Journal of Hepatology
March 2017 Volume 66, Issue 3, Pages 476–477
Hepatitis C virus eradication in the elderly: The challenge worth a long-life elixir?
Ranka Vukotic†, Fabio Conti†, Pietro Andreone
DOI: http://dx.doi.org/10.1016/j.jhep.2016.12.012
Publication History
Published online: December 22, 2016
Older age has been described to be among one of the most implicated host factors in hepatitis C virus (HCV) disease progression [[1], [2]]. The presence of steatosis and insulin resistance is more likely to develop with aging and leads to liver fibrosis progression. Moreover, in chronic liver disease, older age is an independent risk factor for the development of hepatocellular carcinoma [3][3]. The morbidity and mortality in HCV-related liver disease are significantly reduced after viral eradication [[4], [5], [6]]. Nonetheless, the older aged patients have been historically an undertreated subpopulation in chronic hepatitis C, as they are more fragile towards the interferon-containing antiviral regimens. The recent advent of direct-acting antivirals (DAAs) made the HCV clearance a reachable goal with much less effort and encouraged the treatment of difficult-to-treat populations in hepatitis C, which includes patients of older age. Some important studies have recently addressed this [[7], [8], [9], [10]], but only a few of the currently available studies report on extremely old cohorts (>75 years) with an advanced disease stage [[11], [12]].
The current issue of the Journal of Hepatology presents data on a Japanese cohort of 115 HCV-genotype 1 infected patients of ⩾80 years of age, who were treated with daclatasvir (DCV) and asunaprevir (ASV) for 24 weeks and followed-up for 1 year [13][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 also provided a comparison with a historical group (followed between 2004 and 2014) of 336 untreated controls aged ⩾80 years. 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 significant difference in 1-year mortality in these 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 has some limitations in 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 a non-invasive tool for fibrosis detection, has been recently described to possibly overestimate liver fibrosis in 65 years and older subjects [14][14], although these recent conclusions originate from data on NAFLD subjects and not those with HCV-related disease. However, the authors of this study confirm the stage of cirrhosis also by ultrasound and endoscopic findings. In relation to cirrhosis, more information is needed in both the clinical and the safety outcomes according to Child-Turcotte-Pugh class, as addressed by recently published data [15][15]. 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 seem in elderly patients. This is a key aspect of this study, as data from previous trials commonly come from younger cohorts with fewer comorbidities. However, it is still not confirmed how wide the effect of the eradication of HCV on its extrahepatic 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][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 further studies are needed to address this outcome.
Toyoda et al. use an interesting age cut-off to distinguish the study groups. It could be debated whether further age cut-offs should be set within the context of elderly patients. For instance, in a compensated or even mild liver disease, it is undoubtful that the shorter 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 expectance.
Concerns in the use of antiviral treatment in HCV-related disease of elderly patients ranges over the ethical, social and pharmacoeconomic spectra, in addition to the medical ones.
From the ethical point of view, in today’s HCV setting, age itself should not by any means justify the decision not to treat a patient, especially in the high likelihood of a successful outcome and of the excellent profile of safety and tolerability in the currently available all-oral regimens. One of the premises introduced in the study by Toyoda et al. [13][13] was that the age of the HCV-infected population in Japan is progressively increasing [19][19], which underlies the expected social impact of its treatment in the near future. Notably, a similar trend is perceived also in Europe and in the United States [20][20]. Moreover, it should be kept in 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 co-morbidities typical for the elderly, more difficult and lastly more expensive to manage. An awkward question is how many more years do the DAAs-based antiviral therapy give in respects to quality of life in the elderly and extremely old patients.
Indeed, for the pharmacoeconomic implications to be correctly drawn in this setting, long-term observational studies are needed. The work of Toyoda et al., is one of the first studies that contributes to this.
We could already foresee that, as a reduction in drug costs is expected in the near future, the ratio between cost and benefit of the new all-oral anti-HCV strategies will be more and more balanced. Therefore, treating a HCV-infected patient regardless of the life expectation time, will be naturally justified. Indeed, in the present-day setting of HCV-infected elderly patients, improving the remainder of their life (though not a long-life elixir) is the conceivable and worthy goal of a successful antiviral treatment.
http://www.journal-of-hepatology.eu/article/S0168-8278(16)30745-0/fulltext
Linked Article
Survival benefit from HCV eradication using DAAs, even in patients over 80 years old
Efficacy and tolerability of an IFN-free regimen with DCV/ASV for elderly patients infected with HCV genotype 1B
IFN-free therapy with oral direct-acting antiviral drugs (daclatasvir and asunaprevir) for HCV infection showed similar tolerability and antiviral efficacy in patients aged ⩾80 years as in younger patients (patients aged ⩾70 and <80 years and patients aged <70 years), with an SVR rate over 90% and no severe adverse effects. There was a survival benefit from the eradication of HCV even in patients aged ⩾80 years.
Of Interest
January 26, 2017
Hepatitis C virus infection and the risk of cancer among elderly US adults: A registry-based case-control study
HCV is associated with increased risk of cancers other than HCC in the US elderly population, notably bile duct cancers and diffuse large B-cell lymphoma. These results support a possible etiologic role for HCV in an expanded group of cancers. Cancer 2017. © 2017 American Cancer Society.
June 2016 Journal of Hepatology
Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis; Direct acting antivirals for decompensated cirrhosis. Efficacy and safety are now established - Editorial
The current issue of the Journal of Hepatology presents data on a Japanese cohort of 115 HCV-genotype 1 infected patients of ⩾80 years of age, who were treated with daclatasvir (DCV) and asunaprevir (ASV) for 24 weeks and followed-up for 1 year [13][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 also provided a comparison with a historical group (followed between 2004 and 2014) of 336 untreated controls aged ⩾80 years. 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 significant difference in 1-year mortality in these 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 has some limitations in 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 a non-invasive tool for fibrosis detection, has been recently described to possibly overestimate liver fibrosis in 65 years and older subjects [14][14], although these recent conclusions originate from data on NAFLD subjects and not those with HCV-related disease. However, the authors of this study confirm the stage of cirrhosis also by ultrasound and endoscopic findings. In relation to cirrhosis, more information is needed in both the clinical and the safety outcomes according to Child-Turcotte-Pugh class, as addressed by recently published data [15][15]. 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 seem in elderly patients. This is a key aspect of this study, as data from previous trials commonly come from younger cohorts with fewer comorbidities. However, it is still not confirmed how wide the effect of the eradication of HCV on its extrahepatic 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][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 further studies are needed to address this outcome.
Toyoda et al. use an interesting age cut-off to distinguish the study groups. It could be debated whether further age cut-offs should be set within the context of elderly patients. For instance, in a compensated or even mild liver disease, it is undoubtful that the shorter 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 expectance.
Concerns in the use of antiviral treatment in HCV-related disease of elderly patients ranges over the ethical, social and pharmacoeconomic spectra, in addition to the medical ones.
From the ethical point of view, in today’s HCV setting, age itself should not by any means justify the decision not to treat a patient, especially in the high likelihood of a successful outcome and of the excellent profile of safety and tolerability in the currently available all-oral regimens. One of the premises introduced in the study by Toyoda et al. [13][13] was that the age of the HCV-infected population in Japan is progressively increasing [19][19], which underlies the expected social impact of its treatment in the near future. Notably, a similar trend is perceived also in Europe and in the United States [20][20]. Moreover, it should be kept in 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 co-morbidities typical for the elderly, more difficult and lastly more expensive to manage. An awkward question is how many more years do the DAAs-based antiviral therapy give in respects to quality of life in the elderly and extremely old patients.
Indeed, for the pharmacoeconomic implications to be correctly drawn in this setting, long-term observational studies are needed. The work of Toyoda et al., is one of the first studies that contributes to this.
We could already foresee that, as a reduction in drug costs is expected in the near future, the ratio between cost and benefit of the new all-oral anti-HCV strategies will be more and more balanced. Therefore, treating a HCV-infected patient regardless of the life expectation time, will be naturally justified. Indeed, in the present-day setting of HCV-infected elderly patients, improving the remainder of their life (though not a long-life elixir) is the conceivable and worthy goal of a successful antiviral treatment.
http://www.journal-of-hepatology.eu/article/S0168-8278(16)30745-0/fulltext
Linked Article
Survival benefit from HCV eradication using DAAs, even in patients over 80 years old
Efficacy and tolerability of an IFN-free regimen with DCV/ASV for elderly patients infected with HCV genotype 1B
IFN-free therapy with oral direct-acting antiviral drugs (daclatasvir and asunaprevir) for HCV infection showed similar tolerability and antiviral efficacy in patients aged ⩾80 years as in younger patients (patients aged ⩾70 and <80 years and patients aged <70 years), with an SVR rate over 90% and no severe adverse effects. There was a survival benefit from the eradication of HCV even in patients aged ⩾80 years.
Of Interest
January 26, 2017
Hepatitis C virus infection and the risk of cancer among elderly US adults: A registry-based case-control study
HCV is associated with increased risk of cancers other than HCC in the US elderly population, notably bile duct cancers and diffuse large B-cell lymphoma. These results support a possible etiologic role for HCV in an expanded group of cancers. Cancer 2017. © 2017 American Cancer Society.
June 2016 Journal of Hepatology
Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis; Direct acting antivirals for decompensated cirrhosis. Efficacy and safety are now established - Editorial
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