Epidemiology and Outcomes of Hepatitis C Infection in Elderly US Veterans

H. B. El-Serag; J. Kramer; Z. Duan; F. Kanwal

Disclosures

J Viral Hepat. 2016;23(9):687-696. 

In This Article

Discussion

In this large US cohort of patients with CHC, we found that older age was significantly associated with increased risk of developing cirrhosis and HCC. Specifically, we found that patients aged 65–85 years were 1.14, 2.44 and 2.09 times more likely to develop cirrhosis and HCC, respectively, than patients aged 20–49 years. We also found that antiviral treatment was used less frequently in older patients but that, among those who received treatment, there were no age-related differences in SVR12. Older patients with CHC were more to likely to have several comorbid disorders, including diabetes, but also less likely to have alcohol-use disorder, HIV and HBV coinfection, and obesity than younger patients. Adjusting for age-related differences in these comorbidities did not explain the age-related differences in treatment receipt. Importantly, receipt of treatment with SVR12 was associated with a significant decrease in cirrhosis (−22%), HCC (−61%) and mortality risk (−0.67%); and this benefit was seen in all age groups, including the elderly.

We used 65 years and older to define the elderly group with CHC. The definition of what constitutes the 'elderly' is arbitrary and varies between studies. The commonly used age threshold of 65 years of age stems from the designation utilized by the pension programme in Germany in the late nineteenth century. The US Census Bureau has followed this definition and designated elderly as individuals over the age of 65 years. However, we also realize that the age threshold of 60 years is used by the by World Health Organization to define individuals as elderly and by National Health and Nutrition Examination Survey (NHANES) to stratify individuals as those having advanced age.

Therefore, when facing an elderly HCV patient, an important question to answer is whether this patient will progress to liver complications threatening survival and, the second, whether the disease is conditioning health-related quality of life.

In line with the findings of previous observational studies[10,11] our findings suggest that successful HCV antiviral treatment is associated with a significant reduction in HCC and overall mortality. However, this is the first study to demonstrate mortality benefit in all age categories, including those 65–85 years of age. While examining liver disease-specific mortality was not possible, the similar and concomitant reduction in cirrhosis and HCC incidence was highly suggestive that at least part of the mortality reduction was related to improvement in liver disease. Treatment effect might be explained by selection bias in which relatively healthier elderly patients were more likely to be treated.[12] However, the treated group with no SVR had a small but significant increase in the risk of HCC compared with no treatment, a finding which may indicate that the treated group was more likely to have more severe liver disease. The major concerns for the management of HCV in elderly patients have been the common side effects of treatment with IFN and ribavirin including anaemia, neutropenia and thrombocytopenia, which can trigger cardiac events, and promote infectious disease or haemorrhages. Therefore, in a sensitivity analysis, we limited the mortality analyses to elderly patients who received antiviral treatment and compared those with and without SVR12, while adjusting for differences in demographic and clinical comorbidities. The significant benefit, while slightly attenuated, persisted among elderly patients who achieved SVR12 (Table 4).

We considered several possibilities as potential explanations underlying the association between older age and adverse clinical outcomes in CHC with or without treatment. The explanation for the observed age-related increase in HCV-related complications is likely a combination of longer duration of infection and ageing-related impaired repair mechanisms and increased carcinogenic potential. The comparison between decades showed that the major acceleration in the occurrence of cirrhosis was observed after the age of 50 years irrespective of duration of HCV diagnosis. The mechanisms underlying this particularly rapid course in the elderly population have not been clearly understood. The higher vulnerability to environmental factors (especially oxidative stress), the reduction in the rate of hepatic blood flow, the reduced mitochondrial capacity and the impaired immunity are all mechanisms possibly involved in a faster progression of liver damage. Other factors were considered and adjusted for in the analyses, including differences in HCV genotype, other demographics and known HCC risk factors (e.g. alcohol, diabetes, HIV, HBV). We used the date of first HCV treatment as our index date for follow-up and defined SVR12 based on that treatment episode, but this may have missed few patients with SVR resulting from a second treatment episode or received treatment outside the VA. This potential misclassification, which is small because no different meds other than IFN and ribavirin were available during the study period, would have diluted the non-SVR group and attenuated the observed protective effect of treatment. Therefore, our results likely represent a conservative estimate of HCV treatment benefit.

Our findings have implications that involve the entire spectrum of care from antiviral treatment to prevention and screening.[13] Given the accelerated progression to advanced liver disease, elderly patients with CHC constitute a high-risk group that may need to be prioritized in the era of new antiviral treatments. SVR rates with the all-oral regimens seem to have minimal or no age-related differences in efficacy or side effects.[14,15]

Our study is limited by the observational retrospective nature of its design. However, large prospective studies with sufficient long-term follow-up to document clinical outcomes in elderly patients with CHC with and without treatment are not likely to be conducted due to cost, feasibility and ethical issues. Although the generalizability of the age-related biologic processes of cirrhosis progression probably extends to other HCV-infected individuals in the VHA, as well as nonveterans, further research will be needed to confirm our findings.

Older patients treated in the interferon era will likely have different comorbid disease burden than those treated in the direct-acting antiviral era, limiting the generalizability of our findings to patients who might receive treatment in the new era.[16,17] However, our findings suggest that at least a selected group of elderly patients do realize the benefits associated with SVR and that these benefits might be even greater with the newer interferon- and ribavirin-sparing direct-acting antivirals. The use of new oral medications has higher efficacy, shortened treatment duration and a better safety profile than the first-generation treatments. Although in the clinical trials there was no upper age limit, the number of elderly patients was too small to determine whether they respond differently from younger patients.

In summary, older age was significantly associated with the risk of developing cirrhosis and HCC. This association persisted after adjusting for a range of factors, including diabetes and BMI. These data are relevant to the thousands of elderly patients with CHC and to their physicians, who provide care and counselling to this population. The change in HCV treatment with the introduction of interferon-free therapies has dramatically changed the short-term considerations in favour of treatment due to the very high SVR and low side-effect profile. Our findings indicate long-term benefit to SVR among elderly patients while adjusting for other demographic and clinical factors, including comorbidities.

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