Liver International ISSN 1478-3223
ORIGINAL ARTICLE
Loss of hepatitis B surface antigen in a real-life clinical cohort of patients with chronic hepatitis B virus infection my Moenne-Loccoz1, Nicolas Meyer2,4, Evelyne Schvoerer2,3,5,*,†, Francßois Habersetzer1,2,3, Re 1 €l1,2,3 Pauline Simo-Noumbissie , Stavros Dritsas1,‡, Thomas F. Baumert1,2,3 and Michel Doffoe 1 2 3 4 5
^pitaux Universitaires de Strasbourg, Nouvel Ho ^pital Civil, Strasbourg F-67091, France Service d’H epatogastroent erologie, Ho Universit e de Strasbourg, Strasbourg F-67000, France Unit e Inserm 1110, Strasbourg F-67000, France ^pitaux Universitaires de Strasbourg, Strasbourg F-67091, France Service de Sant e Publique, Ho Laboratoire de Virologie, H^ opitaux Universitaires de Strasbourg, Strasbourg F-67091, France
Keywords antiviral therapy – chronic active hepatitis – chronic HBV infection – inactive carrier state – incidence and predictive factors of HBsAg loss – real-life clinical cohort Abbreviations ADV, adefovir dipivoxil; ALT, alanine aminotransferase; BMI, body mass index; CAH, chronic active hepatitis; ETV, entecavir; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HDV, hepatitis D virus; HIV, human immunodeficiency virus; IFN, interferon(s); IFN-a, standard interferon-a; LAM, lamivudine; MCI, maximum cumulative incidence; NA-1, first-generation NA (LAM, ADV); NA-2, second-generation NA (ETV, TDF); NA, nucleos(t)ide analogue(s); PEG-IFNa, pegylated interferon-a; TDF, tenofovir disoproxil fumarate; ULN, upper limit of normal. Correspondence Francßois Habersetzer, MD ^pital Civil, Service Nouvel Ho d’H epatogastroent erologie, 1 Place de ^pital, F-67091 Strasbourg, France l’Ho Tel: +33 3 69 55 10 09 Fax: +33 3 69 55 18 57 e-mail: francois. [email protected]
Abstract Background & Aims: Hepatitis B surface antigen (HBsAg) clearance is the main indicator of viral cure in patients infected with the hepatitis B virus (HBV). We sought to identify the parameters associated with HBsAg loss in a well-characterized real-life clinical cohort of chronically HBV-infected patients. Methods: Patients with chronic HBV infection were prospectively included, classified according to the disease stage, and followed up to determine parameters associated with HBsAg clearance. Results: In total, 315 patients were followed up for a mean of almost 6 years. At study entry, 109 (34.6%) were inactive HBsAg carriers, 204 (64.8%) had chronic active hepatitis (CAH), and two (0.6%) were immune-tolerant carriers. During followup, 128 (62.7%) of the 204 patients with CAH received antiviral therapy. Sixty-nine had HBeAg-positive CAH: 55 (79.7%) were treated and 14 (20.3%) untreated. One hundred thirty-five had HBeAg-negative CAH: 73 (54.1%) were treated and 62 (45.9%) untreated. Inactive carriers showed an annual HBsAg clearance incidence rate of 23.4 cases per 1000 persons-years, which was higher than that of CAH groups. The clearance incidence rates (in cases per 1000 persons-years) of CAH groups were: treated HBeAg-positive (20.7), untreated HBeAg-positive (19.1), treated HBeAg-negative (10.1), and untreated HBeAg-negative (8.1). Older age (P = 0.001) and inactive carrier status (P = 0.019) were independent predictors of HBsAg clearance. Conclusion: In a well-characterized real-life clinical cohort of chronically HBV-infected patients in various disease phases, older age, and inactive HBsAg carrier status were the only predictors of HBsAg clearance, whereas anti-HBV therapy only marginally increased annual incidence of HBsAg loss.
Received 26 February 2014 Accepted 13 August 2014 DOI:10.1111/liv.12661 Liver Int. 2015; 35: 130–139
*Present address: Laboratoire de Virologie, CHU de Nancy, Hoˆpital Brabois – Adultes, Vandoeuvre-les-Nancy F-54511, France † Present address: Equipe d’Accueil 7300, Universit e de Lorraine, Vandoeuvre-les-Nancy F-54505, France ‡ ^pital Jean Minjoz, Besancßon F-25030, France Present address: Service d’H epatogastroenterologie, CHU de Besancon, Ho
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Liver International (2015) © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Habersetzer et al.
Chronic hepatitis B virus (HBV) infection is characterized by three distinct phases: immune-tolerant, immune-active, and inactive (1, 2). The immune-tolerant phase is defined by the presence of hepatitis B e antigen (HBeAg), a normal serum alanine aminotransferase (ALT) level, a high serum HBV DNA level, and minimal or no liver disease. The immune-active phase is characterized by a high serum ALT level, medium or high serum HBV DNA levels, and active hepatitis. Patients in this infection phase may either remain HBeAg-positive or become HBeAg-negative after developing anti-HBe antibodies and clearing HBeAg. The majority of patients who clear HBeAg move into the inactive phase, characterized by sustained normal ALT and low HBV DNA levels (1, 2). Ultimately, patients who clear hepatitis B surface antigen (HBsAg) develop anti-HBs antibodies, improve their long-term prognosis, and are considered as having reached viral resolution (1, 3). Current treatments for chronic HBV infection include interferons [IFN; i.e. standard interferon-a (IFN-a) and pegylated interferon-a (PEG-IFN-a)] and nucleos(t)ide analogues (NA). These latter comprise first-generation NA [NA-1; e.g. lamivudine (LAM), adefovir dipivoxil (ADV)] and second-generation NA [NA-2; entecavir (ETV), tenofovir disoproxil fumarate (TDF)] (1, 2). Treatment is indicated for patients in the immune-active phase who exhibit chronic active hepatitis (CAH) and are at increased risk of liver-related morbidity or mortality (1, 2). IFN are administered for finite durations and act through both antiviral and immunomodulatory effects, while NA are usually administered for many years and only target the HBV polymerase by inducing a strong inhibition of viral replication. Current NA-based therapies have dramatically improved the long-term prognosis of CAH patients. However, complete viral elimination with HBsAg clearance as endpoint appears to be uncommon following NA-based therapy. This end-point is reported to be slightly higher following IFN-based therapy (4). To date, the predictive factors and incidence rate of HBsAg clearance have not been evaluated in a real-life clinical cohort of patients according to the different phases of chronic HBV infection and anti-HBV therapy. A recent study demonstrated that patients with a sustained inactive HBsAg carriage were more likely to spontaneously clear HBsAg than those with HBeAgnegative CAH. However, this study only assessed patients negative for HBeAg and with untreated hepatitis B (5). Thus, the present study sought to evaluate the incidence and determinants of HBsAg clearance in a cohort of non-selected patients followed up in a real-life clinical setting, who were in different and well-characterized chronic HBV infection phases as defined by current international practice guidelines (1, 2), and who received, when indicated, anti-HBV therapy.
Liver International (2015) © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
HBsAg clearance in chronic HBV infection
Patients and methods Patients
Starting August 2006, the patients positive for HBsAg and followed up in the Department of Hepatogastroenterology of the Strasbourg University Hospital (France) were invited to participate in this study. Patients were included if they had chronic HBV infection as defined by HBsAg-positivity for at least 6 months, were followed up over a period of more than 6 months, had no history of hepatocellular carcinoma (HCC) and/or liver transplantation, and were not coinfected with human immunodeficiency virus (HIV), hepatitis C virus (HCV) and/or hepatitis D virus (HDV). Overall, 361 patients consented to participate to this study. Of these, 46 had to be excluded because they met the exclusion criteria, with 41 having a follow-up duration of less than 6 months, two having an HCC, two being co-infected (one with HCV and one with HDV), and one being false-positive for HBsAg. Ultimately, 315 patients were prospectively included and analysed in our study. These patients were in various, well-characterized chronic HBV infection phases (i.e. immune-tolerance, HBeAg-positive or HBeAg-negative CAH, or inactive carriage) as defined by current international practice guidelines (1, 2), and were followed up in a routine clinical setting. Patients received antiviral therapy based on the EASL and AASLD recommendations. This study was conducted in accordance with the Declaration of Helsinki ethical principles. Regulatory requirements and institutional approval were obtained, and all study participants provided informed consent prior to study inclusion. This study was registered at ClinicalTrials.gov under the identifier number NCT01732081. The 315 included patients were followed up over a mean period of 5.7 years ± 3.9. The cohort’s baseline characteristics are shown in Table 1. One hundred twenty-eight patients who had CAH (55 HBeAg-positive and 73 HBeAg-negative) at baseline were treated during follow-up (Table 2). Thirty-six patients with HBeAg-positive CAH were treated exclusively with NA over a mean period of 56.9 months ± 34.7 – seven with NA-1 (i.e. LAM and/or ADV), nine with NA-2 (i.e. ETV and/or TDF), and 20 with NA-1 and NA-2. Fifty-seven patients with HBeAgnegative CAH were treated exclusively with NA over a mean period of 63.8 months ± 40.7 – 14 with NA-1, 19 with NA-2, and 24 with NA-1 and NA-2. Three patients with HBeAg-positive CAH and one with HBeAg-negative CAH were treated exclusively with (PEG-)IFN-a (Table 2). Sixteen patients with HBeAg-positive CAH and 15 with HBeAg-negative CAH were treated with NA and (PEG-)IFN-a, in combination or successively, over a mean period of 101.6 months ± 32.6 for patients with HBeAg-positive CAH and of 97.4 months ± 44.7 for patients with HBeAg-negative CAH (Table 2). The detailed regimen is provided in Table S1.
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Habersetzer et al.
HBsAg clearance in chronic HBV infection
Table 1. Baseline characteristics n = 315
Characteristics Gender, n (%) Male Female Age, median [range], years Ethnic origin, n (%) Caucasian African Asian BMI, median [range], kg/m² Alcohol consumption, n (%) No Yes nd Serum HBV DNA level, median [range], log10 IU/ml Serum ALT Ievel, median [range], fold change in the ULN HBeAg status, n (%) Positive Negative Phase of infection, n (%) Immune-tolerant Inactive HBeAg-positive CAH HBeAg-negative CAH
211 (67.0) 104 (33.0) 35 (12–86) 194 (61.6) 96 (30.5) 25 (7.9) 25 [17-41] 290 (92.1) 18 (5.7) 7 (2.2) 3.5 (0.8–9.0) 0.9 (0.2–39.3)
71 (22.5) 244 (77.5) 2 (0.6) 109 (34.6) 69 (21.9) 135 (42.9)
ALT, alanine aminotransferase; BMI, body mass index; CAH, chronic active hepatitis; nd, not determined; ULN, upper limit of normal.
Table 2. Antiviral therapy administered in patients with HBeAgpositive or HBeAg-negative CAH n = 128 Antiviral treatment(s) NA-1, n (%) NA-2, n (%) NA-1 and NA-2, n (%) (PEG-)IFN-a, n (%) NA (NA-1 and/or NA-2) and (PEG-)IFN-a, n (%)
HBeAg-positive CAH n = 55
HBeAg-negative CAH n = 73
7 (12.7) 9 (16.4) 20 (36.4) 3 (5.5) 16 (29.1)
14 (19.2) 19 (26.0) 24 (32.9) 1 (1.4) 15 (20.5)
CAH, chronic active hepatitis; NA, nucleos(t)ide analogue(s); NA-1, firstgeneration NA; NA-2, second-generation NA; (PEG-)IFN-a, standard and/or pegylated interferon-a.
Follow-up and data collection
Demographical, clinical, virological, biochemical and therapeutic parameters were prospectively collected from baseline (i.e. the beginning of follow-up) until the end of follow-up and stored in a computer database. The end of follow-up corresponded (i) to the time of HBsAg loss or (ii), for patients who did not clear HBsAg, to the date of the patients’ last visit or the
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occurrence of an event leading to withdrawal from this study (death, liver transplantation or HCC). The different parameters were retrospectively collected in patients for whom the beginning of follow-up preceded the start of this study (i.e. before August 2006). All parameters were collected as part of the patients’ routine clinical monitoring. Demographical and clinical parameters comprised gender, age, ethnic origin, body mass index (BMI) and alcohol consumption. Alcohol consumption during follow-up was defined as daily alcohol intake, regardless of the dose. Virological and biochemical parameters included serological markers (HBeAg, HBsAg, anti-HBe antibodies and anti-HBs antibodies), plasma HBV DNA and serum ALT levels. Therapeutic parameters were the type and duration of antiviral treatment(s) administered during follow-up, as well as assessment of the virological response. The virological response to antiviral therapy was defined as a maintained decrease in serum HBV DNA to an undetectable level (quantification with sensitive assays) in patients treated with NA (with or without IFN), or at 107 IU/ml) and normal ALT values [i.e. at or below the upper limit of normal (ULN)]. These parameters were repeatedly tested at the beginning of follow-up over a period of more than 12 months, and no break in tolerance was observed during follow-up of immune-tolerant carriers. CAH phase was defined as HBV DNA >2000/20000 IU/ml and/or ALT levels above the ULN and signs of chronic hepatitis. CAH patients were classified according to their serological phase: HBeAg-positive or HBeAg-negative. In line with current recommendations, a liver biopsy was performed, if needed, to accurately diagnosis the CAH stage and define the indication for treatment. Most patients undergoing a liver biopsy and presenting moderate or severe histological liver damage received antiviral treatment(s) during follow-up. Indeed, only two patients with moderate CAH on liver biopsy were untreated because of a refusal of treatment for personal reasons (Table S2). Otherwise, most of the 76 untreated CAH patients were not considered for antiviral therapy because of a minimal CAH determined by liver biopsy (Table S2). Inactive carrier state was defined as HBeAg-negative, HBV DNA
ORIGINAL ARTICLE
Loss of hepatitis B surface antigen in a real-life clinical cohort of patients with chronic hepatitis B virus infection my Moenne-Loccoz1, Nicolas Meyer2,4, Evelyne Schvoerer2,3,5,*,†, Francßois Habersetzer1,2,3, Re 1 €l1,2,3 Pauline Simo-Noumbissie , Stavros Dritsas1,‡, Thomas F. Baumert1,2,3 and Michel Doffoe 1 2 3 4 5
^pitaux Universitaires de Strasbourg, Nouvel Ho ^pital Civil, Strasbourg F-67091, France Service d’H epatogastroent erologie, Ho Universit e de Strasbourg, Strasbourg F-67000, France Unit e Inserm 1110, Strasbourg F-67000, France ^pitaux Universitaires de Strasbourg, Strasbourg F-67091, France Service de Sant e Publique, Ho Laboratoire de Virologie, H^ opitaux Universitaires de Strasbourg, Strasbourg F-67091, France
Keywords antiviral therapy – chronic active hepatitis – chronic HBV infection – inactive carrier state – incidence and predictive factors of HBsAg loss – real-life clinical cohort Abbreviations ADV, adefovir dipivoxil; ALT, alanine aminotransferase; BMI, body mass index; CAH, chronic active hepatitis; ETV, entecavir; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HDV, hepatitis D virus; HIV, human immunodeficiency virus; IFN, interferon(s); IFN-a, standard interferon-a; LAM, lamivudine; MCI, maximum cumulative incidence; NA-1, first-generation NA (LAM, ADV); NA-2, second-generation NA (ETV, TDF); NA, nucleos(t)ide analogue(s); PEG-IFNa, pegylated interferon-a; TDF, tenofovir disoproxil fumarate; ULN, upper limit of normal. Correspondence Francßois Habersetzer, MD ^pital Civil, Service Nouvel Ho d’H epatogastroent erologie, 1 Place de ^pital, F-67091 Strasbourg, France l’Ho Tel: +33 3 69 55 10 09 Fax: +33 3 69 55 18 57 e-mail: francois. [email protected]
Abstract Background & Aims: Hepatitis B surface antigen (HBsAg) clearance is the main indicator of viral cure in patients infected with the hepatitis B virus (HBV). We sought to identify the parameters associated with HBsAg loss in a well-characterized real-life clinical cohort of chronically HBV-infected patients. Methods: Patients with chronic HBV infection were prospectively included, classified according to the disease stage, and followed up to determine parameters associated with HBsAg clearance. Results: In total, 315 patients were followed up for a mean of almost 6 years. At study entry, 109 (34.6%) were inactive HBsAg carriers, 204 (64.8%) had chronic active hepatitis (CAH), and two (0.6%) were immune-tolerant carriers. During followup, 128 (62.7%) of the 204 patients with CAH received antiviral therapy. Sixty-nine had HBeAg-positive CAH: 55 (79.7%) were treated and 14 (20.3%) untreated. One hundred thirty-five had HBeAg-negative CAH: 73 (54.1%) were treated and 62 (45.9%) untreated. Inactive carriers showed an annual HBsAg clearance incidence rate of 23.4 cases per 1000 persons-years, which was higher than that of CAH groups. The clearance incidence rates (in cases per 1000 persons-years) of CAH groups were: treated HBeAg-positive (20.7), untreated HBeAg-positive (19.1), treated HBeAg-negative (10.1), and untreated HBeAg-negative (8.1). Older age (P = 0.001) and inactive carrier status (P = 0.019) were independent predictors of HBsAg clearance. Conclusion: In a well-characterized real-life clinical cohort of chronically HBV-infected patients in various disease phases, older age, and inactive HBsAg carrier status were the only predictors of HBsAg clearance, whereas anti-HBV therapy only marginally increased annual incidence of HBsAg loss.
Received 26 February 2014 Accepted 13 August 2014 DOI:10.1111/liv.12661 Liver Int. 2015; 35: 130–139
*Present address: Laboratoire de Virologie, CHU de Nancy, Hoˆpital Brabois – Adultes, Vandoeuvre-les-Nancy F-54511, France † Present address: Equipe d’Accueil 7300, Universit e de Lorraine, Vandoeuvre-les-Nancy F-54505, France ‡ ^pital Jean Minjoz, Besancßon F-25030, France Present address: Service d’H epatogastroenterologie, CHU de Besancon, Ho
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Liver International (2015) © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Habersetzer et al.
Chronic hepatitis B virus (HBV) infection is characterized by three distinct phases: immune-tolerant, immune-active, and inactive (1, 2). The immune-tolerant phase is defined by the presence of hepatitis B e antigen (HBeAg), a normal serum alanine aminotransferase (ALT) level, a high serum HBV DNA level, and minimal or no liver disease. The immune-active phase is characterized by a high serum ALT level, medium or high serum HBV DNA levels, and active hepatitis. Patients in this infection phase may either remain HBeAg-positive or become HBeAg-negative after developing anti-HBe antibodies and clearing HBeAg. The majority of patients who clear HBeAg move into the inactive phase, characterized by sustained normal ALT and low HBV DNA levels (1, 2). Ultimately, patients who clear hepatitis B surface antigen (HBsAg) develop anti-HBs antibodies, improve their long-term prognosis, and are considered as having reached viral resolution (1, 3). Current treatments for chronic HBV infection include interferons [IFN; i.e. standard interferon-a (IFN-a) and pegylated interferon-a (PEG-IFN-a)] and nucleos(t)ide analogues (NA). These latter comprise first-generation NA [NA-1; e.g. lamivudine (LAM), adefovir dipivoxil (ADV)] and second-generation NA [NA-2; entecavir (ETV), tenofovir disoproxil fumarate (TDF)] (1, 2). Treatment is indicated for patients in the immune-active phase who exhibit chronic active hepatitis (CAH) and are at increased risk of liver-related morbidity or mortality (1, 2). IFN are administered for finite durations and act through both antiviral and immunomodulatory effects, while NA are usually administered for many years and only target the HBV polymerase by inducing a strong inhibition of viral replication. Current NA-based therapies have dramatically improved the long-term prognosis of CAH patients. However, complete viral elimination with HBsAg clearance as endpoint appears to be uncommon following NA-based therapy. This end-point is reported to be slightly higher following IFN-based therapy (4). To date, the predictive factors and incidence rate of HBsAg clearance have not been evaluated in a real-life clinical cohort of patients according to the different phases of chronic HBV infection and anti-HBV therapy. A recent study demonstrated that patients with a sustained inactive HBsAg carriage were more likely to spontaneously clear HBsAg than those with HBeAgnegative CAH. However, this study only assessed patients negative for HBeAg and with untreated hepatitis B (5). Thus, the present study sought to evaluate the incidence and determinants of HBsAg clearance in a cohort of non-selected patients followed up in a real-life clinical setting, who were in different and well-characterized chronic HBV infection phases as defined by current international practice guidelines (1, 2), and who received, when indicated, anti-HBV therapy.
Liver International (2015) © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
HBsAg clearance in chronic HBV infection
Patients and methods Patients
Starting August 2006, the patients positive for HBsAg and followed up in the Department of Hepatogastroenterology of the Strasbourg University Hospital (France) were invited to participate in this study. Patients were included if they had chronic HBV infection as defined by HBsAg-positivity for at least 6 months, were followed up over a period of more than 6 months, had no history of hepatocellular carcinoma (HCC) and/or liver transplantation, and were not coinfected with human immunodeficiency virus (HIV), hepatitis C virus (HCV) and/or hepatitis D virus (HDV). Overall, 361 patients consented to participate to this study. Of these, 46 had to be excluded because they met the exclusion criteria, with 41 having a follow-up duration of less than 6 months, two having an HCC, two being co-infected (one with HCV and one with HDV), and one being false-positive for HBsAg. Ultimately, 315 patients were prospectively included and analysed in our study. These patients were in various, well-characterized chronic HBV infection phases (i.e. immune-tolerance, HBeAg-positive or HBeAg-negative CAH, or inactive carriage) as defined by current international practice guidelines (1, 2), and were followed up in a routine clinical setting. Patients received antiviral therapy based on the EASL and AASLD recommendations. This study was conducted in accordance with the Declaration of Helsinki ethical principles. Regulatory requirements and institutional approval were obtained, and all study participants provided informed consent prior to study inclusion. This study was registered at ClinicalTrials.gov under the identifier number NCT01732081. The 315 included patients were followed up over a mean period of 5.7 years ± 3.9. The cohort’s baseline characteristics are shown in Table 1. One hundred twenty-eight patients who had CAH (55 HBeAg-positive and 73 HBeAg-negative) at baseline were treated during follow-up (Table 2). Thirty-six patients with HBeAg-positive CAH were treated exclusively with NA over a mean period of 56.9 months ± 34.7 – seven with NA-1 (i.e. LAM and/or ADV), nine with NA-2 (i.e. ETV and/or TDF), and 20 with NA-1 and NA-2. Fifty-seven patients with HBeAgnegative CAH were treated exclusively with NA over a mean period of 63.8 months ± 40.7 – 14 with NA-1, 19 with NA-2, and 24 with NA-1 and NA-2. Three patients with HBeAg-positive CAH and one with HBeAg-negative CAH were treated exclusively with (PEG-)IFN-a (Table 2). Sixteen patients with HBeAg-positive CAH and 15 with HBeAg-negative CAH were treated with NA and (PEG-)IFN-a, in combination or successively, over a mean period of 101.6 months ± 32.6 for patients with HBeAg-positive CAH and of 97.4 months ± 44.7 for patients with HBeAg-negative CAH (Table 2). The detailed regimen is provided in Table S1.
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Habersetzer et al.
HBsAg clearance in chronic HBV infection
Table 1. Baseline characteristics n = 315
Characteristics Gender, n (%) Male Female Age, median [range], years Ethnic origin, n (%) Caucasian African Asian BMI, median [range], kg/m² Alcohol consumption, n (%) No Yes nd Serum HBV DNA level, median [range], log10 IU/ml Serum ALT Ievel, median [range], fold change in the ULN HBeAg status, n (%) Positive Negative Phase of infection, n (%) Immune-tolerant Inactive HBeAg-positive CAH HBeAg-negative CAH
211 (67.0) 104 (33.0) 35 (12–86) 194 (61.6) 96 (30.5) 25 (7.9) 25 [17-41] 290 (92.1) 18 (5.7) 7 (2.2) 3.5 (0.8–9.0) 0.9 (0.2–39.3)
71 (22.5) 244 (77.5) 2 (0.6) 109 (34.6) 69 (21.9) 135 (42.9)
ALT, alanine aminotransferase; BMI, body mass index; CAH, chronic active hepatitis; nd, not determined; ULN, upper limit of normal.
Table 2. Antiviral therapy administered in patients with HBeAgpositive or HBeAg-negative CAH n = 128 Antiviral treatment(s) NA-1, n (%) NA-2, n (%) NA-1 and NA-2, n (%) (PEG-)IFN-a, n (%) NA (NA-1 and/or NA-2) and (PEG-)IFN-a, n (%)
HBeAg-positive CAH n = 55
HBeAg-negative CAH n = 73
7 (12.7) 9 (16.4) 20 (36.4) 3 (5.5) 16 (29.1)
14 (19.2) 19 (26.0) 24 (32.9) 1 (1.4) 15 (20.5)
CAH, chronic active hepatitis; NA, nucleos(t)ide analogue(s); NA-1, firstgeneration NA; NA-2, second-generation NA; (PEG-)IFN-a, standard and/or pegylated interferon-a.
Follow-up and data collection
Demographical, clinical, virological, biochemical and therapeutic parameters were prospectively collected from baseline (i.e. the beginning of follow-up) until the end of follow-up and stored in a computer database. The end of follow-up corresponded (i) to the time of HBsAg loss or (ii), for patients who did not clear HBsAg, to the date of the patients’ last visit or the
132
occurrence of an event leading to withdrawal from this study (death, liver transplantation or HCC). The different parameters were retrospectively collected in patients for whom the beginning of follow-up preceded the start of this study (i.e. before August 2006). All parameters were collected as part of the patients’ routine clinical monitoring. Demographical and clinical parameters comprised gender, age, ethnic origin, body mass index (BMI) and alcohol consumption. Alcohol consumption during follow-up was defined as daily alcohol intake, regardless of the dose. Virological and biochemical parameters included serological markers (HBeAg, HBsAg, anti-HBe antibodies and anti-HBs antibodies), plasma HBV DNA and serum ALT levels. Therapeutic parameters were the type and duration of antiviral treatment(s) administered during follow-up, as well as assessment of the virological response. The virological response to antiviral therapy was defined as a maintained decrease in serum HBV DNA to an undetectable level (quantification with sensitive assays) in patients treated with NA (with or without IFN), or at 107 IU/ml) and normal ALT values [i.e. at or below the upper limit of normal (ULN)]. These parameters were repeatedly tested at the beginning of follow-up over a period of more than 12 months, and no break in tolerance was observed during follow-up of immune-tolerant carriers. CAH phase was defined as HBV DNA >2000/20000 IU/ml and/or ALT levels above the ULN and signs of chronic hepatitis. CAH patients were classified according to their serological phase: HBeAg-positive or HBeAg-negative. In line with current recommendations, a liver biopsy was performed, if needed, to accurately diagnosis the CAH stage and define the indication for treatment. Most patients undergoing a liver biopsy and presenting moderate or severe histological liver damage received antiviral treatment(s) during follow-up. Indeed, only two patients with moderate CAH on liver biopsy were untreated because of a refusal of treatment for personal reasons (Table S2). Otherwise, most of the 76 untreated CAH patients were not considered for antiviral therapy because of a minimal CAH determined by liver biopsy (Table S2). Inactive carrier state was defined as HBeAg-negative, HBV DNA
