Thursday, November 8, 2012

Efficacy and safety of ribavirin plus pegylated interferon alfa in geriatric patients with chronic hepatitis C

Efficacy and safety of ribavirin plus pegylated interferon alfa in geriatric patients with chronic hepatitis C


C.-C. Hu1,2, C.-L. Lin1,2, Y.-L. Kuo1, C.-H. Chien1, S.-W. Chen1, C.-L. Yen1, C.-Y. Lin2,3, R.-N. Chien1,2,*

Article first published online: 5 NOV 2012

DOI: 10.1111/apt.12112

Alimentary Pharmacology & Therapeutics
Early View (Online Version of Record published before inclusion in an issue)
 
Summary
Background
Limited data are available on the efficacy and safety of antiviral therapy in geriatric patients with chronic hepatitis C virus (HCV) infection.

Aim
To evaluate the efficacy and safety of pegylated interferon (pegIFN) plus ribavirin (RBV) therapy in geriatric HCV-infected patients.

Methods
Ninety-one geriatric patients (age ≥65 years; the elderly group) with HCV infection and 91 gender- and HCV genotype-matched middle-aged patients (age 50–64 years; the younger group) were assigned to receive weekly pegIFN injection plus weight-based oral RBV for 24 weeks. The on- and off-treatment virological responses were evaluated for treatment efficacy.

Results
In intention-to-treat analysis, the sustained virological response (SVR) rate was substantially decreased in the elderly patients (elderly group vs. younger group, 40.7% vs. 61.5%, respectively; P = 0.005). The SVR rate was significantly lower in geriatric patients than in middle-aged patients with HCV genotype non-1 (54.3% vs. 82.9%; P = 0.01), but the difference was not significant with HCV genotype 1 (32.1% vs. 48.2%; P = 0.083). Furthermore, the older patients infected with HCV genotype non-1 who achieved a rapid virological response had a similar SVR rate to that of the younger patients. The withdrawal rate was 13.2% in the elderly group and 7.7% in the younger group.

Conclusions
Compared with middle-aged patients, the therapeutic efficacy of pegylated interferon plus ribavirin therapy is lower in hepatitis C virus-infected geriatric patients with an acceptable withdrawal rate. Considering prolonged lifespan in geriatric patients, we recommend treating geriatric hepatitis C virus-infected patients who have significant hepatic fibrosis and no other health problems.

Introduction
Chronic infection with hepatitis C virus (HCV) is a major global health problem and an important cause of morbidity and mortality from sequelae such as liver cirrhosis and hepatocellular carcinoma (HCC).[1-3] HCV has infected approximately 170 million people worldwide, most of whom have chronic disease.[4] It has also been estimated that, globally, 27% of cirrhosis and 25% of HCC cases develop in HCV-infected people.[5] The positive seroprevalence rate of antibodies to HCV (anti-HCV) in the adult population is 1–4% in Taiwan,[6] and there is geographical variation, such that in hyperendemic areas, the seroprevalence rate of positive anti-HCV can be as high as 60%. In addition, the anti-HCV positive rate increases progressively after the age of 20 years and its peak prevalence is at 70–84 years of age.[7] A study carried out on a large population of chronic HCV-infected patients in France has shown that approximately 18% of patients are over 65 years of age.[8] Previous study has shown that the risk of cirrhosis progression is proportional to the duration of HCV infection.[9] Age at onset of HCV infection was also found to be a major factor affecting the rate of progression of fibrosis in chronic hepatitis C (CHC) patients, where cirrhosis developed within the first 20 years in only 2% of patients infected with HCV before the age of 20 years, but it rose to 63% in patients infected over the age of 50 years. Once cirrhosis has developed, the patients are at substantial risk of HCC, with a yearly incidence rate of 2–8%.[3, 10]
 
Geriatric individuals are defined as those aged more than 65 years. Although combination therapy with pegylated interferon (pegIFN) plus ribavirin (RBV) has greatly improved treatment efficacy and is the main treatment strategy for chronic HCV infection,[11-14] it has also been associated with more side effects than has pegIFN monotherapy. Many clinical trials have excluded patients aged more than 65 years because there was a tendency towards a lower sustained virological response (SVR) rate in the elderly patients and a high rate of discontinuation due to adverse effects.[15-18] Nevertheless, older patients with chronic HCV infection are at higher risk of liver disease progression than are younger patients.[9] Furthermore, it was reported that pegIFN therapy reduces the incidence of HCC and liver-related mortality in geriatric patients with CHC significantly in the responders, and even the relapsers could gain a benefit from therapy, with a substantial decrease in the incidence of liver-related complications.[19, 20] However, only a few studies have been focused on the efficacy and safety of the pegIFN and RBV combination therapy in elderly patients with CHC.[8, 17, 18, 21] We therefore conducted a prospective study to evaluate the efficacy and safety of pegIFN combined with RBV therapy in elderly patients with chronic HCV infection. An equal number of gender- and HCV genotype–matched middle-aged patients were also enrolled for comparison.

Patients and Methods
Patients
This prospective case–control study was conducted at our institute from October 2003 to July 2009. The number of patients aged over 65 years with chronic HCV infection, defined as seropositive for anti-HCV and HCV RNA for more than 6 months, screened during this period was 133. Of these, 91 consecutive patients were enrolled in this study (the elderly group). During the same period, another 91 gender- and genotype- (1 vs. non-1) matched patients, aged between 50 and 64 years, were screened from 268 patients and included as a control group (the younger group). None of the patients had received antiviral therapy before enrolment. Concurrent hepatitis B virus (HBV) infection, human immunodeficiency virus (HIV), toxic hepatitis, autoimmune hepatitis, primary biliary cirrhosis and Wilson's disease were excluded. Decompensated liver cirrhosis, chronic alcohol abuse and uncontrolled major depression based on clinical or biochemical evidence were also excluded. The haemogram of the patients enrolled included a leucocyte count of >2300 cells/mm3, a haemoglobin level of >8.1 g/dL, and a platelet count of >45 000 cells/ mm3.

Methods
All 182 patients received weekly subcutaneous pegIFN injection plus daily oral RBV for 24 weeks, in accordance with the reimbursement criteria of the National Health Insurance in Taiwan. The pegIFN treatments prescribed were pegIFN alfa-2a, 180 μg, or weight-based pegIFN alfa-2b, 1.5 μg/kg. For genotype 1 HCV-infected patients, the oral RBV dose was 1000 mg per day for patients of body weight (BW) <75 kg, or 1200 mg for BW ≥75 kg. For genotype non-1 HCV-infected patients, the RBV dose was 800 mg per day. All patients were followed up for 24 weeks after the completion of treatment. During the treatment period, patients attended weekly outpatient visits during the first 4 weeks, biweekly visits between the 5th and 12th weeks and monthly visits during the last 12 weeks. During the 24-week follow-up period, they attended the clinic monthly or bimonthly. Haematological and liver biochemical tests were conducted during each visit. HCV RNA levels were measured before the initiation of treatment, at week 4, at week 12, at the end of treatment and 24 weeks after treatment. All biochemical and virological tests were carried out in the clinical laboratories of Chang Gung Memorial Hospital. Adverse side effects that developed during RBV and pegIFN treatment were also recorded at each visit. Patients completing more than 80% of the recommended RBV and pegIFN dosage for more than 80% of the expected treatment period were defined as having 80/80/80 adherence.[22] Informed consent was obtained from all patients enrolled in this study. The study was performed in accordance with the ethical guidelines of the International Conference on Harmonization for Good Clinical Practice and has been approved by the Institutional Review Board of Chang Gung Memorial Hospital (No. 99–3012C).
 
Anti-HCV tests were conducted using a third-generation enzyme immunoassay kit (AxSYM HCV Version 3.0; Abbott Laboratories, Berkshire, UK). Serum HCV RNA was quantified using a real-time polymerase chain reaction (PCR) assay (COBAS AmpliPrep Instrument and COBAS TaqMan 48; Roche Molecular Systems, Inc., Branchburg, NJ, USA), with a detection limit of 15 IU/mL. HCV genotype was determined with the use of a linear probe assay [VERSANT HCV Genotype Assay (LiPA); Bayer Corporation, NY, USA]. Liver biopsy was routinely advised and obtained if the patient agreed. Advanced fibrosis was defined as a score of ≥4 on the Ishak modification of the Histology Activity Index (HAI). Diagnosis of liver cirrhosis was based on a cirrhosis scoring system described previously[23] with sensitivity and specificity of 80% and 92.8% respectively, by using ultrasonography or an Ishak fibrosis score of ≥5.

Evaluation of the efficacy of combined pegIFN and RBV treatment
On-treatment response was monitored after 4 and 12 weeks of therapy. Patients who had undetectable serum HCV RNA by PCR at week 4 were defined as having a rapid virological response (RVR). A complete early virological response (cEVR) was defined as patients who had undetectable serum HCV RNA at 12 weeks of therapy in the absence of RVR. The treatment efficacy was evaluated after 24 weeks combined pegIFN and RBV therapy (end of treatment; EOT) and at 24 weeks posttreatment follow-up (end of follow-up; EOFU). A sustained virological response (SVR) was defined as achievement of undetectable serum HCV RNA by PCR at the EOT, which was sustained at the EOFU.

Statistical analysis
The statistical test was equivalent in form to a chi-square test statistic. Specifically for geriatric patients, a continuity-corrected chi-square test with a 0.025 two-sided significance level would have 80% power to detect a 22% difference between geriatric and middle-aged control patients. Assuming that the test arm had an SVR rate of 40% and the control arm had an SVR rate of 62%, the sample size in each group would be 80. After adjusting for a 10% withdrawal rate in this study, the final sample size would be 89 in each group.
 
Evaluation of the efficacy of RBV and pegIFN therapy was assessed by intention-to-treat (ITT) analysis. For the ITT analysis, patients who received more than one dose of pegIFN or RBV were enrolled, and drug discontinuation was defined as treatment stopped without completing 80% of the expected dosage. The continuous demographic data were expressed as the mean ± standard deviation (s.d.), and a two-tailed Student's unpaired t-test was employed to evaluate the difference between means. Differences between groups of categorical variables were analysed using a chi-square test or Fisher's exact test. The significant factors were then subjected to multivariate analysis with a stepwise (forward) regression model to test for interactions between the different significant covariates. A P-value of <0.05 was considered statistically significant. The statistical analyses were performed using the spss ver. 12.0 software package (SPSS Inc., Chicago, IL, USA).

Results
Demographic and clinical characteristics of the patients
The baseline characteristics of the 182 patients who underwent pegIFN plus RBV treatment are shown in Table 1. The majority of the patients were female (62%). One hundred and twelve patients were infected with HCV genotype 1 (62%). Most of the demographic and virological characteristics and treatment regimens were similar in both groups, excepting that the mean age of patients in the elderly group was significantly greater than that in the younger group (69.1 ± 3.4 vs. 56.7 ± 4.1 years, respectively; P < 0.001). The mean body weight and body mass index (BMI) were lower in older patients. The mean duration of first known CHC infection was 5.2 years and 6.1 years in the elderly and younger groups, respectively. There was no statistical significance between them. The possible infection route of HCV was largely unknown except in 24 (13%) patients – previous surgery in 14 (7.7%), blood transfusion in 7 (3.8%), surgery plus blood transfusion in 8 (4.4%) and skin tattooing in 1 (0.5%). There was no statistical significance between the elderly and younger groups. The pre-treatment aspartate aminotransferase level (AST) was higher (113.2 ± 65.7 vs. 94.5 ± 55.5 U/L, respectively; P = 0.028), and white blood cell and haemoglobin levels were lower (5.2 ± 1.9 × 103 vs. 5.9 ± 1.6 × 103 cells/L; P = 0.005, and 13.6 ± 1.6 vs. 14.0 ± 1.5 g/dL; P = 0.047), in the elderly patients. Sixty-eight patients in the elderly group and 86 patients in the younger group underwent liver biopsy prior to pegIFN plus RBV therapy. There were more cirrhotic patients in the elderly group than in the younger group (36% vs. 21%; P = 0.022). The proportion of patients with advanced fibrosis in both groups was similar (36.5% vs. 23.9%; P = 0.129). Thirty patients (33%) in the elderly group had a serum HCV RNA viral load of less than 4 × 105 IU/mL, as did 31 patients (34%) in the younger group (P = 0.875).
 
Table 1. Patient demographic characteristics
 
Characteristic
Elderly group
(n = 91)
Younger group
(n = 91)
P-value
  1. AST, aspartate aminotransferase; ALT, alanine aminotransferase; HCV, hepatitis C virus; low viral load, HCV RNA ≤400 000 IU/mL.
  2. Elderly group, patients ≥65 years old.
  3. Younger group, patients 50–64 years old.
  4. * Mean ± s.d.
  5. **No. (%).
Age (range) (years)*69.1 ± 3.4(65–80)56.7 ± 4.1(50–64)<0.001
Male gender**35 (38)35 (38)1
Duration of HCV infection (years)*5.2 ± 3.46.1 ± 4.90.148
Genotype 1**56 (62)56 (62)1
Cirrhosis**33 (36)19 (21)0.022
Fatty liver**32 (35.2)45 (49.5)0.051
Body weight (kg)*59.9 ± 10.363.4 ± 10.90.041
Body mass index (kg/m2)*24.5 ± 3.424.7 ± 3.80.045
Necroinflammatory scores*6.5 ± 2.56.0 ± 2.30.172
Advanced fibrosis**45/68 (66.2)50/86 (58.1)0.308
AST (U/L)*113.2 ± 65.794.5 ± 55.50.028
ALT (U/L)*130.5 ± 82.5135.4 ± 92.20.72
Albumin (g/dL)*4.0 ± 0.44.1 ± 0.50.275
Total bilirubin (mg/dL)*1.1 ± 0.51.0 ± 0.50.265
White blood cell count (×103/μL)*5.2 ± 1.95.9 ± 1.60.005
Haemoglobin level (g/dL)*13.6 ± 1.614.0 ± 1.50.047
Platelet count (×103/μL)*150.5 ± 55.0164.0 ± 54.60.1
HCV RNA (IU/mL)*1.67 ± 2.10 × 1061.97 ± 6.96 × 1060.7
Low viral load**30 (33)31 (34)0.875
Ribavirin per body weight (mg/kg/day)*15.9 ± 2.715.3 ± 3.10.567
Treatment duration (weeks)24241
 
Virological responses to treatment
Virological responses to the combined pegIFN and RBV treatment are shown in Table 2. Sixty-one percent and 87.3% of patients achieved an RVR and cEVR, respectively. The RVR and cEVR rates in the elderly and younger groups were similar (RVR, 56.2% vs. 65.1%; P = 0.249, and cEVR, 83.3% vs. 90.6%; P = 0.174). After stratification by HCV genotype (genotype 1 & non-1), there was no difference in on-treatment response between these 2 groups.
 
Table 2. Virological responses of the different age groups
 
Response
HCV genotype
Elderly group
n/N (%)
Younger group
n/N (%)
P-value
  1. n, number of patients with response; N, total number of patients in group; cEVR, complete early virological response; ETR, end of treatment response; RVR, rapid virological response; SVR, sustained virological response.
  2. Elderly group, patients ≥65 years old.
  3. Younger group, patients 50–64 years old.
RVR41/73 (56.2)56/86 (65.1)0.249
120/45 (44.4)30/53 (56.6)0.23
Non-121/28 (75.0)26/33 (78.8)0.726
cEVR60/72 (83.3)77/85 (90.6)0.174
132/44 (72.7)44/52 (84.6)0.153
Non-128/28 (100)33/33 (100)1
ETR72/91 (79.1)81/91 (89.0)0.068
142/56 (75.0)47/56 (83.9)0.242
Non-130/35 (85.7)34/35 (97.1)0.088
SVR37/91 (40.7)56/91 (61.5)0.005
118/56 (32.1)27/56 (48.2)0.083
Non-119/35 (54.3)29/35 (82.9)0.01
Relapse35/72 (48.6)25/81 (30.9)0.025
124/42 (57.1)20/47 (42.6)0.169
Non-111/30 (36.7)5/34 (14.7)0.043
Withdrawal12/91 (13.2)7/91 (7.7)0.225
16/56 (10.7)5/56 (8.9)0.751
Non-16/35 (17.1)2/35 (5.7)0.133
Dose Reduction23/91 (25.3)15/91 (16.5)0.145
115/56 (26.8)8/56 (14.3)0.102
Non-18/35 (22.9)7/35 (20)0.771
Overall, 153 patients (84.1%) achieved an EOT response (ETR); the proportion was slightly lower in the elderly group than in the younger group with a marginal significance (79.1% vs. 89%; P = 0.068). If these patients were further stratified by HCV genotype, the ETR was similar in HCV genotype 1 patients between the elderly and younger groups (75% vs. 83.9%; P = 0.242). However, for HCV genotype non-1, ETR tended to be lower in the elderly than in the younger groups with a marginal significance (85.7% vs. 97.1%; P = 0.088). Of the 182 patients, 93 (51.1%) achieved SVR. The SVR rate was significantly lower among older patients (elderly group vs. younger group, 40.7% vs. 61.5%; P = 0.005). Among patients with HCV genotype 1, the SVR rate was slightly lower in the elderly group than in the younger group, with a marginal significance (32.1% vs. 48.2%; P = 0.083). However, for patients infected with HCV genotype non-1, the SVR rate was significantly lower in the elderly group (54.3% vs. 82.9%; P = 0.01). The SVR rate was substantially higher in patients with genotype non-1 infection than in those infected with genotype 1 in both patient groups (genotype 1 vs. non-1, 32.1% vs. 54.3% in the elderly group; P = 0.036, and 48.2% vs. 82.9% in the younger group; P = 0.001).
 
The relapse rate was higher among patients with HCV genotype 1 than genotype non-1 (49.4% vs. 25.0%; P = 0.002). It was also higher in the elderly patients (48.6% vs. 30.9%; P = 0.025) (Table 2). Among HCV genotype 1-infected patients, the relapse rate was similar in both patient groups (57.1% vs. 42.6%; P = 0.169). Older patients infected with genotype non-1 showed higher relapse rates than the younger patients (36.7% vs. 14.7%; P = 0.043).
 
In univariate analysis, younger age, male gender, HCV genotype non-1, lower HCV RNA level, noncirrhotic liver, higher haemoglobin and platelet count, 80/80/80 adherence, RVR, and cEVR were predictive factors for SVR. In multivariate analysis to identify predictors of sustained virological response, our final multiple logistic regression model, including those significant factors in univariate analysis, was entered in the final stepwise regression analysis. The results showed that RVR is the strongest predictor for SVR [OR (odds ratio) 3.94, 95% confidence interval (CI) 1.84–8.41, P < 0.001], followed by HCV genotype non-1, male gender, younger age and higher pre-treatment platelet count (Table 3).
 
Table 3. Factors predicting SVR by multivariate analysis
 
FactorsUnivariateMultivariate
OR95% CIP-valueOR95% CIP-value
  1. CI, confidence interval; LVL, low viral load; OR, odds ratio; RVR, rapid virological response.
Age (middle age)2.3351.289–4.2310.0052.5521.195–5.4470.015
Male gender3.2481.730–6.102<0.0012.9711.360–6.4880.006
HCV genotype (non-1)3.2481.730–6.102<0.0013.1101.394–6.9400.006
LVL2.4441.290–4.6290.006
RVR5.3072.653–10.614<0.0013.9391.844–8.412<0.001
Liver cirrhosis0.4880.253–0.9420.032
Haemoglobin level (mg/dL)1.2851.054–1.5670.013
Platelet count (×103/μL)1.0081.002–1.0140.0061.0081.000–1.0150.04
80/80/80 adherence3.7031.557–8.8060.003
 
Virological responses to treatment in patients with a rapid virological response
Among patients with RVR, the SVR rate was 70%, which was substantially higher than in the overall study population. The influence of achieving RVR on the SVR rate was further assessed by comparing the 2 age groups (Table 4). Elderly patients with an RVR still had a lower SVR rate than middle-aged patients (58.5% vs. 78.6%; P = 0.033). However, in HCV genotype non-1–infected patients with an RVR, the SVR rates among older patients were similar to those of middle-aged patients. In addition, among middle-aged patients infected by HCV genotype non-1 without an RVR, the SVR rate was 85.7%, which was significantly higher than that in HCV genotype 1 patients (21.7%) (P = 0.002) (Table 4).
 
Table 4. Virological responses of the different age groups with and without RVR
 
SVR rateOverallElderly groupYounger group
  1. n, number of patients with response; N, total number of patients in group; SVR, sustained virological response; RVR, rapid virological response.
  2. Elderly group, patients ≥65 years old.
  3. Younger group, patients 50–64 years old.
  4. *P = 0.002.
  5. **P = 0.002.
HCV genotypen/N (%)n/N (%)n/N (%)P-value
With RVR68/97 (70.1)24/41 (58.5)44/56 (78.6)0.033
133/50 (66)11/20 (55)22/30 (73.3)0.18
Non-135/47 (74.5)13/21 (61.9)22/26 (84.6)0.076
Without RVR19/62 (30.6)8/32 (25)11/30 (36.7)0.319
110/48 (20.8)*5/25 (20)5/24 (21.7)**0.882
Non-19/14 (64.3)*3/7 (42.9)6/7 (85.7)**0.094
 
Discontinuation of treatment
Twelve patients (13.2%) in the elderly group and 7 patients (7.7%) in the younger group withdrew from therapy because of intolerance to treatment-related adverse effects. Twenty-three patients (25.2%) in the elderly group and 15 patients (16.5%) in the younger group required modification of the dosage regimen during treatment. Reduced pegIFN dose due to adverse effects was required in a greater percentage of elderly patients (14.3% of the elderly group vs. 3% of the younger group; P = 0.034). The main clinical adverse effects included malaise (40%), pruritus (37.4%), insomnia (29.1%), anorexia (29.1%), dizziness (25.3%), dyspnoea (25.3%), fever (22%), myalgia (20%), and skin rash (17%). The patients in both groups had similar adverse effect profiles. However, a greater percentage of elderly patients had anorexia (36.2% of the elderly group vs. 22.1% of the younger group; P = 0.034), dyspnoea (31.9% of the elderly group vs. 19.1% of the younger group; P = 0.004) and skin rash (23.4% of the elderly group vs. 10.3% of the younger group; P = 0.017). With regard to haematological adverse effects, more patients in the elderly than in the younger group developed thrombocytopaenia (19.1% of the elderly group vs. 7.9% of the younger group; P = 0.028) and anaemia (28.6% of the elderly group vs. 18% of the younger group, P = 0.093). Twenty-two patients (24.2%) in the elderly group and 13 patients (14.3%) in the younger group needed erythropoietin therapy because of symptomatic anaemia. One elderly patient developed severe thrombocytopaenia (platelet count, 1 × 103/μL) with bleeding oral ulcers after 4 weeks of combined pegIFN and RBV treatment.

Discussion
Whether to treat geriatric HCV-infected patients using RBV plus pegIFN therapy (standard of care; SOC) is a controversial issue because of lower SVR and higher discontinuation rate in such patients.[21, 24, 25] However, lifespan is gradually increasing in developed countries, including Taiwan.[26] In addition, the therapeutic efficacy of RBV plus pegIFN is good in chronic HCV-infected patients, especially in the Asia-Pacific region. As standard of treatment for chronic HCV infection, the SVR rates of patients infected with HCV genotype-1 after 24 weeks of therapy in Taiwan are 42–66%, which are comparable to SVR rates of 42–52% in Western countries.[11, 13, 14, 27-30] If the treatment duration extends to 48 weeks, the SVR rates of HCV genotype 1–infected patients can increase to 76–79%.[27, 28, 31] Our study further confirms the lower SVR rate in HCV-infected geriatric patients compared with middle-aged patients (41% vs. 62%; P = 0.005) after RBV plus pegIFN therapy for 24 weeks. Referring to HCV genotype, this trend is also obvious in either genotype 1 or non-1 in both geriatric and control patients (32% vs. 48% in genotype 1, P = 0.083; 54% vs. 83% in genotype non-1, P = 0.01). However, patients infected with genotype non-1 HCV showed higher SVR rates than those infected with genotype 1 in both groups. Notably, the treatment duration in both groups is 24 weeks. This is too short in genotype 1 HCV-infected patients, especially in those with high viral load (>4.0 × 5 log IU/mL), regardless of reaching RVR or not. This treatment duration was stipulated in the reimbursement policy of the National Health Insurance in Taiwan at that time, but treatment duration is now determined by response to therapy. In addition, our results are consistent with previous reports in the literature. The reported efficacy using RBV plus pegIFN to treat geriatric HCV-infected patients in the literature showed an SVR rate of 37–70% (Table 5). The SVR rate was higher in those infected with HCV genotype non-1 (66–90%) than in those infected with HCV genotype 1 (23–52%).[21, 24, 25, 32]
 
Table 5. Published studies evaluating the treatment response rates of patients older than 65 years
 
 ( Click here to view table 5)
 
Our study demonstrated that a substantial proportion (40.7%) of elderly patients with CHC could be cured successfully. Although the SVR tended to be lower in geriatric patients than in middle-aged patients (40.7% vs. 61.5%, respectively), this inferiority was found mainly in patients infected with HCV genotype non-1 (54.3% vs. 82.9%; P = 0.01) and was much less significant in those with HCV genotype 1 (32.1% vs. 48.2%; P = 0.083). It was noteworthy that the SVR rate of patients with HCV genotype 1 infection after 24 weeks therapy in our study is comparable to that of patients treated for 48 weeks in other studies (Table 5). The possible explanation might be the susceptibility variation among different races. The possible role of IL-28B in patients is currently being evaluated. Our study showed that age was not a predictive factor of SVR in patients with genotype 1. However, Huang et al.[21] showed that older patients with genotype 1 had a suboptimal SVR compared with younger patients because the older patients had a relatively poor adherence and high treatment discontinuation rate. If the patients adhered to the treatment well as in the per-protocol analysis, the discrimination between the 2 groups disappeared. Furthermore, Kainuma et al.[25] demonstrated that the SVR was significantly higher in patients with genotype 1 who were less than 65 years old (47.3% of 685) than in those aged 65 years or older (22.9% of 253) (P < 0.001); this inferiority of SVR may be due to lower platelet count and higher proportion of prior antiviral treatment in the older patient group. Antonucci et al.[18] demonstrated, compared with patients aged <40 years, older patients showing significantly lower odds of SVR (OR 0.16, 95% CI: 0.05–0.59, P = 0.006; OR 0.13, 95% CI: 0.03–0.49, P = 0.002; OR 0.21, 95% CI: 0.05–0.91, P = 0.037 for patients aged 40–49 years, 50–64 years, and older than 64 years, respectively). In view of HCV genotype-1 being more strongly associated with disease progression and risk of HCC development,[33] it is beneficial for geriatric patients to receive combination therapy under careful monitoring, although the present study showed that geriatric patients have lower SVR.
 
In contrast to the results with genotype 1, our results demonstrated that age was a predictive factor of SVR in patients with genotype non-1 by multivariate analysis (OR 0.25, 95% CI: 0.08–0.74, P = 0.013). Among patients infected with HCV genotype non-1, the SVR rate was significantly lower in the elderly patient group. Our findings are consistent with those in Kainuma's report.[25] They demonstrated that the SVR was higher in patients with genotype 2 who were less than 65 years old (82.9% of 252) than in those aged 65 years or older (65.6% of 61) (P = 0.004). Accordingly, patients infected with HCV genotype non-1 should be treated as early as possible because increasing age could contribute to the inferiority of SVR.
 
From previous studies, the contribution of gender to treatment response is controversial.[12, 34-36] Our study found higher response rates in male than in female patients and was consistent with Sezaki's report.[35] They demonstrated that SVR at 24 weeks after treatment was poorer in women than in men who were aged more than 50 years (22% vs. 53%; P < 0.001). Although either or both of pegIFN and RBV were tolerated to a lesser extent by women than by men, the discrepancy of SVR remained distinct even in patients receiving more than 80% of the dose of pegIFN, RBV or both. In our study, rates of dose reduction between male and female patients were similar (24.3% vs. 18.8%; P = 0.371). Therefore, better response to treatment in male patients could not be explained solely by better tolerance of treatment. On the contrary, McHutchison et al.[12] showed that female gender was a predictor for treatment outcome. Further studies are needed to verify if this is related to altered hormone levels or genetic variation.
 
A previous study from Taiwan[21] has shown that drug discontinuation among patients older than 65 years with hepatitis C was significantly higher than among patients younger than 65 years (21% vs. 6%, respectively; P = 0.001). Kainuma et al.[25] from Japan found that for genotype 1 patients, the discontinuation rate was significantly higher in older patients. However, our study showed that the withdrawal rate of older patients with genotype 1 or non-1 was not different from that of middle-aged patients. This discrepancy between present and previous studies needs further large-scale prospective study for verification.
 
To prevent HCC and liver-related mortality, patients with CHC are often treated with IFN-based therapy to eradicate HCV. Various studies have demonstrated that IFN-based therapy contributes to a reduced incidence of HCC and improved patient survival by decreasing liver-related death.[19, 37-39] Ikeda et al.[38] showed that the incidence of HCC in IFN-treated HCV-infected patients was 7.6% after 10 years of follow-up, compared with 12.4% in untreated patients. Imai et al.[19] reported a follow-up study over 8.2 years for IFN therapy in aged patients with chronic HCV infection. The 8-year survival rates were significantly higher in sustained virological responders and virological nonresponders, compared with untreated patients (94.6%, 86.8% and 73.9%, respectively). Although Arase et al.[20] demonstrated that female gender and low fibrosis stage (F = 1) were associated with prolonged survival in elderly patients with CHC, they also noted that male gender and fibrosis score >2 were associated with increased incidence of HCC. Because pegIFN plus RBV therapy may cause various adverse effects and is costly, the decision on whether to treat an elderly patient is based on various characteristics of the individual patient. The adverse effects and withdrawal rate due to pegIFN plus RBV therapy-related side effects might tend to increase in elderly patients. However, longer duration of HCV infection and older age at infection are associated with disease progression.[9] In addition, elderly HCV-infected patients have a relatively high proportion of significant hepatic fibrosis. Furthermore, a number of pre-treatment factors are known to improve the SVR rate: younger age, low body weight (<75 kg), higher pre-treatment alanine aminotransferase level, high haemoglobin, high platelet count, absence of cirrhosis, low HCV viral load, and HCV genotype non-1.[12-14, 40] The SVR rate of geriatric HCV-infected patients treated with pegIFN plus RBV was 40–70% in the literature.[8, 18, 21, 24, 25, 32] Therefore, when HCV-infected elderly patients without comorbidities are at risk for disease progression but have several factors predictive of favourable response to pegIFN plus RBV therapy, it is recommended to treat them thereby improving patient survival and reducing liver-related complications.
 
Direct-acting antiviral agents (DAAs) are potential novel therapies that specifically target HCV (STAT-C) enzymes involved in viral replication or viral entry into the host cell (e.g. proteases and polymerases). For HCV genotype-1 infected patients, the SVR rate can be improved and is as high as 63–75% in treatment-naïve patients and 59–66% in previous null-responders when DAA is combined with pegIFN plus RBV therapy.[41, 42] This new approach to HCV therapy with DAAs offers future potential and might replace pegIFN with fewer adverse effects, and increases patient convenience with regard to administration.
 
In conclusion, the therapeutic efficacy of pegIFN plus RBV therapy is lower in HCV-infected geriatric patients than in middle-aged patients with an acceptable withdrawal rate. In view of prolonged lifespan and moderate efficacy of combination therapy in geriatric patients, treatment is recommended in geriatric HCV-infected patients with significant hepatic fibrosis and no other health problems.

AuthorShip
Guarantor of the article: Rong-Nan Chien.
Author contributions: Ching-Chih Hu and Chih-Lang Lin performed the research. Ching-Chih Hu, Chih-Lang Lin, Yen-Lin Kuo and Cheng-Hung Chien collected and analysed the data. Ching-Chih Hu and Rong-Nan Chien designed the research study and wrote the paper. Shuo-Wei Chen, Cho-Li Yen and Chun-Yen Lin contributed to the design of the study. All authors approved the final version of the manuscript.

Acknowledgements
Declaration of personal interests: RN chien served as an Asian-Pacific advisory board member for Gilead Science.
Declaration of funding interests: This study was supported by the Chang Gung Memory Hospital Research Grant (CMRPG 280411) and the National Science Council of Taiwan (NSC 99-2314-B-182-030) in part.

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