396 Original article
Comparison of telbivudine efficacy in treatment-naive patients with hepatitis B virus-related compensated and decompensated cirrhosis in 96 weeks Xiaoling Yanga,b, Jia Lib, Li Zhoub, Junjuan Liub, Jinghan Wanga,b and Wei Lub Objective Data are limited for comparison of the longterm efficacy of telbivudine (LdT) between hepatitis B virus (HBV)-related compensated and decompensated cirrhosis. The aim of this study was to compare the efficacy of LdT in treatment-naive patients with HBV-related compensated and decompensated cirrhosis in 96 weeks. Patients and methods We reviewed the data of 65 compensated and 62 decompensated cirrhotic patients treated with LdT for 96 weeks, and compared the difference in the related indicators before and after treatment between the groups. Results Alanine aminotransferase normalized rate was significantly higher in the compensated group than in the decompensated group at weeks 12 and 24 (67.7 vs. 40.3% and 78.5 vs. 53.2%, respectively, P < 0.01). Albumin level was much higher than the baseline at week 24 in the compensated group (35.1±6.2 vs. 39.9±5.1, P < 0.01), but significance was observed from week 48 onwards in the decompensated group (29.8±3.7 vs. 33.7±3.8, P < 0.05). The Child–Turcotte–Puge score either improved or remained steady in both groups. The HBV DNA negativity rate at week 12 (56.9 vs. 32.3%, P < 0.01) was higher, whereas the drug resistance rate was lower (P > 0.05), in the compensated group than in the decompensated group. The degree of esophageal varix was alleviated, including
Introduction Hepatitis B virus (HBV) is the most common hepatitis virus that causes chronic liver infection in humans, affecting more than 400 million individuals, among whom 10–20% of individuals progress to liver cirrhosis (LC) [1,2]. LC is the end stage of the natural history of chronic hepatitis B, which has been classified into two categories, namely, compensated (Child-A) and decompensated (Child-B and Child-C) cirrhosis, according to the Child– Turcotte–Puge (CTP) score [3–5]. Patients with LC eventually progress toward decompensated cirrhosis, among whom 3–4% of compensated cirrhotic patients per annum are at risk of decompensation, and the 5-year cumulative incidence of decompensation is 15% [6]. Patients with decompensated cirrhosis have poor prognoses, and the 5-year survival of untreated patients with HBV-related decompensated cirrhosis is less than 15% compared with the B85% in patients with HBV-related compensated cirrhosis [7]. Clinical studies have indicated that antiviral therapy in patients with chronic c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-691X
11 (16.9%) compensated and four (6.5%) decompensated cirrhotic patients. Liver stiffness was significantly decreased in the compensated group compared with the baseline [19.1 (7.3–32.6) vs. 14.8 (7.4–32.5), P < 0.01]; however, there was no statistical significance in the decompensated group compared with the baseline [30.5 (9.1–55.0) vs. 29.9 (8.4–53.2), P > 0.05]. Conclusion Long-term LdT treatment showed superior virological, biochemical, and clinical efficacy in the compensated cirrhotic patients. Therefore, we emphasized the importance of early antiviral treatment, which may improve the prognosis of cirrhotic patients. Eur J c 2014 Wolters Kluwer Gastroenterol Hepatol 26:396–403 Health | Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2014, 26:396–403 Keywords: chronic hepatitis B, compensated cirrhosis, decompensated cirrhosis, efficacy, telbivudine a Graduate School, Tianjin Medical University and bTianjin Second People’s Hospital, Tianjin Institute of Hepatology, Tianjin, China
Correspondence to Jia Li, MD, Tianjin Second People’s Hospital, Tianjin Institute of Hepatology, No. 7, Sudi South Road, Nankai District, 300192 Tianjin, China Tel: + 86 22 2746 8230/86 13 3021 06853; fax: + 86 22 2746 8606; e-mail: [email protected] Received 28 October 2013 Accepted 17 January 2014
HBV-related liver cirrhosis could improve liver function, reduce complications, and prolong the survival period [8–11]. Telbivudine (L-deoxythymidine, LdT) is a synthetic thymidine nucleoside analogue with potent and specific anti-HBV activity. A study has suggested that LdT treatment has more significant antiviral efficacy and histologic response at 1 year in patients with compensated cirrhosis than in individuals treated with lamivudine; Ishak fibrosis scores of 4–6 improved to 0–3 (where 0 indicates no fibrosis and 6 indicates cirrhosis) in 68% of patients receiving LdT and 61% of patients receiving lamivudine [12]. Another study has indicated that LdT treatment for 104 weeks has a higher rate of patients with both viral suppression and alanine aminotransferase (ALT) normalization, with a trend toward a higher rate of survival and significant improvement in the glomerular filtration rate, compared with lamivudine in decompensated cirrhosis [13]. In addition, Shim et al. [8] showed that the efficacy was similar in patients with HBV-related compensated and decompensated cirrhosis on 1-year entecavir monotherapy. DOI: 10.1097/MEG.0000000000000062
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Telbivudine for HBV cirrhosis Yang et al. 397
However, data for comparison of the efficacy of LdT in treatment-naive patients with chronic HBV-related compensated and decompensated cirrhosis are limited. In the present study, we carried out a retrospective analysis to compare the efficacy of LdT in treatmentnaive patients with HBV-related compensated and decompensated cirrhosis in 96 weeks.
Patients and methods Patients
This retrospective study enrolled 375 patients with chronic HBV-related LC between January 2008 and January 2013 at the Department of Hepatology from Tianjin Second People’s Hospital. LC was diagnosed on the basis of clinical symptoms, laboratory results, endoscopic evidences, sonographic findings, computed tomography, or liver histological data. The classification of compensated and decompensated cirrhosis was made on the basis of the CTP score. Patients were eligible to participate if they were between 16 and 70 years of age, received LdT (600 mg/day) monotherapy at the initiation of treatment (patients with drug resistance could receive add-on adefovir), and the treatment duration was 96 weeks. Exclusion criteria included (i) a history of nucleos(t)ide analogue treatment; (ii) coinfection with hepatitis A, hepatitis C, hepatitis D, or human immunodeficiency viruses; (iii) concomitant etiology for cirrhosis: autoimmunity, drug-induced, cardiogenic, and so on; (iv) hepatocellular carcinoma (HCC) or other malignancies; (v) history of liver or other organ transplantation; (vi) HBV-associated glomerulonephritis or functional renal insufficiency; and (vii) alcoholic liver injury, nonalcoholic steatohepatitis, or Wilson’s disease. On the basis of the inclusion criteria and exclusion criteria, 127 patients, 65 compensated cirrhotic patients and 62 decompensated cirrhotic patients, were enrolled in this study. Methods
Laboratory tests were monitored at the baseline and every 12 weeks. Biochemical indicators, including ALT, cholinesterase (CHE), and albumin (ALB), were tested with a conventional autoanalyzer using commercial reagents. Hepatitis B e antigen was assessed by electrochemiluminescence (Abbott Laboratories, Chicago, Illinois, USA). The serum HBV DNA level was measured using the realtime PCR kit (PG Biotech Company, Shenzhen, China; ABI 7500 PCR Instrument, Foster City, California, USA); with a detection limit of 500 copies/ml, it was defined as HBV negativity. Drug resistance was defined as viral breakthrough with treatment-induced HBV DNA YMDD mutations. HBV DNA YMDD mutations were tested by PCR and direct sequencing. The evaluation standard of CTP score was as follows: improvement indicates that the score decreased by over two points; deterioration indicates that the score increased by over two points; and stabiliza-
tion means that the score changed within one point [14]. Esophagogastric varix examination by endoscopy and liver stiffness (LS) measurement by FibroScan System (Echosens, Pairs, France) were carried out at the baseline at 48 and 96 weeks, respectively. The degree of esophagogastric varix was defined according to previous consensus [15]. Observation indicators include sex, age, any cirrhosisrelated complication (ascites, esophagogastric varix bleeding, hepatic encephalopathy, hepatorenal syndrome, and HCC), and mortality caused by hepatopathy. Disease-related complications were defined according to well-known practice guidelines [16–18]. Statistical analysis
Statistical analysis was carried out using SPSS 17.0 (SPSS Inc., Chicago, Illinois, USA). Data were presented as mean±SD, n (%), or median with range. Independentsamples Student’s t-test and paired-sample Student’s t-test for means, Mann–Whitney U-test for continuous variables or medians between the two groups, and Wilcoxon matched pair signed-rank test were used to evaluate the changes between the baseline and the end of follow-up evaluations for medians, and w2-test for categorized variables. Multiple comparisons at different time points between the two groups were carried out by analysis of variance. Differences were considered statistically significant at P value less than 0.05.
Results Baseline characteristics
From January 2008 to January 2013, 375 patients were diagnosed with HBV-related cirrhosis. According to the inclusion and exclusion criteria, 127 patients, 65 compensated and 62 decompensated cirrhotic, were enrolled in this study. The baseline characteristics are shown in Table 1. No significant difference was observed between the compensated and decompensated groups in sex, age, hepatitis B e antigen status, serum HBV DNA level, and ALT level. Statistical differences in serum ALB and CHE levels, CTP score, degree of esophageal varix, and LS value were noted between the two groups. The serum ALB and CHE levels were significantly higher, whereas the CTP score and the LS value were significantly lower in the compensated group than in the decompensated group. The degree of esophageal varix was more severe in the decompensated group than in the compensated group. Virological response
The HBV DNA negativity rate was higher in the compensated group than in the decompensated group at weeks 12, 24, 48, and 96, with the rate of 56.9 versus 32.3%, 67.7 versus 51.6%, 81.5 versus 75.8%, and 89.2 versus 83.4%, respectively. Statistical difference was only observed at week 12 between the two groups (w2 = 7.804, P = 0.005) (Fig. 1a).
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398 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 4
Table 1
Baseline characteristics of the enrolled patients
Sex (M/F) [n (%)] Age (mean±SD) (years)a HBeAg positivity [n (%)] HBV DNA (log10 copies/ml)a ALT [median (min–max)] (U/l)b ALB (g/l)a CHE (IU/l)a Child–Turcotte–Pugh scorea Esophageal varices [n (%)]c None Mild Moderate Severe Liver stiffness [median (min–max)] (kPa)b
Com (n = 65)
Dec (n = 62)
P
46 (70.8)/19 (29.2) 48.6±9.0 40 (61.5) 5.94±1.38 69.5 (20.5–314.8) 35.1±6.2 4086.6±1737.4 5.7±1.4
45 (72.6)/17 (27.4) 50.5±10.1 35 (56.5) 5.70±1.13 86.2 (43.4–275.2) 29.8±3.7 2801.9±1157.2 8.6±1.2
> 0.05 > 0.05 > 0.05 > 0.05 > 0.05 0.0009 0.0029 < 0.0001
12 28 13 12 19.1
0 18 20 24 30.5
< 0.0001
(18.5) (43.0) (20.0) (18.5) (7.3–32.6)
(0) (29.0) (32.3) (38.7) (9.1–55.0)
0.003
ALB, albumin; ALT, alanine aminotransferase; CHE, cholinesterase; Com, compensated cirrhosis; Dec, decompensated cirrhosis; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus. a Data are expressed as mean±SD. b Data from the skewed distribution are expressed as median (min–max). c Data are compared between the compensated cirrhosis and the decompensated cirrhosis groups by the Mann–Whitney U-test, z = – 4.037.
Fig. 1
(b) 30
80 60
Drug resistance rate (%)
HBV DNA negativity rate (%)
(a) 100
P = 0.033
40 20 0
20
10
0 12
24
48
96
96
48
Weeks
Weeks Dec
Com
(a) HBV DNA negativity rate in compensated and decompensated cirrhotic groups after treatment with LdT. A significant difference was found between the two groups at week 12 (P < 0.01). (b) Comparison of the drug resistance rate in compensated and decompensated cirrhotic groups after treatment with LdT. No significant difference was observed between the two groups (P > 0.05). Com, compensated cirrhosis; Dec, decompensated cirrhosis; HBV, hepatitis B virus; LdT, telbivudine.
The cumulative incidence of drug resistance was lower in the compensated group than in the decompensated group at weeks 48 and 96, with rates of 10.8 versus 16.1% and 21.5 versus 29.0%, respectively. However, no significant statistical difference was observed (w2 = 0.786, P = 0.375; w2 = 0.945, P = 0.331) (Fig. 1b).
at weeks 12 and 24 (67.7 vs. 40.3%, P = 0.002; 78.5 vs. 53.2%, P = 0.003, respectively). With the extension of antiviral treatment, the ALT normalized rate increased gradually in both groups, but the rate was slightly higher in the compensated group than in the decompensated group at weeks 48 and 96 (89.2 vs. 82.3.0%, P = 0.260; 89.2 vs. 85.5%, P = 0.525, respectively) (Fig. 2).
Biochemical response Alanine aminotransferase normalization
Change of serum albumin and cholinesterase
No differences in ALT levels were observed in the two groups at the baseline. However, the ALT normalized rate during the treatment period was significantly higher in the compensated group than in the decompensated group
The mean serum ALB level increased with the extension of treatment in both groups. In the compensated group, the level was much higher than the baseline at week 24 (35.1±6.2 vs. 39.9±5.1, P < 0.01), which increased more
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Telbivudine for HBV cirrhosis Yang et al. 399
significantly and was persistently higher than the baseline at weeks 48 and 96 (P < 0.01). However, the level increased slightly at week 24 in the decompensated group; no significant statistical difference was observed compared with the baseline. The level was significantly higher than the baseline from week 48 onwards in the decompensated group (29.8±3.7 vs. 33.7±3.8, P < 0.05),
and persistently higher at week 96 compared with the level at the baseline, at weeks 12 and 24 (P < 0.01) (Table 2).
Fig. 2
Change of Child–Turcotte–Puge score 100
The CTP score improved or remained stable for all patients in the compensated group; 28 of the 65 (43.1%) patients showed improvement and 37 (56.9%) showed steady condition. However, the CTP score improved or remained stable for 95.2% of the patients in the decompensated group; 25 of the 62 (40.3%) patients showed improvement, 34 (54.9%) showed steady condition, and three (4.8%) showed deterioration, without statistical difference in the change in the CTP score between the two groups (Table 3).
89.2
89.2 78.5
ALT normalized rate (%)
80
67.7
60
P = 0.003
85.5
82.3
P = 0.002 53.2
Com
40
Dec
40.3
The serum CHE level increased gradually with the extension of treatment in both groups, which performed the highest at week 96, but without statistical difference compared with the baseline at weeks 12, 24, 48, and 96 (P > 0.05) (Table 2).
20
Degree of esophageal varices
0 12
24
48
96
Weeks Change in the ALT normalized rate in compensated and decompensated cirrhotic groups after treatment with LdT. A significant difference was found between the two groups at week 12 and 24 (P < 0.05). ALT, alanine aminotransferase; Com, compensated cirrhosis; Dec, decompensated cirrhosis; LdT, telbivudine.
All patients were examined for esophageal varices by endoscopy. The degree of esophageal varices was alleviated after the treatment. Eleven of the 65 (16.9%) compensated cirrhotic patients showed an alleviated degree of esophageal varices, including three severe degrees alleviated to moderate degrees, one severe degree alleviated to moderate degree; three moderate degrees alleviated to mild degrees, two moderate degrees alleviated to none; and two mild degrees alleviated to none. Four of the 62 (6.5%) decompensated cirrhotic patients showed an alleviated degree of
Change in albumin (g/l) and cholinesterase (IU/l) in the compensated and decompensated cirrhosis groups after treatment with telbivudine
Table 2
Number
0 week
12 weeks
24 weeks
48 weeks
96 weeks
F
P
65 62
35.1±6.2 29.8±3.7
37.4±5.6 30.0±5.2
39.9±5.1** 31.8±4.7
40.6±5.5** 33.7±3.8a
41.2±5.2** 36.3±5.3b
5.91 8.81
0.0002 < 0.0001
65 62
4086.6±1737.4 2801.9±1157.2
4488.6±1795.9 3298.3±1221.0
4521.7±1988.7 3346.7±1371.1
4878.6±1970.1 3561.0±1349.6
5308.0±1898.8 3645.3±1297.5
2.04 1.65
0.0900 0.1700
ALB Com Dec CHE Com Dec
ALB, albumin; CHE, cholinesterase; Com, compensated cirrhosis; Dec, decompensated cirrhosis. a P < 0.05 compared with the baseline and 12 weeks, respectively. b P < 0.01 compared with the baseline, 12 weeks, and 24 weeks, respectively. **P < 0.01 compared with the baseline.
Table 3
Change in the Child–Turcotte–Puge score and clinical events [n (%)] CTP score (96 weeks)
Number Com Dec w2 P
65 62
Clinical events (96 weeks)
Improvement (decrease Z 2)
Stabilization (absolute change r 1)
Deterioration (increase Z 2)
HCC
Esophageal varix bleeding
Ascites
Death
28 (43.1) 25 (40.3) 0.099 > 0.05
37 (56.9) 34 (54.9) 0.056 > 0.05
0 (0) 3 (4.8) 1.465 > 0.05
3 (4.6) 8 (12.9) 2.755 > 0.05
0 (0) 3 (4.8) 1.465 > 0.05
0 (0) 10 (16.1) 9.265 0.002
0 (0) 4 (6.5) 2.473 > 0.05
Com, compensated cirrhosis; CTP, Child–Turcotte–Puge; Dec, decompensated cirrhosis; HCC, hepatocellular carcinoma.
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European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 4
Fig. 3
Fig. 4
P < 0.0001
8
12
11
60
22
24
P = 0.003
P = 0.085 P < 0.0001
30 28
12
16
0 week
96 weeks Com
20
20
18
20
0 0 week
0 96 weeks Dec
None
Moderate
Mild
Severe
Change in the degree of esophageal varices in compensated and decompensated cirrhotic groups after treatment with LdT. A total of 11 compensated cirrhotic patients showed alleviated degree of esophageal varices (three severe degrees alleviated to moderate degrees, one severe degree alleviated to mild degree, three moderate degrees alleviated to mild degrees, two moderate degrees alleviated to none, and two mild degrees alleviated to none). Four decompensated cirrhotic patients showed alleviated degree of esophageal varices (two severe degrees alleviated to moderate degrees and two moderate degrees alleviated to mild degrees). Com, compensated cirrhosis; Dec, decompensated cirrhosis; LdT, telbivudine.
esophageal varices, including two severe degrees alleviated to moderate degrees and two moderate degrees alleviated to mild degrees (Fig. 3). Liver stiffness value
The LS values were significantly lower in the compensated group than in the decompensated group at the baseline [19.1 (7.3–32.6) vs. 30.5 (9.1–55.0), z = – 2.933, P = 0.003], and decreased with the extension of treatment in both groups. The LS values was significantly decreased in the compensated group compared with the baseline [14.8 (7.4–32.5) vs. 19.1 (7.3–32.6), z = – 4.237, P < 0.0001]; however, there was no statistically significant significance in the decompensated group compared with the baseline [29.9 (8.4–53.2) vs. 30.5 (9.1–55.0), z = – 1.724, P = 0.085]. Statistical differences at week 96 were also observed between the two groups [14.8 (7.4–32.5) vs. 29.9 (8.4–53.2), z = – 4.464, P < 0.0001] (Fig. 4).
Liver stiffness value (kPa)
13
40
20
0 Com
Dec 0 week
Com
Dec
96 weeks
Change in the liver stiffness value in compensated and decompensated cirrhotic groups after treatment with LdT. Significant differences were found between the Com group and the Dec group at 0 week and 96 weeks, respectively (P = 0.003, P < 0.0001), and a significant difference was found between 0 week and 96 weeks in the compensated cirrhotic group (P < 0.0001). No significant difference was observed between 0 week and 96 weeks in the decompensated cirrhotic group (P = 0.085). The box and whiskers plot shows the range of the liver stiffness value: median (min and max). Com, compensated cirrhosis; Dec, decompensated cirrhosis; LdT, telbivudine.
Patterns of clinical adverse events, including infrequent muscle-related symptoms (fatigue, etc.), correlated poorly with elevations in creatine kinase levels and were similar in the two groups. Myopathy, characterized by muscle pain and weakness, was not observed in the two groups after the initiation of LdT.
Clinical events
Four (6.5%) patients died because of disease progression in the decompensated group. The most frequent causes of death were HCC, esophagogastric varix bleeding, and hepatic failure. No death was related to the study drug. LC-related complications were observed as follows: three (4.6%) and eight (12.9%) patients progressed to HCC in the compensated and the decompensated group, respectively. In the decompensated group, three (4.8%) patients experienced esophageal varix bleeding and 10 (16.1%) had ascites repeatedly. Patients had ascites repeatedly within week 48 of the treatment (Table 3).
During the treatment period, no serious clinical adverse events were observed. Of note, elevations in creatine kinase levels were observed in four and six patients in the compensated and the decompensated group, respectively; the elevated range was 208–557 U/l, but decreased to normal spontaneously during continued drug therapy.
Patients experiencing drug resistance were detected with the HBV DNA YMDD mutation. The results of HBV DNA YMDD mutation were M204I mutations, the patients who experienced drug resistence were treated with add-on adefovir.
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Telbivudine for HBV cirrhosis Yang et al.
Discussion HBV persistent infection is an important risk factor for the development of LC or for the occurrence of HCC. For HBV-related cirrhotic patients, long-term HBV suppression may prove to be necessary even with a low ALT level and HBV replication [19]. LdT is an effective antiviral agent. A study showed that in the treatment of decompensated cirrhotic patients with LdT for 104 weeks, in 49% of the patients, HBV DNA of less than 103 copies/ml were detected and 61% showed ALT normalization [13]. The present study compared the efficacy of LdT in treatment-naive patients with HBVrelated compensated and decompensated cirrhosis; LdT showed superior efficacy in the compensated cirrhotic patients than in the decompensated cirrhotic patients. High serum HBV DNA levels always indicate disease progression. Reduction of the serum HBV DNA level is an important predictor of response. The main endpoint of antiviral therapy is complete and durable suppression of HBV to reduce progression of disease. Previous data suggested that nondetectable serum HBV DNA at treatment week 24 was the strongest predictor for optimal outcomes at 2 years during LdT treatment [20]. In addition, the biochemical remission is one goal of antiviral therapy and is related to favorable outcomes [19,21]. HBV DNA negativity and hepatic inflammation improvement are beneficial for the regression of liver fibrosis or cirrhosis, thereby reducing or preventing progression to decompensated cirrhosis, decreasing the need for liver transplantation, and ultimately prolonging patient survival [21]. In our study, we observed that the HBV negativity rate and ALT normalized rate were significantly higher in the compensated group than in the decompensated group in the early period of treatment; the rates were similar between the two groups with the extension of treatment. These results indicated that HBV negativity and improvement in hepatic inflammation occurred earlier and faster in the compensated cirrhotic stage. Although hepatic inflammation can also be controlled ultimately with a long duration of antiviral therapy in the decompensated group, a longer time is needed compared with the compensated group. In addition, drug resistance was a common problem of nucleos(t)ide analogues therapy. Lower drug resistance rates were observed in the compensated group compared with the decompensated group, which may be beneficial for obtaining a better virological response in the compensated cirrhotic stage. Thus, earlier HBV negativity and ALT normalization were beneficial in preventing the development of hepatic fibrosis, which was a good predictor of treatment response. Serum ALB and CHE are mostly synthesized by the liver, which reflect the function of liver synthesis and reserve in patients with LC. The levels of ALB and CHE were always decreased in cirrhotic patients [22]. A previous study has reported that lamivudine treatment can increase serum ALB levels by 0.185 g/dl per year, largely
401
because of an increase in cirrhotic patients [23]. Consistent with previous findings, we also found that serum ALB levels tended to increase during the treatment period with LdT among cirrhotic patients; especially in the compensated cirrhotic patients, the ALB level increased more significantly in the early period of treatment compared with the decompensated group. This finding indicated that the liver synthetic function improved earlier and noticeably under LdT treatment in the compensated cirrhotic stage than in the decompensated cirrhotic stage. In addition, we found that 10 patients developed ascites repeatedly in the decompensated group during the treatment within week 48, further confirming that the liver synthetic function improved slowly in the decompensated cirrhotic stage. Thus, ascites inevitably occurred in the early period of antiviral treatment. Therefore, we highlighted that LC patients should receive early antiviral therapy in the compensated cirrhotic stage to improve liver synthetic function rapidly and reduce LC-related complications ultimately. Serum CHE levels increased gradually during the treatment with LdT in the two groups, indicating that the liver reserve function improved under LdT treatment. However, no statistically significant difference in the improvement in the CHE levels was observed between the two groups, possibly because of the sample size. The CTP score is an efficient evaluation system for assessment of liver function and prognosis of LC patients. Previous studies have indicated that the CTP score decreased by three points or more in 69% of patients under lamivudine treatment, thereby decreasing hepatic decompensation and liver-related mortality [24,25]. The current study also reported an improvement in the CTP score at the 1-year follow-up evaluation of patients with decompensated cirrhosis who received entecavir and tenofovir [26]. Our study found that the CTP scores improved or remained stable in the compensated group and in 95.2% of the decompensated group, suggesting that long-term treatment with LdT may stabilize or improve liver function, delay the progression of LC, and reduce LC-related complications. Esophagogastric varix is a result of portal hypertension in LC patients. Moreover, esophagogastric varix bleeding is the most risky complication of LC. A study has indicated that antiviral therapy can reduce the portal hypertension of LC patients [27]. In this study, we observed that the degree of esophageal varices was alleviated to a certain extent in both groups, with a percentage of 16.9 and 6.5, respectively, in the compensated and decompensated groups. One of the purposes of antiviral therapy is to alleviate the degree of liver fibrosis or prevent the development of liver fibrosis. A number of studies have indicated that long-term antiviral therapy can reverse liver fibrosis or cirrhosis [28–30]. Portal hypertension decreased with the reversal of liver fibrosis or cirrhosis. Moreover, the alleviation of the degree of esophagogastric
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European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 4
varices was the most direct and powerful evidence of portal hypertension improvement. Thus, this study showed that liver fibrosis or cirrhosis and portal hypertension improved with long-term LdT treatment, whether in compensated or decompensated cirrhotic patients, and thus reduced the LC-related complications. Transient elastography (FibroScan) is a rapid, noninvasive, and reproducible method for measurement of LS to evaluate the degree of liver fibrosis. The value of LS is correlated significantly with fibrosis stage [31–33]. Previous studies have indicated that for patients with chronic HBV or HCV infection, the value of LS decreased significantly compared with that at pretreatment. However, the value of LS tended to increase in patients without antiviral treatment, suggesting that effective antiviral therapy can decrease the value of LS [33–35]. In our study, we found that the value of LS decreased significantly compared with pretreatment under a long duration of LdT treatment in the compensated group. However, the decrease in the value of LS showed no statistical significance in the decompensated group. These results showed that the degree of liver fibrosis or cirrhosis can be obviously reversed or improved in the compensated cirrhotic stage with longterm LdT treatment, further confirming the conclusion of alleviation in the degree of esophageal varices. This lower value of LS may be because of HBV persistent suppression and regression of hepatic inflammation. Thus, the obvious reduction in the value of LS may reflect the better response of antiviral treatment. The clinical adverse events in this study were consistent with previous findings [11–13], which suggested the safety of LdT. Elevations in creatine kinase levels were more frequent with LdT but were not predictors of muscle-related adverse events, but any persistent, unexplained muscle-related symptoms should be evaluated during the treatment period. In addition, LC-related complications were not observed in the compensated cirrhotic patients through week 96, whereas some complications were still observed in the decompensated cirrhotic patients, which suggested that the development of hepatic decompensation did not occur in compensated cirrhotic patients during the treatment period, further confirming the superior effectiveness of antiviral therapy in the compensated cirrhosis stage. Of course, these results may need a follow-up study for confirmation.
more significantly. Especially, the value of LS decreased more obviously. These results showed that the efficacy of antiviral therapy was more significant in compensated cirrhotic patients and emphasized the importance of early antiviral treatment in the compensated cirrhotic stage, which may improve the prognosis of cirrhotic patients. However, because of the small patient sample, some results need to be confirmed in a larger series.
Acknowledgements Jia Li and Wei Lu designed the study. Xiaoling Yang, Li Zhou, Junjuan Liu, and Jinghan Wang carried out the study, collected the data, and drafted the manuscript. Jia Li and Xiaoling Yang finalized the manuscript. Conflicts of interest
There are no conflicts of interest.
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In conclusion, long-term antiviral treatment with LdT can persistently inhibit HBV replication, improve liver inflammation, increase the function of synthesis and reserve, and alleviate the degree of esophageal varices and LS, ultimately reducing HBV-related complications whether in compensated or in decompensated cirrhotic patients. However, in the compensated cirrhotic patients, ALT normalization and HBV DNA negativity were achieved earlier and faster. The liver function improved
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Comparison of telbivudine efficacy in treatment-naive patients with hepatitis B virus-related compensated and decompensated cirrhosis in 96 weeks Xiaoling Yanga,b, Jia Lib, Li Zhoub, Junjuan Liub, Jinghan Wanga,b and Wei Lub Objective Data are limited for comparison of the longterm efficacy of telbivudine (LdT) between hepatitis B virus (HBV)-related compensated and decompensated cirrhosis. The aim of this study was to compare the efficacy of LdT in treatment-naive patients with HBV-related compensated and decompensated cirrhosis in 96 weeks. Patients and methods We reviewed the data of 65 compensated and 62 decompensated cirrhotic patients treated with LdT for 96 weeks, and compared the difference in the related indicators before and after treatment between the groups. Results Alanine aminotransferase normalized rate was significantly higher in the compensated group than in the decompensated group at weeks 12 and 24 (67.7 vs. 40.3% and 78.5 vs. 53.2%, respectively, P < 0.01). Albumin level was much higher than the baseline at week 24 in the compensated group (35.1±6.2 vs. 39.9±5.1, P < 0.01), but significance was observed from week 48 onwards in the decompensated group (29.8±3.7 vs. 33.7±3.8, P < 0.05). The Child–Turcotte–Puge score either improved or remained steady in both groups. The HBV DNA negativity rate at week 12 (56.9 vs. 32.3%, P < 0.01) was higher, whereas the drug resistance rate was lower (P > 0.05), in the compensated group than in the decompensated group. The degree of esophageal varix was alleviated, including
Introduction Hepatitis B virus (HBV) is the most common hepatitis virus that causes chronic liver infection in humans, affecting more than 400 million individuals, among whom 10–20% of individuals progress to liver cirrhosis (LC) [1,2]. LC is the end stage of the natural history of chronic hepatitis B, which has been classified into two categories, namely, compensated (Child-A) and decompensated (Child-B and Child-C) cirrhosis, according to the Child– Turcotte–Puge (CTP) score [3–5]. Patients with LC eventually progress toward decompensated cirrhosis, among whom 3–4% of compensated cirrhotic patients per annum are at risk of decompensation, and the 5-year cumulative incidence of decompensation is 15% [6]. Patients with decompensated cirrhosis have poor prognoses, and the 5-year survival of untreated patients with HBV-related decompensated cirrhosis is less than 15% compared with the B85% in patients with HBV-related compensated cirrhosis [7]. Clinical studies have indicated that antiviral therapy in patients with chronic c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-691X
11 (16.9%) compensated and four (6.5%) decompensated cirrhotic patients. Liver stiffness was significantly decreased in the compensated group compared with the baseline [19.1 (7.3–32.6) vs. 14.8 (7.4–32.5), P < 0.01]; however, there was no statistical significance in the decompensated group compared with the baseline [30.5 (9.1–55.0) vs. 29.9 (8.4–53.2), P > 0.05]. Conclusion Long-term LdT treatment showed superior virological, biochemical, and clinical efficacy in the compensated cirrhotic patients. Therefore, we emphasized the importance of early antiviral treatment, which may improve the prognosis of cirrhotic patients. Eur J c 2014 Wolters Kluwer Gastroenterol Hepatol 26:396–403 Health | Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2014, 26:396–403 Keywords: chronic hepatitis B, compensated cirrhosis, decompensated cirrhosis, efficacy, telbivudine a Graduate School, Tianjin Medical University and bTianjin Second People’s Hospital, Tianjin Institute of Hepatology, Tianjin, China
Correspondence to Jia Li, MD, Tianjin Second People’s Hospital, Tianjin Institute of Hepatology, No. 7, Sudi South Road, Nankai District, 300192 Tianjin, China Tel: + 86 22 2746 8230/86 13 3021 06853; fax: + 86 22 2746 8606; e-mail: [email protected] Received 28 October 2013 Accepted 17 January 2014
HBV-related liver cirrhosis could improve liver function, reduce complications, and prolong the survival period [8–11]. Telbivudine (L-deoxythymidine, LdT) is a synthetic thymidine nucleoside analogue with potent and specific anti-HBV activity. A study has suggested that LdT treatment has more significant antiviral efficacy and histologic response at 1 year in patients with compensated cirrhosis than in individuals treated with lamivudine; Ishak fibrosis scores of 4–6 improved to 0–3 (where 0 indicates no fibrosis and 6 indicates cirrhosis) in 68% of patients receiving LdT and 61% of patients receiving lamivudine [12]. Another study has indicated that LdT treatment for 104 weeks has a higher rate of patients with both viral suppression and alanine aminotransferase (ALT) normalization, with a trend toward a higher rate of survival and significant improvement in the glomerular filtration rate, compared with lamivudine in decompensated cirrhosis [13]. In addition, Shim et al. [8] showed that the efficacy was similar in patients with HBV-related compensated and decompensated cirrhosis on 1-year entecavir monotherapy. DOI: 10.1097/MEG.0000000000000062
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Telbivudine for HBV cirrhosis Yang et al. 397
However, data for comparison of the efficacy of LdT in treatment-naive patients with chronic HBV-related compensated and decompensated cirrhosis are limited. In the present study, we carried out a retrospective analysis to compare the efficacy of LdT in treatmentnaive patients with HBV-related compensated and decompensated cirrhosis in 96 weeks.
Patients and methods Patients
This retrospective study enrolled 375 patients with chronic HBV-related LC between January 2008 and January 2013 at the Department of Hepatology from Tianjin Second People’s Hospital. LC was diagnosed on the basis of clinical symptoms, laboratory results, endoscopic evidences, sonographic findings, computed tomography, or liver histological data. The classification of compensated and decompensated cirrhosis was made on the basis of the CTP score. Patients were eligible to participate if they were between 16 and 70 years of age, received LdT (600 mg/day) monotherapy at the initiation of treatment (patients with drug resistance could receive add-on adefovir), and the treatment duration was 96 weeks. Exclusion criteria included (i) a history of nucleos(t)ide analogue treatment; (ii) coinfection with hepatitis A, hepatitis C, hepatitis D, or human immunodeficiency viruses; (iii) concomitant etiology for cirrhosis: autoimmunity, drug-induced, cardiogenic, and so on; (iv) hepatocellular carcinoma (HCC) or other malignancies; (v) history of liver or other organ transplantation; (vi) HBV-associated glomerulonephritis or functional renal insufficiency; and (vii) alcoholic liver injury, nonalcoholic steatohepatitis, or Wilson’s disease. On the basis of the inclusion criteria and exclusion criteria, 127 patients, 65 compensated cirrhotic patients and 62 decompensated cirrhotic patients, were enrolled in this study. Methods
Laboratory tests were monitored at the baseline and every 12 weeks. Biochemical indicators, including ALT, cholinesterase (CHE), and albumin (ALB), were tested with a conventional autoanalyzer using commercial reagents. Hepatitis B e antigen was assessed by electrochemiluminescence (Abbott Laboratories, Chicago, Illinois, USA). The serum HBV DNA level was measured using the realtime PCR kit (PG Biotech Company, Shenzhen, China; ABI 7500 PCR Instrument, Foster City, California, USA); with a detection limit of 500 copies/ml, it was defined as HBV negativity. Drug resistance was defined as viral breakthrough with treatment-induced HBV DNA YMDD mutations. HBV DNA YMDD mutations were tested by PCR and direct sequencing. The evaluation standard of CTP score was as follows: improvement indicates that the score decreased by over two points; deterioration indicates that the score increased by over two points; and stabiliza-
tion means that the score changed within one point [14]. Esophagogastric varix examination by endoscopy and liver stiffness (LS) measurement by FibroScan System (Echosens, Pairs, France) were carried out at the baseline at 48 and 96 weeks, respectively. The degree of esophagogastric varix was defined according to previous consensus [15]. Observation indicators include sex, age, any cirrhosisrelated complication (ascites, esophagogastric varix bleeding, hepatic encephalopathy, hepatorenal syndrome, and HCC), and mortality caused by hepatopathy. Disease-related complications were defined according to well-known practice guidelines [16–18]. Statistical analysis
Statistical analysis was carried out using SPSS 17.0 (SPSS Inc., Chicago, Illinois, USA). Data were presented as mean±SD, n (%), or median with range. Independentsamples Student’s t-test and paired-sample Student’s t-test for means, Mann–Whitney U-test for continuous variables or medians between the two groups, and Wilcoxon matched pair signed-rank test were used to evaluate the changes between the baseline and the end of follow-up evaluations for medians, and w2-test for categorized variables. Multiple comparisons at different time points between the two groups were carried out by analysis of variance. Differences were considered statistically significant at P value less than 0.05.
Results Baseline characteristics
From January 2008 to January 2013, 375 patients were diagnosed with HBV-related cirrhosis. According to the inclusion and exclusion criteria, 127 patients, 65 compensated and 62 decompensated cirrhotic, were enrolled in this study. The baseline characteristics are shown in Table 1. No significant difference was observed between the compensated and decompensated groups in sex, age, hepatitis B e antigen status, serum HBV DNA level, and ALT level. Statistical differences in serum ALB and CHE levels, CTP score, degree of esophageal varix, and LS value were noted between the two groups. The serum ALB and CHE levels were significantly higher, whereas the CTP score and the LS value were significantly lower in the compensated group than in the decompensated group. The degree of esophageal varix was more severe in the decompensated group than in the compensated group. Virological response
The HBV DNA negativity rate was higher in the compensated group than in the decompensated group at weeks 12, 24, 48, and 96, with the rate of 56.9 versus 32.3%, 67.7 versus 51.6%, 81.5 versus 75.8%, and 89.2 versus 83.4%, respectively. Statistical difference was only observed at week 12 between the two groups (w2 = 7.804, P = 0.005) (Fig. 1a).
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398 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 4
Table 1
Baseline characteristics of the enrolled patients
Sex (M/F) [n (%)] Age (mean±SD) (years)a HBeAg positivity [n (%)] HBV DNA (log10 copies/ml)a ALT [median (min–max)] (U/l)b ALB (g/l)a CHE (IU/l)a Child–Turcotte–Pugh scorea Esophageal varices [n (%)]c None Mild Moderate Severe Liver stiffness [median (min–max)] (kPa)b
Com (n = 65)
Dec (n = 62)
P
46 (70.8)/19 (29.2) 48.6±9.0 40 (61.5) 5.94±1.38 69.5 (20.5–314.8) 35.1±6.2 4086.6±1737.4 5.7±1.4
45 (72.6)/17 (27.4) 50.5±10.1 35 (56.5) 5.70±1.13 86.2 (43.4–275.2) 29.8±3.7 2801.9±1157.2 8.6±1.2
> 0.05 > 0.05 > 0.05 > 0.05 > 0.05 0.0009 0.0029 < 0.0001
12 28 13 12 19.1
0 18 20 24 30.5
< 0.0001
(18.5) (43.0) (20.0) (18.5) (7.3–32.6)
(0) (29.0) (32.3) (38.7) (9.1–55.0)
0.003
ALB, albumin; ALT, alanine aminotransferase; CHE, cholinesterase; Com, compensated cirrhosis; Dec, decompensated cirrhosis; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus. a Data are expressed as mean±SD. b Data from the skewed distribution are expressed as median (min–max). c Data are compared between the compensated cirrhosis and the decompensated cirrhosis groups by the Mann–Whitney U-test, z = – 4.037.
Fig. 1
(b) 30
80 60
Drug resistance rate (%)
HBV DNA negativity rate (%)
(a) 100
P = 0.033
40 20 0
20
10
0 12
24
48
96
96
48
Weeks
Weeks Dec
Com
(a) HBV DNA negativity rate in compensated and decompensated cirrhotic groups after treatment with LdT. A significant difference was found between the two groups at week 12 (P < 0.01). (b) Comparison of the drug resistance rate in compensated and decompensated cirrhotic groups after treatment with LdT. No significant difference was observed between the two groups (P > 0.05). Com, compensated cirrhosis; Dec, decompensated cirrhosis; HBV, hepatitis B virus; LdT, telbivudine.
The cumulative incidence of drug resistance was lower in the compensated group than in the decompensated group at weeks 48 and 96, with rates of 10.8 versus 16.1% and 21.5 versus 29.0%, respectively. However, no significant statistical difference was observed (w2 = 0.786, P = 0.375; w2 = 0.945, P = 0.331) (Fig. 1b).
at weeks 12 and 24 (67.7 vs. 40.3%, P = 0.002; 78.5 vs. 53.2%, P = 0.003, respectively). With the extension of antiviral treatment, the ALT normalized rate increased gradually in both groups, but the rate was slightly higher in the compensated group than in the decompensated group at weeks 48 and 96 (89.2 vs. 82.3.0%, P = 0.260; 89.2 vs. 85.5%, P = 0.525, respectively) (Fig. 2).
Biochemical response Alanine aminotransferase normalization
Change of serum albumin and cholinesterase
No differences in ALT levels were observed in the two groups at the baseline. However, the ALT normalized rate during the treatment period was significantly higher in the compensated group than in the decompensated group
The mean serum ALB level increased with the extension of treatment in both groups. In the compensated group, the level was much higher than the baseline at week 24 (35.1±6.2 vs. 39.9±5.1, P < 0.01), which increased more
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Telbivudine for HBV cirrhosis Yang et al. 399
significantly and was persistently higher than the baseline at weeks 48 and 96 (P < 0.01). However, the level increased slightly at week 24 in the decompensated group; no significant statistical difference was observed compared with the baseline. The level was significantly higher than the baseline from week 48 onwards in the decompensated group (29.8±3.7 vs. 33.7±3.8, P < 0.05),
and persistently higher at week 96 compared with the level at the baseline, at weeks 12 and 24 (P < 0.01) (Table 2).
Fig. 2
Change of Child–Turcotte–Puge score 100
The CTP score improved or remained stable for all patients in the compensated group; 28 of the 65 (43.1%) patients showed improvement and 37 (56.9%) showed steady condition. However, the CTP score improved or remained stable for 95.2% of the patients in the decompensated group; 25 of the 62 (40.3%) patients showed improvement, 34 (54.9%) showed steady condition, and three (4.8%) showed deterioration, without statistical difference in the change in the CTP score between the two groups (Table 3).
89.2
89.2 78.5
ALT normalized rate (%)
80
67.7
60
P = 0.003
85.5
82.3
P = 0.002 53.2
Com
40
Dec
40.3
The serum CHE level increased gradually with the extension of treatment in both groups, which performed the highest at week 96, but without statistical difference compared with the baseline at weeks 12, 24, 48, and 96 (P > 0.05) (Table 2).
20
Degree of esophageal varices
0 12
24
48
96
Weeks Change in the ALT normalized rate in compensated and decompensated cirrhotic groups after treatment with LdT. A significant difference was found between the two groups at week 12 and 24 (P < 0.05). ALT, alanine aminotransferase; Com, compensated cirrhosis; Dec, decompensated cirrhosis; LdT, telbivudine.
All patients were examined for esophageal varices by endoscopy. The degree of esophageal varices was alleviated after the treatment. Eleven of the 65 (16.9%) compensated cirrhotic patients showed an alleviated degree of esophageal varices, including three severe degrees alleviated to moderate degrees, one severe degree alleviated to moderate degree; three moderate degrees alleviated to mild degrees, two moderate degrees alleviated to none; and two mild degrees alleviated to none. Four of the 62 (6.5%) decompensated cirrhotic patients showed an alleviated degree of
Change in albumin (g/l) and cholinesterase (IU/l) in the compensated and decompensated cirrhosis groups after treatment with telbivudine
Table 2
Number
0 week
12 weeks
24 weeks
48 weeks
96 weeks
F
P
65 62
35.1±6.2 29.8±3.7
37.4±5.6 30.0±5.2
39.9±5.1** 31.8±4.7
40.6±5.5** 33.7±3.8a
41.2±5.2** 36.3±5.3b
5.91 8.81
0.0002 < 0.0001
65 62
4086.6±1737.4 2801.9±1157.2
4488.6±1795.9 3298.3±1221.0
4521.7±1988.7 3346.7±1371.1
4878.6±1970.1 3561.0±1349.6
5308.0±1898.8 3645.3±1297.5
2.04 1.65
0.0900 0.1700
ALB Com Dec CHE Com Dec
ALB, albumin; CHE, cholinesterase; Com, compensated cirrhosis; Dec, decompensated cirrhosis. a P < 0.05 compared with the baseline and 12 weeks, respectively. b P < 0.01 compared with the baseline, 12 weeks, and 24 weeks, respectively. **P < 0.01 compared with the baseline.
Table 3
Change in the Child–Turcotte–Puge score and clinical events [n (%)] CTP score (96 weeks)
Number Com Dec w2 P
65 62
Clinical events (96 weeks)
Improvement (decrease Z 2)
Stabilization (absolute change r 1)
Deterioration (increase Z 2)
HCC
Esophageal varix bleeding
Ascites
Death
28 (43.1) 25 (40.3) 0.099 > 0.05
37 (56.9) 34 (54.9) 0.056 > 0.05
0 (0) 3 (4.8) 1.465 > 0.05
3 (4.6) 8 (12.9) 2.755 > 0.05
0 (0) 3 (4.8) 1.465 > 0.05
0 (0) 10 (16.1) 9.265 0.002
0 (0) 4 (6.5) 2.473 > 0.05
Com, compensated cirrhosis; CTP, Child–Turcotte–Puge; Dec, decompensated cirrhosis; HCC, hepatocellular carcinoma.
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European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 4
Fig. 3
Fig. 4
P < 0.0001
8
12
11
60
22
24
P = 0.003
P = 0.085 P < 0.0001
30 28
12
16
0 week
96 weeks Com
20
20
18
20
0 0 week
0 96 weeks Dec
None
Moderate
Mild
Severe
Change in the degree of esophageal varices in compensated and decompensated cirrhotic groups after treatment with LdT. A total of 11 compensated cirrhotic patients showed alleviated degree of esophageal varices (three severe degrees alleviated to moderate degrees, one severe degree alleviated to mild degree, three moderate degrees alleviated to mild degrees, two moderate degrees alleviated to none, and two mild degrees alleviated to none). Four decompensated cirrhotic patients showed alleviated degree of esophageal varices (two severe degrees alleviated to moderate degrees and two moderate degrees alleviated to mild degrees). Com, compensated cirrhosis; Dec, decompensated cirrhosis; LdT, telbivudine.
esophageal varices, including two severe degrees alleviated to moderate degrees and two moderate degrees alleviated to mild degrees (Fig. 3). Liver stiffness value
The LS values were significantly lower in the compensated group than in the decompensated group at the baseline [19.1 (7.3–32.6) vs. 30.5 (9.1–55.0), z = – 2.933, P = 0.003], and decreased with the extension of treatment in both groups. The LS values was significantly decreased in the compensated group compared with the baseline [14.8 (7.4–32.5) vs. 19.1 (7.3–32.6), z = – 4.237, P < 0.0001]; however, there was no statistically significant significance in the decompensated group compared with the baseline [29.9 (8.4–53.2) vs. 30.5 (9.1–55.0), z = – 1.724, P = 0.085]. Statistical differences at week 96 were also observed between the two groups [14.8 (7.4–32.5) vs. 29.9 (8.4–53.2), z = – 4.464, P < 0.0001] (Fig. 4).
Liver stiffness value (kPa)
13
40
20
0 Com
Dec 0 week
Com
Dec
96 weeks
Change in the liver stiffness value in compensated and decompensated cirrhotic groups after treatment with LdT. Significant differences were found between the Com group and the Dec group at 0 week and 96 weeks, respectively (P = 0.003, P < 0.0001), and a significant difference was found between 0 week and 96 weeks in the compensated cirrhotic group (P < 0.0001). No significant difference was observed between 0 week and 96 weeks in the decompensated cirrhotic group (P = 0.085). The box and whiskers plot shows the range of the liver stiffness value: median (min and max). Com, compensated cirrhosis; Dec, decompensated cirrhosis; LdT, telbivudine.
Patterns of clinical adverse events, including infrequent muscle-related symptoms (fatigue, etc.), correlated poorly with elevations in creatine kinase levels and were similar in the two groups. Myopathy, characterized by muscle pain and weakness, was not observed in the two groups after the initiation of LdT.
Clinical events
Four (6.5%) patients died because of disease progression in the decompensated group. The most frequent causes of death were HCC, esophagogastric varix bleeding, and hepatic failure. No death was related to the study drug. LC-related complications were observed as follows: three (4.6%) and eight (12.9%) patients progressed to HCC in the compensated and the decompensated group, respectively. In the decompensated group, three (4.8%) patients experienced esophageal varix bleeding and 10 (16.1%) had ascites repeatedly. Patients had ascites repeatedly within week 48 of the treatment (Table 3).
During the treatment period, no serious clinical adverse events were observed. Of note, elevations in creatine kinase levels were observed in four and six patients in the compensated and the decompensated group, respectively; the elevated range was 208–557 U/l, but decreased to normal spontaneously during continued drug therapy.
Patients experiencing drug resistance were detected with the HBV DNA YMDD mutation. The results of HBV DNA YMDD mutation were M204I mutations, the patients who experienced drug resistence were treated with add-on adefovir.
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Telbivudine for HBV cirrhosis Yang et al.
Discussion HBV persistent infection is an important risk factor for the development of LC or for the occurrence of HCC. For HBV-related cirrhotic patients, long-term HBV suppression may prove to be necessary even with a low ALT level and HBV replication [19]. LdT is an effective antiviral agent. A study showed that in the treatment of decompensated cirrhotic patients with LdT for 104 weeks, in 49% of the patients, HBV DNA of less than 103 copies/ml were detected and 61% showed ALT normalization [13]. The present study compared the efficacy of LdT in treatment-naive patients with HBVrelated compensated and decompensated cirrhosis; LdT showed superior efficacy in the compensated cirrhotic patients than in the decompensated cirrhotic patients. High serum HBV DNA levels always indicate disease progression. Reduction of the serum HBV DNA level is an important predictor of response. The main endpoint of antiviral therapy is complete and durable suppression of HBV to reduce progression of disease. Previous data suggested that nondetectable serum HBV DNA at treatment week 24 was the strongest predictor for optimal outcomes at 2 years during LdT treatment [20]. In addition, the biochemical remission is one goal of antiviral therapy and is related to favorable outcomes [19,21]. HBV DNA negativity and hepatic inflammation improvement are beneficial for the regression of liver fibrosis or cirrhosis, thereby reducing or preventing progression to decompensated cirrhosis, decreasing the need for liver transplantation, and ultimately prolonging patient survival [21]. In our study, we observed that the HBV negativity rate and ALT normalized rate were significantly higher in the compensated group than in the decompensated group in the early period of treatment; the rates were similar between the two groups with the extension of treatment. These results indicated that HBV negativity and improvement in hepatic inflammation occurred earlier and faster in the compensated cirrhotic stage. Although hepatic inflammation can also be controlled ultimately with a long duration of antiviral therapy in the decompensated group, a longer time is needed compared with the compensated group. In addition, drug resistance was a common problem of nucleos(t)ide analogues therapy. Lower drug resistance rates were observed in the compensated group compared with the decompensated group, which may be beneficial for obtaining a better virological response in the compensated cirrhotic stage. Thus, earlier HBV negativity and ALT normalization were beneficial in preventing the development of hepatic fibrosis, which was a good predictor of treatment response. Serum ALB and CHE are mostly synthesized by the liver, which reflect the function of liver synthesis and reserve in patients with LC. The levels of ALB and CHE were always decreased in cirrhotic patients [22]. A previous study has reported that lamivudine treatment can increase serum ALB levels by 0.185 g/dl per year, largely
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because of an increase in cirrhotic patients [23]. Consistent with previous findings, we also found that serum ALB levels tended to increase during the treatment period with LdT among cirrhotic patients; especially in the compensated cirrhotic patients, the ALB level increased more significantly in the early period of treatment compared with the decompensated group. This finding indicated that the liver synthetic function improved earlier and noticeably under LdT treatment in the compensated cirrhotic stage than in the decompensated cirrhotic stage. In addition, we found that 10 patients developed ascites repeatedly in the decompensated group during the treatment within week 48, further confirming that the liver synthetic function improved slowly in the decompensated cirrhotic stage. Thus, ascites inevitably occurred in the early period of antiviral treatment. Therefore, we highlighted that LC patients should receive early antiviral therapy in the compensated cirrhotic stage to improve liver synthetic function rapidly and reduce LC-related complications ultimately. Serum CHE levels increased gradually during the treatment with LdT in the two groups, indicating that the liver reserve function improved under LdT treatment. However, no statistically significant difference in the improvement in the CHE levels was observed between the two groups, possibly because of the sample size. The CTP score is an efficient evaluation system for assessment of liver function and prognosis of LC patients. Previous studies have indicated that the CTP score decreased by three points or more in 69% of patients under lamivudine treatment, thereby decreasing hepatic decompensation and liver-related mortality [24,25]. The current study also reported an improvement in the CTP score at the 1-year follow-up evaluation of patients with decompensated cirrhosis who received entecavir and tenofovir [26]. Our study found that the CTP scores improved or remained stable in the compensated group and in 95.2% of the decompensated group, suggesting that long-term treatment with LdT may stabilize or improve liver function, delay the progression of LC, and reduce LC-related complications. Esophagogastric varix is a result of portal hypertension in LC patients. Moreover, esophagogastric varix bleeding is the most risky complication of LC. A study has indicated that antiviral therapy can reduce the portal hypertension of LC patients [27]. In this study, we observed that the degree of esophageal varices was alleviated to a certain extent in both groups, with a percentage of 16.9 and 6.5, respectively, in the compensated and decompensated groups. One of the purposes of antiviral therapy is to alleviate the degree of liver fibrosis or prevent the development of liver fibrosis. A number of studies have indicated that long-term antiviral therapy can reverse liver fibrosis or cirrhosis [28–30]. Portal hypertension decreased with the reversal of liver fibrosis or cirrhosis. Moreover, the alleviation of the degree of esophagogastric
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European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 4
varices was the most direct and powerful evidence of portal hypertension improvement. Thus, this study showed that liver fibrosis or cirrhosis and portal hypertension improved with long-term LdT treatment, whether in compensated or decompensated cirrhotic patients, and thus reduced the LC-related complications. Transient elastography (FibroScan) is a rapid, noninvasive, and reproducible method for measurement of LS to evaluate the degree of liver fibrosis. The value of LS is correlated significantly with fibrosis stage [31–33]. Previous studies have indicated that for patients with chronic HBV or HCV infection, the value of LS decreased significantly compared with that at pretreatment. However, the value of LS tended to increase in patients without antiviral treatment, suggesting that effective antiviral therapy can decrease the value of LS [33–35]. In our study, we found that the value of LS decreased significantly compared with pretreatment under a long duration of LdT treatment in the compensated group. However, the decrease in the value of LS showed no statistical significance in the decompensated group. These results showed that the degree of liver fibrosis or cirrhosis can be obviously reversed or improved in the compensated cirrhotic stage with longterm LdT treatment, further confirming the conclusion of alleviation in the degree of esophageal varices. This lower value of LS may be because of HBV persistent suppression and regression of hepatic inflammation. Thus, the obvious reduction in the value of LS may reflect the better response of antiviral treatment. The clinical adverse events in this study were consistent with previous findings [11–13], which suggested the safety of LdT. Elevations in creatine kinase levels were more frequent with LdT but were not predictors of muscle-related adverse events, but any persistent, unexplained muscle-related symptoms should be evaluated during the treatment period. In addition, LC-related complications were not observed in the compensated cirrhotic patients through week 96, whereas some complications were still observed in the decompensated cirrhotic patients, which suggested that the development of hepatic decompensation did not occur in compensated cirrhotic patients during the treatment period, further confirming the superior effectiveness of antiviral therapy in the compensated cirrhosis stage. Of course, these results may need a follow-up study for confirmation.
more significantly. Especially, the value of LS decreased more obviously. These results showed that the efficacy of antiviral therapy was more significant in compensated cirrhotic patients and emphasized the importance of early antiviral treatment in the compensated cirrhotic stage, which may improve the prognosis of cirrhotic patients. However, because of the small patient sample, some results need to be confirmed in a larger series.
Acknowledgements Jia Li and Wei Lu designed the study. Xiaoling Yang, Li Zhou, Junjuan Liu, and Jinghan Wang carried out the study, collected the data, and drafted the manuscript. Jia Li and Xiaoling Yang finalized the manuscript. Conflicts of interest
There are no conflicts of interest.
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In conclusion, long-term antiviral treatment with LdT can persistently inhibit HBV replication, improve liver inflammation, increase the function of synthesis and reserve, and alleviate the degree of esophageal varices and LS, ultimately reducing HBV-related complications whether in compensated or in decompensated cirrhotic patients. However, in the compensated cirrhotic patients, ALT normalization and HBV DNA negativity were achieved earlier and faster. The liver function improved
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