Chronic hepatitis C infection in the elderly

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 dissimilarities 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.

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 seropositivity 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], [3], [4], [5], [6], [7], [8]]. Age itself seems to be a more important factor than age at 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 disadvantage 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 10–15 years older than in Western countries [[11], [12], [13]]. 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 individuals of 40–49 years of age to become more proactive in confronting this issue [14].

Table 1.

Seroprevalence of anti‐HCV positivity in various countries

Country	General population	Age group
No trend for increase in the elderly
		50–59 y	≥60 y
USA [14]	1.6%	1.6%	0.9%
		>65 y
England and Wales [37]	0.7–1.1%	0.4%
Trend for increase in the elderly
		60–69 y	70–79 y	≥80 y
Taiwan [38]	4.4%	4.3%	6.3%	8.8%
		60–69 y	≥ 70 y
Italy [39]	2.6%	7.0%	7.7%
		50–59 y	60–69 y
Japan [40]	0.5%	1.8%	3.4%
		55–64 y	≥65 y
Spain [41]	2.5%	4.9%	5.1%
		40–49 y	50–59 y	60–69 y
France [42], a	0.8%	2.2%	1% b	2.2%

^aPrevalence of female subjects.

^bRoughly 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

Efficacy and safety

The efficacy and safety of treating elderly patients remain a source of significant debate (Table 3). It has been suggested that elderly patients are affected by either higher rates of drug modification or suffer increasingly more adverse effects on conventional interferon‐based therapy [[15], [16], [17], [18]]. 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 adherence has led to inferior treatment outcomes in the elderly [[17], [18], [19], [20], [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 suboptimal 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 substantially 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 (600–1000 mg/day) [25]. 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.

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, 50–59, ≥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, 60–64, ≥65	IFN 7%, 5%, 6%	RBV 5%, 9%, 8%	1H c 34%, 17%, 16% a
		RBV 20%, 25%, 24%	IFN + RBV 11%, 20%, 29% a	non‐1H c 84%, 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, 40–49, 50–64, ≥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]	50–64, ≥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

1H = patients with HCV genotype 1 and high viral load; HCV‐1 = hepatitis C virus genotype 1; HCV‐2/3 = hepatitis C virus genotype 2/3; IFN = interferon; N/A = not available; non‐1H = patients with HCV genotype 2 or low viral load; Peg‐IFN = pegylated interferon; RBV = ribavirin; SVR = sustained virological response.

^aStatistically significant difference.

^bA significant difference existed only between patients <40 and ≥40 years of age.

^c1H: patients with HCV genotype 1 and high viral loads; non‐1H: patients with HCV genotype 2 or low viral loads.

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 [[26], [27], [28]]. 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 4.29–22.05) [29]. A similar result was observed by Arase et al., who demonstrated that the 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 demonstrated that patients with lower baseline platelet counts (<150 × 1000/mm³) rather than all elderly patients could significantly benefit from such treatment in the long term, as indicated by 15–20 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 population 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 contraindications 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.

Table 4.

Recommendations for managing elderly patients with chronic hepatitis C infection

1. Identify and treat HCV patients before they reach 50–60 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