Journal of Viral Hepatitis, 2014
doi:10.1111/jvh.12358
Long-term entecavir or tenofovir disoproxil fumarate therapy in treatment-na€ıve chronic hepatitis B patients in the real-world setting R. Idilman,1 F. Gunsar,2 M. Koruk,3 O. Keskin,1 C. E. Meral,2 M. Gulsen,2 A. H. Elhan,4 U. S. Akarca2 and C. Yurdaydin1 1Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey; 2
Department of Gastroenterology, Ege University Faculty of Medicine, Izmir, Turkey; 3Department of Gastroenterology, Gaziantep University Faculty
of Medicine, Gaziantep, Turkey; and 4Department of Biostatistics, Ankara University School of Medicine, Ankara, Turkey Received July 2014; accepted for publication September 2014
SUMMARY. The aim of this study was to determine the
long-term efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) on the natural course of disease in chronic hepatitis B patients (CHB) with/without cirrhosis in clinical practice. A total of 355 treatment-na€ıve CHB patients were enrolled into the study. The primary outcome measure was viral suppression as defined by serum HBV DNA level 1 log10 decline in baseline serum HBV DNA level at week 48. A virological breakthrough was defined as >1 log10 increase in serum HBV DNA level above nadir or confirmed detectability of HBV DNA after having an undetectable result.
Patients This was a retro/prospective multicenter study. Between February 2007 and February 2013, a total of 355 treatment-naive CHB patients (M/F: 249/106) seen in the Liver Diseases Outpatient Clinics, Departments of Gastroenterology of Ankara, Ege, Gaziantep Universities Schools of Medicine were enrolled into the study. The diagnosis of CHB was made on the basis of biochemical, serological, virological and histological data, when available. All patients with CHB, except patients with cirrhosis underwent liver biopsy according to regulation of the insurance body in Turkey to receive antiviral medication free of charge. Cirrhosis was defined clinically (thrombocytopenia, increased prothrombin time, the presence of splenomegaly and signs of decompensation) and histologically when available. Patients with CHB who were co-infected with hepatitis C virus, delta virus and human immunodeficiency virus were excluded. Among the 355 patients, 183 patients were treated with ETV, 0.5 mg daily, while 172 were treated with TDF, 245 mg daily, at the discretion of the investigators. All patients were screened for HCC before antiviral therapy started. All patients were followed for at least 6 months. Data were collected from outpatient visit charts. This study was approved by the local ethical committee of Ankara University School of Medicine.
Methods Hepatitis B virus DNA levels were measured using the Roche COBAS TaqMan assay (lower limit of quantification 120 copies/mL or 20 IU/mL). HBsAg and HBeAg loss, seroconversion and drug resistance were monitored.
Follow-up Patients were seen at 3-month intervals in the outpatient clinic during the follow-up period. The Model for End-Stage Liver Disease (MELD) score was used for assessing the severity of chronic liver disease. Further investigations included surveillance for HCC with radiological imaging and alpha-fetoprotein determinations every 6–12 months. If necessary, dynamic computed tomography or magnetic resonance imaging was performed. Possible AEs of the antiviral agents were assessed.
Statistical analyses Mean, standard deviation, median and percentage were used for descriptive statistics. Comparison between two groups was assessed by Mann–Whitney U-test for non-normally distributed variables. Nominal variables were evaluated by chi-square test. Longitudinal measured dichotomous variables were modelled by generalized linear models using logit link function and binomial probability distribution for outcome variable. This way, differences among both predictive factors and treatment groups were analysed. The cumulative survival estimations were performed using the method of Kaplan–Meier algorithm, and the comparison between groups was evaluated with logrank test. To define independent risk factors of outcome variable, multiple logistic regression analysis was used and adjusted odds ratios were calculated with 95% confidence intervals. A P value 0.5 mg/dL) and estimated creatinine clearance ( 0.05). HBsAg loss occurred in four patients (two were cirrhotic); one was on ETV and three were on TDF treatment. The patient on ETV was HBeAg-positive, noncirrhotic, with a high baseline HBV DNA level of 7 log10 IU/mL. In the remaining three patients with TDF treatment, one was HBeAg-positive, noncirrhotic, with a high baseline HBV DNA level of 8 log10 IU/mL and the remaining two were HBeAg-negative: one noncirrhotic with a high HBV DNA
3
level of 8 log10 IU/mL and 1 cirrhotic with a low HBV DNA level of 600 IU/mL. The HBeAg-negative, noncirrhotic patient had experienced HBsAg seroconversion 14 months after TDF therapy.
Development of HCC Hepatocellular carcinoma was diagnosed in 17 patients (4.8%, 17/355). The cumulative probability of the development of HCC was 3.3% at 1 year, 4.2% at 2 years, 5.9% at 3 years and 7.3% at 4 years of antiviral therapy. HCC occurred more frequently in patients with cirrhosis (11.5%, 16/139) than in those without cirrhosis (0.05%, 1/216, P < 0.001) (Fig. 2a), but there was no significant difference among patients treated with ETV or TDF (Fig. 2b). Cirrhotic patients with HCC showed a tendency to be older compared with cirrhotic patients without HCC (55.4 7.9 vs 50.9 11.8 years, P = 0.08). Of note, only one CHB patient without cirrhosis was diagnosed with HCC at 10 months of ETV treatment (1/216). With logistic regression analysis, the development of HCC was significantly associated with older age (adjusted OR: 4.2, P = 0.031) and the presence of cirrhosis (adjusted OR: 20.7, P = 0.004) (Table 2). Among 17 patients with HCC, seven were on ETV treatment, whereas 10 were on TDF treatment. Twelve were diagnosed as HCC in the first year of the antiviral treatment, one in the second year and four in the third and fourth years of the treatment. At the time of the HCC diagnosis, 10 patients had VR, whereas the remaining seven had a detectable serum HBV DNA level. Four of the 17 patients with HCC were treated with radiofrequency ablation (RF), four with transarterial chemoembolization (TACE), one with percutaneous ethanol injection and one with radionucleotide therapy; two patients underwent successful liver transplantation, and five patients died because of disease progression.
Table 1 Characteristics of chronic hepatitis B patients with/without cirrhosis
Age (year) Gender (M/F) Baseline ALT (U/L) Baseline HBV DNA Log10 IU/mL HBeAg positivity Baseline total bilirubin (mg/dL) Baseline GGT (U/L) Baseline albumin (g/dL) Platelet count (9109/L) Baseline creatinine mg/dL Baseline histological activity index Baseline Ishak fibrosis score
Overall (n = 355)
Noncirrhotics (n = 216)
Cirrhotics (n = 139)
P
46.2 12.7 (47) 249/106 102.6 146.0 (61.0) 5.97 1.72 (6.23) 29.6% (n = 105) 0.97 0.78 (0.80) 57.7 67.4 (34) 4.1 0.62 (4.3) 180.1 84.0 (178) 0.86 0.23 (0.85) -
43.1 12.6 (44) 140/76 118.6 169.7 (68) 6.28 1.57 (6.48) 34.3% (n = 74) 0.76 0.52 (0.67) 43.0 49.2 (30) 4.35 0.47 (4.4) 217.9 74.0 (213) 0.88 0.20 (0.87) 7.4 3.1 (7.0) 2.2 1.49 (2.0)
50.9 11.3 (52) 109/30 77.1 92.4 (45.5) 5.50 1.85 (6.00) 22.3% (n = 31) 1.29 0.99 (1.06) 81.3 84.2 (56.5) 3.77 0.67 (3.8) 122.6 63.1 (117) 0.84 0.26 (0.82) -
doi:10.1111/jvh.12358
Long-term entecavir or tenofovir disoproxil fumarate therapy in treatment-na€ıve chronic hepatitis B patients in the real-world setting R. Idilman,1 F. Gunsar,2 M. Koruk,3 O. Keskin,1 C. E. Meral,2 M. Gulsen,2 A. H. Elhan,4 U. S. Akarca2 and C. Yurdaydin1 1Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey; 2
Department of Gastroenterology, Ege University Faculty of Medicine, Izmir, Turkey; 3Department of Gastroenterology, Gaziantep University Faculty
of Medicine, Gaziantep, Turkey; and 4Department of Biostatistics, Ankara University School of Medicine, Ankara, Turkey Received July 2014; accepted for publication September 2014
SUMMARY. The aim of this study was to determine the
long-term efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) on the natural course of disease in chronic hepatitis B patients (CHB) with/without cirrhosis in clinical practice. A total of 355 treatment-na€ıve CHB patients were enrolled into the study. The primary outcome measure was viral suppression as defined by serum HBV DNA level 1 log10 decline in baseline serum HBV DNA level at week 48. A virological breakthrough was defined as >1 log10 increase in serum HBV DNA level above nadir or confirmed detectability of HBV DNA after having an undetectable result.
Patients This was a retro/prospective multicenter study. Between February 2007 and February 2013, a total of 355 treatment-naive CHB patients (M/F: 249/106) seen in the Liver Diseases Outpatient Clinics, Departments of Gastroenterology of Ankara, Ege, Gaziantep Universities Schools of Medicine were enrolled into the study. The diagnosis of CHB was made on the basis of biochemical, serological, virological and histological data, when available. All patients with CHB, except patients with cirrhosis underwent liver biopsy according to regulation of the insurance body in Turkey to receive antiviral medication free of charge. Cirrhosis was defined clinically (thrombocytopenia, increased prothrombin time, the presence of splenomegaly and signs of decompensation) and histologically when available. Patients with CHB who were co-infected with hepatitis C virus, delta virus and human immunodeficiency virus were excluded. Among the 355 patients, 183 patients were treated with ETV, 0.5 mg daily, while 172 were treated with TDF, 245 mg daily, at the discretion of the investigators. All patients were screened for HCC before antiviral therapy started. All patients were followed for at least 6 months. Data were collected from outpatient visit charts. This study was approved by the local ethical committee of Ankara University School of Medicine.
Methods Hepatitis B virus DNA levels were measured using the Roche COBAS TaqMan assay (lower limit of quantification 120 copies/mL or 20 IU/mL). HBsAg and HBeAg loss, seroconversion and drug resistance were monitored.
Follow-up Patients were seen at 3-month intervals in the outpatient clinic during the follow-up period. The Model for End-Stage Liver Disease (MELD) score was used for assessing the severity of chronic liver disease. Further investigations included surveillance for HCC with radiological imaging and alpha-fetoprotein determinations every 6–12 months. If necessary, dynamic computed tomography or magnetic resonance imaging was performed. Possible AEs of the antiviral agents were assessed.
Statistical analyses Mean, standard deviation, median and percentage were used for descriptive statistics. Comparison between two groups was assessed by Mann–Whitney U-test for non-normally distributed variables. Nominal variables were evaluated by chi-square test. Longitudinal measured dichotomous variables were modelled by generalized linear models using logit link function and binomial probability distribution for outcome variable. This way, differences among both predictive factors and treatment groups were analysed. The cumulative survival estimations were performed using the method of Kaplan–Meier algorithm, and the comparison between groups was evaluated with logrank test. To define independent risk factors of outcome variable, multiple logistic regression analysis was used and adjusted odds ratios were calculated with 95% confidence intervals. A P value 0.5 mg/dL) and estimated creatinine clearance ( 0.05). HBsAg loss occurred in four patients (two were cirrhotic); one was on ETV and three were on TDF treatment. The patient on ETV was HBeAg-positive, noncirrhotic, with a high baseline HBV DNA level of 7 log10 IU/mL. In the remaining three patients with TDF treatment, one was HBeAg-positive, noncirrhotic, with a high baseline HBV DNA level of 8 log10 IU/mL and the remaining two were HBeAg-negative: one noncirrhotic with a high HBV DNA
3
level of 8 log10 IU/mL and 1 cirrhotic with a low HBV DNA level of 600 IU/mL. The HBeAg-negative, noncirrhotic patient had experienced HBsAg seroconversion 14 months after TDF therapy.
Development of HCC Hepatocellular carcinoma was diagnosed in 17 patients (4.8%, 17/355). The cumulative probability of the development of HCC was 3.3% at 1 year, 4.2% at 2 years, 5.9% at 3 years and 7.3% at 4 years of antiviral therapy. HCC occurred more frequently in patients with cirrhosis (11.5%, 16/139) than in those without cirrhosis (0.05%, 1/216, P < 0.001) (Fig. 2a), but there was no significant difference among patients treated with ETV or TDF (Fig. 2b). Cirrhotic patients with HCC showed a tendency to be older compared with cirrhotic patients without HCC (55.4 7.9 vs 50.9 11.8 years, P = 0.08). Of note, only one CHB patient without cirrhosis was diagnosed with HCC at 10 months of ETV treatment (1/216). With logistic regression analysis, the development of HCC was significantly associated with older age (adjusted OR: 4.2, P = 0.031) and the presence of cirrhosis (adjusted OR: 20.7, P = 0.004) (Table 2). Among 17 patients with HCC, seven were on ETV treatment, whereas 10 were on TDF treatment. Twelve were diagnosed as HCC in the first year of the antiviral treatment, one in the second year and four in the third and fourth years of the treatment. At the time of the HCC diagnosis, 10 patients had VR, whereas the remaining seven had a detectable serum HBV DNA level. Four of the 17 patients with HCC were treated with radiofrequency ablation (RF), four with transarterial chemoembolization (TACE), one with percutaneous ethanol injection and one with radionucleotide therapy; two patients underwent successful liver transplantation, and five patients died because of disease progression.
Table 1 Characteristics of chronic hepatitis B patients with/without cirrhosis
Age (year) Gender (M/F) Baseline ALT (U/L) Baseline HBV DNA Log10 IU/mL HBeAg positivity Baseline total bilirubin (mg/dL) Baseline GGT (U/L) Baseline albumin (g/dL) Platelet count (9109/L) Baseline creatinine mg/dL Baseline histological activity index Baseline Ishak fibrosis score
Overall (n = 355)
Noncirrhotics (n = 216)
Cirrhotics (n = 139)
P
46.2 12.7 (47) 249/106 102.6 146.0 (61.0) 5.97 1.72 (6.23) 29.6% (n = 105) 0.97 0.78 (0.80) 57.7 67.4 (34) 4.1 0.62 (4.3) 180.1 84.0 (178) 0.86 0.23 (0.85) -
43.1 12.6 (44) 140/76 118.6 169.7 (68) 6.28 1.57 (6.48) 34.3% (n = 74) 0.76 0.52 (0.67) 43.0 49.2 (30) 4.35 0.47 (4.4) 217.9 74.0 (213) 0.88 0.20 (0.87) 7.4 3.1 (7.0) 2.2 1.49 (2.0)
50.9 11.3 (52) 109/30 77.1 92.4 (45.5) 5.50 1.85 (6.00) 22.3% (n = 31) 1.29 0.99 (1.06) 81.3 84.2 (56.5) 3.77 0.67 (3.8) 122.6 63.1 (117) 0.84 0.26 (0.82) -
