Project

(A070001), Ministry of Health & Welfare, Republic of Korea.

Abstract word count: 274

Text word count including references: 5,111

Corresponding author:

Jong Young Choi, M.D.

Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of

Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul 137-701,

Republic of Korea

E-mail: [email protected]

Telephone: +82-2-2258-2075, Fax: +82-2-3481-4025.

Page 2 of 39Hepatology


3/38

Jang Page 3

ABSTRACT

The effect of viral suppression on long-term disease outcome after decompensation in patients

with hepatitis B virus (HBV)-related cirrhosis has not been established. The aim of this study

was to determine the long-term effect of antiviral therapy in patients with HBV-related

decompensated cirrhosis. This was a multicenter, prospective, inception cohort study of 707

patients who presented with first-onset decompensated complications, including 284 untreated patients and 423 antiviral-treated patients (58 previously treated, 253 with early treatment, and

112 with delayed treatment). The primary endpoint was 5-year liver transplantation (LT)-free

survival. Secondary endpoints included virologic/serologic response and improvement in liver

function. Despite baseline high HBV activity and worse liver function, antiviral-treated patients

had significantly better transplant-free survival than untreated patients (5-year survival rates of

59.7% vs. 46.0%, respectively), with more apparent benefits from antivirals in Child-Turcotte-

Pugh class B/C and high-viremia groups. The 5-year cumulative rate of virologic response and

HBeAg seroconversion in antiviral-treated patients was 14.2% and 49.1%, respectively. A

significant improvement in liver function was observed in treated versus untreated patients, with

33.9% of treated patients delisted for LT. Patients with early treatment had better clinical

outcomes than those with delayed treatment. Survival was dependent on antiviral response, being

significantly better in responders than in non responders or untreated cases The initial benefit of

Page 3 of 39 Hepatology


4/38

Jang Page 4

INTRODUCTION

An estimated 350 million individuals are chronically infected with hepatitis B virus

(HBV) worldwide.1 The annual incidence of cirrhosis among chronic HBV carriers was reported

to be approximately 2.1%−6.0%.2 After advancement to cirrhosis, liver disease may continue to

progress and decompensated complications can occur, especially in those with active HBV

replication. Hepatic decompensation among chronic HBV carriers is associated with highmortality and has a reported 5-year survival rate of 14%−35%, which is significantly lower than

the rate of 80%−85% among those with compensated cirrhosis.1-4

A substantial proportion of

cirrhotic patients still have active HBV replication as evidenced by positive hepatitis B e antigen

(HBeAg) or high HBV DNA levels,5 which are the strongest factors for disease progression.

6,7

Although understanding the natural history of HBV-related diseases may help to optimizethe care of chronic HBV carriers, information on the course of illness after the onset of

decompensation is too scanty or at best inconclusive because of the tremendous heterogeneity in

patient inclusion criteria across studies. Clinical studies to date have revealed that oral antivirals

are generally safe and effective in HBV suppression, with an improvement in liver disease in

patients presenting with HBV-related decompensation.2,8

Recent studies also showed that

profound viral suppression with newer, more potent antivirals shows short-term efficacy as

9 12



5/38

Jang Page 5

PATIENTS and METHODS

Study population

This multicenter, prospective, observational, inception cohort study was conducted as

part of a study project of the Liver Cirrhosis Clinical Research Center (LCCRC) in Korea.14

Between 2005 and 2012, patients at seven Korean referral centers who met the following criteria

were entered into the study: age ≥18 years; hepatitis B surface antigen (HBsAg) carrier for ≥6

months; pathologic or clinical evidence of cirrhosis including nodularity/splenomegaly on liver

imaging and/or thrombocytopenia; presentation with the first episode of liver decompensation

defined as the occurrence of complications, such as ascites, variceal bleeding, encephalopathy,

spontaneous bacterial peritonitis (SBP), or hepatorenal syndrome. Patients with hepatocellular

carcinoma (HCC) at baseline, a history of other malignancy, and any other form of liver disease

including hepatitis C virus, serious alcoholic disease (consumption >20 grams/day), or

autoimmune hepatitis were excluded. This study (KC10RIMI0483) was approved by the local

Ethics Committees in accordance with the 1975 Declaration of Helsinki. Each patient provided

informed consent.

Assessments and follow-up

Baseline and on-study laboratory assessments included routine hematologic tests,



6/38

Jang Page 6

For all patients, complications were appropriately managed according to current

guidelines in all centers.16,17

A low-salt diet and diuretics were prescribed for patients with

ascites. Patients with variceal bleeding received endoscopic band ligation/sclerotherapy or

transjugular intrahepatic portosystemic shunt, and were discharged with β-blocker secondary

prophylaxis unless contraindications were documented. Antibiotic therapy was initiated

appropriately for bacterial infection including SBP. Prophylactic antibiotics were administered

for patients with prior SBP and variceal bleeding. LT allocation was based on the Korean

Network for Organ Sharing criteria: Status 1, intensive care unit-bound fulminant liver failure

with expected survival


7/38

Jang Page 7

criteria, antiviral therapy was delayed until follow-up ALT/HBV DNA tests met the strict criteria

due to the high costs of antivirals in Korea, unless the patient was willing to receive antivirals

without reimbursement. Early treatment was defined as antiviral treatment initiated within 3

months of decompensation and delayed treatment if treatment was initiated after 3 months of

decompensation. In Korea, lamivudine was the only first-line agent until 2007, entecavir and

clevudine have been available since 2007, and telbivudine since 2010. Adefovir was approved

only as rescue therapy for lamivudine resistance and given as monotherapy or in combination

with continued lamivudine, depending on the patient’s liver function.

Statistical analysis

Data were expressed as the mean ± standard deviation or median (range). Categorical

variables were compared with the Chi-square test or Fisher’s exact test, means were analyzed by

the Student’s t-test and medians by the Wilcoxon rank-sum test.

Survival time was calculated as the time interval from the date of first-episode

decompensation to LT, death, or the end of follow-up. LT-free survival curves were constructed

using the Kaplan-Meier method, and differences were assessed by log-rank test. Bonferroni

correction was used for multiple comparisons (LT-free survival according to response). The

cumulative probability of HBeAg seroconversion and HCC development was determined for the

groups, with death and loss to follow-up being considered as competing risks. Continuous



8/38

Jang Page 8

We were able to match 127 patients with antiviral treatment to 127 patients without treatment.

Stratified Cox regression with patients matched on propensity score was used to estimate the

treatment effect on survival. A two-sided P value


9/38

Jang Page 9

(14.4%) were not eligible for assessment of response due to early death, LT, or loss to follow-up

after treatment initiation. The rate of virologic response in the whole antiviral-treated group was

41.4% and 14.2% at 12 and 60 months after study inclusion, respectively. Of the 117 evaluable

non-responders, 19 eventually switched to adefovir and 17 to entecavir (1.0 mg), 50 had adefovir

add-on therapy, and 31 had no change in antivirals at further follow-up. The most common

resistance pattern observed in these patients was rtL180M + rtM204I/V (79.4%; Supplemental

table 1).

Normalization of ALT at 12 months was achieved in 63.7% (170/267) of antiviral-treated

patients with a baseline ALT above the upper limit of normal; the remainder showed no ALT

normalization (57), or were lost to follow-up (8) or LT/death (32). Overall, HBeAg

seroconversion was achieved in 81 (27.3%) of 297 HBeAg-positive patients. The probability of

HBeAg seroconversion was 13.4%, 34.7%, and 49.1% at 12, 36, and 60 months for the whole

antiviral-treated group, whereas the corresponding probability in the untreated group was 10.9%,

15.7%, and 35.1%, respectively; the rate of HBeAg seroconversion was not different between the

two groups ( P =0.2021; Figure 2A). However, when treatment time was taken into account, the

early treatment group showed a significantly higher rate of HBeAg seroconversion than the

untreated group, with a corresponding rate of 17.8%, 40.8%, and 57.4%, respectively ( P =0.0155;

Figure 2C), whereas the previous or delayed treatment groups did not show an increase in

HBeAg seroconversion ( P >0.05; Supplemental figure 1).



10/38

Jang Page 10

untreated patients, respectively, remained in CTP class A ( P


11/38

Jang Page 11

and 73.0% in the responder group; 76.1%, 58.2%, and 42.7% in the non-responder group; and

73.2%, 55.8%, and 46.0% in the control group, respectively (Figure 2E).

Prognostic factors

To evaluate factors that affected survival, the clinical variables listed in Table 2 were

included in the analysis. Cox proportional hazard regression analysis showed that sex, age,

decompensated complications, CTP class, MELD score, and antiviral therapy were

independently predictive of LT-free survival. When analyzed within the antiviral-treated group,

age, MELD scores and response to antiviral therapy remained independently predictive of

survival (Table 3). The adjusted survival was significantly better in antiviral-treated patients than

in untreated patients (hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.32−2.12, P


12/38

Jang Page 12

first few years, but this difference was negated during continued follow-up and survival was

comparable to that of untreated controls after 5 years ( P =0.3664).

Finally, we analyzed the incidence of HCC in this propensity score-matched cohort.

Overall, 56 patients of the cohort developed HCC; 46 developed HCC after 1 year, while 10

developed HCC within 1 year. These 10 were excluded from the analysis, because they were

presumed to have pre-existing HCC that was not detected at baseline. The cumulative incidence

of HCC at 5 years was 35.1% and 29.4% in the antiviral-treated and untreated groups,

respectively ( P =0.6452). When the whole cohort was taken into account, the corresponding

incidence was 32.3% and 27.2%, respectively ( P =0.3033). For both cohort analyses, there was

no difference in the incidence of HCC between patients with and without treatment.

DISCUSSION

The major strength of our study is that it represents the largest prospective study ever

reported and one of the longest followed cohort studies of HBV-related decompensated cirrhosis.

Moreover, the current study enlisted subjects at a uniform point in the course of liver disease

(first onset decompensated complications) under strict inclusion criteria The inclusion of an


P 13 f 39 H t l


13/38

Jang Page 13

CTP or MELD scores at 5 years. In contrast to earlier studies in this setting with follow-up

limited to 1−2 years,9-12

our study presented long-term results, indicating that the improvement in

liver function by treatment can be maintained for up to 5 years, thus delaying or avoiding the

need for LT in approximately 60% of patients who were otherwise considered for LT.

Specifically, 33.9% of antiviral-treated patients were eventually delisted for LT within 1 year.

Lastly, antiviral therapy significantly prolonged survival, which was better in patients with than

without response or untreated patients. The overall benefits of antiviral therapy appear even more

solid, given that the treated cohort had unfavorable baseline characteristics, including more

patients with higher HBV activity and worse liver biochemical profiles, compared with the

untreated controls. This underscores the fundamental need for antiviral administration in these

patients.

Although regional practice guidelines recommend early antiviral therapy for HBV-

related decompensated cirrhosis,1,18,19 it is not certain if initiating treatment earlier would

improve the rate of response and translate into a meaningful long-term outcome. Importantly, our

findings addressed this issue and confirmed the superior effects of early antiviral intervention in

these patients. Efficacy measures were significantly better in patients with early initiation of

antivirals upon presentation of decompensation than in those with delayed therapy. Intriguingly,

our study is the first to demonstrate a higher rate of HBeAg seroconversion in patients who

received early antiviral treatment compared with untreated controls, which has not been observed




14/38

Jang Page 14

patients with compensated diseases to the setting of decompensated cirrhosis,23

demonstrating

that the antiviral effect remains valid even after developing decompensation. Considering that

maintaining potent suppression of HBV led to better long-term results and that HBeAg, HBV

DNA, and aminotransferase levels had little impact on the outcomes, our findings again support

the current guidelines that recommend tenofovir or entecavir as a preferred first-line choice for

patients with liver cirrhosis, even when HBV DNA and aminotransferase levels are only

modest.1,18,19

Despite these long-term beneficial effects of treatment, not all treated patients survived

an episode of decompensation, especially during the early period of therapy. In our results, 13.4%

(34/253) of patients, mostly those with severe hepatic dysfunction, died within 6 months,

compatible with previous observations.8 This implies that, because it takes several months for

liver function to recover after initiating antivirals,5,13

any patient with severe decompensation

should be considered for LT even if antiviral therapy is initiated. Recently, anti-HBV therapy

was shown to reduce the risk of HCC in patients with compensated cirrhosis.23-25

However, we

found no protective effect in patients with decompensated cirrhosis. This might be due to the

relatively short survival of these patients, but another possible explanation is that genetic

alterations in cirrhotic nodules may have pre-existed before initiation of antivirals. Thus, patients

presenting with decompensation should be started early with antiviral therapy and monitored

closely with regular HCC surveillance while under consideration for LT.




15/38

Jang Page 15

observed in untreated cases. Indeed, there were only five deaths other than early mortality in

these groups with early treatment (data not shown). Thus, the beneficial effect of antivirals in

these low-risk groups will likely become obvious with more extended follow-up. It may also be

argued that the treatment group included more patients with acute decompensation secondary to

hepatitis flares, who were likely to have a better prognosis2 and thus contributed to the increased

survival compared to untreated controls. However, exclusion of patients with hepatitis flares

from the analysis did not significantly change the results.

It would not be ethically justifiable to include untreated controls in studies of cirrhosis.

However, reimbursement for anti-HBV agents strictly limited to specified indications in Korea

provided us a unique and valuable opportunity to explore the natural history following

decompensation and the long-term effects of antiviral therapy with the inclusion of contemporary

untreated controls. Our study has additional limitations. Changes in hepatic function were

assessed in surviving patients with tests at index time points. Such a select picture may lead to

the potential for overestimating treatment effects by excluding those with missing data. The cut-

off value defining virologic response (400 IU/mL) was arbitrary and insensitive because non-

PCR assays were used for HBV DNA testing during the first few years of the study initiation.

However, by definition, most of our patients achieving response were entecavir-treated or

successfully rescued patients who continued to have undetectable HBV DNA levels even usingPCR methods during extended follow-up. It is possible that a subset of critically ill patients who




16/38

Jang Page 16

In conclusion, anti-HBV therapy significantly modifies the natural history of

decompensated cirrhosis, improving liver function and increasing survival. Early intervention

with potent antivirals provides better virologic and serologic responses in these patients.

Maintained virologic response in patients under antiviral therapy leads to better long-term LT-

free survival, compared with non-responders or untreated patients. Liver function continues to

improve and is maintained for up to 5 years, delaying the need for LT especially in responders.

Thus, antiviral interventions to achieve potent and durable suppression of HBV should be

promptly initiated in patients with decompensated cirrhosis under consideration for LT.




17/38

Jang Page 17

Acknowledgements

We thank Professor Hyeon Woo Yim and Mi Sun Park for their helpful statistical

assistance. The study protocol was approved by the Institutional Review Boards at all of the

participating hospitals (approval number KC10RIMI0483; Title of the study, “Clinical Study for

Epidemiologic, Clinical Features, Survival, and Prognosis of the Patients with Liver Cirrhosis in

Korea”). The results presented herein are part of the aforementioned study. The overall study

projects were supported by the Liver Cirrhosis Clinical Research Center (LCCRC), which has

been supervised by National Strategic Coordinating Center for Clinical Research, Ministry of

Health and Welfare, Republic of Korea (HI10C2020). Additional information on the study

projects is available at: http://www.lc-center.org.




18/38

Jang Page 18

REFERENCES

1. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J

Hepatol 2012;57:167-185.2. Chu CM, Liaw YF. Hepatitis B virus-related cirrhosis: natural history and treatment.

Semin Liver Dis 2006;26:142-152.

3. de Jongh FE, Janssen HL, de Man RA, Hop WC, Schalm SW, van Blankenstein M.Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver.

Gastroenterology 1992;103:1630-1635.

4. Fattovich G, Giustina G, Schalm SW, Hadziyannis S, Sanchez-Tapias J, Almasio P, et al.

Occurrence of hepatocellular carcinoma and decompensation in western European patients withcirrhosis type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis. Hepatology

1995;21:77-82.

5. Peng CY, Chien RN, Liaw YF. Hepatitis B virus-related decompensated liver cirrhosis: benefits of antiviral therapy. J Hepatol 2012;57:442-450.

6. Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, et al. Hepatitis B e antigen and

the risk of hepatocellular carcinoma. N Engl J Med 2002;347:168-174.7. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ, et al. Predicting cirrhosis risk based

on the level of circulating hepatitis B viral load. Gastroenterology 2006;130:678-686.8. Fontana RJ, Hann HW, Perrillo RP, Vierling JM, Wright T, Rakela J, et al. Determinants

of early mortality in patients with decompensated chronic hepatitis B treated with antiviraltherapy. Gastroenterology 2002;123:719-727.

9. Shim JH, Lee HC, Kim KM, Lim YS, Chung YH, Lee YS, et al. Efficacy of entecavir in

treatment-naive patients with hepatitis B virus-related decompensated cirrhosis. J Hepatol2010;52:176-182.

10. Liaw YF, Sheen IS, Lee CM, Akarca US, Papatheodoridis GV, Suet-Hing Wong F, et al.

Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients withdecompensated chronic hepatitis B liver disease. Hepatology 2011;53:62-72.

11 Li YF R l Gi i M Ch i H S i SK T d T L N l




19/38

Jang Page 19

16. de Franchis R. Evolving consensus in portal hypertension. Report of the Baveno IV

consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol

2005;43:167-176.17. European Association for the Study of the Liver. EASL clinical practice guidelines on the

management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis.

J Hepatol 2010;53:397-417.18. Liaw YF, Leung N, Kao JH, Piratvisuth T, Gane E, Han KH, et al. Asian-Pacific

consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int

2008;2:263-283.19. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009;50:661-662.

20. Bruix J, Sherman M, American Association for the Study of Liver D. Management ofhepatocellular carcinoma: an update. Hepatology 2011;53:1020-1022.

21. Bae SH, Yoon SK, Jang JW, Kim CW, Nam SW, Choi JY, et al. Hepatitis B virusgenotype C prevails among chronic carriers of the virus in Korea. J Korean Med Sci

2005;20:816-820.

22. Singal AK, Fontana RJ. Meta-analysis: oral anti-viral agents in adults withdecompensated hepatitis B virus cirrhosis. Aliment Pharmacol Ther 2012;35:674-689.

23. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients

with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:1521-1531.24. Papatheodoridis GV, Lampertico P, Manolakopoulos S, Lok A. Incidence of

hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a

systematic review. J Hepatol 2010;53:348-356.

25. Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis: Treatment of hepatitis Binfection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther 2008;28:1067-1077.

g p gy



20/38

Jang Page 20

FIGURE LEGENDS

Figure 1. Flow diagram of patient enrollment. FU, follow-up; ARDS, adult respiratory distress

syndrome.

Figure 2. Cumulative rate of HBeAg seroconversion and transplant-free survival in (A-B) the

whole cohort and (C-D) early treatment group. *Adjusted for age and sex. (E) Survival according

to treatment response in the whole cohort. **Bonferroni-adjusted P value.

Figure 3. Mean changes from baseline in (A) Child-Pugh score, and (B) MELD score, at 6, 12,

36, and 60 months for the control and each treatment group. Tx, treatment. * P


21/38

Hepatology


22/38

Table 2. Factors for transplant-free survival

HR, Hazard ratio; HBV, hepatitis B virus; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CTP, Child-Turcotte-Pugh; MELD

Disease.

Entire cohort (n = 707) Propensity-score matched cohort (n = 254)

Univariate Multivariate Univariate Multivaria

HR (95% CI) P Adjusted HR (95% CI) P HR (95% CI) P Adjusted HR

Male sex 1.43 (1.12−1.82) 0.003 1.42 (1.10−1.83) 0.006 1.20 (0.60−2.38) 0.602

Age > 55 years 1.39 (1.12−1.73) 0.003 1.35 (1.06−1.70) 0.012 2.30 (1.20−4.42) 0.012 3.24 (1.28−

Multiple complications 1.98 (1.51−2.58) 70 IU/L 1.32 (1.06−1.65) 0.012 1.01 (0.78−1.31) 0.890 1.38 (0.75−2.54) 0.288

ALT > 40 IU/L 1.15 (0.92−1.43) 0.210 1.04 (0.58−1.87) 0.882

CTP class C 1.43 (1.28−1.60)


23/38

Table 3. Factors for transplant-free survival among the antiviral-treated group

HR, Hazard ratio; HBV, hepatitis B virus; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CTP, Child-Turcotte-Pugh; MELD

Disease.


Univariate Multivariate Univariate Multivaria

HR (95% CI) P Adjusted HR (95% CI) P HR (95% CI) P Adjusted HR

Male sex 1.28 (0.93−1.77) 0.126 1.28 (0.70−2.35) 0.414

Age > 55 years 1.60 (1.18−2.17) 0.002 1.58 (1.16−2.15) 0.003 2.14 (1.11−4.14) 0.023 1.93 (0.99−

Multiple complications 1.69 (1.14−2.50) 0.008 1.37 (0.91−2.05) 0.123 1.60 (0.78−3.27) 0.192

HBeAg seropositivity 1.18 (0.87−1.60) 0.278 1.21 (0.72−2.04) 0.467

High HBV activity 1.37 (0.76−2.46) 0.291 1.19 (0.61−2.30) 0.600

AST > 70 IU/L 1.14 (0.84−1.55) 0.384 1.17 (0.69−1.98) 0.543

ALT > 40 IU/L 1.04 (0.76−1.43) 0.768 1.39 (0.82−2.36) 0.211

CTP class C 1.29 (1.11−1.51) 0.001 1.08 (0.81−1.44) 0.579 1.48 (0.87−2.52) 0.140

MELD score > 15 2.31 (1.69−3.14)


24/38

Figure 1253x189mm (300 x 300 DPI)



25/38

Figure 2AB251x148mm (300 x 300 DPI)



26/38

Figure 2CD251x148mm (300 x 300 DPI)



27/38

Figure 2E

200x156mm (300 x 300 DPI)



28/38

Figure 3A251x149mm (300 x 300 DPI)



29/38

Figure 3B

251x151mm (300 x 300 DPI)


30/38



31/38

Figure 4B

200x156mm (300 x 300 DPI)



32/38

Supplemental Table 1. Genotypic resistant profiles observed in patients with drug

resistance

Resistant profiles Patients ( n = 68)

Lamivudine-resistance mutation

rtM204I/V 10 (14.7%)

rtL180M 1 (1.5%)

rtL180M + rtM204I/V 54 (79.4%)rtL80V + rtL180M + rtM204I/V 1 (1.5%)

Adefovir-resistance mutation

rtN236T 1 (1.5%)

rtA181V/T + rtN236T 1 (1.5%)

The remaining 36 patients with drug resistance were not tested for genotypic mutation (n =30) or showed no mutation (n = 6), but all of them showed viral rebound (increase in serum

HBV DNA by > 10-fold) above nadir during therapy.



33/38

Supplemental Table 2. Factors for transplant-free survival among the antiviral-treated group

HR, Hazard ratio; HBV, hepatitis B virus; AST, aspartate aminotransferase; ALT, alanine aminotransferase; MELD, Model for End-Stage Liver Disease.*MELD score: continuous variable

**Comparison between the early and delayed treatment groups


Univariate Multivariate Univariate Multivariate

HR (95% CI) P Adjusted HR (95% CI) P HR (95% CI) P Adjusted HR (95% CI) P

Male sex 1.28 (0.93- 1.77) 0.126 1.28 (0.70- 2.35) 0.414

Age > 55 years 1.60 (1.18- 2.17) 0.002 1.63 (1.20- 2.22) 0.002 2.14 (1.11- 4.14) 0.023 2.20 (1.12- 4.30) 0.021

Multiple complications 1.69 (1.14- 2.50) 0.008 1.10 (0.73- 1.70) 0.598 1.60 (0.78- 3.27) 0.192

HBeAg seropositivity 1.18 (0.87- 1.60) 0.278 1.21 (0.72- 2.04) 0.467

High HBV activity 1.37 (0.76- 2.46) 0.291 1.19 (0.61- 2.30) 0.600

AST > 70 IU/L 1.14 (0.84- 1.55) 0.384 1.17 (0.69- 1.98) 0.543

ALT > 40 IU/L 1.04 (0.76- 1.43) 0.768 1.39 (0.82- 2.36) 0.211

Child-Pugh class C 1.29 (1.11- 1.51) 0.001 1.05 (0.74- 1.48) 0.782 1.48 (0.87- 2.52) 0.140

MELD score (cont.)* 1.08 (1.06- 1.11)


34/38

SUPPLEMENTARY DATA

Supplemental figure 1. HBeAg seroconversion according to treatment groups. The

probability of HBeAg seroconversion of either group was compared with untreated patients

(No Tx) as a reference group. Previous Tx versus No Tx, P = 0.6560; Early Tx versus No Tx,

P = 0.0155; Delayed Tx versus No Tx, P = 0.7159.

Tx, treatment.

Supplemental figures 2. Liver transplantation-free survival in the (A) Child-Turcotte-Pugh

class A, (B) class B, and (C) class C groups. The cumulative survival rate was significantly

higher in antiviral-treated patients than in untreated patients among the Child-Turcotte-Pugh

class B (P = 0.0117) and class C (P < 0.0001) groups, whereas the survival rate was not

significantly different between treated and untreated patients among the class A group (P =

0.9112). Analysis was done in patients with early antiviral treatment.

Supplemental figures 3. Liver transplantation-free survival in the MELD scores (A) < 13

and (B) ³13 groups. The cumulative survival rate was significantly higher in treated than in

t t d ti t f b th th ith l MELD ( 13) (P 0 0262) d th



36/38

Hepatology




37/38

Hepatology




38/38

Hepatology


Documents

2015 Hepatol Long Term Antivirals in Decomp HBV Cirrhosis