46 Original article
Entecavir has high efficacy and safety in white patients with chronic hepatitis B and comorbidities Maria Butia, Rosa M. Morillasg, Juan Pérezn, Martín Prietot, Ricard Solàb, Antonio Palaue, Moisés Diagou, Lucía Bonetf, Adolfo Gallegoc, Javier García-Samaniegoh, Milagros Testillanom, Manuel Rodríguezp, Gregorio Castellanoi, María L. Gutiérrezq, Manuel Delgador, Antoni Masd, Manuel Romero-Gómezo, José L. Callejaj, Agustina González-Guiradok, Juan I. Arenass, Luisa García-Bueyl, Raúl Andradev, Ana Gilaw and the ORIENTE-2 study group Objectives The aim of this study was to evaluate the efficacy and safety of entecavir monotherapy in nucleos(t) ide-naive chronic hepatitis B patients and to analyse the influence of the comorbidity burden on therapy outcome. Methods We retrospectively analysed data from 237 nucleos(t)ide-naive chronic hepatitis B white patients treated with entecavir (0.5 mg/day) at 23 Spanish centres. For the efficacy and safety analyses, patients were grouped according to their baseline comorbidities. Results The mean age of the cohort was 43 years (range: 19–82 years); 73% were male, 83% were white, and 33% were hepatitis B e antigen (HBeAg) positive. At baseline, the median hepatitis B virus DNA level was 6.20 log10 IU/ml. Of the patients, 18% had cirrhosis, 9.7% had diabetes, 16.3% had hypertension, and 15.7% had obesity; 13.4% of patients had more than one comorbid condition. Virological and ORIENTE-2 study group: Edurne Almandoz (H. U. Donostia), Mari Alonso (H. U. La Princesa, Madrid), Raúl Andrade (H. Virgen de la Victoria, Málaga), Juan Ignacio Arenas (H. U. Donostia), Lucía Bonet (H. Son Espases, Palma de Mallorca), Maria Alonso Burgal (H. General Universitario de Castellón), Maria Buti (H. Vall d'Hebron, Barcelona), José Luis Calleja (H. Puerta del Hierro, Madrid), Gregorio Castellano (H. U. 12 de Octubre, Madrid), Manuel Delgado (H. U. de La Coruña), Moisés Diago (H. U. General de Valencia), Rafael Esteban (H. Vall d'Hebron, Barcelona), Conrado Fernández (H. U. Fundación Alcorcón), Adolfo Gallego (H. de la Santa Creu i Sant Pau, Barcelona), Rocío Gallego (H. U. de Valme, Sevilla), Javier García-Samaniego (H. Carlos III, Madrid), Luisa GarcíaBuey (H. U. La Princesa, Madrid), Cristina Gely Vila (H. de la Santa Creu i Sant Pau, Barcelona), Ana Gila (H. U. San Cecilio, Granada), Dolors Giménez (H. del Mar, Barcelona), Maca Gómez (H. Puerta del Hierro, Madrid), Alexandra Gómez García (H. U. Donostia), María Luisa González-Diéguez (H. Central de Asturias, Oviedo), Agustina González-Guirado (Fundación Jiménez Díaz, Madrid), María Luisa Gutiérrez (H. U. Fundación Alcorcón), Antonio Madejón (H. Carlos III, Madrid), María Luisa Manzano (H. U. 12 de Octubre, Madrid), Antoni Mas (H. Clínic, Barcelona), Inmaculada Moreno Herrera (H. Virgen de la Victoria, Málaga), Rosa Maria Morillas (H. U. Germans Trias i Pujol, Badalona), Carmen A. Navascués (H. Central de Asturias, Oviedo), Antonio Palau (H. General Universitario de Castellón), Juan Pérez (H. Virgen Macarena, Sevilla), Ramon Planas (H. U. Germans Trias i Pujol, Badalona), Juan Carlos Porres Cubero (Fundación Jiménez Díaz, Madrid), Martín Prieto (H. Universitario y Politécnico La Fe, Valencia), Ioana Riaño Fernández (H. U. Donostia), Manuel Rodríguez (H. Central de Asturias, Oviedo), Manuel Romero-Gómez (H. U. de Valme, Sevilla), Javier Salmerón (H. U. San Cecilio, Granada), José María Sánchez-Tapias (H. Clínic, Barcelona), Ricard Solà (H. del Mar, Barcelona), Roser Sotelo (H. Vall d'Hebron, Barcelona), Milagros Testillano (H. de Cruces, Bizkaia), Carmen Vinaixa (H. Universitario y Politécnico La Fe, Valencia). 0954-691X © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
biochemical responses at month 36 were obtained independently of the patients’ baseline comorbid condition. Of 10 HBeAg-positive patients who discontinued treatment after HBeAg seroconversion, those who had not also cleared HBsAg (six) experienced virological recurrence in a median 5.6 months. There were no treatment discontinuations due to adverse events. Three patients were diagnosed with hepatocellular carcinoma at months 12, 30 and 54, and six experienced hepatic decompensation during follow-up. The median serum creatinine levels did not increase after 36 months of treatment, even in patients with comorbidities. Conclusion Entecavir is safe, well tolerated, and highly effective, even in patients with comorbid condition(s). Discontinuation of treatment in patients who have not been cleared of HBsAg may lead to virological recurrence. Eur J Gastroenterol Hepatol 27:46–54 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2015, 27:46–54 Keywords: chronic hepatitis B, clinical practice, comorbidity, drug safety, entecavir a
CIBER on Liver and Digestive Diseases (CIBERehd), Hospital Vall d'Hebron, Hospital del Mar, IMIM, Universitat Autònoma de Barcelona, cHospital de la Santa Creu i Sant Pau, dHospital Clínic, Barcelona, eCIBERehd H. La Fe, Hospital General Universitario de Castellón, Castellón, fHospital Son Espases, Palma de Mallorca, gCIBERehd, Hospital Universitari Germans Trias i Pujol, Badalona, hCIBERehd, Hospital Carlos III, iHospital Universitario 12 de Octubre, j Hospital Puerta del Hierro, kFundación Jiménez Díaz, lCIBERehd, Hospital Universitario La Princesa, Madrid, mHospital de Cruces, Bizkaia, nHospital Virgen Macarena, oCIBERehd, Hospital Universitario de Valme, Sevilla, pHospital Central de Asturias, Oviedo, qHospital Universitario Fundación Alcorcón, Alcorcón, r Hospital Universitario de La Coruña, A Coruña, sHospital Universitario Donostia, Donostia, tCIBERehd, Hospital Universitario y Politécnico La Fe, uHospital General Universitario de Valencia, Valencia, vCIBERehd, Hospital Virgen de la Victoria, Málaga and wHospital Universitario San Cecilio, Granada, Spain b
Correspondence to Maria Buti, PhD, Hospital Vall d’Hebron, Passeig de la Vall d’Hebron, 119-129, 08035 Barcelona, Spain Tel: + 34 93 275 61 40; fax: + 34 93 427 44 95; e-mail: [email protected] Received 6 June 2014 Accepted 23 July 2014
Introduction According to the WHO, nearly 360 million individuals are chronically infected with hepatitis B virus (HBV) [1]. DOI: 10.1097/MEG.0000000000000195
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Entecavir monotherapy in patients with comorbidities Buti et al. 47
In Europe, despite strict blood screening, vaccination, and improved healthcare standards, over 14 700 cases of HBV infection are reported yearly to the European Centre for Disease Control [2]. Spain accounts for 4.5% of all HBV infections occurring in Europe and has an infection rate of 1.44 cases/100 000 inhabitants. Patients with untreated chronic hepatitis B (CHB) have an increased risk of developing hepatic cirrhosis, decompensated liver function and hepatocellular carcinoma (HCC) [3,4]. Overall, HBV-related liver disorders (including HCC) account for over 600 000 deaths/year worldwide [1]. Because of the persistence of covalently closed circular DNA in the nucleus of infected hepatocytes, HBV cannot be completely eradicated [5]. However, lowering the levels of circulating HBV DNA decreases the risk of liver-related mortality [6,7] and leads to higher hepatitis B e antigen (HBeAg) seroconversion rates, an important goal related to clinical remission and a necessary step in the transition to inactive HBV carrier status [8]. Maintaining circulating HBV DNA at undetectable levels is therefore a key endpoint of CHB treatment [9,10]. The European Association for the Study of Liver recommends the nucleos(t)ide analogues (NAs) tenofovir and entecavir as first-line therapy for patients with CHB [9,11]. The guanosine analogue entecavir is a potent and selective inhibitor of HBV replication with a high barrier-to-viral resistance [12–14], and it has proven to reduce the incidence of HCC in the overall population of CHB patients [13] and to reverse fibrosis or cirrhosis in CHB patients with advanced disease [15]. Current clinical guidelines recommend stopping treatment with NAs at the time of HBsAg seroconversion in HBeAg-negative patients, and at 12 months after HBeAg seroconversion in HBeAg-positive patients [9]. Nonetheless, several authors have reported virological recurrence following treatment discontinuation despite HBeAg seroconversion [16–18], suggesting that treatment in HBeAg-positive patients should be extended at least until HBsAg has been also cleared [17,19]. Despite the proven efficacy of entecavir in CHB treatment, HBsAg clearance rarely occurs in more than 1% of patients during the first year of NA treatment [20] and usually requires long periods of treatment. However, safety data on long-term real-life use of entecavir are limited, particularly in the white population. Phase II and III clinical trials exhaustively collect safety data, but usually exclude older patients and those with liverrelated comorbidities such as cirrhosis; hence, the participant profile differs from that of real-life patients. Older age and underlying cirrhosis are risk factors for HCC in CHB patients [8,21], whereas comorbidities such as hypertension and diabetes mellitus can affect renal function [22,23], which could make patients more susceptible to potential renal toxicity associated with longterm drug therapies, including NAs [24,25]. The strict
inclusion/exclusion criteria of most clinical trials are necessary to clearly establish the differences between a tested drug and the current standard of care; however, they can also overestimate the efficacy and safety of the drug in real-life practice. Indeed, the potential renal toxicity reported for some NAs in real-life practice had not been previously observed in the corresponding registration studies [24,26], suggesting that the differing characteristics of patients included in clinical studies and patients encountered in everyday clinical practice should be considered when analysing the safety profile of entecavir in long-term use. The aim of this study was to evaluate the safety and efficacy outcomes of 3 years of entecavir monotherapy in a highly heterogeneous cohort of Spanish NA-naive CHB patients. Further, we analysed the influence of the baseline comorbidity burden on the clinical outcome of entecavir treatment, as well as the durability of the response after treatment discontinuation.
Methods Study population
The cohort consisted of 237 adult nucleotide-naive CHB patients from 23 Spanish centres, including 190 patients from the ORIENTE study cohort [27] and 47 additional patients treated with entecavir (Baraclude; Bristol-Myers Squibb, Anagni, Italy) monotherapy (0.5 mg film-coated tablet once daily) for at least 36 months as the only nucleotide-based therapy. For study inclusion, patients had to have compensated liver function and confirmed HBeAg-positive or HBeAg-negative status before beginning follow-up. Patients with hepatitis C infection, hepatitis D infection, or HIV infection were excluded, as were pregnant women. The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki in effect at the time (59th, Seoul 2008). The ethics committees of the participating centres approved the study, and local requirements for obtaining informed consent were followed. Data collection
The main purpose of this retrospective observational study was to collect data from CHB patients over 36 months of entecavir treatment. Data on adverse events and long-term entecavir resistance were collected for an additional 24 months (every 6 months after month 36). Sociodemographic data (age, sex and country of origin), information on underlying comorbidities obtained from the patients’ medical records, and CHB characteristics (time with HBV infection, previous interferon treatment and biopsy and elastography studies) were recorded at baseline. Data from physical examination, from laboratory tests results [serum alanine aminotransferase (ALT), bilirubin, albumin and creatinine levels, and routine haematological assessments], on virological parameters (HBV DNA levels) and on serological parameters [HBeAg, antibody against HBeAg (anti-HBeAg), HBsAg
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48 European Journal of Gastroenterology & Hepatology 2015, Vol 27 No 1
and antibody against HBsAg (anti-HBsAg)] were collected at baseline, at months 3 and 6, and every 6 months thereafter, up to the end of the study. Efficacy analysis
The primary endpoint of the study was the percentage of patients who achieved a virological response (defined as serum HBV DNA levels < 50 IU/ml on PCR) after 36 months of treatment with entecavir. The secondary endpoints included the percentage of patients who achieved a biochemical response [ALT normalization, defined as ALT ≤ 1 × upper limit of normal (ULN)] and a serological response (HBeAg loss, HBeAg seroconversion, HBsAg loss, and/or HBsAg seroconversion) up to the end of treatment with entecavir. For the analysis of the main efficacy endpoints, patients were studied as an overall population, according to their HBeAg-positive or HBeAg-negative status, and according to their comorbid condition, dividing them into patients without comorbidities and patients with one or more comorbidity. In patients who showed no virological response at completion of the study, the presence of resistance mutations (determined by reverse hybridization) was analysed for. Virological recurrence was defined as having serum HBV DNA levels of 50 IU/ml or higher after achieving virological response. Laboratory tests
HBV DNA levels were measured using a real-time PCRbased assay. Most centres used the TaqMan HBV test (CAP-CTM Roche; Molecular Systems Inc., Branchburg, New Jersey, USA) for serum HBV DNA determination, and samples from centres equipped with other systems were reanalysed using this technique. The virological response was arbitrarily set at less than 50 IU/ml to enable assessment of consistency with the virological response observed in the registration studies, defined as HBV DNA levels less than 300 copies/ml (∼50 IU/ml). HBV polymerase gene mutations were detected using the INNOLiPA assay (Innogenetics, Ghent, Belgium). Serological parameters (HBsAg, anti-HBsAg, HBeAg and anti-HBeAg levels) were determined using a commercially available enzyme immunoassay. ALT and serum creatinine levels were determined using the routine technique from each centre, and results are expressed in multiples of ULN, according to the limits set by each centre. Safety
Data on adverse events were collected from the patients’ medical history records and graded according to the WHO Toxicity Grading Scale for Determining the Severity of Adverse Events [28]. Liver disease decompensations and on-treatment HCCs were recorded. Serum creatinine was used as a marker for kidneymediated abnormalities, and serum albumin, bilirubin and ALT were used as biochemical markers of liver disease. Serum creatinine elevations were classified
as grade 1 (1.1–1.5 × ULN), grade 2 (1.6–3.0 × ULN) or grade 3 (3.1–6.0 × ULN), and serum ALT elevations as grade 1 (1.25–2.5 × ULN), grade 2 (2.6–5.0 × ULN), grade 3 (5.1–0.0 × ULN) or grade 4 (>10.0 × ULN). Ontreatment ALT flares (defined as ALT > 10 × ULN or > 2 × baseline value) were also recorded. For the data analysis of serum creatinine elevations, patients were grouped according to their baseline comorbid conditions into three groups: those without comorbidities, those with one or more comorbidity and those with hypertension and diabetes mellitus. Statistical analysis
The main categorical variables are expressed as frequency and percentage at each visit in the overall population and in each group of interest. Quantitative variables are expressed as mean and SD, median and interquartile range (IQR) or maximum and minimum. Seven patients with undetectable HBV DNA levels at months 30 and 42 were assumed to also have undetectable HBV DNA levels at month 36, even though values from that visit were missing. Other patients with missing data were excluded from analyses. Categories were compared using the χ2-test or Fisher’s exact test, medians using the Mann–Whitney U-test and means using the ttest. A Kaplan–Meier analysis, on the basis of rightcensored observations, was carried out to estimate the time to achieve virological and serological responses. Statistical significance was set at a P-value of less than 0.05. Statistical analyses were carried out using SPSS version 15.0 for Windows (SPSS Inc., Chicago, Illinois, USA).
Results Patient characteristics
The studied cohort comprised 237 patients: 77 (32%) HBeAg positive and 160 (68%) HBeAg negative. The baseline characteristics of the study population are shown in Table 1. HBeAg-positive patients had significantly higher baseline HBV DNA levels (7.72 vs. 5.38; P < 0.001) and ALT levels (91.0 vs. 59.0 U/l; P = 0.002). Four main comorbidities were identified in the study population: 18% of patients had cirrhosis (including patients previously diagnosed with cirrhosis and those with baseline fibrosis grade of 4 or higher [29]), 16% had hypertension (including patients previously diagnosed with hypertension and those with systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg [22]), 10% had diabetes mellitus (including patients previously diagnosed with diabetes mellitus and those with fasting serum glucose levels ≥ 126 mg/dl [23]), and 16% had obesity (patients with BMI ≥ 30 kg/m2 [30]). The baseline characteristics of patients with comorbidities and patients without comorbidities are shown in Table 2. A total of 201 patients completed the study at month 36, and 119, 91, 47 and 14 patients were additionally followed up for adverse events
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Entecavir monotherapy in patients with comorbidities Buti et al. 49
Table 1
Baseline patient demographics and disease characteristics Overall (N = 237)
Age (years)a Male [n (%)] Ethnic group [n (%)] White Asian Black Other BMIb Time with infection (months)b HBV DNA (log10 IU/ml)b HBV DNA [n (%)] ≤ 6 log10 IU/ml > 6 to < 8 log10 IU/ml ≥ 8 log10 IU/ml Elevated ALT (>1 × ULN) [n (%)] Total serum bilirubin (mg/dl)b Platelets (×103/μl)b Previous treatment with IFN [n (%)] Biopsy [n (%)] Fibrosis stage [n (%)]c F0–F2 F3–F6 Cirrhotic [n (%)] Serum creatinine (mg/dl)b Fasting serum glucose (mg/dl)b
HBeAg positive (N = 77)
43 (19–82) 172 (73)
HBeAg negative (N = 160)
39 (19–82) 54 (70)
44 (19–75) 118 (74)
197 26 9 5 25.4 96 6.23
(83) (11) (4) (2) (23.5–27.8) (12–225) (4.58–7.64)
57 16 1 3 25.6 24 7.72
(74) (21) (1) (4) (23.4–27.8) (12–120) (6.86–8.04)
140 10 8 2 25.3 138 5.38
(88) (7) (5) (1) (23.5–27.7) (36–276) (4.25–6.77)
109 85 43 184 0.77 195 36 130
(46) (36) (18) (78) (0.58–1.10) (152–240) (15) (55)
10 37 30 67 0.79 204 4 34
(13) (48) (39) (87) (0.59–1.06) (152–249) (5) (44)
99 48 13 117 0.76 193 32 96
(62) (30) (8) (73) (0.58–1.10) (154–240) (20) (60)
105 46 42 0.93 93
(70) (30) (18) (0.80–1.10) (87–102)
32 12 10 0.92 93
(73) (27) (14) (0.79–1.11) (85–103)
73 34 32 1.11 93
(68) (32) (20) (0.80–1.09) (87–102)
ALT, alanine aminotransferase; HBV, hepatitis B virus; IFN, interferon; ULN, upper limit of normal. Median (range). b Median (interquartile range). c Assessed by biopsy and/or elastography (Fibroscan). Proportion of patients in whom fibrosis stage was determined. a
Table 2
Baseline characteristics of patients with and without comorbidities Patients without comorbidities (N = 139) a
Age (years) Male [n (%)] BMIb Time with infection (months)b HBV DNA (log10 IU/ml)b ALT (U/l)b Elevated ALT (>1 × ULN) [n (%)] Total serum bilirubin (mg/dl)b Platelets (×103/μl)b Fibrosis stage [n (%)]c F0–F2 F3–F6 Serum creatinine (mg/dl)b
40 103 24.5 108 6.3 75.0 110 0.70 202
(19–70) (74) (23.2–26.2) (12–228) (4.7–7.8) (45.0–111.0) (79) (0.53–1.10) (171–237)
76 (85) 13 (15) 0.90 (0.80–1.00)
Patients with comorbidities (N = 97) 50 68 27.4 84 6.1 60.0 79 0.79 186
(19–82) (70) (24.5–31.2) (12–216) (4.3–7.3) (43.0–131.0) (75) (0.60–1.10) (140–249)
29 (47) 33 (53) 0.96 (0.83–1.14)
ALT, alanine aminotransferase; HBV, hepatitis B virus; ULN, upper limit of normal. a Median (range). b Median (interquartile range). c Assessed by biopsy and/or elastography (Fibroscan). Proportion of patients in whom fibrosis stage was determined.
until months 42, 48, 54 and 60, respectively. Seven patients were lost to follow-up: three at month 12, three at month 18 and two at month 30. Virological and biochemical responses
After 36 months of treatment with entecavir, 96% of patients (89% in the HBeAg-positive group and 98% in the HBeAg-negative group) achieved virological response (Fig. 1a) and 86% of patients (82% in the HBeAg-positive group and 89% in the HBeAg-negative group) achieved biochemical response. Virological and biochemical responses at month 36 were both achieved independently of the patients’ baseline HBV DNA levels, ALT levels, and HBeAg-positive or HBeAg-
negative status. The presence of underlying comorbidities did not influence virological response over 36 months of treatment (Fig. 1b). Six patients who had liver decompensation during follow-up ended the study with undetectable HBV DNA levels. Overall, a primary treatment response (defined as a ≥ 1 log10 IU/ml decrease in HBV DNA from baseline to month 3) was observed in 94% of patients (95% in the HBeAg-negative group and 92% in the HBeAg-positive group). Sixteen of the 237 patients did not achieve virological response before completing the study: four patients required additional treatment with tenofovir (three at month 12 and one at month 36), eight either withdrew or reported lack of adherence to the treatment schedule and five showed
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50 European Journal of Gastroenterology & Hepatology 2015, Vol 27 No 1
Fig. 1
(a)
(b) Overall
HBeAg positive
HBeAg negative
Overall
Without comorbidities
With comorbidities
100 90 80 70 60 50 40 30 20 10 0
Proportion of patients (%)
100 90 80 70 60 50 40 30 20 10 0 Treatment month No. of evaluable patients
M3 174 60 114
M6
M12
M18
M24
186 64 122
230 75 155
194 61 133
197 58 139
M30
M3
M36
183 59 201 55 124 146
M6
174 73 186 75 100 110
M12
M18
M24
230 91 138
194 85 108
197 80 116
M30
M36
183 76 201 81 106 119
Proportion of patients achieving virological response over 36 months of treatment with entecavir according to (a) the HBeAg condition and (b) the baseline comorbidity burden. HBeAg, hepatitis B e antigen.
Fig. 2
Incidence of patients with undetectable HBV DNA (6 to 6 to 10 × ULN and > 2 × baseline value). Six patients had a grade 3 ALT elevation and one had grade 4 elevation during follow-up. In all patients (seven) who started the study with impaired hepatic function (bilirubin > 2.5 mg/dl and/or albumin < 3 g/dl), serum bilirubin and albumin values returned to normal before the end of the follow-up period.
Discussion This retrospective, observational study in clinical practice shows that entecavir monotherapy is safe and well tolerated in NA-naive CHB patients and successfully reduces HBV DNA levels even in patients with baseline comorbidities, such as cirrhosis, diabetes, hypertension and obesity. In addition, we observed that discontinuation of treatment in HBeAg-positive patients who have not cleared HBsAg may lead to virological recurrence.
Our results corroborate the previously reported overall efficacy of entecavir in real-life practice [12–14,20]. In addition, we compared the efficacy of entecavir between patients with and those without associated comobridities, finding no significant differences in the time to virological response, even in those patients with underlying cirrhosis. Only HBeAg status and baseline HBV DNA levels appeared to have a significant influence on the time needed to achieve virological response: response was faster in HBeAg-negative patients and in those with low HBV DNA levels at baseline (particularly in those patients with HBV DNA ≤ 6 log10 IU/ml). As in other studies on NA monotherapy, we observed a moderate serological response rate after 36 months of entecavir treatment. Only 13 patients cleared HBsAg after 36 months of treatment, and one of them experienced HBsAg recurrence 6 months after HBsAg loss. The HBeAg seroconversion rate increased rapidly from 9.8% at month 3 to 21.9% at month 12. However, in contrast to the relationship between early virological response and further serological response found in our previous study [27], the current results show no relationship between achieving virological response at month 3 and seroconverting to anti-HBeAg at month 12. An unresolved issue in CHB management is the identification of markers to predict successful NA treatment discontinuation [9]. Some authors have reported virological recurrence after treatment discontinuation in HBeAg-positive patients despite HBeAg seroconversion [16–18]. However, the small number of HBeAg-positive patients who discontinue treatment because of efficacy in most studies limits the data on virological recurrence after treatment discontinuation. In our study only 10 HBeAgpositive patients discontinued treatment after HBeAg seroconversion, and only those who had also cleared HBsAg maintained virological response until the end of the study. Our results suggest that HBsAg loss may be
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Entecavir monotherapy in patients with comorbidities Buti et al. 53
a more reliable indicator for treatment discontinuation in HBeAg-positive patients than HBeAg seroconversion, as has been suggested by Reijnders et al. [17] and Frenette and Gish [19]. Another unmet need in CHB management is to study the long-term safety profile of the current first-line NAs entecavir and tenofovir [9]. The European Association for the Study of Liver guidelines for CHB management suggests that lifelong NA therapy may be needed in many patients [9]. However, many real-life studies have short data collection periods [20,31–33] and/or mainly focus on the efficacy features of entecavir therapy [14,34, 35]. In general, long-term use of most NAs has been associated with potential renal toxicity [24]. The use of tenofovir has been associated with dose-dependent renal toxicity only in patients infected with HIV [36], whereas the rates of renal toxicity observed in clinical practice with adefovir are higher than those reported in registration studies [26]. In the case of entecavir, although it is one of the preferred NAs to be used in patients with kidney disease [25], in a rollover study including 46% white patients, serum creatinine increase was observed in 1% of patients, the majority of whom had existing risk factors for renal impairment [37]. In our study, the safety of entecavir was assessed during at least 3 years of treatment. As was expected, patients with underlying hypertension and/or diabetes mellitus had higher serum creatinine levels over the entire follow-up period, including the baseline visit. However, with the exception of one patient with chronic kidney disease, who reached a serum creatinine level of 6.1 mg/dl at month 24, no significant increases in serum creatinine levels were observed in this group over 36 months of treatment, suggesting that the safety profile of entecavir in patients with comorbidities – including those associated with impaired creatinine clearance – is consistent with that observed to date in the overall population [20,38]. The heterogeneity of our cohort (i.e. a wide age range of patients, with the potential for a higher comorbidity burden) is a valuable feature. However, the study has some limitations. First, it is a retrospective analysis. Second, although the sample size (237) was adequate, grouping the patients by specific comorbidities reduced the size of the analysed groups, and missing data in some patients at a particular visit contributed to the problem. Finally, as in other studies on CHB management, the low rates of HBeAg seroconversion and HBsAg clearance led to a limited number of candidates discontinuing treatment. Hence, further studies are needed to clearly confirm HBsAg clearance as a suitable marker for NA treatment discontinuation in HBeAg-positive patients. In summary, our results show that the safety and efficacy profile of entecavir in the overall CHB population is maintained when it is used as monotherapy in patients with comorbidities, including those associated with an
increased risk for renal impairment. However, the slightly elevated serum creatinine values observed during entecavir treatment in patients with hypertension and diabetes mellitus suggests that on-treatment creatinine clearance should be monitored during long-term entecavir use in those patients.
Acknowledgements The authors thank FLS-Research Support for coordination: particularly Roser Escrig for monitoring and Arelly Ornelas for statistical analysis. Medical writing assistance was provided by Gerard Carot-Sans and funded by FLSResearch Support. This study received financial support from Bristol-Meyers Squibb.
Conflicts of interest
Maria Buti has served as a speaker and advisory board member for Bristol-Myers Squibb (BMS), Gilead Sciences and Novartis, and has received research funding from BMS and Gilead Sciences. Rosa Maria Morillas has served as a speaker and advisory board member for Roche Pharma, Gilead Sciences, BMS, Merck, Sharp and Dohme S.A. (MSD), Janssen-Cilag and Abbvie. Martín Prieto has served as a speaker and advisory board member for BMS and Gilead Sciences. Ricard Solà is currently receiving consulting fees from BMS, Gilead Sciences, Novartis, Roche Pharma, Roche Genentech and JanssenCilag, lecture fees from BMS, Gilead Sciences, Novartis, Roche Pharma and Roche Genentech and grant support from Gilead Sciences, Roche Pharma, Roche Genentech, and MSD. Antonio Palau-Canós has served as a speaker and advisory board member for BMS. Moisés Diago has served as a speaker for BMS. Javier García-Samaniego has served as a speaker and advisory board member for Gilead Sciences, BMS and Roche Pharma, and has received research funding from Gilead Sciences and Roche Pharma. Manuel Rodríguez has served as a speaker and advisory board member for BMS and Gilead Sciences. Manuel Delgado has served as a speaker and advisory board member for Bayer, BMS and MSD. José Luís Calleja has served as a speaker and advisory board member for Gilead Sciences, BMS, Janssen-Cilag and MSD, and has received research funding from Gilead Sciences, BMS, Janssen-Cilag and MSD. Juan Ignacio Arenas has served as a speaker and advisory board member for Janssen-Cilag, MSD, Abbvie, BMS and Gilead Sciences. Luisa García-Buey has served as a speaker and advisory board member for MSD and Janssen-Cilag. Raúl Andrade has served as a speaker and advisory board member for Abbvie, Bayer, BMS, Gilead Sciences, Gore, Janssen-Cilag, MSD, Novartis and Roche Pharma, and has received research funding from Boehringer-Ingelheim and Madaus-Cerafarm. For the remaining authors there are no conflicts of interest.
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54 European Journal of Gastroenterology & Hepatology 2015, Vol 27 No 1
References 1 2
3
4 5
6
7
8
9
10 11
12
13
14
15 16
17
18
19 20
World Health Organization. Hepatitis B vaccines. Wkly Epidemiol Rec 2009; 84:405–420. European Centre for Disease Prevention and Control. Annual Epidemiological Report 2012. Available at: http://www.ecdc.europa.eu/en/ publications/Publications/Annual-Epidemiological-Report-2012.pdf. [Accessed 25 April 2014]. Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 295:65–73. Iloeje UH, Yang HI, Chen CJ. Natural history of chronic hepatitis B: What exactly has REVEAL revealed? Liver Int 2012; 32:1333–1341. Bréchot C, Hadchouel M, Scotto J, Fonck M, Potet F, Vyas GN, et al. State of hepatitis B virus DNA in hepatocytes of patients with hepatitis B surface antigen-positive and -negative liver diseases. Proc Natl Acad Sci USA 1981; 78:3906–3910. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006; 130:678–686. Mommeja-Marin H, Mondou E, Blum MR, Rousseau F. Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: analysis and review of the literature. Hepatology 2003; 37:1309–1319. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 2008; 48:335–352. European Association for the Study of Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol 2012; 20:427–429. Lok ASF, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009; 50:661–662. European Association for the Study of Liver. EASL clinical practice guidelines: management of chronic hepatitis B. J Hepatol 2009; 50:227–242. Cheng PN, Chang TT. Entecavir: a potent antiviral with minimal long-term resistance in nucleoside-naive chronic hepatitis B patients. Expert Rev Anti Infect Ther 2008; 6:569–579. Hosaka T, Suzuki F, Kobayashi M, Seko Y, Kawamura Y, Sezaki H, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology 2013; 58:98–107. Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy. Hepatology 2009; 49:1503–1514. Lai CL, Yuen MF. Reduction of cirrhosis and hepatocellular carcinoma with antiviral therapy in chronic hepatitis B. Hepatology 2013; 58:1857. Shouval D, Lai CL, Chang TT, Cheinquer H, Martin P, Carosi G, et al. Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: the case for continuous antiviral therapy. J Hepatol 2009; 50:289–295. Reijnders JGP, Perquin MJ, Zhang N, Hansen BE, Janssen HLA. Nucleos(t) ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B. Gastroenterology 2010; 139:491–498. Ridruejo E, Marciano S, Galdame O, Reggiardo MV, Muñoz AE, Adrover R, et al. Relapse rates in chronic hepatitis B naïve patients after discontinuation of antiviral therapy with entecavir. J Viral Hepat 2013; 21:590–596. Frenette CT, Gish RG. Editorial: To “be” or not to “be”: that is the question. Am J Gastroenterol 2009; 104:1948–1952. Pol S, Lampertico P. First-line treatment of chronic hepatitis B with entecavir or tenofovir in “real-life” settings: from clinical trials to clinical practice. J Viral Hepat 2012; 19:377–386.
21
22
23
24 25
26
27
28
29
30
31
32
33
34
35
36
37
38
Fattovich G, Giustina G, Schalm SW, Hadziyannis S, Sanchez-Tapias J, Almasio P, et al. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. Hepatology 1995; 21:77–82. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013; 34:2159–2219. Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, et al. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the task force on diabetes, prediabetes, and cardiovascular diseases of the European Society of Cardiology (ESC). Eur Heart J 2013; 34:3035–3087. Fontana RJ. Side effects of long-term oral antiviral therapy for hepatitis B. Hepatology 2009; 49 (Suppl 5):S185–S195. Pipili C, Cholongitas E, Papatheodoridis G. Review article: nucleos(t)ide analogues in patients with chronic hepatitis B virus infection and chronic kidney disease. Aliment Pharmacol Ther 2014; 39:35–46. Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003; 348:808–816. Buti M, Morillas RM, Prieto M, Diago M, Pérez J, Solà R, et al. Efficacy and safety of entecavir in clinical practice in treatment-naive Caucasian chronic hepatitis B patients. Eur J Gastroenterol Hepatol 2012; 24:535–542. World Health Organization. WHO toxicity grading scale for determining the severity of adverse events. 2003. Available at: http://www.icssc.org/ Documents/Resources/AEManual2003AppendicesFebruary_06_2003 final.pdf. [Accessed 25 April 2014]. Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003; 29:1705–1713. Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen M-R, Wiklund O, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32:1769–1818. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006; 354:1011–1020. Gish RG, Lok AS, Chang T, de Man RA, Gadano A, Sollano J, et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology 2007; 133:1437–1444. Lok AS, Trinh H, Carosi G, Akarca US, Gadano A, Habersetzer F, et al. Efficacy of entecavir with or without tenofovir disoproxil fumarate for nucleos (t)ide-naïve patients with chronic hepatitis B. Gastroenterology 2012; 147:619–628.e1. Ridruejo E, Adrover R, Cocozzella D, Reggiardo MV, Estepo C, Schroder T, et al. Effectiveness of entecavir in chronic hepatitis B NUC-naive patients in routine clinical practice. Int J Clin Pract 2011; 65:866–870. Chang TT, Lai CL, Kew Yoon S, Lee SS, Coelho HSM, Carrilho FJ, et al. Entecavir treatment for up to 5 years in patients with hepatitis B e antigenpositive chronic hepatitis B. Hepatology 2010; 51:422–430. Duarte-Rojo A, Heathcote EJ. Efficacy and safety of tenofovir disoproxil fumarate in patients with chronic hepatitis B. Therap Adv Gastroenterol 2010; 3:107–119. Manns MP, Akarca US, Chang TT, Sievert W, Yoon SK, Tsai N, et al. Longterm safety and tolerability of entecavir in patients with chronic hepatitis B in the rollover study ETV-901. Expert Opin Drug Saf 2012; 11:361–368. Keating GM. Entecavir: a review of its use in the treatment of chronic hepatitis B in patients with decompensated liver disease. Drugs 2011; 71:2511–2529.
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Entecavir has high efficacy and safety in white patients with chronic hepatitis B and comorbidities Maria Butia, Rosa M. Morillasg, Juan Pérezn, Martín Prietot, Ricard Solàb, Antonio Palaue, Moisés Diagou, Lucía Bonetf, Adolfo Gallegoc, Javier García-Samaniegoh, Milagros Testillanom, Manuel Rodríguezp, Gregorio Castellanoi, María L. Gutiérrezq, Manuel Delgador, Antoni Masd, Manuel Romero-Gómezo, José L. Callejaj, Agustina González-Guiradok, Juan I. Arenass, Luisa García-Bueyl, Raúl Andradev, Ana Gilaw and the ORIENTE-2 study group Objectives The aim of this study was to evaluate the efficacy and safety of entecavir monotherapy in nucleos(t) ide-naive chronic hepatitis B patients and to analyse the influence of the comorbidity burden on therapy outcome. Methods We retrospectively analysed data from 237 nucleos(t)ide-naive chronic hepatitis B white patients treated with entecavir (0.5 mg/day) at 23 Spanish centres. For the efficacy and safety analyses, patients were grouped according to their baseline comorbidities. Results The mean age of the cohort was 43 years (range: 19–82 years); 73% were male, 83% were white, and 33% were hepatitis B e antigen (HBeAg) positive. At baseline, the median hepatitis B virus DNA level was 6.20 log10 IU/ml. Of the patients, 18% had cirrhosis, 9.7% had diabetes, 16.3% had hypertension, and 15.7% had obesity; 13.4% of patients had more than one comorbid condition. Virological and ORIENTE-2 study group: Edurne Almandoz (H. U. Donostia), Mari Alonso (H. U. La Princesa, Madrid), Raúl Andrade (H. Virgen de la Victoria, Málaga), Juan Ignacio Arenas (H. U. Donostia), Lucía Bonet (H. Son Espases, Palma de Mallorca), Maria Alonso Burgal (H. General Universitario de Castellón), Maria Buti (H. Vall d'Hebron, Barcelona), José Luis Calleja (H. Puerta del Hierro, Madrid), Gregorio Castellano (H. U. 12 de Octubre, Madrid), Manuel Delgado (H. U. de La Coruña), Moisés Diago (H. U. General de Valencia), Rafael Esteban (H. Vall d'Hebron, Barcelona), Conrado Fernández (H. U. Fundación Alcorcón), Adolfo Gallego (H. de la Santa Creu i Sant Pau, Barcelona), Rocío Gallego (H. U. de Valme, Sevilla), Javier García-Samaniego (H. Carlos III, Madrid), Luisa GarcíaBuey (H. U. La Princesa, Madrid), Cristina Gely Vila (H. de la Santa Creu i Sant Pau, Barcelona), Ana Gila (H. U. San Cecilio, Granada), Dolors Giménez (H. del Mar, Barcelona), Maca Gómez (H. Puerta del Hierro, Madrid), Alexandra Gómez García (H. U. Donostia), María Luisa González-Diéguez (H. Central de Asturias, Oviedo), Agustina González-Guirado (Fundación Jiménez Díaz, Madrid), María Luisa Gutiérrez (H. U. Fundación Alcorcón), Antonio Madejón (H. Carlos III, Madrid), María Luisa Manzano (H. U. 12 de Octubre, Madrid), Antoni Mas (H. Clínic, Barcelona), Inmaculada Moreno Herrera (H. Virgen de la Victoria, Málaga), Rosa Maria Morillas (H. U. Germans Trias i Pujol, Badalona), Carmen A. Navascués (H. Central de Asturias, Oviedo), Antonio Palau (H. General Universitario de Castellón), Juan Pérez (H. Virgen Macarena, Sevilla), Ramon Planas (H. U. Germans Trias i Pujol, Badalona), Juan Carlos Porres Cubero (Fundación Jiménez Díaz, Madrid), Martín Prieto (H. Universitario y Politécnico La Fe, Valencia), Ioana Riaño Fernández (H. U. Donostia), Manuel Rodríguez (H. Central de Asturias, Oviedo), Manuel Romero-Gómez (H. U. de Valme, Sevilla), Javier Salmerón (H. U. San Cecilio, Granada), José María Sánchez-Tapias (H. Clínic, Barcelona), Ricard Solà (H. del Mar, Barcelona), Roser Sotelo (H. Vall d'Hebron, Barcelona), Milagros Testillano (H. de Cruces, Bizkaia), Carmen Vinaixa (H. Universitario y Politécnico La Fe, Valencia). 0954-691X © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
biochemical responses at month 36 were obtained independently of the patients’ baseline comorbid condition. Of 10 HBeAg-positive patients who discontinued treatment after HBeAg seroconversion, those who had not also cleared HBsAg (six) experienced virological recurrence in a median 5.6 months. There were no treatment discontinuations due to adverse events. Three patients were diagnosed with hepatocellular carcinoma at months 12, 30 and 54, and six experienced hepatic decompensation during follow-up. The median serum creatinine levels did not increase after 36 months of treatment, even in patients with comorbidities. Conclusion Entecavir is safe, well tolerated, and highly effective, even in patients with comorbid condition(s). Discontinuation of treatment in patients who have not been cleared of HBsAg may lead to virological recurrence. Eur J Gastroenterol Hepatol 27:46–54 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2015, 27:46–54 Keywords: chronic hepatitis B, clinical practice, comorbidity, drug safety, entecavir a
CIBER on Liver and Digestive Diseases (CIBERehd), Hospital Vall d'Hebron, Hospital del Mar, IMIM, Universitat Autònoma de Barcelona, cHospital de la Santa Creu i Sant Pau, dHospital Clínic, Barcelona, eCIBERehd H. La Fe, Hospital General Universitario de Castellón, Castellón, fHospital Son Espases, Palma de Mallorca, gCIBERehd, Hospital Universitari Germans Trias i Pujol, Badalona, hCIBERehd, Hospital Carlos III, iHospital Universitario 12 de Octubre, j Hospital Puerta del Hierro, kFundación Jiménez Díaz, lCIBERehd, Hospital Universitario La Princesa, Madrid, mHospital de Cruces, Bizkaia, nHospital Virgen Macarena, oCIBERehd, Hospital Universitario de Valme, Sevilla, pHospital Central de Asturias, Oviedo, qHospital Universitario Fundación Alcorcón, Alcorcón, r Hospital Universitario de La Coruña, A Coruña, sHospital Universitario Donostia, Donostia, tCIBERehd, Hospital Universitario y Politécnico La Fe, uHospital General Universitario de Valencia, Valencia, vCIBERehd, Hospital Virgen de la Victoria, Málaga and wHospital Universitario San Cecilio, Granada, Spain b
Correspondence to Maria Buti, PhD, Hospital Vall d’Hebron, Passeig de la Vall d’Hebron, 119-129, 08035 Barcelona, Spain Tel: + 34 93 275 61 40; fax: + 34 93 427 44 95; e-mail: [email protected] Received 6 June 2014 Accepted 23 July 2014
Introduction According to the WHO, nearly 360 million individuals are chronically infected with hepatitis B virus (HBV) [1]. DOI: 10.1097/MEG.0000000000000195
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Entecavir monotherapy in patients with comorbidities Buti et al. 47
In Europe, despite strict blood screening, vaccination, and improved healthcare standards, over 14 700 cases of HBV infection are reported yearly to the European Centre for Disease Control [2]. Spain accounts for 4.5% of all HBV infections occurring in Europe and has an infection rate of 1.44 cases/100 000 inhabitants. Patients with untreated chronic hepatitis B (CHB) have an increased risk of developing hepatic cirrhosis, decompensated liver function and hepatocellular carcinoma (HCC) [3,4]. Overall, HBV-related liver disorders (including HCC) account for over 600 000 deaths/year worldwide [1]. Because of the persistence of covalently closed circular DNA in the nucleus of infected hepatocytes, HBV cannot be completely eradicated [5]. However, lowering the levels of circulating HBV DNA decreases the risk of liver-related mortality [6,7] and leads to higher hepatitis B e antigen (HBeAg) seroconversion rates, an important goal related to clinical remission and a necessary step in the transition to inactive HBV carrier status [8]. Maintaining circulating HBV DNA at undetectable levels is therefore a key endpoint of CHB treatment [9,10]. The European Association for the Study of Liver recommends the nucleos(t)ide analogues (NAs) tenofovir and entecavir as first-line therapy for patients with CHB [9,11]. The guanosine analogue entecavir is a potent and selective inhibitor of HBV replication with a high barrier-to-viral resistance [12–14], and it has proven to reduce the incidence of HCC in the overall population of CHB patients [13] and to reverse fibrosis or cirrhosis in CHB patients with advanced disease [15]. Current clinical guidelines recommend stopping treatment with NAs at the time of HBsAg seroconversion in HBeAg-negative patients, and at 12 months after HBeAg seroconversion in HBeAg-positive patients [9]. Nonetheless, several authors have reported virological recurrence following treatment discontinuation despite HBeAg seroconversion [16–18], suggesting that treatment in HBeAg-positive patients should be extended at least until HBsAg has been also cleared [17,19]. Despite the proven efficacy of entecavir in CHB treatment, HBsAg clearance rarely occurs in more than 1% of patients during the first year of NA treatment [20] and usually requires long periods of treatment. However, safety data on long-term real-life use of entecavir are limited, particularly in the white population. Phase II and III clinical trials exhaustively collect safety data, but usually exclude older patients and those with liverrelated comorbidities such as cirrhosis; hence, the participant profile differs from that of real-life patients. Older age and underlying cirrhosis are risk factors for HCC in CHB patients [8,21], whereas comorbidities such as hypertension and diabetes mellitus can affect renal function [22,23], which could make patients more susceptible to potential renal toxicity associated with longterm drug therapies, including NAs [24,25]. The strict
inclusion/exclusion criteria of most clinical trials are necessary to clearly establish the differences between a tested drug and the current standard of care; however, they can also overestimate the efficacy and safety of the drug in real-life practice. Indeed, the potential renal toxicity reported for some NAs in real-life practice had not been previously observed in the corresponding registration studies [24,26], suggesting that the differing characteristics of patients included in clinical studies and patients encountered in everyday clinical practice should be considered when analysing the safety profile of entecavir in long-term use. The aim of this study was to evaluate the safety and efficacy outcomes of 3 years of entecavir monotherapy in a highly heterogeneous cohort of Spanish NA-naive CHB patients. Further, we analysed the influence of the baseline comorbidity burden on the clinical outcome of entecavir treatment, as well as the durability of the response after treatment discontinuation.
Methods Study population
The cohort consisted of 237 adult nucleotide-naive CHB patients from 23 Spanish centres, including 190 patients from the ORIENTE study cohort [27] and 47 additional patients treated with entecavir (Baraclude; Bristol-Myers Squibb, Anagni, Italy) monotherapy (0.5 mg film-coated tablet once daily) for at least 36 months as the only nucleotide-based therapy. For study inclusion, patients had to have compensated liver function and confirmed HBeAg-positive or HBeAg-negative status before beginning follow-up. Patients with hepatitis C infection, hepatitis D infection, or HIV infection were excluded, as were pregnant women. The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki in effect at the time (59th, Seoul 2008). The ethics committees of the participating centres approved the study, and local requirements for obtaining informed consent were followed. Data collection
The main purpose of this retrospective observational study was to collect data from CHB patients over 36 months of entecavir treatment. Data on adverse events and long-term entecavir resistance were collected for an additional 24 months (every 6 months after month 36). Sociodemographic data (age, sex and country of origin), information on underlying comorbidities obtained from the patients’ medical records, and CHB characteristics (time with HBV infection, previous interferon treatment and biopsy and elastography studies) were recorded at baseline. Data from physical examination, from laboratory tests results [serum alanine aminotransferase (ALT), bilirubin, albumin and creatinine levels, and routine haematological assessments], on virological parameters (HBV DNA levels) and on serological parameters [HBeAg, antibody against HBeAg (anti-HBeAg), HBsAg
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48 European Journal of Gastroenterology & Hepatology 2015, Vol 27 No 1
and antibody against HBsAg (anti-HBsAg)] were collected at baseline, at months 3 and 6, and every 6 months thereafter, up to the end of the study. Efficacy analysis
The primary endpoint of the study was the percentage of patients who achieved a virological response (defined as serum HBV DNA levels < 50 IU/ml on PCR) after 36 months of treatment with entecavir. The secondary endpoints included the percentage of patients who achieved a biochemical response [ALT normalization, defined as ALT ≤ 1 × upper limit of normal (ULN)] and a serological response (HBeAg loss, HBeAg seroconversion, HBsAg loss, and/or HBsAg seroconversion) up to the end of treatment with entecavir. For the analysis of the main efficacy endpoints, patients were studied as an overall population, according to their HBeAg-positive or HBeAg-negative status, and according to their comorbid condition, dividing them into patients without comorbidities and patients with one or more comorbidity. In patients who showed no virological response at completion of the study, the presence of resistance mutations (determined by reverse hybridization) was analysed for. Virological recurrence was defined as having serum HBV DNA levels of 50 IU/ml or higher after achieving virological response. Laboratory tests
HBV DNA levels were measured using a real-time PCRbased assay. Most centres used the TaqMan HBV test (CAP-CTM Roche; Molecular Systems Inc., Branchburg, New Jersey, USA) for serum HBV DNA determination, and samples from centres equipped with other systems were reanalysed using this technique. The virological response was arbitrarily set at less than 50 IU/ml to enable assessment of consistency with the virological response observed in the registration studies, defined as HBV DNA levels less than 300 copies/ml (∼50 IU/ml). HBV polymerase gene mutations were detected using the INNOLiPA assay (Innogenetics, Ghent, Belgium). Serological parameters (HBsAg, anti-HBsAg, HBeAg and anti-HBeAg levels) were determined using a commercially available enzyme immunoassay. ALT and serum creatinine levels were determined using the routine technique from each centre, and results are expressed in multiples of ULN, according to the limits set by each centre. Safety
Data on adverse events were collected from the patients’ medical history records and graded according to the WHO Toxicity Grading Scale for Determining the Severity of Adverse Events [28]. Liver disease decompensations and on-treatment HCCs were recorded. Serum creatinine was used as a marker for kidneymediated abnormalities, and serum albumin, bilirubin and ALT were used as biochemical markers of liver disease. Serum creatinine elevations were classified
as grade 1 (1.1–1.5 × ULN), grade 2 (1.6–3.0 × ULN) or grade 3 (3.1–6.0 × ULN), and serum ALT elevations as grade 1 (1.25–2.5 × ULN), grade 2 (2.6–5.0 × ULN), grade 3 (5.1–0.0 × ULN) or grade 4 (>10.0 × ULN). Ontreatment ALT flares (defined as ALT > 10 × ULN or > 2 × baseline value) were also recorded. For the data analysis of serum creatinine elevations, patients were grouped according to their baseline comorbid conditions into three groups: those without comorbidities, those with one or more comorbidity and those with hypertension and diabetes mellitus. Statistical analysis
The main categorical variables are expressed as frequency and percentage at each visit in the overall population and in each group of interest. Quantitative variables are expressed as mean and SD, median and interquartile range (IQR) or maximum and minimum. Seven patients with undetectable HBV DNA levels at months 30 and 42 were assumed to also have undetectable HBV DNA levels at month 36, even though values from that visit were missing. Other patients with missing data were excluded from analyses. Categories were compared using the χ2-test or Fisher’s exact test, medians using the Mann–Whitney U-test and means using the ttest. A Kaplan–Meier analysis, on the basis of rightcensored observations, was carried out to estimate the time to achieve virological and serological responses. Statistical significance was set at a P-value of less than 0.05. Statistical analyses were carried out using SPSS version 15.0 for Windows (SPSS Inc., Chicago, Illinois, USA).
Results Patient characteristics
The studied cohort comprised 237 patients: 77 (32%) HBeAg positive and 160 (68%) HBeAg negative. The baseline characteristics of the study population are shown in Table 1. HBeAg-positive patients had significantly higher baseline HBV DNA levels (7.72 vs. 5.38; P < 0.001) and ALT levels (91.0 vs. 59.0 U/l; P = 0.002). Four main comorbidities were identified in the study population: 18% of patients had cirrhosis (including patients previously diagnosed with cirrhosis and those with baseline fibrosis grade of 4 or higher [29]), 16% had hypertension (including patients previously diagnosed with hypertension and those with systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg [22]), 10% had diabetes mellitus (including patients previously diagnosed with diabetes mellitus and those with fasting serum glucose levels ≥ 126 mg/dl [23]), and 16% had obesity (patients with BMI ≥ 30 kg/m2 [30]). The baseline characteristics of patients with comorbidities and patients without comorbidities are shown in Table 2. A total of 201 patients completed the study at month 36, and 119, 91, 47 and 14 patients were additionally followed up for adverse events
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Entecavir monotherapy in patients with comorbidities Buti et al. 49
Table 1
Baseline patient demographics and disease characteristics Overall (N = 237)
Age (years)a Male [n (%)] Ethnic group [n (%)] White Asian Black Other BMIb Time with infection (months)b HBV DNA (log10 IU/ml)b HBV DNA [n (%)] ≤ 6 log10 IU/ml > 6 to < 8 log10 IU/ml ≥ 8 log10 IU/ml Elevated ALT (>1 × ULN) [n (%)] Total serum bilirubin (mg/dl)b Platelets (×103/μl)b Previous treatment with IFN [n (%)] Biopsy [n (%)] Fibrosis stage [n (%)]c F0–F2 F3–F6 Cirrhotic [n (%)] Serum creatinine (mg/dl)b Fasting serum glucose (mg/dl)b
HBeAg positive (N = 77)
43 (19–82) 172 (73)
HBeAg negative (N = 160)
39 (19–82) 54 (70)
44 (19–75) 118 (74)
197 26 9 5 25.4 96 6.23
(83) (11) (4) (2) (23.5–27.8) (12–225) (4.58–7.64)
57 16 1 3 25.6 24 7.72
(74) (21) (1) (4) (23.4–27.8) (12–120) (6.86–8.04)
140 10 8 2 25.3 138 5.38
(88) (7) (5) (1) (23.5–27.7) (36–276) (4.25–6.77)
109 85 43 184 0.77 195 36 130
(46) (36) (18) (78) (0.58–1.10) (152–240) (15) (55)
10 37 30 67 0.79 204 4 34
(13) (48) (39) (87) (0.59–1.06) (152–249) (5) (44)
99 48 13 117 0.76 193 32 96
(62) (30) (8) (73) (0.58–1.10) (154–240) (20) (60)
105 46 42 0.93 93
(70) (30) (18) (0.80–1.10) (87–102)
32 12 10 0.92 93
(73) (27) (14) (0.79–1.11) (85–103)
73 34 32 1.11 93
(68) (32) (20) (0.80–1.09) (87–102)
ALT, alanine aminotransferase; HBV, hepatitis B virus; IFN, interferon; ULN, upper limit of normal. Median (range). b Median (interquartile range). c Assessed by biopsy and/or elastography (Fibroscan). Proportion of patients in whom fibrosis stage was determined. a
Table 2
Baseline characteristics of patients with and without comorbidities Patients without comorbidities (N = 139) a
Age (years) Male [n (%)] BMIb Time with infection (months)b HBV DNA (log10 IU/ml)b ALT (U/l)b Elevated ALT (>1 × ULN) [n (%)] Total serum bilirubin (mg/dl)b Platelets (×103/μl)b Fibrosis stage [n (%)]c F0–F2 F3–F6 Serum creatinine (mg/dl)b
40 103 24.5 108 6.3 75.0 110 0.70 202
(19–70) (74) (23.2–26.2) (12–228) (4.7–7.8) (45.0–111.0) (79) (0.53–1.10) (171–237)
76 (85) 13 (15) 0.90 (0.80–1.00)
Patients with comorbidities (N = 97) 50 68 27.4 84 6.1 60.0 79 0.79 186
(19–82) (70) (24.5–31.2) (12–216) (4.3–7.3) (43.0–131.0) (75) (0.60–1.10) (140–249)
29 (47) 33 (53) 0.96 (0.83–1.14)
ALT, alanine aminotransferase; HBV, hepatitis B virus; ULN, upper limit of normal. a Median (range). b Median (interquartile range). c Assessed by biopsy and/or elastography (Fibroscan). Proportion of patients in whom fibrosis stage was determined.
until months 42, 48, 54 and 60, respectively. Seven patients were lost to follow-up: three at month 12, three at month 18 and two at month 30. Virological and biochemical responses
After 36 months of treatment with entecavir, 96% of patients (89% in the HBeAg-positive group and 98% in the HBeAg-negative group) achieved virological response (Fig. 1a) and 86% of patients (82% in the HBeAg-positive group and 89% in the HBeAg-negative group) achieved biochemical response. Virological and biochemical responses at month 36 were both achieved independently of the patients’ baseline HBV DNA levels, ALT levels, and HBeAg-positive or HBeAg-
negative status. The presence of underlying comorbidities did not influence virological response over 36 months of treatment (Fig. 1b). Six patients who had liver decompensation during follow-up ended the study with undetectable HBV DNA levels. Overall, a primary treatment response (defined as a ≥ 1 log10 IU/ml decrease in HBV DNA from baseline to month 3) was observed in 94% of patients (95% in the HBeAg-negative group and 92% in the HBeAg-positive group). Sixteen of the 237 patients did not achieve virological response before completing the study: four patients required additional treatment with tenofovir (three at month 12 and one at month 36), eight either withdrew or reported lack of adherence to the treatment schedule and five showed
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50 European Journal of Gastroenterology & Hepatology 2015, Vol 27 No 1
Fig. 1
(a)
(b) Overall
HBeAg positive
HBeAg negative
Overall
Without comorbidities
With comorbidities
100 90 80 70 60 50 40 30 20 10 0
Proportion of patients (%)
100 90 80 70 60 50 40 30 20 10 0 Treatment month No. of evaluable patients
M3 174 60 114
M6
M12
M18
M24
186 64 122
230 75 155
194 61 133
197 58 139
M30
M3
M36
183 59 201 55 124 146
M6
174 73 186 75 100 110
M12
M18
M24
230 91 138
194 85 108
197 80 116
M30
M36
183 76 201 81 106 119
Proportion of patients achieving virological response over 36 months of treatment with entecavir according to (a) the HBeAg condition and (b) the baseline comorbidity burden. HBeAg, hepatitis B e antigen.
Fig. 2
Incidence of patients with undetectable HBV DNA (6 to 6 to 10 × ULN and > 2 × baseline value). Six patients had a grade 3 ALT elevation and one had grade 4 elevation during follow-up. In all patients (seven) who started the study with impaired hepatic function (bilirubin > 2.5 mg/dl and/or albumin < 3 g/dl), serum bilirubin and albumin values returned to normal before the end of the follow-up period.
Discussion This retrospective, observational study in clinical practice shows that entecavir monotherapy is safe and well tolerated in NA-naive CHB patients and successfully reduces HBV DNA levels even in patients with baseline comorbidities, such as cirrhosis, diabetes, hypertension and obesity. In addition, we observed that discontinuation of treatment in HBeAg-positive patients who have not cleared HBsAg may lead to virological recurrence.
Our results corroborate the previously reported overall efficacy of entecavir in real-life practice [12–14,20]. In addition, we compared the efficacy of entecavir between patients with and those without associated comobridities, finding no significant differences in the time to virological response, even in those patients with underlying cirrhosis. Only HBeAg status and baseline HBV DNA levels appeared to have a significant influence on the time needed to achieve virological response: response was faster in HBeAg-negative patients and in those with low HBV DNA levels at baseline (particularly in those patients with HBV DNA ≤ 6 log10 IU/ml). As in other studies on NA monotherapy, we observed a moderate serological response rate after 36 months of entecavir treatment. Only 13 patients cleared HBsAg after 36 months of treatment, and one of them experienced HBsAg recurrence 6 months after HBsAg loss. The HBeAg seroconversion rate increased rapidly from 9.8% at month 3 to 21.9% at month 12. However, in contrast to the relationship between early virological response and further serological response found in our previous study [27], the current results show no relationship between achieving virological response at month 3 and seroconverting to anti-HBeAg at month 12. An unresolved issue in CHB management is the identification of markers to predict successful NA treatment discontinuation [9]. Some authors have reported virological recurrence after treatment discontinuation in HBeAg-positive patients despite HBeAg seroconversion [16–18]. However, the small number of HBeAg-positive patients who discontinue treatment because of efficacy in most studies limits the data on virological recurrence after treatment discontinuation. In our study only 10 HBeAgpositive patients discontinued treatment after HBeAg seroconversion, and only those who had also cleared HBsAg maintained virological response until the end of the study. Our results suggest that HBsAg loss may be
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Entecavir monotherapy in patients with comorbidities Buti et al. 53
a more reliable indicator for treatment discontinuation in HBeAg-positive patients than HBeAg seroconversion, as has been suggested by Reijnders et al. [17] and Frenette and Gish [19]. Another unmet need in CHB management is to study the long-term safety profile of the current first-line NAs entecavir and tenofovir [9]. The European Association for the Study of Liver guidelines for CHB management suggests that lifelong NA therapy may be needed in many patients [9]. However, many real-life studies have short data collection periods [20,31–33] and/or mainly focus on the efficacy features of entecavir therapy [14,34, 35]. In general, long-term use of most NAs has been associated with potential renal toxicity [24]. The use of tenofovir has been associated with dose-dependent renal toxicity only in patients infected with HIV [36], whereas the rates of renal toxicity observed in clinical practice with adefovir are higher than those reported in registration studies [26]. In the case of entecavir, although it is one of the preferred NAs to be used in patients with kidney disease [25], in a rollover study including 46% white patients, serum creatinine increase was observed in 1% of patients, the majority of whom had existing risk factors for renal impairment [37]. In our study, the safety of entecavir was assessed during at least 3 years of treatment. As was expected, patients with underlying hypertension and/or diabetes mellitus had higher serum creatinine levels over the entire follow-up period, including the baseline visit. However, with the exception of one patient with chronic kidney disease, who reached a serum creatinine level of 6.1 mg/dl at month 24, no significant increases in serum creatinine levels were observed in this group over 36 months of treatment, suggesting that the safety profile of entecavir in patients with comorbidities – including those associated with impaired creatinine clearance – is consistent with that observed to date in the overall population [20,38]. The heterogeneity of our cohort (i.e. a wide age range of patients, with the potential for a higher comorbidity burden) is a valuable feature. However, the study has some limitations. First, it is a retrospective analysis. Second, although the sample size (237) was adequate, grouping the patients by specific comorbidities reduced the size of the analysed groups, and missing data in some patients at a particular visit contributed to the problem. Finally, as in other studies on CHB management, the low rates of HBeAg seroconversion and HBsAg clearance led to a limited number of candidates discontinuing treatment. Hence, further studies are needed to clearly confirm HBsAg clearance as a suitable marker for NA treatment discontinuation in HBeAg-positive patients. In summary, our results show that the safety and efficacy profile of entecavir in the overall CHB population is maintained when it is used as monotherapy in patients with comorbidities, including those associated with an
increased risk for renal impairment. However, the slightly elevated serum creatinine values observed during entecavir treatment in patients with hypertension and diabetes mellitus suggests that on-treatment creatinine clearance should be monitored during long-term entecavir use in those patients.
Acknowledgements The authors thank FLS-Research Support for coordination: particularly Roser Escrig for monitoring and Arelly Ornelas for statistical analysis. Medical writing assistance was provided by Gerard Carot-Sans and funded by FLSResearch Support. This study received financial support from Bristol-Meyers Squibb.
Conflicts of interest
Maria Buti has served as a speaker and advisory board member for Bristol-Myers Squibb (BMS), Gilead Sciences and Novartis, and has received research funding from BMS and Gilead Sciences. Rosa Maria Morillas has served as a speaker and advisory board member for Roche Pharma, Gilead Sciences, BMS, Merck, Sharp and Dohme S.A. (MSD), Janssen-Cilag and Abbvie. Martín Prieto has served as a speaker and advisory board member for BMS and Gilead Sciences. Ricard Solà is currently receiving consulting fees from BMS, Gilead Sciences, Novartis, Roche Pharma, Roche Genentech and JanssenCilag, lecture fees from BMS, Gilead Sciences, Novartis, Roche Pharma and Roche Genentech and grant support from Gilead Sciences, Roche Pharma, Roche Genentech, and MSD. Antonio Palau-Canós has served as a speaker and advisory board member for BMS. Moisés Diago has served as a speaker for BMS. Javier García-Samaniego has served as a speaker and advisory board member for Gilead Sciences, BMS and Roche Pharma, and has received research funding from Gilead Sciences and Roche Pharma. Manuel Rodríguez has served as a speaker and advisory board member for BMS and Gilead Sciences. Manuel Delgado has served as a speaker and advisory board member for Bayer, BMS and MSD. José Luís Calleja has served as a speaker and advisory board member for Gilead Sciences, BMS, Janssen-Cilag and MSD, and has received research funding from Gilead Sciences, BMS, Janssen-Cilag and MSD. Juan Ignacio Arenas has served as a speaker and advisory board member for Janssen-Cilag, MSD, Abbvie, BMS and Gilead Sciences. Luisa García-Buey has served as a speaker and advisory board member for MSD and Janssen-Cilag. Raúl Andrade has served as a speaker and advisory board member for Abbvie, Bayer, BMS, Gilead Sciences, Gore, Janssen-Cilag, MSD, Novartis and Roche Pharma, and has received research funding from Boehringer-Ingelheim and Madaus-Cerafarm. For the remaining authors there are no conflicts of interest.
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54 European Journal of Gastroenterology & Hepatology 2015, Vol 27 No 1
References 1 2
3
4 5
6
7
8
9
10 11
12
13
14
15 16
17
18
19 20
World Health Organization. Hepatitis B vaccines. Wkly Epidemiol Rec 2009; 84:405–420. European Centre for Disease Prevention and Control. Annual Epidemiological Report 2012. Available at: http://www.ecdc.europa.eu/en/ publications/Publications/Annual-Epidemiological-Report-2012.pdf. [Accessed 25 April 2014]. Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 295:65–73. Iloeje UH, Yang HI, Chen CJ. Natural history of chronic hepatitis B: What exactly has REVEAL revealed? Liver Int 2012; 32:1333–1341. Bréchot C, Hadchouel M, Scotto J, Fonck M, Potet F, Vyas GN, et al. State of hepatitis B virus DNA in hepatocytes of patients with hepatitis B surface antigen-positive and -negative liver diseases. Proc Natl Acad Sci USA 1981; 78:3906–3910. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006; 130:678–686. Mommeja-Marin H, Mondou E, Blum MR, Rousseau F. Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: analysis and review of the literature. Hepatology 2003; 37:1309–1319. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 2008; 48:335–352. European Association for the Study of Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol 2012; 20:427–429. Lok ASF, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009; 50:661–662. European Association for the Study of Liver. EASL clinical practice guidelines: management of chronic hepatitis B. J Hepatol 2009; 50:227–242. Cheng PN, Chang TT. Entecavir: a potent antiviral with minimal long-term resistance in nucleoside-naive chronic hepatitis B patients. Expert Rev Anti Infect Ther 2008; 6:569–579. Hosaka T, Suzuki F, Kobayashi M, Seko Y, Kawamura Y, Sezaki H, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology 2013; 58:98–107. Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy. Hepatology 2009; 49:1503–1514. Lai CL, Yuen MF. Reduction of cirrhosis and hepatocellular carcinoma with antiviral therapy in chronic hepatitis B. Hepatology 2013; 58:1857. Shouval D, Lai CL, Chang TT, Cheinquer H, Martin P, Carosi G, et al. Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: the case for continuous antiviral therapy. J Hepatol 2009; 50:289–295. Reijnders JGP, Perquin MJ, Zhang N, Hansen BE, Janssen HLA. Nucleos(t) ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B. Gastroenterology 2010; 139:491–498. Ridruejo E, Marciano S, Galdame O, Reggiardo MV, Muñoz AE, Adrover R, et al. Relapse rates in chronic hepatitis B naïve patients after discontinuation of antiviral therapy with entecavir. J Viral Hepat 2013; 21:590–596. Frenette CT, Gish RG. Editorial: To “be” or not to “be”: that is the question. Am J Gastroenterol 2009; 104:1948–1952. Pol S, Lampertico P. First-line treatment of chronic hepatitis B with entecavir or tenofovir in “real-life” settings: from clinical trials to clinical practice. J Viral Hepat 2012; 19:377–386.
21
22
23
24 25
26
27
28
29
30
31
32
33
34
35
36
37
38
Fattovich G, Giustina G, Schalm SW, Hadziyannis S, Sanchez-Tapias J, Almasio P, et al. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. Hepatology 1995; 21:77–82. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013; 34:2159–2219. Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, et al. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the task force on diabetes, prediabetes, and cardiovascular diseases of the European Society of Cardiology (ESC). Eur Heart J 2013; 34:3035–3087. Fontana RJ. Side effects of long-term oral antiviral therapy for hepatitis B. Hepatology 2009; 49 (Suppl 5):S185–S195. Pipili C, Cholongitas E, Papatheodoridis G. Review article: nucleos(t)ide analogues in patients with chronic hepatitis B virus infection and chronic kidney disease. Aliment Pharmacol Ther 2014; 39:35–46. Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003; 348:808–816. Buti M, Morillas RM, Prieto M, Diago M, Pérez J, Solà R, et al. Efficacy and safety of entecavir in clinical practice in treatment-naive Caucasian chronic hepatitis B patients. Eur J Gastroenterol Hepatol 2012; 24:535–542. World Health Organization. WHO toxicity grading scale for determining the severity of adverse events. 2003. Available at: http://www.icssc.org/ Documents/Resources/AEManual2003AppendicesFebruary_06_2003 final.pdf. [Accessed 25 April 2014]. Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003; 29:1705–1713. Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen M-R, Wiklund O, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32:1769–1818. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006; 354:1011–1020. Gish RG, Lok AS, Chang T, de Man RA, Gadano A, Sollano J, et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology 2007; 133:1437–1444. Lok AS, Trinh H, Carosi G, Akarca US, Gadano A, Habersetzer F, et al. Efficacy of entecavir with or without tenofovir disoproxil fumarate for nucleos (t)ide-naïve patients with chronic hepatitis B. Gastroenterology 2012; 147:619–628.e1. Ridruejo E, Adrover R, Cocozzella D, Reggiardo MV, Estepo C, Schroder T, et al. Effectiveness of entecavir in chronic hepatitis B NUC-naive patients in routine clinical practice. Int J Clin Pract 2011; 65:866–870. Chang TT, Lai CL, Kew Yoon S, Lee SS, Coelho HSM, Carrilho FJ, et al. Entecavir treatment for up to 5 years in patients with hepatitis B e antigenpositive chronic hepatitis B. Hepatology 2010; 51:422–430. Duarte-Rojo A, Heathcote EJ. Efficacy and safety of tenofovir disoproxil fumarate in patients with chronic hepatitis B. Therap Adv Gastroenterol 2010; 3:107–119. Manns MP, Akarca US, Chang TT, Sievert W, Yoon SK, Tsai N, et al. Longterm safety and tolerability of entecavir in patients with chronic hepatitis B in the rollover study ETV-901. Expert Opin Drug Saf 2012; 11:361–368. Keating GM. Entecavir: a review of its use in the treatment of chronic hepatitis B in patients with decompensated liver disease. Drugs 2011; 71:2511–2529.
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