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- Patients and Methods
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. It has also been estimated that, globally, 27% of cirrhosis and 25% of HCC cases develop in HCV-infected people. The positive seroprevalence rate of antibodies to HCV (anti-HCV) in the adult population is 1–4% in Taiwan, 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. 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. Previous study has shown that the risk of cirrhosis progression is proportional to the duration of HCV infection. 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. 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.
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- Patients and Methods
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. 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
|RF||Author, year||Number|| ||Study design||Regimen|| ||GT||VR at EOT||SVR||Fu (wks)|
|  ||Thabut, 2006|| ||NA||RP||pegIFN plus RBV||NA||1, 2/3||NA|| ||24|
|  ||Antonucci, 2007|| ||NA||RP||pegIFNα-2a or -2b plus RBV||NA||1, 2/3||76.7% (all), 45.5% (G1), 94.7% (G2/3)|| ||24|
|  || || ||68.3||PP, case-control, ITT||pegIFNα-2a 180 μg weekly plus RBV 1000–1200 mg/d (G1) or 800 mg/d (G2/3)|| || || || ||24|
|  || ||115; (G1:93; G2:22)||67.9||Nonrandomised, PP, ITT|| |
pegIFNα-2b 1.5 μg/kg weekly plus RBV 600–1000 mg/d
(<60 kg: 600 mg; 60–80 kg:
|48–72 (G1); 24 (G2)|| ||NA||37.4% (all)||24|
|  ||Kainuma, 2010|| ||68.6(G1), 69.2(G2)||PP, ITT|| |
pegIFNα-2b 1.5 μg/kg weekly plus RBV 600–1000 mg/d
(<60 kg: 600 mg; 60–80 kg:
| || || || ||24|
|  ||Giannini, 2010|| ||67||PP, ITT|| |
pegIFNα-2a 180 μg or pegIFNα-2b 1.5 μg/kg weekly plus RBV 800–1200 mg/d
(<65 kg: 800 mg; 65–85 kg:
1000 mg; >85 kg: 1200 mg)
| || ||67% (all)||44% (all)||24|
|[*]|| || ||69.1||PP, control, ITT|| |
pegIFNα-2a 180 μg or pegIFNα-2b 1.5 μg/kg weekly plus RBV [G1: 1000 mg/d
(<75 kg) or 1200 mg/d (≥75 kg);
|24||1, 2/3||79% (all), 75% (G1), 85.7% (G2/3)|| ||24|
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. 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. 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. 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, 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. 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. 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. 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 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. 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. 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. 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. 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. 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.