- Email: [email protected]
Hepatitis C virus eradication in the elderly: The challenge worth a long-life elixir?
Accepted Manuscript Hepatitis C virus eradication in elderly: The challenge worth a long-life elixir? Ranka Vukotic, Fabio Conti, Pietro Andreone PII: DOI: Reference:
S0168-8278(16)30745-0 http://dx.doi.org/10.1016/j.jhep.2016.12.012 JHEPAT 6363
To appear in:
Journal of Hepatology
Received Date: Accepted Date:
11 December 2016 12 December 2016
Please cite this article as: Vukotic, R., Conti, F., Andreone, P., Hepatitis C virus eradication in elderly: The challenge worth a long-life elixir?, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep.2016.12.012
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
HEPATITIS C VIRUS ERADICATION IN ELDERLY: THE CHALLENGE WORTH A LONG-LIFE ELIXIR? Ranka Vukotic1*, Fabio Conti1*, Pietro Andreone1. 1
Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca per lo Studio delle Epatiti, Università
degli Studi di Bologna, Bologna, Italy *
equally contributing co-first authors
Corresponding Author Pietro Andreone, MD, Professor of Internal Medicine Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna Policlinico Sant’Orsola-Malpighi, Azienda Ospedaliero-Universitaria di Bologna Via Massarenti, 9, 40138 Bologna, Italy. Tel.: +39 051 2143618; fax: +39 051 345806; e-mail: [email protected]
Word count: 1208. List of abbreviations: HCV, hepatitis C virus HCC, hepatocellular carcinoma DAAs, direct acting antivirals SVR, sustained virological response PegIFN, pegylated interferon DSV, daclatasvir ASV, asunaprevir CTP, Child-Turcotte-Pugh
Senectus enim insanabilis morbus est. Lucius Annaeus Seneca, c. 65 AD.
Editorial The older age has been demonstrated to be among most implicated host factors in the hepatitis C virus (HCV) disease progression (1, 2). Some of confirmed boosters of liver fibrosis progression, as the presence of steatosis and insulin resistance are more likely to develop with aging. Moreover, in chronic liver disease, the advanced age is an independent risk factor for the development of hepatocellular carcinoma (3). The morbidity and mortality in HCV-related liver disease are significantly reduced after viral eradication (4-6). Nonetheless, the elderly has been historically an undertreated category in chronic hepatitis C, since considered fragile towards the interferoncontaining antiviral regimens. The recent advent of direct acting antivirals (DAAs) made the HCV clearance a reachable goal with much less effort. This revolutionary scenario founded the expectations for all difficult-to-treat, or anyhow challenging, populations in hepatitis C, including the patients in advanced age. Some important contributions have been recently given to this setting (7-10), but only a few of the currently available experiences report on extremely old cohorts and with an advanced disease stage (11, 12). The current issue of the Journal presents the data on the Japanese cohort of 115 HCV-genotype 1 infected and ≥80 years old patients, treated with daclatasvir (DCV) and asunaprevir (ASV) for 24 weeks and followed-up for 1 year afterwards (13). The comparison with 151 patients ≥70 and <80 years old and with 115 patients <70 years, who underwent the same antiviral treatment and accurately matched by propensity score matching, was performed. The Authors provided also the comparison with a historical group (followed between 2004 and 2014) of 336 untreated controls aged ≥80. The group of extremely old patients obtained similar, excellent virological outcome as the groups of younger subjects treated in this study with a satisfactory safety profile. The most eloquent data from the study is the significantly different 1-year mortality in the cured patients
compared to the large untreated cohort. Furthermore, the patients who achieved SVR showed a null 1-year mortality due to liver-related complications. Whereas the 1-year rate of HCC was similar between SVR and untreated patients with cirrhosis, none among SVR patients experienced hepatic decompensation during the entire study period. This study is slightly less solid in the clearness of the definition of cirrhosis, which was detected in approximately one-third of the extremely elderly (≥80 years) study group. For instance, the FIB-4 score, which was used as non-invasive tool for fibrosis detection, has been recently indicated to possibly overestimate liver fibrosis in 65 years and older subjects (14), although these recent conclusions originate from data on subjects with NAFLD and not with HCV-related disease. However, the Authors furnish the affirmative data of cirrhotic stage also by ultrasound and endoscopic findings. When it comes to cirrhosis, it would be useful to have a closer look to both the clinical and the safety outcomes according to Child-Turcotte-Pugh class and, although some studies already do give some clear hint on this issue (15), more information is needed in this context. The focus on a specific antiviral combination (DCV+ASV) makes the study population more homogeneous and strengthens the interpretation of the results, although it should be of note that ASV is currently unaffordable in Europe. This in part hampers the generalizability of the present study to the European real-life clinical context, where more information is demanded on the outcomes of authorized antiviral schedules in elderly cohorts, possibly with homogenously advanced disease. The information on the comorbidities identified in this large and well-studied cohort underline how the interferon-free regimens allow a successful antiviral therapy regardless of the co-presence of different chronic diseases typical for the elderly. This outcome is of highest interest since the data from trials commonly come from younger cohorts with much less comorbidities. However, it is still not fully clarified how wide is the effect of the eradication of HCV on its extra-hepatic manifestations, i.e. type 2 diabetes, cardiovascular and rheumatologic manifestations, lymphoma etc. (16, 17). Of note, the health-related quality of life of patients with hepatitis C was shown to
correlate with the concomitantly affecting illness (18). The overall improvement of the quality of life (which should be the ultimate goal of any medical intervention in the elderly) due to the eradication of HCV per se could be here speculated, but the dedicated studies are needed to properly target this outcome. Toyoda et al. use an interesting age cut-off to distinguish the study groups. It could be debated whether further age cut-off should be set within the context of elderly. For instance, in a compensated or even mild liver disease, it is undoubtful that the shorter is the life expectation, the less probable are the long-term complications. Namely, the patients between 70 and 80 years are a fairly suitable population to focus the long-term outcomes on, since this sub-group reflects the overt elderly subjects but with a consistent average life expectation. The spectrum of concerns in the antiviral treatment of HCV-related disease of the elderly ranges over the ethical, social and pharmacoeconomic, besides the medical ones. These concerns could be poorly addressed through the data derived from the clinical trials, which mostly did not include patients >75 years. From the ethical point of view, in the today’s HCV setting, the age itself should not by any means justify the decision not to treat, in the light of the high likelihood of a successful outcome and of the excellent profile of safety and tolerability of the currently available all-oral regimens. One of the premises that introduced the study by Toyoda and coll. (13) was that the age of the HCV-infected population in Japan is progressively increasing (19), which underlies the expected social impact of its treatment in the near future. Notably, a similar trend is indeed perceived also in Europe and in the United States (20). Moreover, it should be kept on mind that the ultimate goal of the antiviral treatment in hepatitis C, besides curing the single patient, is to halt the spread of the infection. Finally, the healthcare economy measures should take into account that the time-honoured complications of hepatitis C are expected to be both more probable and, given the context of comorbidities typical for the elderly, more difficult and lastly more expensive to manage. How many years of how much better life will the DAAs-based antiviral therapy be worth of in an elderly and in
an extremely old is an awkward question. Indeed, for the pharmacoeconomic implications to be correctly drawn in this setting, the studies with long-term observations are what is needed. The work of Toyoda et coll. is among the first ones concretely contributing to this purpose. We could already foresee that, due to the drugs costs reduction in the near future, the ratio between cost and benefit of the new all-oral anti-HCV strategies will be more and more balanced. This will likely bring the treatment to be naturally justified in any HCV-infected subject, regardless of the life expectation time. Whether the old age itself is an incurable illness, is a matter of fact. Still, in the present-day setting of HCV-infected elderly, a better rest of life (though not a long-life elixir) is the conceivable and worthy goal of a successful antiviral treatment.
Conflict of interest PA has served as speaker, consultant and advisory board member for AbbVie, BMS, Boehringer Ingelheim, Gilead Sciences, Janssen Cilag, MSD, Roche and Intercept and has received research funding from Gilead Sciences, MSD and Roche. The other Authors declare no conflict of interests. Financial support No financial support has been received with concern to this Editorial. Authors’ contributions Concept, interpretation, drafting and critical revision of the manuscript: all Authors.
REFERENCES 1
Poynard T, Bedossa P, Opolon P, for the OBSVIRC, METAVIR, CLINIVIR, and
DOSVIRC groups. Natural history of liver fibrosis progression in chronic hepatitis C. Lancet 1997;349:825-32. 2
Massard J, Ratziu V, Thabut D et al. Natural history and predictors of disease severity in
chronic hepatitis C. J Hepatol 2006;44(1 Suppl):S19-24.
3
Janjua NZ, Chong M, Kuo M, et al. Long-term effect of sustained virological response
on hepatocellular carcinoma in patients with hepatitis C in Canada. J Hepatol. 2016 Nov 4. doi: 10.1016/j.jhep.2016.10.028. [Epub ahead of print] 4
Singal AG, Volk ML, Jensen D, et al. A sustained viral response is associated with reduced
liver related morbidity and mortality in patients with hepatitis C virus. Clin Gastroenterol Hepatol 2010;8:280-8. 5
Van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological
response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 2012;308:2584-93. 6
Bruno S, Di Marco V, Iavarone M, et al. Survival of patients with HCV cirrhosis and
sustained virologic response is similar to the general population. J Hepatol. 2016;64:1217-23. 7
Saab S, Prk SH, Mikozami M, et al. Safety and Efficacy of Ledipasvir/Sofosbuvir for the
Treatment of Genotype 1 Hepatitis C in Subjects Aged 65 Years or Older. Hepatology 63:1112-9. doi: 10.1002/hep.28425. 8
Pellicelli AM, Pace Palitti V, Vignally P, et al.; CLEO Group. Liver Int. 2016 Oct 26. doi:
10.1111/liv.13288. [Epub ahead of print] 9
Vermehren J, Peiffer KH, Welsch C, et al. The efficacy and safety of direct acting antiviral
treatment and clinical significance of drug-drug interactions in elderly patients with chronic hepatitis C virus infection. Aliment Pharmacol Ther. 2016;44:856-65. doi: 10.1111/apt.13769. 10
Ogawa E, Furusyo N, Nomura H, et al; Kyushu University Liver Disease Study (KULDS)
Group. Effectiveness and safety of sofosbuvir plus ribavirin for HCV genotype 2 patients 65 and over with or without cirrhosis. Antiviral Res. 2016;136:37-44. doi: 10.1016/j.antiviral.2016.10.012. 11
Ogawa E, Furusyo N, Yamashita N, et al.; Kyushu University Liver Disease Study
(KULDS) Group.. Effectiveness and safety of daclatasvir plus asunaprevir for HCV genotype 1b
patients aged 75 and over with or without cirrhosis. Hepatol Res. 2016 May 3. doi: 10.1111/hepr.12738. [Epub ahead of print] 12
Morio Morio R, Imamura M, Kawakami Y, et al. Safety and efficacy of dual therapy with
daclatasvir and asunaprevir for older patients with chronic hepatitis C. J Gastroenterol. 2016 Sep 8. [Epub ahead of print] 13
Toyoda H, Kumada T, Tada T, et al. Efficacy, Tolerability and Benefits of an IFN-free
Regimen with DCV/ASV for Extremely Aged Patients Infected with HCV Genotype 1B. J Hepatol 2016, in press. 14
McPherson S, Hardy T, Dufour JF, et al. Age as a Confounding Factor for the Accurate
Non-Invasive Diagnosis of Advanced NAFLD Fibrosis. Am J Gastroenterol. 2016 Oct 11. doi: 10.1038/ajg.2016.453. [Epub ahead of print] 15
Conti F, Brillanti S, Buonfiglioli F, et al. Safety and efficacy of direct acting antivirals for
the treatment of chronic hepatitis C in a real-world population aged 65 years and older. J Viral Hepat 2016, in press. 16
Gragnani L, Piluso A, Urraro T, et al. Virological and Clinical Response to Interferon-Free
Regimens in Patients with HCV-Related Mixed Cryoglobulinemia: Preliminary Results of a Prospective Pilot Study. Curr Drug Targets. 2016 Feb 8. [Epub ahead of print] 17
Arcaini L, Besson C, Frigeni M, et al. Interferon-free antiviral treatment in B-cell
lymphoproliferative disorders associated with hepatitis C virus infection. Blood 2016;128:252732; doi: http://dx.doi.org/10.1182/blood-2016-05-714667. 18
Hsu PC, Federico CA, Krajden M, et al. Health utilities and psychometric quality of life in
patients with early- and late-stage hepatitis C virus infection. J Gastroenterol Hepatol. 2012;27:14957. doi: 10.1111/j.1440-1746.2011.06813.x. 19
Toyoda H, Kumada T, Takaguchi K, Shimada N, Tanaka J. Changes in hepatitis C virus
genotype distribution in Japan. Epidemiol Infect. 2014;142: 2624-8.
20
Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C virus (HCV)-infected persons in
the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 2010;138:513-21.
S0168-8278(16)30745-0 http://dx.doi.org/10.1016/j.jhep.2016.12.012 JHEPAT 6363
To appear in:
Journal of Hepatology
Received Date: Accepted Date:
11 December 2016 12 December 2016
Please cite this article as: Vukotic, R., Conti, F., Andreone, P., Hepatitis C virus eradication in elderly: The challenge worth a long-life elixir?, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep.2016.12.012
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
HEPATITIS C VIRUS ERADICATION IN ELDERLY: THE CHALLENGE WORTH A LONG-LIFE ELIXIR? Ranka Vukotic1*, Fabio Conti1*, Pietro Andreone1. 1
Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca per lo Studio delle Epatiti, Università
degli Studi di Bologna, Bologna, Italy *
equally contributing co-first authors
Corresponding Author Pietro Andreone, MD, Professor of Internal Medicine Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna Policlinico Sant’Orsola-Malpighi, Azienda Ospedaliero-Universitaria di Bologna Via Massarenti, 9, 40138 Bologna, Italy. Tel.: +39 051 2143618; fax: +39 051 345806; e-mail: [email protected]
Word count: 1208. List of abbreviations: HCV, hepatitis C virus HCC, hepatocellular carcinoma DAAs, direct acting antivirals SVR, sustained virological response PegIFN, pegylated interferon DSV, daclatasvir ASV, asunaprevir CTP, Child-Turcotte-Pugh
Senectus enim insanabilis morbus est. Lucius Annaeus Seneca, c. 65 AD.
Editorial The older age has been demonstrated to be among most implicated host factors in the hepatitis C virus (HCV) disease progression (1, 2). Some of confirmed boosters of liver fibrosis progression, as the presence of steatosis and insulin resistance are more likely to develop with aging. Moreover, in chronic liver disease, the advanced age is an independent risk factor for the development of hepatocellular carcinoma (3). The morbidity and mortality in HCV-related liver disease are significantly reduced after viral eradication (4-6). Nonetheless, the elderly has been historically an undertreated category in chronic hepatitis C, since considered fragile towards the interferoncontaining antiviral regimens. The recent advent of direct acting antivirals (DAAs) made the HCV clearance a reachable goal with much less effort. This revolutionary scenario founded the expectations for all difficult-to-treat, or anyhow challenging, populations in hepatitis C, including the patients in advanced age. Some important contributions have been recently given to this setting (7-10), but only a few of the currently available experiences report on extremely old cohorts and with an advanced disease stage (11, 12). The current issue of the Journal presents the data on the Japanese cohort of 115 HCV-genotype 1 infected and ≥80 years old patients, treated with daclatasvir (DCV) and asunaprevir (ASV) for 24 weeks and followed-up for 1 year afterwards (13). The comparison with 151 patients ≥70 and <80 years old and with 115 patients <70 years, who underwent the same antiviral treatment and accurately matched by propensity score matching, was performed. The Authors provided also the comparison with a historical group (followed between 2004 and 2014) of 336 untreated controls aged ≥80. The group of extremely old patients obtained similar, excellent virological outcome as the groups of younger subjects treated in this study with a satisfactory safety profile. The most eloquent data from the study is the significantly different 1-year mortality in the cured patients
compared to the large untreated cohort. Furthermore, the patients who achieved SVR showed a null 1-year mortality due to liver-related complications. Whereas the 1-year rate of HCC was similar between SVR and untreated patients with cirrhosis, none among SVR patients experienced hepatic decompensation during the entire study period. This study is slightly less solid in the clearness of the definition of cirrhosis, which was detected in approximately one-third of the extremely elderly (≥80 years) study group. For instance, the FIB-4 score, which was used as non-invasive tool for fibrosis detection, has been recently indicated to possibly overestimate liver fibrosis in 65 years and older subjects (14), although these recent conclusions originate from data on subjects with NAFLD and not with HCV-related disease. However, the Authors furnish the affirmative data of cirrhotic stage also by ultrasound and endoscopic findings. When it comes to cirrhosis, it would be useful to have a closer look to both the clinical and the safety outcomes according to Child-Turcotte-Pugh class and, although some studies already do give some clear hint on this issue (15), more information is needed in this context. The focus on a specific antiviral combination (DCV+ASV) makes the study population more homogeneous and strengthens the interpretation of the results, although it should be of note that ASV is currently unaffordable in Europe. This in part hampers the generalizability of the present study to the European real-life clinical context, where more information is demanded on the outcomes of authorized antiviral schedules in elderly cohorts, possibly with homogenously advanced disease. The information on the comorbidities identified in this large and well-studied cohort underline how the interferon-free regimens allow a successful antiviral therapy regardless of the co-presence of different chronic diseases typical for the elderly. This outcome is of highest interest since the data from trials commonly come from younger cohorts with much less comorbidities. However, it is still not fully clarified how wide is the effect of the eradication of HCV on its extra-hepatic manifestations, i.e. type 2 diabetes, cardiovascular and rheumatologic manifestations, lymphoma etc. (16, 17). Of note, the health-related quality of life of patients with hepatitis C was shown to
correlate with the concomitantly affecting illness (18). The overall improvement of the quality of life (which should be the ultimate goal of any medical intervention in the elderly) due to the eradication of HCV per se could be here speculated, but the dedicated studies are needed to properly target this outcome. Toyoda et al. use an interesting age cut-off to distinguish the study groups. It could be debated whether further age cut-off should be set within the context of elderly. For instance, in a compensated or even mild liver disease, it is undoubtful that the shorter is the life expectation, the less probable are the long-term complications. Namely, the patients between 70 and 80 years are a fairly suitable population to focus the long-term outcomes on, since this sub-group reflects the overt elderly subjects but with a consistent average life expectation. The spectrum of concerns in the antiviral treatment of HCV-related disease of the elderly ranges over the ethical, social and pharmacoeconomic, besides the medical ones. These concerns could be poorly addressed through the data derived from the clinical trials, which mostly did not include patients >75 years. From the ethical point of view, in the today’s HCV setting, the age itself should not by any means justify the decision not to treat, in the light of the high likelihood of a successful outcome and of the excellent profile of safety and tolerability of the currently available all-oral regimens. One of the premises that introduced the study by Toyoda and coll. (13) was that the age of the HCV-infected population in Japan is progressively increasing (19), which underlies the expected social impact of its treatment in the near future. Notably, a similar trend is indeed perceived also in Europe and in the United States (20). Moreover, it should be kept on mind that the ultimate goal of the antiviral treatment in hepatitis C, besides curing the single patient, is to halt the spread of the infection. Finally, the healthcare economy measures should take into account that the time-honoured complications of hepatitis C are expected to be both more probable and, given the context of comorbidities typical for the elderly, more difficult and lastly more expensive to manage. How many years of how much better life will the DAAs-based antiviral therapy be worth of in an elderly and in
an extremely old is an awkward question. Indeed, for the pharmacoeconomic implications to be correctly drawn in this setting, the studies with long-term observations are what is needed. The work of Toyoda et coll. is among the first ones concretely contributing to this purpose. We could already foresee that, due to the drugs costs reduction in the near future, the ratio between cost and benefit of the new all-oral anti-HCV strategies will be more and more balanced. This will likely bring the treatment to be naturally justified in any HCV-infected subject, regardless of the life expectation time. Whether the old age itself is an incurable illness, is a matter of fact. Still, in the present-day setting of HCV-infected elderly, a better rest of life (though not a long-life elixir) is the conceivable and worthy goal of a successful antiviral treatment.
Conflict of interest PA has served as speaker, consultant and advisory board member for AbbVie, BMS, Boehringer Ingelheim, Gilead Sciences, Janssen Cilag, MSD, Roche and Intercept and has received research funding from Gilead Sciences, MSD and Roche. The other Authors declare no conflict of interests. Financial support No financial support has been received with concern to this Editorial. Authors’ contributions Concept, interpretation, drafting and critical revision of the manuscript: all Authors.
REFERENCES 1
Poynard T, Bedossa P, Opolon P, for the OBSVIRC, METAVIR, CLINIVIR, and
DOSVIRC groups. Natural history of liver fibrosis progression in chronic hepatitis C. Lancet 1997;349:825-32. 2
Massard J, Ratziu V, Thabut D et al. Natural history and predictors of disease severity in
chronic hepatitis C. J Hepatol 2006;44(1 Suppl):S19-24.
3
Janjua NZ, Chong M, Kuo M, et al. Long-term effect of sustained virological response
on hepatocellular carcinoma in patients with hepatitis C in Canada. J Hepatol. 2016 Nov 4. doi: 10.1016/j.jhep.2016.10.028. [Epub ahead of print] 4
Singal AG, Volk ML, Jensen D, et al. A sustained viral response is associated with reduced
liver related morbidity and mortality in patients with hepatitis C virus. Clin Gastroenterol Hepatol 2010;8:280-8. 5
Van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological
response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 2012;308:2584-93. 6
Bruno S, Di Marco V, Iavarone M, et al. Survival of patients with HCV cirrhosis and
sustained virologic response is similar to the general population. J Hepatol. 2016;64:1217-23. 7
Saab S, Prk SH, Mikozami M, et al. Safety and Efficacy of Ledipasvir/Sofosbuvir for the
Treatment of Genotype 1 Hepatitis C in Subjects Aged 65 Years or Older. Hepatology 63:1112-9. doi: 10.1002/hep.28425. 8
Pellicelli AM, Pace Palitti V, Vignally P, et al.; CLEO Group. Liver Int. 2016 Oct 26. doi:
10.1111/liv.13288. [Epub ahead of print] 9
Vermehren J, Peiffer KH, Welsch C, et al. The efficacy and safety of direct acting antiviral
treatment and clinical significance of drug-drug interactions in elderly patients with chronic hepatitis C virus infection. Aliment Pharmacol Ther. 2016;44:856-65. doi: 10.1111/apt.13769. 10
Ogawa E, Furusyo N, Nomura H, et al; Kyushu University Liver Disease Study (KULDS)
Group. Effectiveness and safety of sofosbuvir plus ribavirin for HCV genotype 2 patients 65 and over with or without cirrhosis. Antiviral Res. 2016;136:37-44. doi: 10.1016/j.antiviral.2016.10.012. 11
Ogawa E, Furusyo N, Yamashita N, et al.; Kyushu University Liver Disease Study
(KULDS) Group.. Effectiveness and safety of daclatasvir plus asunaprevir for HCV genotype 1b
patients aged 75 and over with or without cirrhosis. Hepatol Res. 2016 May 3. doi: 10.1111/hepr.12738. [Epub ahead of print] 12
Morio Morio R, Imamura M, Kawakami Y, et al. Safety and efficacy of dual therapy with
daclatasvir and asunaprevir for older patients with chronic hepatitis C. J Gastroenterol. 2016 Sep 8. [Epub ahead of print] 13
Toyoda H, Kumada T, Tada T, et al. Efficacy, Tolerability and Benefits of an IFN-free
Regimen with DCV/ASV for Extremely Aged Patients Infected with HCV Genotype 1B. J Hepatol 2016, in press. 14
McPherson S, Hardy T, Dufour JF, et al. Age as a Confounding Factor for the Accurate
Non-Invasive Diagnosis of Advanced NAFLD Fibrosis. Am J Gastroenterol. 2016 Oct 11. doi: 10.1038/ajg.2016.453. [Epub ahead of print] 15
Conti F, Brillanti S, Buonfiglioli F, et al. Safety and efficacy of direct acting antivirals for
the treatment of chronic hepatitis C in a real-world population aged 65 years and older. J Viral Hepat 2016, in press. 16
Gragnani L, Piluso A, Urraro T, et al. Virological and Clinical Response to Interferon-Free
Regimens in Patients with HCV-Related Mixed Cryoglobulinemia: Preliminary Results of a Prospective Pilot Study. Curr Drug Targets. 2016 Feb 8. [Epub ahead of print] 17
Arcaini L, Besson C, Frigeni M, et al. Interferon-free antiviral treatment in B-cell
lymphoproliferative disorders associated with hepatitis C virus infection. Blood 2016;128:252732; doi: http://dx.doi.org/10.1182/blood-2016-05-714667. 18
Hsu PC, Federico CA, Krajden M, et al. Health utilities and psychometric quality of life in
patients with early- and late-stage hepatitis C virus infection. J Gastroenterol Hepatol. 2012;27:14957. doi: 10.1111/j.1440-1746.2011.06813.x. 19
Toyoda H, Kumada T, Takaguchi K, Shimada N, Tanaka J. Changes in hepatitis C virus
genotype distribution in Japan. Epidemiol Infect. 2014;142: 2624-8.
20
Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C virus (HCV)-infected persons in
the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 2010;138:513-21.