REVIEW ARTICLE
Chronic hepatitis C infection in the elderly
Chung-Feng Huang
a,b, Wan-Long Chuang
c,d, Ming-Lung Yu
d,e,*
aDepartment of Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
bDepartment of Preventive Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
cHepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital,
Kaohsiung, Taiwan
d
Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
eDepartment of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
Received 15 February 2011; accepted 19 March 2011
Available online 25 November 2011
KEYWORDS
HCV;
Elderly;
Treatment
Abstract The prevalence of chronic hepatitis C virus (HCV) tends to be higher in the elderly in many countries. Aging is regarded as an unfavorable factor for liver disease progression and treatment outcome in HCV infection. The efficacy and safety of treating elderly patients remain a source of significant debate. Discrepancies in results may be attributed to dissimilar-ities in study design and treatment regimens. The long-term benefits of administering interferon-based therapy to elderly patients with HCV infection is a critical issue when taking the patient’s remaining life expectancy into consideration. Rapid virological response is the most notable on-treatment response factor that is predictive of treatment success in elderly patients. A shortened treatment course may reduce drug-related side effects and promote treatment adherence, especially in the elderly. A regimen tailored towards super-responders might provide insights for treatment strategies in elderly patients.
Copyrightª 2011, Elsevier Taiwan LLC. All rights reserved.
Introduction
Hepatitis C virus (HCV) infection remains a major threat to
humans and affects an estimated 170 million people
worldwide
[1]
. Age is an important factor when treating
chronic HCV infection. The prevalence of anti-HCV
sero-positivity tends to be higher in the elderly compared to
younger individuals in many countries across the world
(
Table 1
). Aging is regarded as an unfavorable factor for
liver disease progression and treatment outcome in HCV
infection (
Table 2
). Aging and age at infection are two
factors that influence the progression of liver fibrosis and
the development of hepatocellular carcinoma
[2
e8]
. Age
itself seems to be a more important factor than age at
* Corresponding author. Department of Internal Medicine,Kaohsiung Municipal Ta-Tung Hospital, No. 100, Tzyou 1st Road, Kaohsiung 807, Taiwan.
E-mail addresses:[email protected],[email protected] (M.-L. Yu).
1607-551X/$36 Copyrightª 2011, Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.kjms.2011.10.020
Available online at
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journal home page: http:/ /www.kjms-onli ne.com Kaohsiung Journal of Medical Sciences (2011) 27, 533e537
infection in predicting the progression of liver disease
[7,8]
especially after an individual reaches 65 years of age
[7]
.
From this perspective, it can be argued that elderly
patients are most in need of antiviral treatment. Ironically,
advanced liver fibrosis, which is one of the unfavorable
factors, may put elderly patients at a significant
disad-vantage regarding achievement of a sustained virological
response (SVR)
[9,10]
. Moreover, underlying co-morbidities
render elderly patients more vulnerable to poor drug
compliance. Physicians therefore usually regard such
patients as a lower priority group for treatment owing to
difficulties in dealing with the numerous side effects.
However, it is becoming increasingly important to confront
this issue in countries such as Japan and Taiwan, where the
average age of patients who receive antiviral therapy is
approximately 10e15 years older than in Western countries
[11e13]
. Over the course of the next two decades, it will
also be critical for countries such as the USA where the
peak prevalence of anti-HCV seropositivity is among
indi-viduals of 40
e49 years of age to become more proactive in
confronting this issue
[14]
.
Efficacy and safety
The efficacy and safety of treating elderly patients remain
a source of significant debate (
Table 3
). It has been
sug-gested that elderly patients are affected by either higher
rates of drug modification or suffer increasingly more
adverse effects on conventional interferon-based therapy
[15e18]
. Interestingly, results from some studies were
similar
[19,20]
, while other studies using
pegylated-interferon-based therapy to treat the elderly revealed
different results
[21]
. Accordingly, poor treatment
adher-ence has led to inferior treatment outcomes in the elderly
[17e20,22]
, but these results are not globally consistent
[15,16,21,23,24]
. The discrepancies may be attributed to
dissimilarities in study design and treatment regimens;
most were carried out retrospectively and/or with
subop-timal regimens. In a prospective study, Huang et al. found
that two-thirds of Taiwanese chronic HCV patients
65
years of age could achieve SVR on current standard-of-care
regimens, specifically 48 weeks for HCV genotype 1 (HCV-1)
infection and 24 weeks of treatment for HCV genotype 2/3
(HCV-2/3) infection. The treatment response was
substan-tially lower in elderly patients than in patients between the
ages of 50 and 64 years. The lower treatment efficacy in
elderly patients was observed in HCV-1 patients (51.9% vs.
75.9%), but not in HCV-2/3 (76.7% vs. 80.2%) patients. Elderly
patients, especially those infected with HCV-1 who received
48 weeks of treatment, had significantly higher rates of
grade 3 or 4 adverse side effects, dose modification and
discontinued treatment that were primarily responsible for
the inferior efficacy. Most importantly, elderly patients with
a rapid virological response (RVR) showed high SVR rates
(80%) for both HCV-1 and HCV-2/3 that were comparable to
rates in their younger counterparts
[24]
. Kainuma and
colleagues recruited another Japanese cohort on the current
recommended treatment duration for HCV-1/2 but with
a relatively lower ribavirin dosage (600e1000 mg/day)
[25]
.
Table 1 Seroprevalence of anti-HCV positivity in variouscountries
Country General population
Age group No trend for increase in the elderly
50e59 y 60 y USA[14] 1.6% 1.6% 0.9% >65 y England and Wales[37] 0.7e1.1% 0.4%
Trend for increase in the elderly
60e69 y 70e79 y 80 y Taiwan[38] 4.4% 4.3% 6.3% 8.8% 60e69 y 70 y Italy[39] 2.6% 7.0% 7.7% 50e59 y 60e69 y Japan[40] 0.5% 1.8% 3.4% 55e64 y 65 y Spain[41] 2.5% 4.9% 5.1%
40e49 y 50e59 y 60e69 y France[42]a 0.8% 2.2% 1%b 2.2%
aPrevalence of female subjects. b Roughly estimated.
Table 2 Age as an unfavorable factor in chronic HCV infection
Study Time frame Clinical impact
Poynard et al.[6] >40 y at infection Rapid fibrosis progression Pradat et al.[4] Age at infection>37 y Fast fibrosis progression
Minola et al.[43] >40 y at infection Increased risk of developing cirrhosis Ryder et al.[5] Age at time of biopsy Fibrosis progression
Thabut et al.[7] 65 or <65 y More intense fibrosis at time of liver biopsy regardless of infection duration; more initial presentations of decompensated liver disease Reddy et al.[33] >50 or 50 y Higher proportion of cirrhosis in the elderly (16% vs. 34%, p<0.0001) Tong et al.[3] 50 or <50 y Increased risk of liver cirrhosis and hepatocarcinoma development Hamada et al.[8] 56 or <56 y Increased risk of hepatocarcinoma development; age is a more important
factor than infection duration
Iwasaki et al.[11] 60 or <60 y Increased incidence of hepatocarcinogenesis after successful antiviral treatment Ikeda et al.[44] >60 or 60 y Increased incidence of hepatocarcinogenesis after successful antiviral treatment Tokita et al.[45] 65 or <65 y Increased incidence of hepatocarcinogenesis after successful antiviral treatment
Compared to patients of
<65 years of age, elderly patients
had a significantly lower SVR rate not only for HCV-1 (22.9%
vs. 47.3%), but also for HCV-2 infection (65.6% vs. 82.9%); in
accordance with findings by Huang and co-workers, a higher
treatment discontinuation rate was noted in the elderly, but
was mainly restricted to HCV-1 patients.
Long-term outcome
Another important question is whether it is appropriate to
modify treatment strategies for elderly patients after
considering patient age (remaining life expectancy).
Peg-interferon and ribavirin combination therapy has been
recommended for HCV patients to clear the virus and to
halt the progression of liver fibrosis, thereby reducing
hepatocarcinogenesis and prolonging survival
[26e28]
. The
long-term benefits of interferon-based therapy in elderly
patients with HCV infection have also been addressed. In
a retrospective study using a conventional interferon-based
regimen, Imai and co-workers found a significantly lower
liver-related mortality rate in elderly patients compared
with their untreated counterparts (odds ratio 10.70, 95%
confidence interval 4.29e22.05)
[29]
. A similar result
was observed by Arase et al., who demonstrated that the
Table 3 Safety and efficacy of various treatments in the elderly
Study Ag, (y) Safety Efficacy
Dose
reduction/modification
Treatment discontinuation
SVR rate Honda et al.[15] <60, 60 IFN 15.6% vs. 16.7% IFN 14.9% vs. 21.2% 38.3% vs. 31.8%
RBV 29.9% vs. 42.4% RBV 20.8% vs. 33.3%a
Kumada et al.[16] <65, 65 IFN 14.5% vs. 17.0% IFN 17.8% vs.23.4% 39.4% vs. 25.2% RBV 29.0% vs. 42.6%a RBV 21.6% vs. 34.0%a
Iwasaki et al.[17] <50, 50e59, 60 38%, 48%, 77%a 15%, 18%, 30% All patients 50%, 34%, 32% HCV-1 27%, 9%, 16% HCV-2 82%, 85%, 65% Hiramatsu et al.[18] <60, 60e64, 65 IFN 7%, 5%, 6% RBV 5%, 9%, 8% 1Hc34%, 17%, 16%a
RBV 20%, 25%, 24% IFNþ RBV 11%, 20%, 29%a non-1Hc84%, 100%, 79% Alessi et al.[23] <60, 60 N/A 1% vs. 8% 20% vs.18%
Floreani et al.[19] 45.2 8.9 vs. 70.2 1.2
N/A 12.2% vs. 24.2% 69.7% vs.45.5%a
Nudo et al.[20] <60, 60 29.3% vs. 43.3% 34% vs. 53% 51.2% vs.33.3% Antonucci et al.[21] <40, 40e49,
50e64, 65 N/A 15.8%, 11.4%, 19.5%, 16.7% HCV-1/4 80.0%, 31.2%, 31.8%, 36.3%b HCV-2/3 92.3%, 89.3%, 78.9%, 89.5%
Huang et al.[24] 50e64, 65 HCV-1 53.7% vs. 48.1% HCV-1 7.4% vs. 33.3%a HCV-1 75.9% vs. 51.9%a
HCV 2/3 38.4% vs. 41.9% HCV-2/3 5.8% vs. 14.0% HCV-2/3 80.2% vs. 76.7% Honda et al.[34] <65, 65 Peg-IFN 33.2% vs. 39.1% 17.0% vs. 32.2%a 51.5% vs. 37.4%a
RBV 39.9% vs. 56.5%a
Kainuma et al.[25] <65, 65 N/A HCV-1 24.4% vs. 42.9%a HCV-1 47.3% vs. 22.9%a
HCV-2 13.1% vs. 13.1% HCV-2 82.9% vs. 65.6%a
1HZ patients with HCV genotype 1 and high viral load; HCV-1 Z hepatitis C virus genotype 1; HCV-2/3 Z hepatitis C virus genotype 2/3; IFNZ interferon; N/A Z not available; non-1H Z patients with HCV genotype 2 or low viral load; Peg-IFN Z pegylated interferon; RBVZ ribavirin; SVR Z sustained virological response.
a Statistically significant difference.
b A significant difference existed only between patients<40 and 40 years of age.
c 1H: patients with HCV genotype 1 and high viral loads; non-1H: patients with HCV genotype 2 or low viral loads.
Table 4 Recommendations for managing elderly patients with chronic hepatitis C infection
1. Identify and treat HCV patients before they reach 50e60 years of age
2. Weigh the benefits and risks of antiviral therapy based on current status of liver disease and residual life
expectancy
3. Preselect elderly without prominent underlying diseases, particularly severe cardiopulmonary and renal diseases 4. Manage HCV-2/3 patients more aggressively because of
the ease of cure
5. Manage patients with advanced liver disease more actively in consideration of long-term benefits 6. Monitor patients more frequently and manage side
effects more aggressively during therapy
7. Consider abbreviating treatment course in patients with a rapid virological response to enhance drug compliance and reduce adverse events in the elderly
8. Carry out interleukin-28B and inosine triphosphatase genetic testing to enhance treatment decisions and drug modification on an individualized basis
incidence of hepatocarcinogenesis and liver-related deaths
was significantly lower in patients over the age of 60
years with SVR
[30]
. Ikeda and colleagues further
demon-strated that patients with lower baseline platelet counts
(<150 1000/mm
3) rather than all elderly patients could
significantly benefit from such treatment in the long term,
as indicated by 15e20 years of observations post-treatment
[31]
. There was no strict definition of old age and the upper
limit for patient age allowed for interferon-based therapy.
Physicians should consider residual life expectancy without
interferon therapy and the cost, side effects, and risks
caused by interferon for more stratified age groups in the
elderly. Taking the Japanese as an example, it has been
suggested that the life expectancy is 18.0 and 23.1 years for
65-year-old Japanese men and women, respectively. In
view of the median age (65 years) of untreated elderly
patients with HCV infection, the survival of patients with
high platelet counts, representing less advanced liver
disease, was almost the same as that of the general
pop-ulation in Japan
[31]
. Instead, antiviral therapy should be
considered for elderly patients whose life expectancy is
expected to be directly influenced by liver-related disease
due to advanced liver fibrosis.
Conclusions
Patients with HCV are more likely to be identified and
aggressively treated if they are less than 50 years of age
[32]
.
The side effects associated with treatment are typically less
severe for this population, especially if patients are infected
with difficult-to-treat genotypes that require a prolonged
course of treatment. Treatment for the elderly should be
individualized (
Table 4
). In elderly patients infected with
easy-to-treat HCV genotypes or characterized by factors
predictive of better outcomes, treatment should be initiated
under careful monitoring if there are no obvious
contrain-dications or major co-morbidities that would compromise
the patient’s life expectancy. Long-term benefits such as
a reduction in hepatocarcinogenesis and liver-related deaths
are desirable. RVR remains the most notable on-treatment
response factor that is predictive of treatment success in
elderly patients
[24,33,34]
. On the whole, patients with
an RVR could possibly receive a tailored regimen without
compromising treatment efficacy
[35,36]
. A shortened
treatment course may reduce drug-related side effects and
promote treatment adherence in the elderly. Additional
studies are warranted to explore the efficacy and safety of
the clinical outcome for tailored regimens administered to
selected elderly patients with an RVR.
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