Wednesday, July 12, 2017

Safety and Efficacy of Direct-Acting Antivirals for the Treatment of Chronic Hepatitis C in a Real-world Population Aged 65 Years and Older

News & Perspective > Journal of Viral Hepatitis

Are direct-acting antivirals safe and effective in elderly patients with HCV-related advanced fibrosis or cirrhosis?

Safety and Efficacy of Direct-Acting Antivirals for the Treatment of Chronic Hepatitis C in a Real-world Population Aged 65 Years and Older
F. Conti; S. Brillanti; F. Buonfiglioli; R. Vukotic; M. C. Morelli; C. Lalanne; M. Massari; F. G. Foschi; V. Bernabucci; I. Serio; G. M. Prati; E. Negri; L. Badia; P. Caraceni; P. Muratori; G. Vitale; A. Porro; M. Morotti; G. Mazzella; P. Andreone Disclosures J Viral Hepat. 2017;24(6):454-463. 

The availability of direct-acting antiviral agents (DAA) regimens has expanded the pool of patients eligible for treatment. However, data on the virologic response and tolerability of DAAs in elderly patients are lacking. We evaluated the efficacy and safety of DAAs in patients with advanced fibrosis/cirrhosis in real-life practice with the focus on those aged ≥65 years. Between January and December 2015, all consecutive patients with HCV-related advanced fibrosis/cirrhosis treated with DAA at eleven tertiary referral centres in Emilia Romagna (Italy) were enrolled. Regimen choice was based on viral genotype and stage of disease, according to guidelines. The primary end point was sustained virologic response 12 weeks after the end of treatment (SVR12). Overall, 282 of 556 (50.7%) patients evaluated were elderly, most of them with cirrhosis. Antiviral therapy was stopped prematurely in four (1.4%) patients. Two patients, both with cirrhosis, died during treatment due to worsening of liver/renal function. SVR12 was achieved by 94.7% and was comparable to that obtained in patients aged <65 (P = .074). Similar data were also reported in subgroup of patients aged ≥75 years. All patients with advanced fibrosis achieved virologic response. SVR12 was 80.8% in Child-Pugh-Turcotte (CTP)-B cirrhosis and 95.4% in CTP-A (P = .013). According to genotype, the SVR12 was achieved in 172 of 181 (95%) with genotype 1b cirrhosis and in 44 of 48 (91.7%) with genotype 2 cirrhosis.

In conclusions, in a real-world setting, DAAs are safe and effective in elderly patients with HCV-related advanced fibrosis/cirrhosis, but SVR12 is lower with worsening CTP class.

Discussion Only
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Older patients with CHC will become an increasingly larger group over the next decade, and they are expected to develop more cirrhosis and liver cancer with a significant increase in health-related disease costs. Therefore, achieving a SVR could halt the progression of liver disease. In Southern Europe and especially in Italy, the treatment of aged patients with CHC is an important issue, because of the higher prevalence of HCV infection, and the older age of HCV carriers, compared to other European countries, thus contributing to the disease burden and complications.[27–30] Progress in pharmacotherapy will continue to extend healthy life expectancy and a chance for HCV eradication in the elderly, historically considered poor candidates to IFN-based treatments, is now offered by new all-oral DAA regimens. Despite this, the experience with IFN-free regimens in these patients has been very limited in phase three studies, in which only few patients older than 65 years were included, often without advanced fibrosis or cirrhosis. Hence, evidence for the benefit of virologic response in elderly patients has yet to be clearly demonstrated.

In our knowledge, this study represents the largest experience on all-oral antiviral therapy in HCV patients aged ≥65 years with advanced liver disease, in a real-life setting. It reports the efficacy and safety of the available DAA regimens, but its retrospective cohort design and the real-life setting do not allow comparing the efficacy and safety of the different DAA regimens.
Several important findings emerged from our study. First, the results of our analysis demonstrate that all-oral DAA treatments were quite effective in elderly patients with advanced CHC and that older age was not a barrier to achieve a SVR12. Second, older age was not associated with increased SAEs during antiviral treatment.

In contrast with clinical trials,[31] where patients over 65 years old with advanced fibrosis or cirrhosis were underrepresented, this study was carried out in a clinical practice setting where about 50% of this population consisted of elderly patients. As expected, in comparison with younger patients treated during the same period, elderly had more severe liver disease, a higher prevalence of HCC history and comorbidities as arterial hypertension and renal disease. During IFN era, elderly patients were generally less treated than younger probably because they were excluded from the randomized controlled trials and physicians are reluctant to treat elderly patients with antiviral therapy because of possible side effects.[32] In our country, the majority of elderly patients have a HCV genotype-1b or 2 infection, and this epidemiology has influenced the choice of antiviral regimens in our cohort and led to highly effective results. In fact, response rates were 100% in patients with advanced fibrosis and 94.7% in patients with cirrhosis (95% in GT-1b and 91.7% in GT-2). The high SVR12 rate observed in the latter group was also probably due to a high prevalence of subjects in CTP-A class (about 90%).

High efficacy in a real-world setting was recently reported also by Vermehren et al.[33] even if the sample size of elderly patients was lower than in our study and less than 50% had cirrhosis.
The majority of patients were treated with SOF/SMV regimen, and viral eradication was obtained in 82/89 (92.1%) of those with cirrhosis. These results confirm data recently reported in a large prospective observational cohort study by Sulkowski et al.[34] Efficacy of other DAA regimens (as SOF/DCV±RBV and LDV/SOF±RBV) was even more encouraging even if the limited sample size does not allow definitive conclusions. Furthermore, the SVR12 rates observed in patients with genotype 2 treated with SOF plus RBV have yielded very favourable results, comparable to those of our younger population and higher than those reported in previous real-life studies.[35,36] In these clinical practice studies, authors reported SVR12 rates lower in patients with liver cirrhosis (83–87%) than in our cohort. Probably this difference is due to the use of a 24-week regimen of SOF and RBV in about 50% of our patients with cirrhosis, considering that extended treatment duration in cirrhotics has been shown to increase SVR.[37]

Interestingly, and probably unexpectedly, our data showed that sex, diabetes, genotype 1, renal function, previous treatment failure and RBV use were not negatively associated with SVR12 in elderly patients with cirrhosis. Only severity of liver disease at baseline had a significant impact on SVR12. In fact, patients with CTP-A at the time of treatment initiation were more likely to achieve SVR12 compared to those in CTP-B class (95.4% vs 80.8%, respectively, P = .010). Similar trend has been previously reported in other studies.[38,39]

RBV was not used in 34.6% (66/191) of elderly patients with HCV genotype 1 or 4 cirrhosis due to the presence of anaemia at baseline (68.2%) or concomitant cardiovascular disease (18.2%), for intolerance to a previous RBV-containing treatment (7.6%) and for treating physicians' choice (6%). Despite this, no difference was found in terms of SVR12 compared to patients treated with RBV. In HCV genotype 2 or 3 patients treated with SOF+RBV (which was the only schedule available for these genotypes during the study period), hematopoietic growth factor supplementation and dose reduction were successful used to manage the anaemia.

Our study confirms previous observations reported by others[40] that undetectable viremia after 4 weeks of treatment is not a predictor of SVR12. Conversely, also in our experience, SVR4 continues to be a strong predictor of SVR12 and only two patients relapsed in our cohort after achieving SVR4.[41]

All the DAA regimens were generally well tolerated, with only less than 2% of patients discontinuing treatment due to adverse events. SAEs were observed in about 5% of patients; nevertheless, two patients died during treatment due to worsening of liver and/or renal function. Anaemia was frequent in this cohort of patients aged ≥65 years and mostly managed with RBV dose reductions or discontinuation. Hyperbilirubinemia was well tolerated in most patients, did not require premature discontinuation of treatment and resolved within a few weeks after treatment discontinuation. Most common AEs corresponded to those previously reported in pivotal phase III studies.[12–18]

In addition, our findings demonstrated that the rate of AEs in patients aged 65–74 years was not different from that observed in patients aged 75 years or older. In this setting, fatigue and skin complaints were confirmed to be the most common AEs. Finally, some complications of liver disease occurred during the short period of the study, including HCC. Recently some studies, also from our group,[42–44] reported increased rates of HCC recurrence in patients treated with DAAs suspecting a deregulation of the antitumour response after the sharp decrease of HCV viral load induced by DAA. To date, data on the effect of HCV eradication after DAA in patients who have already developed HCC are still few and not conclusive and it is as yet unclear whether interferon-free treatment could result in patients being free from the HCC occurrence.[45–47] Until now, there are no findings supporting the role of the age per se as a risk factor for the development of HCC after interferon-free treatment. Therefore, all patients with cirrhosis remain at increased risk for HCC even after they have been cleared HCV. This observation highlights the need for these patients to continue a regular screening for liver complications, even after SVR.

Some limitations should be considered in the interpretation of our results, including the retrospective design and the lack of data on the emergence of resistance-associated viral strains. Furthermore, the short follow-up period (12 weeks) limits our ability to assess the long-term impact of SVR on those patients. Another objection could be that we arbitrarily defined as "elderly" those patients aged 65 years or above. Nonetheless, in the cohort of patients over 75 years of age data about efficacy and safety of IFN-free regimens were superimposable, suggesting that prescription of these new treatments should not be limited by any age.

In conclusion, the results of this study demonstrate that age per se does not influence the success of IFN-free treatments in elderly patients with CHC and that all the DAA regimens seem well tolerated and safe, also in subjects with advanced liver disease and in those aged 75 years or older. Based on these evidences, there are no reasons to deny treatment with new DAA using the age as a criterion for prescription. Nonetheless, some conditions may limit the use of these drugs in elderly subjects such as the presence of severe comorbidities, affecting the short-term life expectancy, and/or the risk of serious drug interactions. Therefore, a careful assessment of the patient's geriatric status is mandatory. Finally, a longer follow-up of this cohort may provide additional useful information about the lifetime utility of HCV eradication in terms of reduction in outcomes and survival.

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