Liver International ISSN 1478-3223
VIRAL HEPATITIS
Tenofovir disoproxil fumarate has a substantial efficacy against multidrug-resistant strains of hepatitis B virus Bulent Baran1, Ozlem Mutluay Soyer2, Asli Cifcibasi Ormeci2, Suut Gokturk2, Sami Evirgen2, Filiz Akyuz2, Cetin Karaca2, Kadir Demir2, Fatih Besisik2, Derya Onel3, Mine Gulluoglu4, Selim Badur3 and Sabahattin Kaymakoglu2 1 2 3 4
Department of Gastroenterology, Kocß University Hospital, Zeytinburnu, Istanbul, Turkey Department of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Capa, Istanbul, Turkey Department of Microbiology, Istanbul Faculty of Medicine, Istanbul University, Capa, Istanbul, Turkey Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Capa, Istanbul, Turkey
Liver Int. 2015; 35: 2265–2274. DOI: 10.1111/liv.12831
Abstract Background & Aims; To evaluate the efficacy of tenofovir in chronic hepatitis B (CHB) patients with adefovir resistance (ADF-R) and suboptimal response to adefovir (ADF-S). Methods: Nucleos(t)ide analogue (NA)-na€ıve patients and patients with previous adefovir failure receiving tenofovir therapy for at least 6 months were included in the study. Biochemical and virological tests were obtained at baseline and 3-month intervals in the first year and every 6 months thereafter. The primary outcome measure was complete virological response (CVR) (HBVDNA < 20 IU/ml). CVR rates were calculated by Kaplan–Meier analysis, and a multivariate Cox proportional hazard model was generated to find out factors independently associated with CVR. Results: A total of 165 patients (118 men, mean age 42 ± 12, 64 HBeAg+) were included in the study. There were 105 patients in NA-na€ıve, 32 patients in ADF-S and 28 patients in ADF-R groups. All patients in the ADF-R group had multidrug resistance patterns. Mean duration of tenofovir treatment was 29 ± 14 months. CVR rates in NA-na€ıve, ADF-S and ADF-R groups were 65% vs. 75% vs. 58% at 12th month, 77% vs. 87% vs. 79% at 24th month and 83% vs. 94% vs. 79% at 36th month respectively. According to multivariate Cox regression model, HBeAg positivity (HR = 0.56, 95%CI 0.36–0.86, P = 0.008), high baseline HBVDNA level (HR = 0.64, 95%CI 0.55–0.74, P < 0.001) and ADF-R (HR = 0.47, 95% CI 0.28–0.81, P = 0.006) were independent predictors for CVR. Seven patients encountered mild renal dysfunction and were managed by dose adjustments. Conclusion: CVR rates during the follow-up show that tenofovir has a decreased, yet still potent in vivo efficacy against multidrug-resistant strains of HBV. Keywords adefovir failure – chronic hepatitis B – genotypic resistance – tenofovir disoproxil fumarate
The introduction of lamivudine into clinical practice has dramatically changed the management of chronic hepatitis B (CHB) which had been dominated by interferons. Although viral suppression achieved by lamivudine treatment encouraged hepatologists during early years of the drug, long-term efficacy was compromised by rapid selection of lamivudine-resistant mutants (1,
2). As demonstrated in several studies, incidence of lamivudine resistance increases with longer duration of therapy, especially in patients with inadequate response, and can reach up to 65–70% by 5 years (3, 4). After the introduction of adefovir dipivoxil into the clinical practice, add-on combination therapy with lamivudine became the standard of care for patients with
Abbreviations ADF-S, adefovir suboptimal response; ADF-R, adefovir resistance; ALT, alanine aminotransferase; CHB, chronic hepatitis B; CVR, complete virological response; CI, confidence interval; EASL, European Association for the Study of the Liver; HBV, hepatitis B virus; TDF, tenofovir disoproxil fumarate; HBeAg, hepatitis B ‘e’ antigen; NA, nucleos(t)ide analogue; HBsAg, hepatitis B surface antigen; MDRD, Modification of Diet in Renal Disease; MDR, multidrug resistance; SD, standard deviation; HR, hazard ratio. Correspondence Sabahattin Kaymakoglu, M.D., Professor, Department of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Capa 34390, Istanbul, Turkey Tel: +902124142000 – 31140; Fax: +902126319743 e-mail: [email protected] Handling Editor: Stanislas Pol Received 14 October 2014; Accepted 16 March 2015
Liver International (2015) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
2265
Baran et al.
Tenofovir therapy in adefovir resistance
Key points
Tenofovir has a potent and comparable efficacy in nucleos(t)ide analogue-na€ıve patients and patients with suboptimal response to adefovir. Adefovir resistance is associated with a significantly delayed virological response to tenofovir therapy in terms of both median change in HBVDNA and achieving undetectable HBVDNA. Nevertheless, antiviral efficacy of tenofovir is stable in long term. This study confirms that tenofovir is the treatment of choice in patients infected with lamivudine- and/ or adefovir-resistant strains of HBV. A partial virological response to tenofovir at 48 weeks in patients with prior resistance to adefovir may indicate adding entecavir treatment in selected cases. lamivudine-resistant hepatitis B virus (HBV) infection (5). Unfortunately, this approach was proved to be less than optimal for the management of lamivudine resistance due to suboptimal virological response to adefovir, which is characterized by a slow decrease in viral replication in most cases (5–7). The characteristic weak and delayed response to adefovir has been reported to be associated with the development of high resistance rates up to 28% after 5 years of treatment in NA-naive patients (8). Cumulative resistance rates after 5 years of treatment were also high in lamivudine-resistant patients who were switched to adefovir monotherapy or received add-on combination therapy (9, 10). However, the resistance rates in patients under adefovir add-on treatment are significantly lower than in patients switched to adefovir monotherapy (11). There are three mutations, rtA181V, rtA181T and rtN236T, which are associated with decreased susceptibility to adefovir. Those mutations are mapped in the B and D domains of the HBV polymerase gene (12). The selection of adefovir-resistant strains is associated with the loss of efficacy. It occurs relatively late compared to the emergence of lamivudine resistance; however, the recent European Association for the Study of the Liver (EASL) guideline recommends a switch to a more potent drug in patients with partial response to adefovir at week 48, preferably to an agent without cross-resistance (13). Tenofovir disoproxil fumarate (TDF), which is the oral prodrug of tenofovir, was licensed in 2008 for the treatment of CHB in many countries. It is structural congener of adefovir and has a potent and selective inhibitor activity against HBV DNA polymerase reverse transcriptase in vitro (14). Two prospective ongoing randomized trials, which included mostly treatmentna€ıve patients, showed the superiority of TDF 300 mg/ day compared to adefovir 10 mg/day in both hepatitis B e antigen (HBeAg)-negative (Study 102) and hepatitis B e antigen (HBeAg)-positive patients (Study 103) (15).
2266
The cumulative clinical and published experience indicates that TDF has a substantial antiviral efficacy against wild-type and lamivudine-resistant strains of HBV (15– 18). However, the evidence regarding the long-term efficacy of TDF in adefovir resistance (ADF-R) is limited. TDF is an acyclic nucleos(t)ide analogue (NA), and structural similarities with adefovir can make crossresistance possible. Several studies have demonstrated a reduced susceptibility to TDF in patients infected with adefovir-resistant HBV. A recent study suggested ongoing selection of adefovir-resistant HBV variants during TDF monotherapy (19), but clinical implications of this finding are not yet available. In this study, we aimed to investigate the long-term efficacy of TDF in patients with previous adefovir failure (genotypic resistance or suboptimal response to adefovir) in comparison with NA-na€ıve patients. Materials and methods Patients
This study included HBeAg-positive and HBeAg-negative patients with CHB who were under follow-up in Istanbul University, Istanbul Faculty of Medicine, Department of Gastroenterohepatology. An institutional ethics committee approval was not required, due to retrospective analysis of the patient records, in accordance with the National Code on Clinical Research published in Official Gazette numbered with 28617 at 13 April 2013 (20). All patients had detectable hepatitis B surface antigen (HBsAg) for at least 6 months, histological evidence of chronic hepatitis and an indication for antiviral treatment according to the EASL guideline (13). Further eligibility criteria were as follows: (1) being NA-na€ıve, (2) emergence of ADFR or suboptimal virological response to adefovir (HBVDNA >50 IU/ml after at least 12 months of adefovir treatment) and (3) a negative serology for human immunodeficiency virus, hepatitis C and D virus. ADFR was defined as the presence of mutations that confer reduced susceptibility to adefovir (rtA181V/T and/or rtN236T). Patients selected in accordance with the inclusion criteria between June 2008 and January 2013 were considered for TDF treatment after obtaining informed consent to start antiviral therapy. All patients had detectable HBVDNA before initiation of TDF therapy, and any patient who received TDF 1.5 mg/dl received TDF with a dose adjustment according to the calculated creatinine clearance by ‘Modification of Diet in Renal Disease’ (MDRD) formula (24). Primary endpoint of the study was the proportion of patients achieving complete virological response (CVR) defined as undetectable HBVDNA (0.05
77 (19–706) 82 (78) 40 (38)
38 (12–385) 13 (41) 10 (31)
39 (20–273) 13 (46) 14 (50)
7.12 (2.09–9.13) Not tested – – – –
4.58 (1.84–9.96) 18 (56) 17 (53) 0 (0) 0 (0) 0 (0)
5.29 (2.08–8.04) 28 (100) 14 (50) 25 (89) 12 (43) 28 (100)
0 (0)a 57 (60.6)a 25 (26.6)a 8 (8.5)a 2 (2.1)a 2 (2.1)a 7 (5–14) 30 (29) None None
4 (19)b 7 (33.3)b 7 (33.3)a 2 (9.5)a 1 (4.8)a 0 (0)a,b 6 (5–13) 6 (19) 25 (78) 32 (100)
105 (100) 0 (0) 3.4 (2.7–4.6) 93.5 (58–221) 28 ± 14 28 (6–52)
6 (24)b 11 (44)a,b 3 (12)a 0 (0)a 2 (8)a 3 (12)b 5 (4–16)
VIRAL HEPATITIS
Tenofovir disoproxil fumarate has a substantial efficacy against multidrug-resistant strains of hepatitis B virus Bulent Baran1, Ozlem Mutluay Soyer2, Asli Cifcibasi Ormeci2, Suut Gokturk2, Sami Evirgen2, Filiz Akyuz2, Cetin Karaca2, Kadir Demir2, Fatih Besisik2, Derya Onel3, Mine Gulluoglu4, Selim Badur3 and Sabahattin Kaymakoglu2 1 2 3 4
Department of Gastroenterology, Kocß University Hospital, Zeytinburnu, Istanbul, Turkey Department of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Capa, Istanbul, Turkey Department of Microbiology, Istanbul Faculty of Medicine, Istanbul University, Capa, Istanbul, Turkey Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Capa, Istanbul, Turkey
Liver Int. 2015; 35: 2265–2274. DOI: 10.1111/liv.12831
Abstract Background & Aims; To evaluate the efficacy of tenofovir in chronic hepatitis B (CHB) patients with adefovir resistance (ADF-R) and suboptimal response to adefovir (ADF-S). Methods: Nucleos(t)ide analogue (NA)-na€ıve patients and patients with previous adefovir failure receiving tenofovir therapy for at least 6 months were included in the study. Biochemical and virological tests were obtained at baseline and 3-month intervals in the first year and every 6 months thereafter. The primary outcome measure was complete virological response (CVR) (HBVDNA < 20 IU/ml). CVR rates were calculated by Kaplan–Meier analysis, and a multivariate Cox proportional hazard model was generated to find out factors independently associated with CVR. Results: A total of 165 patients (118 men, mean age 42 ± 12, 64 HBeAg+) were included in the study. There were 105 patients in NA-na€ıve, 32 patients in ADF-S and 28 patients in ADF-R groups. All patients in the ADF-R group had multidrug resistance patterns. Mean duration of tenofovir treatment was 29 ± 14 months. CVR rates in NA-na€ıve, ADF-S and ADF-R groups were 65% vs. 75% vs. 58% at 12th month, 77% vs. 87% vs. 79% at 24th month and 83% vs. 94% vs. 79% at 36th month respectively. According to multivariate Cox regression model, HBeAg positivity (HR = 0.56, 95%CI 0.36–0.86, P = 0.008), high baseline HBVDNA level (HR = 0.64, 95%CI 0.55–0.74, P < 0.001) and ADF-R (HR = 0.47, 95% CI 0.28–0.81, P = 0.006) were independent predictors for CVR. Seven patients encountered mild renal dysfunction and were managed by dose adjustments. Conclusion: CVR rates during the follow-up show that tenofovir has a decreased, yet still potent in vivo efficacy against multidrug-resistant strains of HBV. Keywords adefovir failure – chronic hepatitis B – genotypic resistance – tenofovir disoproxil fumarate
The introduction of lamivudine into clinical practice has dramatically changed the management of chronic hepatitis B (CHB) which had been dominated by interferons. Although viral suppression achieved by lamivudine treatment encouraged hepatologists during early years of the drug, long-term efficacy was compromised by rapid selection of lamivudine-resistant mutants (1,
2). As demonstrated in several studies, incidence of lamivudine resistance increases with longer duration of therapy, especially in patients with inadequate response, and can reach up to 65–70% by 5 years (3, 4). After the introduction of adefovir dipivoxil into the clinical practice, add-on combination therapy with lamivudine became the standard of care for patients with
Abbreviations ADF-S, adefovir suboptimal response; ADF-R, adefovir resistance; ALT, alanine aminotransferase; CHB, chronic hepatitis B; CVR, complete virological response; CI, confidence interval; EASL, European Association for the Study of the Liver; HBV, hepatitis B virus; TDF, tenofovir disoproxil fumarate; HBeAg, hepatitis B ‘e’ antigen; NA, nucleos(t)ide analogue; HBsAg, hepatitis B surface antigen; MDRD, Modification of Diet in Renal Disease; MDR, multidrug resistance; SD, standard deviation; HR, hazard ratio. Correspondence Sabahattin Kaymakoglu, M.D., Professor, Department of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Capa 34390, Istanbul, Turkey Tel: +902124142000 – 31140; Fax: +902126319743 e-mail: [email protected] Handling Editor: Stanislas Pol Received 14 October 2014; Accepted 16 March 2015
Liver International (2015) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
2265
Baran et al.
Tenofovir therapy in adefovir resistance
Key points
Tenofovir has a potent and comparable efficacy in nucleos(t)ide analogue-na€ıve patients and patients with suboptimal response to adefovir. Adefovir resistance is associated with a significantly delayed virological response to tenofovir therapy in terms of both median change in HBVDNA and achieving undetectable HBVDNA. Nevertheless, antiviral efficacy of tenofovir is stable in long term. This study confirms that tenofovir is the treatment of choice in patients infected with lamivudine- and/ or adefovir-resistant strains of HBV. A partial virological response to tenofovir at 48 weeks in patients with prior resistance to adefovir may indicate adding entecavir treatment in selected cases. lamivudine-resistant hepatitis B virus (HBV) infection (5). Unfortunately, this approach was proved to be less than optimal for the management of lamivudine resistance due to suboptimal virological response to adefovir, which is characterized by a slow decrease in viral replication in most cases (5–7). The characteristic weak and delayed response to adefovir has been reported to be associated with the development of high resistance rates up to 28% after 5 years of treatment in NA-naive patients (8). Cumulative resistance rates after 5 years of treatment were also high in lamivudine-resistant patients who were switched to adefovir monotherapy or received add-on combination therapy (9, 10). However, the resistance rates in patients under adefovir add-on treatment are significantly lower than in patients switched to adefovir monotherapy (11). There are three mutations, rtA181V, rtA181T and rtN236T, which are associated with decreased susceptibility to adefovir. Those mutations are mapped in the B and D domains of the HBV polymerase gene (12). The selection of adefovir-resistant strains is associated with the loss of efficacy. It occurs relatively late compared to the emergence of lamivudine resistance; however, the recent European Association for the Study of the Liver (EASL) guideline recommends a switch to a more potent drug in patients with partial response to adefovir at week 48, preferably to an agent without cross-resistance (13). Tenofovir disoproxil fumarate (TDF), which is the oral prodrug of tenofovir, was licensed in 2008 for the treatment of CHB in many countries. It is structural congener of adefovir and has a potent and selective inhibitor activity against HBV DNA polymerase reverse transcriptase in vitro (14). Two prospective ongoing randomized trials, which included mostly treatmentna€ıve patients, showed the superiority of TDF 300 mg/ day compared to adefovir 10 mg/day in both hepatitis B e antigen (HBeAg)-negative (Study 102) and hepatitis B e antigen (HBeAg)-positive patients (Study 103) (15).
2266
The cumulative clinical and published experience indicates that TDF has a substantial antiviral efficacy against wild-type and lamivudine-resistant strains of HBV (15– 18). However, the evidence regarding the long-term efficacy of TDF in adefovir resistance (ADF-R) is limited. TDF is an acyclic nucleos(t)ide analogue (NA), and structural similarities with adefovir can make crossresistance possible. Several studies have demonstrated a reduced susceptibility to TDF in patients infected with adefovir-resistant HBV. A recent study suggested ongoing selection of adefovir-resistant HBV variants during TDF monotherapy (19), but clinical implications of this finding are not yet available. In this study, we aimed to investigate the long-term efficacy of TDF in patients with previous adefovir failure (genotypic resistance or suboptimal response to adefovir) in comparison with NA-na€ıve patients. Materials and methods Patients
This study included HBeAg-positive and HBeAg-negative patients with CHB who were under follow-up in Istanbul University, Istanbul Faculty of Medicine, Department of Gastroenterohepatology. An institutional ethics committee approval was not required, due to retrospective analysis of the patient records, in accordance with the National Code on Clinical Research published in Official Gazette numbered with 28617 at 13 April 2013 (20). All patients had detectable hepatitis B surface antigen (HBsAg) for at least 6 months, histological evidence of chronic hepatitis and an indication for antiviral treatment according to the EASL guideline (13). Further eligibility criteria were as follows: (1) being NA-na€ıve, (2) emergence of ADFR or suboptimal virological response to adefovir (HBVDNA >50 IU/ml after at least 12 months of adefovir treatment) and (3) a negative serology for human immunodeficiency virus, hepatitis C and D virus. ADFR was defined as the presence of mutations that confer reduced susceptibility to adefovir (rtA181V/T and/or rtN236T). Patients selected in accordance with the inclusion criteria between June 2008 and January 2013 were considered for TDF treatment after obtaining informed consent to start antiviral therapy. All patients had detectable HBVDNA before initiation of TDF therapy, and any patient who received TDF 1.5 mg/dl received TDF with a dose adjustment according to the calculated creatinine clearance by ‘Modification of Diet in Renal Disease’ (MDRD) formula (24). Primary endpoint of the study was the proportion of patients achieving complete virological response (CVR) defined as undetectable HBVDNA (0.05
77 (19–706) 82 (78) 40 (38)
38 (12–385) 13 (41) 10 (31)
39 (20–273) 13 (46) 14 (50)
7.12 (2.09–9.13) Not tested – – – –
4.58 (1.84–9.96) 18 (56) 17 (53) 0 (0) 0 (0) 0 (0)
5.29 (2.08–8.04) 28 (100) 14 (50) 25 (89) 12 (43) 28 (100)
0 (0)a 57 (60.6)a 25 (26.6)a 8 (8.5)a 2 (2.1)a 2 (2.1)a 7 (5–14) 30 (29) None None
4 (19)b 7 (33.3)b 7 (33.3)a 2 (9.5)a 1 (4.8)a 0 (0)a,b 6 (5–13) 6 (19) 25 (78) 32 (100)
105 (100) 0 (0) 3.4 (2.7–4.6) 93.5 (58–221) 28 ± 14 28 (6–52)
6 (24)b 11 (44)a,b 3 (12)a 0 (0)a 2 (8)a 3 (12)b 5 (4–16)
