Abstract
A previous study found that lamivudine, if started early enough, may improve the chance of survival in chronic hepatitis B virus (HBV) with severe acute exacerbation (SAE). The aim of this study was to investigate the effect of early entecavir treatment before the bilirubin level exceeds 20 mg/dl for chronic HBV with SAE. Consecutive patients with chronic HBV with SAE and a serum bilirubin level of <20 mg/dl who received lamivudine or entecavir were enrolled. Short-term (4 months) survival was evaluated. One hundred fourteen patients received lamivudine, and 53 patients received entecavir. The baseline characteristics were similar for the two groups except that the entecavir group was older and had a lower alanine aminotransferase (ALT) level. Three patients (8.0%) in the entecavir group and 9 patients (7.9%) in the lamivudine group died (P = 1.000). If only patients who started antiviral treatment before serum bilirubin level rose to more than 15 mg/dl were included, 3 patients (8.3%) in the entecavir group and 3 patients (3.0%) in the lamivudine group died (P = 0.189). If only patients with an HBV DNA level higher than 105 copies/ml and a bilirubin level lower than 15 mg/dl were included, 5 out of 40 patients (12.5%) in the entecavir group died and 1 out of 59 patients (1.7%) in the lamivudine group died. Multivariate analysis found that entecavir treatment was associated with more mortality than lamivudine (P = 0.035). Early entecavir treatment in patients with high viral load is associated with more short-term mortality than lamivudine for chronic HBV with severe acute exacerbation.
INTRODUCTION
Chronic hepatitis B virus (HBV) infection is a major global health problem, with an estimated 400 million HBV carriers worldwide (1). In the natural history of chronic HBV, spontaneous acute exacerbation (AE) is not uncommon, with a cumulative incidence of 10 to 30% every year (2–5). These exacerbations can be mild, but some patients may develop hepatic decompensation and even death (6, 7).
Lamivudine (LAM) is the first approved antiviral agent for HBV. Lamivudine is effective and safe for the treatment of compensated and decompensated chronic HBV infection (8–10). Several nonrandomized studies have found that lamivudine did not increase the survival rate for the treatment of chronic HBV with severe AE (SAE) (11, 12). A recent study by Chien et al. found that early lamivudine treatment before the bilirubin level is above 20 mg/dl is associated with an improved outcome (13). Another recent study by Sun et al. also found that lamivudine treatment can improve the outcome for patients with a Model for End-Stage Liver Disease (MELD) score less than 30 (14). However, lamivudine is associated with a high resistance rate (15). In randomized studies, entecavir (ETV) demonstrated superior antiviral efficacy to and a lower resistance rate than lamivudine (16, 17). However, a recent study from Hong Kong unexpectedly demonstrated that entecavir resulted in an increased short-term mortality rate over that of lamivudine in chronic HBV with severe AE (18). The aim of this study was to investigate the effect of early entecavir use for the treatment of chronic HBV with severe AE.
MATERIALS AND METHODS
Consecutive patients with chronic hepatitis B with severe AE admitted to Kaohsiung Veterans General Hospital from January 2000 to December 2006 who received lamivudine and from July 2008 to December 2012 who received entecavir were included. All patients had a history of HBV infection for more than 6 months. Severe AE was defined as abrupt rise of alanine aminotransferase (ALT) to more than 5× the upper limit of normal (ULN; the ULN is 40 U/liter), accompanied by a total bilirubin level of more than 2.0 mg/dl or prolongation of the prothrombin time (PT) by more than 3 s. Patients with alcohol use of more than 30 g/day, who took hepatotoxic agents, and who had evidence of liver cirrhosis or hepatocellular carcinoma were excluded. Patients with a total bilirubin level of more than 20 mg/dl before antiviral treatment were excluded. Patients who had previously received antiviral therapy including interferon or nucleoside or nucleotide analogues were also excluded. Liver cirrhosis was diagnosed by histology or by characteristic ultrasonography findings (19).
Liver biochemistry values, including serum albumin, bilirubin, aspartate transaminase (AST), ALT, PT, creatinine, complete blood counts, and HBV DNA were determined upon admission to the hospital. The liver biochemistry data, PT, and renal function were monitored once or twice per week until the patients' conditions stabilized. All biochemical tests were performed in the clinical pathology laboratories of Kaohsiung Veterans General Hospital using routine automated techniques. The serological markers HBsAg, HBeAg, IgM anti-HBc, and IgM anti-HAV were assayed by immunoenzymatic assay (Abbott Laboratories, Ltd., Germany). Anti-HCV was assayed using an enzyme immunoassay (EIA) kit (Abbott Laboratories, Ltd., Germany). The quantification of HBV DNA was performed by real-time PCR as previously described (20).
The values are expressed as means ± standard deviations. Categorical variables were analyzed with chi-square test or Fisher's exact test as appropriate, and continuous variables were analyzed by Mann-Whitney test. Logistic regression test was applied to analyze the independent association of various variables with the outcome. A P value of <0.05 was regarded as significant.
This study was approved by the Institutional Review Board of Kaohsiung Veterans General Hospital (VGHKS13-CT7-13).
RESULTS
In patients who fulfilled the inclusion and exclusion criteria, 53 received entecavir (ETV), and 114 received lamivudine (LAM). The findings for baseline ASL, bilirubin, prolongation of PT, platelets, albumin, HBV DNA level, and HBeAg status were similar for the two groups. Patients in the ETV group were older than those in the LAM group and had a lower level of ALT (Table 1). Six out of 53 patients (11.3%) in the ETV group died, and 9 out of 114 patients (7.9%) in the LAM group died. The observed difference in the mortality rate between ETV and LAM group is not statistically significant (P = 0.325). All of the deaths in ETV or LAM group were caused by liver failure. If only patients who received antiviral treatment before the bilirubin level rose by more than 15 mg/dl were included, patients in the ETV group were older than those in the LAM group and had a lower level of ALT. The baseline AST, bilirubin, prolongation of PT, platelets, albumin, HBV DNA level, and HBeAg status were similar for the two groups (Table 2). Five out of 50 patients (10%) in the ETV group died, and 3 out of 100 patients (3%) in the LAM group died. The observed difference in the mortality rate between ETV and LAM groups is not statistically significant (P = 0.083). In patients with a baseline HBV DNA level higher than 105 copies/ml who had started antiviral treatment before the bilirubin level was greater than 15 mg/dl, those in the ETV group were older than those in the LAM group and had a lower level of ALT, but the findings for the baseline AST, bilirubin, prolongation of PT, platelets, albumin, HBV DNA level, and HBeAg status were similar between the two groups (Table 3). Five out of 40 patients (12.5%) in the ETV group died, and 1 out of 59 patients (1.7%) in the LAM group died. Multivariate analysis showed that ETV treatment (relative risk, 17.6; 95% confidence interval, 1.230 to 251.0; P = 0.035) and prothrombin time international normalized ratio (INR) (relative risk, 16.3; 95% confidence interval, 2.24 to 118.3; P = 0.006) were associated with a greater mortality (Table 4).
TABLE 1.
Demographic and clinical data in patients under entecavir or lamivudine treatment before bilirubin level reached >20 mg/dl
| Parameter | Value for group |
P | |
|---|---|---|---|
| Entecavir (n = 53) | Lamivudine (n = 114) | ||
| Age (yrs)a | 49 ± 13 | 43 ± 15 | 0.006 |
| Sex (M/Fb) | 38/15 | 88/26 | 0.446 |
| AST (U/liter)a | 838 ± 690 | 1,051 ± 1,010 | 0.166 |
| ALT (U/liter)a | 1,287 ± 788 | 1,629 ± 1,011 | 0.031 |
| Albumin (g/dl)a | 3.6 ± 0.6 | 3.5 ± 0.5 | 0.183 |
| Bilirubin (mg/dl)a | 6.3 ± 4.5 | 7.7 ± 5.1 | 0.087 |
| Creatinine (mg/dl)a | 0.9 ± 0.2 | 0.9 ± 0.2 | 0.943 |
| Prothrombin time (INR)a | 1.4 ± 0.5 | 1.5 ± 0.5 | 0.308 |
| Platelet (cells × 109 /ml)a | 156 ± 59 | 175 ± 60 | 0.071 |
| HBeAg (positive/negative) | 15/38 | 47/67 | 0.123 |
| HBV DNA (×105copies/ml)a | 1,442 ± 338 | 1,642 ± 448 | 0.783 |
| Mortality | 6/53 (11.3%) | 9/114 (7.9%) | 0.325 |
Data presented as means ± standard deviations.
M, male; F, female.
TABLE 2.
Demographic and clinical data in patients under entecavir or lamivudine treatment before bilirubin level reached >15 mg/dl
| Parameter | Value for group |
P | |
|---|---|---|---|
| Entecavir (n = 50) | Lamivudine (n = 100) | ||
| Age (yrs)a | 49 ± 13 | 42 ± 14 | 0.002 |
| Sex (M/Fb) | 36/14 | 78/22 | 0.424 |
| AST (U/liter)a | 809 ± 667 | 1,037 ± 1,024 | 0.156 |
| ALT (U/liter)a | 1,258 ± 741 | 1,629 ± 1,021 | 0.023 |
| Albumin (g/dl)a | 3.7 ± 0.6 | 3.5 ± 0.6 | 0.144 |
| Bilirubin (mg/dl)a | 5.7 ± 3.7 | 6.4 ± 3.8 | 0.273 |
| Creatinine (mg/dl)a | 0.9 ± 0.2 | 0.9 ± 0.2 | 0.480 |
| Prothrombin time (INR)a | 1.3 ± 0.3 | 1.4 ± 0.3 | 0.393 |
| Platelet (cells x 109 /ml)a | 157 ± 59 | 174 ± 60 | 0.081 |
| HBeAg (positive/negative) | 15/35 | 43/57 | 0.086 |
| HBV DNA (×105copies/ml)a | 1,507 ± 348 | 1,770 ± 478 | 0.741 |
| Mortality | 5/50 (10%) | 3/100 (3%) | 0.082 |
Data presented as means ± standard deviations.
M, male; F, female.
TABLE 3.
Demographic and clinical data in patients with an HBV DNA level of >105 copies/ml under entecavir or lamivudine treatment before bilirubin level reached >15 mg/dl
| Parameter | Value for group |
P | |
|---|---|---|---|
| Entecavir (n = 40) | Lamivudine (n = 59) | ||
| Age (yrs)a | 49 ± 14 | 40 ± 15 | 0.002 |
| Sex (M/Fb) | 27/13 | 43/16 | 0.654 |
| AST (U/liter)a | 890 ± 718 | 1,277 ± 1,243 | 0.079 |
| ALT (U/liter)a | 1,277 ± 752 | 1,826 ± 1,120 | 0.008 |
| Albumin (g/dl)a | 3.7 ± 0.6 | 3.5 ± 0.6 | 0.068 |
| Bilirubin (mg/dl)a | 5.6 ± 3.5 | 6.8 ± 3.7 | 0.088 |
| Creatinine (mg/dl)a | 0.9 ± 0.2 | 0.9 ± 0.2 | 0.606 |
| Prothrombine time (INR)a | 1.4 ± 0.4 | 1.4 ± 0.4 | 0.292 |
| Platelet (cells × 109 /ml)a | 150 ± 55 | 164 ± 49 | 0.188 |
| HBeAg (positive/negative) | 13/27 | 29/30 | 0.147 |
| HBV DNA (×105copies/ml)a | 1,809 ± 3,747 | 2,311 ± 5,358 | 0.609 |
Data presented as means ± standard deviations.
M, male; F, female.
TABLE 4.
Factors associated with overall mortality at 4 months in patients with HBV DNA > 105 copies/ml under entecavir or lamivudine treatment before bilirubin level > 15 mg/dl
| Parameter | Hazard ratio | 95% CI | P | Hazard ratio | 95% CI | P |
|---|---|---|---|---|---|---|
| Age (yrs) | 1.060 | 0.999–1.125 | 0.054 | |||
| Sex (M/Fa) | 2.154 | 0.241–19.28 | 0.493 | |||
| AST (U/liter) | 1.000 | 1.000–1.001 | 0.221 | |||
| ALT (U/liter) | 1.000 | 0.999–1.001 | 0.836 | |||
| Albumin (g/dl) | 0.440 | 0.113–1.713 | 0.236 | |||
| Bilirubin (mg/dl) | 1.248 | 0.988–1.578 | 0.064 | |||
| Creatinine (mg/dl) | 5.395 | 0.177–14.40 | 0.334 | |||
| Prothrombin time (INR) | 8.693 | 1.694–44.59 | 0.010 | 16.3 | 2.240–118.3 | 0.006 |
| Platelet (cells × 109 /ml) | 0.999 | 0.983–1.015 | 0.888 | |||
| HBV DNA (×105copies/ml) | 1.000 | 1.000–1.000 | 0.590 | |||
| ETV vs LAM | 8.286 | 0.930–73.86 | 0.058 | 17.6 | 1.230–251.0 | 0.035 |
M, male; F, female.
DISCUSSION
In this study, we found that in chronic HBV with AE and a high viral load, early ETV treatment before the bilirubin level exceeds 15 mg/dl is associated with more short-term mortality than LAM treatment.
Several nonrandomized studies have found that lamivudine did not increase the survival rate for the treatment of chronic HBV with severe AE (11, 12). A recent study by Sun et al. found that lamivudine treatment can improve the outcome for patients with a MELD score less than 30 (14). Another recent study by Chien et al. found that early lamivudine treatment before the bilirubin level exceeds 20 mg/dl is associated with an improved outcome, but in patients with a bilirubin level of ≥20 mg/dl, lamivudine treatment did not have survival benefit over the control (14). In this study, if we enrolled only patients who received antiviral therapy before bilirubin level rose to more than 15 mg/dl and with a HBV DNA level greater than 105 copies/ml, the LAM treatment group had a mortality rate of 1.7%. The mortality rate for this study is similar to that for the study by Chien et al., who found that no patients who received LAM treatment before the bilirubin level exceeded 20 mg/dl died (13). Previous studies found that ETV has better antiviral efficacy and lower resistance rate than LAM in chronic HBV (16, 17). However, a recent nonrandomized study from Hong Kong found that ETV treatment was associated with increased short-term mortality compared with LAM treatment in patients with chronic HBV and severe AE (18). Our study demonstrated that early ETV treatment did not result in decreased survival, compared with early LAM treatment, if the HBV viral load was not considered, but in patients with a higher HBV viral load, early ETV treatment resulted in a worse outcome than LAM treatment.
A previous study by our group found that for patients with chronic HBV with severe AE who had not received antiviral treatment, the HBV DNA level was not associated with an adverse outcome (21). This is consistent with the findings of another study from Hong Kong (22). For patients who received LAM treatment, several studies have also found that the baseline HBV DNA level was not related to survival (11–13). In the study by Chien et al., a lower HBV DNA level was shown to be associated with a higher bilirubin level (13). Some patients with chronic HBV with severe AE actually did not have a high HBV DNA level. In this study, we also found that the baseline HBV DNA level was not associated with the outcome of antiviral treatment. In the subgroup analysis for this study, which included only patients with an HBV DNA level higher than 105 copies/ml, early LAM treatment appeared to result in improved survival compared with ETV treatment. The significance of HBV DNA level and the outcome of antiviral therapy for chronic HBV with severe AE require more studies to clarify.
The clinical course of chronic HBV with AE can be divided into four stages according to the change of HBV DNA level. In the ascending limb, a HBV DNA level less than 105 copies/ml is stage I and a level greater or equal to 105 copies/ml is stage II. In the descending limb, a HBV DNA level greater or equal to 105 copies/ml is stage III and a level less than 105 copies/ml is stage IV. Patients in stage I are usually asymptomatic and will seldom seek medical help. Therefore, in clinical practice, patients who visit the hospital due to chronic HBV with SAE are usually in stage II, III, or IV. If patients visited the doctor at stage IV, the immune storm due to flare-up of HBV has already been initiated and become exacerbated, so success of antiviral treatment is not anticipated. Besides, patients in stage IV have a low HBV DNA level which is also declining rapidly, so the benefits of antiviral treatment are expected to be low. The study from Chien et al. found that early lamivudine treatment before the bilirubin level exceeds 20 mg/dl is associated with an improved outcome (14), but that study did not determine the level of viral load at which LAM treatment is beneficial. Previous studies with patients of chronic HBV with SAE did not demonstrate significant benefits for lamivudine treatment. This may be due to the fact that these studies used not only stage II and III patients but also stage IV patients. The only randomized study from India, which found that tenofovir is associated with a better survival rate than the control, enrolled only patients with an HBV DNA level of more than 105 copies/ml. It is believed that if this study had also used patients with an HBV DNA level of less than 105 copies/ml, the benefit of tenofovir may probably disappear. A recent study by Hsu et al. (23) compared the outcomes of LAM and ETV treatment in decompensated HBV. But the study used patients with high and low viral loads, and the outcomes of ETV and LAM treatment were not different. In this study, if we enrolled patients with high and low viral loads, the outcomes of LAM and ETV treatment were similar, but if only patients with a high viral load were considered, LAM had a significantly higher survival rate than ETV.
This study has some limitations. This was not a randomized study, and the number of cases in the ETV treatment group was relatively small. Further randomized studies are required to determine whether ETV or LAM treatment produces a better treatment outcome for chronic HBV with severe AE. Since general patient care is expected to improve over time, the higher mortality in the more recent cohort receiving entecavir treatment was a negative bias and further supported the result of this study. Besides, patients in the ETV group were older than those in the LAM group, but multivariate analysis did not identify age as an independent factor of mortality. In the study by Wong et al., age was also not shown to be significantly associated with the outcome of entecavir or lamivudine treatment in chronic HBV patients with SAE (18). Similarly, in the study by Chien et al., age was also not shown to be associated with the outcome of lamivudine treatment in chronic HBV patients with SAE (13). The difference in the age of the two groups did not explain the inferior outcome of ETV.
Conclusions.
Early entecavir treatment in patients with high viral load is associated with more short-term mortality than lamivudine in chronic HBV with severe acute exacerbation.
Footnotes
Published ahead of print 13 January 2014
REFERENCES
- 1.Lee W. 1997. Hepatitis B infection. N. Engl. J. Med. 337:1733–1745. 10.1056/NEJM199712113372406 [DOI] [PubMed] [Google Scholar]
- 2.Seeff LB, Koff RS. 1986. Evolving concepts of the clinical and serological consequences of hepatitis B infection. Semin. Liver Dis. 6:11–22. 10.1055/s-2008-1040788 [DOI] [PubMed] [Google Scholar]
- 3.Lok AS, Lai CL. 1990. Acute exacerbations in Chinese patients with chronic hepatitis B virus (HBV) infection. Incidence, predisposing factors and etiology. J. Hepatol. 10:29–34 [DOI] [PubMed] [Google Scholar]
- 4.Liaw YF. 1995. Acute exacerbation and superinfection in patients with chronic viral hepatitis. J. Formos. Med. Assoc. 94:521–528 [PubMed] [Google Scholar]
- 5.Perrillo RP. 2001. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology 120:1009–1022. 10.1053/gast.2001.22461 [DOI] [PubMed] [Google Scholar]
- 6.Sheen IS, Laiw YF, Tai DI, Chu CM. 1985. Hepatic decompensation associated with hepatitis B e antigen clearance in chronic type B hepatitis. Gastroenterology 89:732–735 [DOI] [PubMed] [Google Scholar]
- 7.Davis GL, Hoofnagle JH, Waggoner JG. 1985. Reactivation of chronic type B hepatitis B presenting as acute viral hepatitis. Ann. Intern. Med. 102:762–765. 10.7326/0003-4819-102-6-762 [DOI] [PubMed] [Google Scholar]
- 8.Yeo W, Steinberg JL, Tam JS, Chan PK, Leung NW, Lam KC, Mok TS, Johnson PJ. 1999. Lamivudine in the treatment of hepatitis B virus reactivation during cytotoxic chemotherapy. J. Med. Virol. 59:263–269. [DOI] [PubMed] [Google Scholar]
- 9.Villeneuve JP, Condreay LD, Willems Pomier-Layrargues B G, Fenyves D, Bilodeau M, Leduc R, Peltekian K, Wong F, Margulies M, Heathcote EJ. 2000. Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B. Hepatology 31:207–210. 10.1002/hep.510310130 [DOI] [PubMed] [Google Scholar]
- 10.Yao FY, Bass NM. 2000. Lamivudine treatment in patients with severely decompensated cirrhosis due to replicating hepatitis B infection. J. Hepatol. 33:301–307. 10.1016/S0168-8278(00)80371-2 [DOI] [PubMed] [Google Scholar]
- 11.Chan HL, Tsang SW, Hui Y, Leung NW, Chan FK, Sung JJ. 2002. The role of lamivudine and predictors of mortality in severe flare-up of chronic hepatitis B with jaundice. J. Viral Hepat. 9:424–428. 10.1046/j.1365-2893.2002.00385.x [DOI] [PubMed] [Google Scholar]
- 12.Tsubota A, Arase Y, Suzuki Y, Sezaki H, Hosaka T, Akuta N, Someya T, Kobayashi M, Saitoh S, Ikeda K, Kumada H. 2005. Lamivudine monotherapy for spontaneous severe acute exacerbation of chronic hepatitis B. J. Gastroenterol. Hepatol. 20:426–432. 10.1111/j.1440-1746.2004.03534.x [DOI] [PubMed] [Google Scholar]
- 13.Chien RN, Lin CH, Laiw YF. 2003. The effect of lamivudine therapy in hepatic decompensation during acute exacerbation of chronic hepatitis B. J. Hepatol. 38:322–327. 10.1016/S0168-8278(02)00419-1 [DOI] [PubMed] [Google Scholar]
- 14.Sun LJ, Yu JW, Zhao YH, Kang P, Li SC. 2010. Influential factors of prognosis in lamivudine treatment for patients with acute-on-chronic hepatitis B liver failure. J. Gastroenterol. Hepatol. 25:583–590. 10.1111/j.1440-1746.2009.06089.x [DOI] [PubMed] [Google Scholar]
- 15.Yuen MF, Sablon E, Hui CK, Yuan HJ, Decraemer H, Lai CL. 2001. Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy. Hepatology 34(4 Part 1):785–791. 10.1053/jhep.2001.27563 [DOI] [PubMed] [Google Scholar]
- 16.Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, Han KH, Goodman Z, Zhu J, Cross A, DeHertogh D, Wilber R, Colonno R, Apelian D, BEHoLD AI463022 Study Group. 2006. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N. Engl. J. Med. 354:1001–1010. 10.1056/NEJMoa051285 [DOI] [PubMed] [Google Scholar]
- 17.Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A, Colonno R, Fernandes L, BEHoLD AI463027 Study Group 2006. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N. Engl. J. Med. 354:1011–1020. 10.1056/NEJMoa051287 [DOI] [PubMed] [Google Scholar]
- 18.Wong VW, Wong GL, Yiu KK, Chim AM, Chu SH, Chan HY, Sung JJ, Chan HL. 2011. Entecavir treatment in patients with severe acute exacerbation of chronic hepatitis B. J. Hepatol. 54:236–242. 10.1016/j.jhep.2010.06.043 [DOI] [PubMed] [Google Scholar]
- 19.Lin DY, Sheen IS, Chiu CT, Lin SM, Kuo YC, Liaw YF. 1993. Ultrasonographic changes of early liver cirrhosis in chronic hepatitis B: a longitudinal study. J. Clin. Ultrasound 21:303–308. 10.1002/jcu.1870210502 [DOI] [PubMed] [Google Scholar]
- 20.Cane PA, Cook P, Ratcliffe D, Mutimer D, Pillay D. 1999. Use of real-time PCR and fluorimetry to detect lamivudine resistance-associated mutations in hepatitis B virus. Antimicrob. Agents Chemother. 43:1600–1608 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Tsai WL, Lo GH, Hsu PI, Lai KH, Lin CK, Chan HH, Chen WC, Cheng JS, Liu YC, Huang TS, Ger SLP, Lin HH. 2008. Role of genotype and precore/basal core promoter mutations of hepatitis B virus in patients of chronic hepatitis B with acute exacerbation. Scand. J. Gastroenterol. 43:196–201. 10.1080/00365520701745693 [DOI] [PubMed] [Google Scholar]
- 22.Yuen MF, Sablon E, Hui CK, Yuan HJ, Wong KH, Doutreloigne J, Bogaerts V, Wong BC, Fan ST, Lai CL. 2003. Prognostic factors in severe exacerbation of chronic hepatitis B. Clin. Infect. Dis. 36:979–984 [DOI] [PubMed] [Google Scholar]
- 23.Hsu YC, Mo LR, Chang CY, Perng DS, Tseng CH, Lo GH, Tai CM, Lin CW, Hsu CC, Hsu CY, Huang SC, Lin JT. 2012. Entecavir versus lamivudine in the treatment of chronic hepatitis B patients with hepatic decompensation. Antivir. Ther. 17:605–612 [DOI] [PubMed] [Google Scholar]