Treating hepatitis C in the elderly: the future is near?

Review

Treating hepatitis C in the elderly: the future is near?

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by The University of Manchester on 10/15/14 For personal use only.

Fabio Conti, Giovanni Vitale & Pietro Andreone† †

University of Bologna, Department of Medical and Surgical Sciences, Bologna, Italy

1.

Introduction

2.

Pegylated IFN and ribavirin treatment

3.

First-generation direct-acting antivirals: telaprevir and boceprevir

4.

Interferon-free AND/OR RBV-free regimens: the next standard of care?

5.

Expert opinion

Introduction: The population of patients with hepatitis C is aging. In some countries, the prevalence of hepatitis C virus (HCV) is actually greater in older patients than in younger individuals. It is also anticipated that hepatitis C will increasingly become a disease of older persons. However, patients older than 70 years are typically excluded from clinical trials. The decision to treat older patients is complex and cannot be made at the sole discretion of the physician. Areas covered: There is an urgent need to analyze treatment outcomes in the elderly to examine response rates in order to aid in therapeutic decision making. Expert opinion: In geriatric HCV-infected patients, dual therapy with pegylated IFN plus ribavirin is associated with a lower sustained virologic response and a higher discontinuation rate. Even the first-generation protease inhibitors are associated with high rates of side effects, in particular in elderly patients with a high prevalence of comorbidities. The recent development of interferon-sparing regimens could change the treatment paradigm in this setting, and a much larger number of patients could have access to the antiviral therapy programs. Keywords: aged, antiviral treatment, elderly, hepatitis C virus Expert Opin. Pharmacother. (2014) 15(14):2019-2028

1.

Introduction

Although there are commonly used definitions of old age, there is no general agreement on at what age a person becomes old. Most developed world countries have accepted the chronological age of 65 years as a definition of an elderly or older person. In general, adults above this age have a higher prevalence of comorbidities compared with younger individuals, particularly cardiovascular, renal, pulmonary and hematological diseases. However, this definition is somewhat arbitrary because aging is a continuous and dynamic process that has its own dynamics and is not linked to chronological age. This consideration is also valid when we evaluate liver disease in the elderly and in regard to antiviral treatment in these categories of patients. In fact, although the incidence and prevalence of hepatitis C virus (HCV) infection continues to decline, particularly among younger individuals, the increasing life expectancy in industrialized societies and the long-standing course of chronic HCV infection make it likely that physicians will face a growing number of elderly patients with chronic hepatitis C (CHC) in the next 10 -- 20 years [1-4]. In the United States, the peak of the age-specific prevalence of HCV infection has shifted from patients aged 30 -- 39 years to patients aged 40 -- 49 years during the last decade, and an increase among the elderly is expected in the near future [5]. The US Centers for Disease Control has recommended to screen for HCV all subjects born between 1945 and 1965, many of whom will be over the age of 60. This group represents 75% of all Americans infected with HCV infection [6]. In Asia and Europe, this is not recommended. In developing countries, low political, provider and community awareness of hepatitis C as a significant health threat, cost-related 10.1517/14656566.2014.945422 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

2019

F. Conti et al.

Article highlights. .

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In industrialized societies, the average age of patients with chronic hepatitis C is increasing and its prevalence increases with advancing age. Elimination of hepatitis C virus (HCV) after antiviral therapy significantly reduces the risk of mortality, liver failure and cancer. There are few data available regarding current antiviral treatment of the elderly and also for treatment in the pipeline. Although current practice guidelines do not establish an upper age limit for antiviral therapy, elderly individuals with HCV infection are more likely to have contraindications to antiviral therapy than younger adults and older age is an independent factor associated with a lower likelihood of being considered for antiviral therapy. Several new drugs against HCV have reached the market and many others, including direct-acting antivirals and host-targeted agents, are in clinical development. These highly efficient and well-tolerated treatments could facilitate access to care for the elderly.

This box summarizes key points contained in the article.

factors (e.g., lack of health insurance) and lack of HCV screening policies led to deprioritization of testing and other preventive health services. In some countries, such as Japan [7] and Italy [8], the prevalence of HCV infection is low among children and young adults, but it increases at the age of 40 years and continues to increase during aging. Thus, there is a pressing need for the management of chronic HCV infection in this particular patient population. Previous studies have shown that the risk of cirrhosis progression is proportional to the duration of HCV infection [9-11]. Age at onset of HCV infection was also found to be a major factor affecting the rate of progression of fibrosis in CHC patients; 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 [12,13]. Additionally, age itself appears to be an indicator of liver disease progression, particularly in those ‡ 65 years [14,15]. A study conducted on 6865 patients older than 65 years demonstrated a significant association with age and more intense fibrosis at liver biopsy, regardless of the duration of infection [16]. The mechanisms underlying the relatively rapid progression of liver disease in older adults are not known. A higher vulnerability to environmental factors, a reduction in the rate of hepatic blood flow and a reduced mitochondrial capacity could be possible mechanisms for explaining the role of aging in fibrosis progression [17]. Furthermore, the prevalence of genotype 1b, which is associated with advanced liver damage, is higher among elderly persons [18]. Another cause of faster fibrosis progression was hormonal changes typical of aging. In fact, the decrease of estrogen levels and estradiol/ testosterone ratio during the menopause explains why the fibrosis progression is more linear and severe in men and 2020

discontinuous in women, in whom it is very slow during reproductive age and accelerating rapidly after menopause [19]. With the progression of liver fibrosis, the occurrence of hepatocellular carcinoma (HCC) accelerates with an annual incidence rate of 2 -- 7% [20]. The risk of HCC increases significantly with age, most likely due to age-related changes in the ability to repair DNA [21] and to the prolonged interval from the time of infection. Elimination of HCV after antiviral therapy significantly reduces the risk of HCC and death in all categories of patients. Recent studies have evaluated the association between achieving a sustained virologic response (SVR) and reductions in mortality, liver failure and cancer [22-24]. Nevertheless, elderly patients are progressively understudied in parallel with increasing age [25]. Another factor limiting antiviral therapy in elderly is represented by the presence of comorbid conditions as reported in a nationwide US retrospective cohort study where older age and presence of comorbidities were associated with a lower quality of HCV care [26]. This under management most likely reflects the low likelihood of clinicians to prescribe antiviral treatment to the elderly. Although current practice guidelines do not establish an upper age limit for antiviral therapy, elderly individuals with HCV infection are more likely to have contraindications to antiviral therapy than younger adults [25,27]. This attitude denies elderly patients the chance to achieve an SVR, which may indeed arrest the progression of fibrosis and reduce the risk of HCC. Although the elderly constitute a category that is difficult to treat, it is not appropriate to withhold antiviral therapy based purely on advanced age; however, close attention must be paid to life expectancy, comorbid conditions and tolerance for potential side effects. 2.

Pegylated IFN and ribavirin treatment

In the early 2000s, the combination of pegylated IFN (PegIFN) plus ribavirin (RBV) became the standard antiviral treatment for HCV infection. Overall, the SVR rates of patients treated with the dual therapy for 48 weeks are ~ 55%; SVR is achieved in ~ 50% of patients infected with HCV genotype 1 treated for 48 weeks and ~ 80% of patients infected with HCV genotype 2 or 3 treated for 24 weeks. Indeed, limited data are currently available on antiviral therapy of CHC in elderly patients. Only a few patients aged ‡ 65 years have been included in the largest trials of PegIFN and RBV, and a very limited number of studies, most of them conducted in the Japanese population, have focused on dual therapy in elderly patients. In this section, we selected all studies, prospective or retrospective, that included patients with CHC who were aged ‡ 65 years. As expected, older patients had a comparatively lower SVR rate than younger patients, even after excluding those who discontinued treatment (Table 1). The first study [28] enrolled patients aged 65 or older and was conducted in 39 European centers. Only 2 of 224 patients aged ‡ 65 years received antiviral therapy, and one obtained an SVR. Another

Expert Opin. Pharmacother. (2014) 15(14)

N/A 16.7 32.2 21.4 36.3 23.9 13.9 21.1 21.1 13.2 50 89.5 63.6 76.7 65.6 63.6 86.4 84 80 54.3 N/A 36.4 31.2 51.9 22.9 27 40.7 30.8 30.5 32.1 50 70 37.4 67.1 31.2 35.4 50 65.8 42.9 40.7 0/2 11/19 93/22 27/43 253/61 185/55 86/22 13/25 27/43 56*/35 CHC: Chronic hepatitis C; PegIFN: Pegylated IFN; N/A: Not available; SVR: Sustained virologic response.

2 30 115 70 314 240 108 38 140 91 2b 2a/2b 2b 2a 2b 2b 2b 2a/2b 2a 2a/2b 39 European centers Italy Japan Taiwan Japan Japan Japan Korea China Taiwan Zeuzem et al. (2004) [28] Antonucci et al. (2007) [29] Honda et al. (2010) [30] Huang et al. (2010) [31] Kainuma et al. (2010) [32] Oze et al. (2011) [33] Nishikawa et al. (2012) [34] Kim et al. (2012) [35] Yu et al. (2012) [36] Hu et al. (2013) [37]

Prospective Retrospective Prospective Prospective Prospective Retrospective Retrospective Retrospective Prospective Prospective

G 1 -- 4 SVR (%) Overall SVR (%) Genotype (1 -- 4/2 -- 3) No. of patients Type of Peg-IFN Study design Country Study (ref.)

Table 1. Efficacy and safety of PegIFN plus RBV in patients aged $ 65 years with CHC.


G 2 -- 3 SVR (%)

Discontinuation rate (%)

Treating hepatitis C in the elderly

retrospective study, by Antonucci et al. [29], investigated the SVR in four different age groups (< 40, 40 -- 49, 50 -- 64 and ‡ 65 years) and included 30 elderly patients who were compared with 123 younger patients. All were treated with PegIFN-a2a or 2b plus RBV for 6 -- 12 months according to their HCV genotype. The authors showed that patients aged < 40 years had a significantly higher chance of achieving an SVR compared with older patients in the subgroup of those infected with HCV genotype 1 or 4 (80 vs 32.6%). Interestingly, in the other age categories, the rate of SVR was similar (31.2% at 40 -- 49 years, 31.8% at 50 -- 64 years and 36.4% at ‡ 65 years). By contrast, no statistically significant difference between age groups was found in patients with genotype 2 -- 3. The higher rate of treatment discontinuation or dose reductions due to a higher incidence of side effects during the 48 weeks of therapy may explain the lower efficacy of treatment in age groups ‡ 40 years. A prospective Japanese study [30] was designed to examine the efficacy of PegIFN-a2b and RBV combination therapy according to gender in older patients and to identify which patients would achieve an SVR in this patient population; 115 older (‡ 65 years) and 476 younger patients (< 65 years) were enrolled. Elderly patients had a significantly lower SVR (37.4 vs 51.5%) and a significantly higher discontinuation rate (32.2 vs 17%) than younger patients. Despite at baseline there were no differences in terms of genotype distribution and HCV-RNA concentration between two groups, multivariate analysis revealed that these two factors were significantly associated with SVR in elderly patients. In particular, dual therapy was the most beneficial for elderly male patients with genotype 1 and HCV-RNA concentrations < 2,000,000 IU/ml and for patients with genotype 2. Another Asiatic study [31] evaluated PegIFN-a2a and RBV treatment efficacy in 70 elderly patients (‡ 65 years) and compared them with sex- and HCV genotype-matched controls (50 -- 64 years) at a 1:2 ratio. Older patients had a significantly higher rate of treatment discontinuation (21.4 vs 6.4%) and grade 3 or 4 adverse events (34.3 vs 20%) than younger patients. The SVR rate was substantially lower among the elderly (67.1 vs 78.6%, p = 0.07), particularly among patients with HCV genotype 1 (51.9 vs 75.9%), but not among genotype 2 or 3 (76.7 vs 80.2%, p = 0.65). When the elderly obtained a rapid virologic response (RVR), those with genotype 1 or genotype 2/3 had similar SVR rates (80 and 87.9%, respectively). Lower SVR rates for genotypes 1 and 2 were observed (22.9 and 65.6%, respectively) in a multicenter study [32] that enrolled 314 older Japanese patients treated with PegIFN-a2b plus RBV. No statistically significant difference was observed between males and females. In comparison with 937 younger patients, the SVR was lower and the discontinuation rate was significantly higher in elderly patients with either genotypes. In a retrospective study [33], Oze et al. evaluated combination treatment with PegIFN-a2b in 1040 naive patients, of whom 240 (23%) were aged over 65 years. In the presence of genotype 1, the


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SVR rate was 44.4% among patients aged < 65 years and declined to 27% among patients aged ‡ 65 years. In multivariate analysis, being male and achieving an early virological response (EVR) were significantly associated with an SVR in elderly patients. In the presence of genotype 2, the SVR rate was 81.9% in the younger group but was lower in the elderly (63.6%), particularly among those ‡ 70 years of age (43%). Nishikawa et al. [34] retrospectively compared the effect and safety of PegIFN-a2b plus RBV combination therapy in 319 younger patients and 108 elderly patients. There was no significant difference in the SVR rates in the two groups according to HCV genotype (41.5 vs 40.7% for genotype 1 and 89.7 vs 86.4% for genotype 2, respectively). There was also no significant difference in the treatment discontinuation rate between the two age groups (10.3 vs 13.9%). There were no serious adverse events requiring hospitalization. Gender, HCV genotype, platelet count and the presence of an RVR or EVR contributed significantly to an SVR in elderly patients. However, upon multivariate analysis, the presence of an EVR was the only significant factor associated with an SVR. Another retrospective study in Korea [35] analyzed 38 subjects aged ‡ 65 years and 143 aged < 65 years who were treated with PegIFN-a2a or 2b plus RBV. The overall SVR was lower in the elderly group than in the non-elderly group, but it was not significantly different (65.8 vs 76.2%). However, for genotype 1, the elderly group had a significantly lower SVR rate than the non-elderly group (30.8 vs 66%), whereas for genotype 2 or 3, the SVR rates were comparable (84 vs 81.3%, respectively). The efficacies of PegIFN-a2a and RBV have also been prospectively analyzed in a Chinese population [36]. The patients were divided into two groups according to age: 140 aged ‡ 65 years and 277 aged < 65 years. There were no significant differences in SVR rates between the two groups for patients with genotype 2. By contrast, patients aged ‡ 65 years with genotype 1 had a significantly higher relapse rate (50.0 vs 29.2%, respectively) and a lower SVR rate (40 vs 60%, respectively) than patients aged < 65 years. Additionally, RBV reduction or discontinuation was more frequent in patients aged ‡ 65 years than in patients aged < 65 years (37.1 vs 20.2%, respectively). In a multivariate logistic regression analysis, male sex, genotype non-1, RBV dose reduction and RVR were independent factors associated with an SVR in patients aged ‡ 65 years. In a recent prospective study [37], Hu et al. evaluated 91 geriatric patients (age ‡ 65 years) and 91 gender- and genotypematched middle-aged patients (age 50 -- 64 years) receiving PegIFN-a2a or 2b plus RBV for 24 weeks. In the intentionto-treat analysis, the SVR rate was significantly decreased in the elderly patients (40.7 vs 61.5%, respectively). The SVR rate was significantly lower in geriatric patients than in middle-aged patients with genotype non-1 (54.3 vs 82.9%, respectively); however, in those with genotype 1, the difference was not significant (32.1 vs 48.2%, respectively). Furthermore, the older patients with genotype non-1 who achieved an RVR had a similar SVR rate to that of the 2022

younger patients. The withdrawal rate was 13.2% in the elderly group and 7.7% in the younger group. In conclusion, all studies show that dual therapy with PegIFN and RBV in patients aged ‡ 65 years can be effectively used in older patients with CHC even if age is a negative predictor in terms of SVR, particularly for genotype 1. In fact, in older patients infected by genotype 2 or 3 the efficacy of dual therapy is more similar to younger. Some studies suggest a positive impact of the male gender on SVR, but this relation is not universally recognized. The different SVR in male is probably due to the difference in terms of race, genetics and hormonal factors in the study populations. However, older patients more frequently experience adverse effects, increasing treatment discontinuation and leading to a reduced treatment efficacy. Decisions to treat such patients with dual therapy should be made on an individual basis considering comorbidities, predictive factors of response or nonresponse and risk/benefit analysis. In addition, it may be better to initiate treatment under careful monitoring, excluding obvious contraindications or major comorbidities that might compromise the patient’s life expectancy.

First-generation direct-acting antivirals: telaprevir and boceprevir

3.

The introduction of the first direct-acting antivirals (DAAs), Boceprevir (BOC) and Telaprevir (TVR), in 2011 represented an important advance in the treatment of CHC. Triple therapy with PegIFN, RBV and either BOC or TVR has the potential to increase the rate of SVR to ~ 70% in previously untreated patients and 65% in previously treated patients who are infected with HCV genotype 1. TVR and BOC play an important role in the treatment of patients who are chronically infected with HCV genotype 1 but not in those infected with non-genotype 1 strains. Typically, major clinical trials have included only few individuals older than 65 years of age; the mean age of the patients included in the most important randomized controlled trials on BOC and TVR was significantly lower than 60 years (Table 2) [38-46]. A recent retrospective cross-sectional study [47] investigated the proportion of patients who began triple therapy in the 12 months after the FDA approval of BOC and TVR in the United States. Only 91/487 patients received triple therapy, and among reasons for deferring therapy, advanced age was reported as the only reason for not treating 5.5% of the population considered for treatment. Although not statistically significant upon univariate analysis, younger age, as a continuous variable, is associated with triple therapy initiation in multivariate analysis (odds ratio [OR] = 0.96, 95% CI 0.93 -- 0.99). Earlier studies of DAA-based regimens for CHC have not shown any correlation between age and virological outcome. Furthermore, few data are currently available on the efficacy and safety of triple therapy in older patients. Only two studies conducted in Japan (where the favorable IL28B genotype is found in ~ 75% of the population) have



Table 2. Age of patients enrolled in clinical trials utilizing triple therapy with TVR and BOC. Telaprevir Clinical trial

PROVE-1

PROVE-2

PROVE-3

ADVANCE

ILLUMINATE

REALIZE

Reference Median age Range (min -- max)

[38]

[39]

[40]

[41]

[42]

[43]

49 -- 50 21 -- 63

44 -- 46 18 -- 65

50 -- 53 18 -- 69

49 18 -- 69

50 -- 52 19 -- 70

50 -- 51 21 -- 70


Boceprevir Clinical trial

SPRINT-1

SPRINT-2

RESPOND-2


[44]

[45]

[46]

46.4 N/A

N/A 38 -- 60

52.7 N/A

BOC: Boceprevir; N/A: Not available; TVR: Telaprevir.

explored differences between treatment in elderly and younger patients and assessed predictive factors for SVR. The first study [48] compared 154 younger (£ 65 years) and 58 older (> 65 years) genotype 1 patients treated with TVR (2250 or 1500 mg/day) associated with PegIFN-a2b and RBV for 12 weeks and then switched to PegIFN-a2b and RBV dual therapy for an additional 12 weeks. The initial TVR dose was not associated with the rate of SVR. The SVR rate for older patients was slightly but significantly lower than that for younger patients (69 vs 82%, respectively). SVR was more likely to be achieved in treatment-naive patients and prior relapsers than in prior nonresponders in both younger (94 vs 57%, respectively) and older patients (84 vs 50%, respectively). In the older group, the SVR rate for patients with the IFNL4 TT/TT genotype was significantly higher than that in patients with the TT/DG or DG/DG genotype (81.8 and 42.9%, respectively). In multivariate regression analysis, rapid virological response and the IFNL4 TT/TT genotype were identified as significant independent predictors of SVR in older patients. Discontinuation of treatment was observed in 25/154 of younger patients (16.2%) and 19/58 of older patients (32.8%) (p = 0.013). The decreases in hemoglobin and increases in serum creatinine were greater in older patients than in younger patients, but the reduction of the initial TVR dose to 1500 mg/day alleviated these adverse events without compromising the SVR rate in older patients. In the second prospective multicenter study [49], 120 patients with chronic hepatitis or cirrhosis were enrolled and categorized into two groups: age > 60 years (n = 64) and age < 60 years (n = 56). For 12 weeks, the patients were treated with triple therapy (TVR 2250 mg/day, PegIFN-a2b 60 -- 150 mcg/week and RBV 600 -- 1000 mg/day), followed by 12 weeks of dual therapy (PegIFN-a2b plus RBV). This study confirmed that there is no impact of age on the virological outcome of TVR-based triple therapy. No significant differences in the SVR rate were found between the two groups (72.5 vs 83.7%, respectively). Multiple logistic regression analysis indicated that the only two factors independently

associated with achieving an SVR in the elderly group were the IL28B TT genotype and RVR. The treatment discontinuation rates due to adverse effects were comparable in older and younger patients (12.5 vs 10%, respectively); no significant differences in drug-induced skin disorders were found. There was a significant difference only in the occurrence of severe anemia between the two groups. No episodes of death or hepatic decompensation were observed. In a recent observational intention-to-treat cohort analysis [50] of patients treated with TVR- or BOC-based regimens in routine medical practice, the SVR rate was lower than that in previous studies (~ 50%), but age > 60 years was not a negative predictor of a reduced likelihood of achieving an SVR. However, it is known that the triple therapy regimens are associated with an increased risk of certain adverse events, particularly hematological events (anemia, neutropenia and thrombocytopenia) with BOC and rash and anemia with TVR. Nonetheless, there was no clear increase in the risk of serious adverse events with the use of protease inhibitors, and these appear to be selflimiting following drug discontinuation. These observations were confirmed in an open-label expanded access program with a TVR-based regimen; the program included 1587 patients with advanced liver fibrosis or cirrhosis [51]. Not unexpectedly, anemia (defined as a hemoglobin level below 10 g/dl at any time during treatment) more often occurred in patients aged > 65 years (OR = 2.31, 95% CI 1.46 -- 3.65,), likely reflecting an increased susceptibility to treatment-related bone marrow and renal toxicity. Of the seven patients who died during dual therapy, only one was > 65 years old, and this patient died for reasons not related to treatment. A similar rate of anemia was reported in the French field practice study CUPIC [52], in which age ‡ 65 years was found to be an independent predictor of anemia (hemoglobin < 8 g/dl) or blood transfusion (OR 3.04, 95% CI 1.54 -- 6.02). Many elderly patients take drugs for other diseases, and this requires particular attention in daily clinical practice. BOC and TVR are both substrates and inhibitors of the hepatic enzyme CYP 3A and the drug


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Table 3. Age of patients enrolled in clinical trials utilizing SPV and SOF. Simeprevir Clinical trial

QUEST-1

QUEST-2

CONCERTO-1

PROMISE


[55]

[56]

[57]

[58]

48 18 -- 73

46 18 -- 73

55 23 -- 69

52 20 -- 70


Sofosbuvir Clinical trial

NEUTRINO

FISSION

POSITRON

FUSION


[59]

[59]

[60]

[60]

52 19 -- 70

48 20 -- 72

52 21 -- 75

54 24 -- 70

SOF: Sofosbuvir; SPV: Simeprevir.

transporter P-glycoprotein, predisposing these agents to many drug interactions. Many different types of medication, ranging from statins to antiretroviral drugs for HIV, are processed by the CYP3A4 enzyme [53]. Agents that inhibit or slow processing can increase the levels of other drugs, whereas agents that induce or increase the rate of processing can decrease drug levels. In conclusion, the antiviral treatment methods for CHC genotype 1 have changed substantially, with the introduction of DAAs in association with PegIFN and RBV. However, TVR and BOC can cause severe adverse events such as rash and severe anemia, particularly in elderly patients [51,52]. Although the data are inconsistent, it is conceivable that triple therapies are effective for the elderly but further studies are needed to determine the real safety and efficacy of triple therapies in elderly patients. Therefore, this new therapy does not solve the problems encountered when treating aged patients.

Interferon-free AND/OR RBV-free regimens: the next standard of care? 4.

Second-generation treatments showing great promise in terms of treatment efficacy have emerged. These new oral drugs have the following advantages: higher efficacy with more patient candidates for a shortened treatment duration (12 -- 24 weeks, instead of 48 weeks) and a better safety profile than the first-generation treatments. In 2013, two new medications, Sofosbuvir (SOF) and Simeprevir (SPV), were approved by the US FDA. The AASLD/ISDA guidelines recommend the use of SOF or SPV in combination with PegIFN and RBV for treatment-naive patients with HCV genotype 1 and 4 for 12/24 weeks; in genotype 1 or 4, not eligible to IFN, SOF and SPV can be used in combination for 12 weeks. SOF plus RBV was the recommended regimen for treatment-naive patients with HCV genotype 2 or 3 for 12 or 24 weeks, respectively [54]. Although in SOF and SPV trials [55-60] there was no upper age limit (Table 3), the number of elderly patients was too small to draw definitive 2024

conclusions. However, the available data on elderly patients treated with SOF (Figure 1) are encouraging [61]. Thus, future regimens may not require the use of IFN injections. A large number of new antiviral drugs, including DAAs and hosttargeted agents, have now been investigated. Three all-oral, IFN-free strategies are being investigated in Phase II and III trials. These include nucleoside/nucleotide analogue-based regimens, nucleoside/nucleotide-free triple combinations of drugs with low barriers to resistance and nucleoside/nucleotide-free double combinations that include at least one drug with a high barrier to resistance [62]. However, clinical studies on these treatments do not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Even so, the excellent safety profile and the lack of significant adverse events will allow the broad use of these drugs in more difficult-to-treat cases. According to these data, interferon-free combination regimens appear to be on the horizon, providing a new option for geriatric patients in particular. In November 2013, during the 64th annual meeting of the American Association for the Study of Liver Diseases, Chayama et al. presented the results of an open-label Phase III study [63] demonstrating that the 24-week, all-oral, interferonfree and RBV-free regimen of Daclatasvir (60 mg once daily) and Asunaprevir (100 mg twice daily) achieved an overall SVR of 84.7% in Japanese patients with CHC genotype 1b who were either interferon ineligible/intolerant (87.4%) or nonresponders (null and partial) to interferon-based therapies (80.5%). In this study, patients aged ‡ 65 years (89/222) had SVR rates similar to those in patients aged < 65 years, and age did not appear to impact response rates. The SVR rate for those aged ‡ 65 years was 91.9% (57/62) in the ineligible/intolerant elderly patient population and 85.2% (23/27) in the nonresponder elderly population. The most common adverse event leading to discontinuation was alanine transaminase (ALT)/ aspartate transaminase (AST) elevation. This first all-oral, interferon and RBV-free regimen submitted for regulatory approval in Japan represents clinically meaningful improvements in both



G1,4-6

G2

G3

100 90 80 SVR 12 (%)

70 60 50 40 30 Expert Opin. Pharmacother. Downloaded from informahealthcare.com by The University of Manchester on 10/15/14 For personal use only.

20 10 0 Neutrino < 65 years 280/307 ≥ 65 years 15/20

Fission 64/66 4/4

Positron Fusion12 Fusion16 91/96 10/13

29/34 2/2

28/30 2/2

Fission 99/180 3/3

Positron Fusion12 Fusion16 59/96 1/2

19/62 0/2

36/60 3/3

Figure 1. SVR rates to SOF according to age. Adapted with permission from [61]. SOF: Sofosbuvir; SVR: Sustained virologic response.

safety and efficacy compared to the current standard of care. Additionally, a shortened treatment course may reduce drugrelated side effects and promote treatment adherence, particularly in the elderly. 5.

Expert opinion

Hepatitis C has a high prevalence in the elderly population, particularly in countries such as Italy and Japan, and in the coming years, we will often need to treat elderly patients with advanced fibrosis or decompensated cirrhosis. For this reason, studies that consider the efficacy and safety of antiviral treatment in the elderly will be of great help to establish guidelines for treatment in real-life cases. The first important point to be considered is to decide who should be treated and determine which is an upper age that will be used as a cutoff not to treat. Although SVR has now been shown to reduce all-cause of mortality and cirrhosis-related complications among patients infected with HCV, the number of years of benefit to be gained from treatment in elderly is obviously lower than in younger. In decision making to using or withholding the antiviral treatment, it’s important to take into account the natural history and risk of progression but also the presence of comorbidities, the risk of complications, the life expectancy and the patient’s preference and priorities. We must not make the mistake of considering the chronological age, but we evaluate the biological age of patient. The choice is complex and cannot be taken at the sole discretion of an experienced hepatologist but in accordance with the patient and his or her family. Another important issue to consider is what tools are available to treat aged patients with CHC. To date, the available studies conducted on the geriatric population have often been

retrospective and have evaluated only treatment with dual therapy. No pivotal studies have been performed to evaluate the efficacy and tolerability in an elderly population. The introduction of first-generation protease inhibitors does not appear to have improved the success of antiviral therapy in this group of patients, most likely due to a worse tolerability. A number of direct antiviral agents for the treatment of HCV infection are currently in active development. The deep therapeutic innovation that is emerging with IFN-free regimens should prompt us to evaluate their efficacy and tolerability even in the elderly. The availability of short-term, safe and highly effective therapies appears to be another major step forward for HCV eradication and will likely change the way we select patients for treatment. Future studies conducted in older patient populations are desirable to obtain data on the efficacy and tolerability of the different drugs used in IFN-free regimens as well as data on drug interactions. Until then, IFN-free regimens remain only an intriguing prospect, although most likely in the near future, this will become the new standard of care for the treatment of hepatitis C. Probably a larger number of elderly HCVinfected patients will be able to access the antiviral therapy programs. Since these drugs are expected to have very high costs, their assignment will need a careful rationalization because there are not enough resources for all. However, the good tolerability profile, the increasing of SVR rate and the shorter duration of new antiviral treatments appear to increase the cost-effectiveness as reported in a recent study [64]. Certainly, more choice will likely mean greater options both in terms of different regimens to choose and perhaps lower costs. There is an urgent need to develop specific studies able to define the virological, epidemiological and clinical profiles of aged patients who may benefit from


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therapy to help the physician in the decision on the treatment of elderly patients and to estimate the nationwide expenditure for HCV. These future research should not only help us to clearly assess the long-term outcomes of virus on aged patients’ survival and extrahepatic diseases but also to make better use of economic resources. So we could fully appreciate and recognize the total impact of HCV burden in this setting on the patients and the society.


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P Andreone has participated on advisory boards for Janssen, Roche, HSD, Abbvie, Gilead and Boehringer Ingelheim. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Affiliation Fabio Conti1 MD, Giovanni Vitale1 MD & Pietro Andreone†2 MD † Author for correspondence 1 University of Bologna, Department of Medical and Surgical Sciences, Via Massarenti, 9, 40138 Bologna, Italy 2 Professor, University of Bologna, Department of Medical and Surgical Sciences, Via Massarenti, 9, 40138 Bologna, Italy Tel: +39 051 6363618; Fax: +39 051 345806; E-mail: [email protected]

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