Tuesday, March 7, 2017

Increasing risk of cataract in HCV patients receiving anti-HCV therapy: A nationwide cohort study

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HCV Infection May Increase Risk of Cataracts, Study Finds
Researchers conducted a population-based study with 11,652 HCV-infected patients for just over five years. The patients were registered with the National Health Insurance (NHI) database of Taiwan, and were age- and sex-matched against a group of non-HCV patients.
Rates of cataract development were compared between groups after controlling for possible confounding variables, such as hypertension, high cholesterol, asthma, chronic obstructive pulmonary disease (COPD), coronary artery disease, and anxiety.
Researchers found that HCV-infected patients were more likely to develop cataracts than non-HCV infected patients. Overall, the incidence rate of cataracts was 1.36 times higher in the HCV group than in the non-HCV group.
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Increasing risk of cataract in HCV patients receiving anti-HCV therapy: A nationwide cohort study
Shih-Yi Lin, Cheng-Li Lin, Shu-Woei Ju, I-Kuan Wang, Cheng-Chieh Lin, Chih-Hsueh Lin, Wu-Huei Hsu, Ji-An Liang

Published: March 6, 2017

http://dx.doi.org/10.1371/journal.pone.0173125

Abstract
Purpose

Hepatitis C virus (HCV) infection is associated with increased systemic oxidative stress, which leads to cardiovascular events, diabetes, and chronic kidney disease. Similarly, cataract is also associated with increased oxidative stress. The association between HCV infection and increased risk of cataract remains unclear.

Methods
A total of 11,652 HCV-infected patients and 46,608 age- and sex-matched non-HCV infected patients were identified during 2003–2011. All patient data were tracked until a diagnosis of cataract, death, or the end of 2011. Cumulative incidences and hazard ratios (HRs) were calculated.

Results
The mean follow-up durations were 5.29 and 5.86 years for the HCV and non-HCV cohorts, respectively. The overall incidence density rate for cataract was 1.36 times higher in the HCV cohort than in the non-HCV cohort (1.86 and 1.37 per 100 person-y, respectively). After adjusting for age, sex, comorbidities of diabetes, hypertension, hyperlipidemia, asthma, chronic obstructive pulmonary disease, coronary artery disease, and anxiety, patients with HCV infection had an increased risk of cataract compared with those without HCV infection [adjusted HR = 1.23, 95% confidence interval (CI) = 1.14–1.32]. HCV-infected patients receiving interferon–ribavirin therapy had a 1.83 times higher (95% CI = 1.40–2.38) risk of cataract than non-HCV infected patients did.

Conclusion
HCV infection, even without the complication of cirrhosis, is associated with an increased risk of cataract, and this risk is higher in HCV-infected patients undergoing interferon–ribavirin therapy.

Discussion Only
In this population-based cohort study, we observed that HCV infection, even in the absence of cirrhosis, was associated with an increased risk of cataract. HCV-infected patients receiving interferon–ribavirin therapy had a 1.83 times higher risk of cataract compared with those without HCV infection and not receiving interferon–ribavirin therapy. This suggested that all patients with HCV, regardless of receiving HCV treatment, should be closely monitored for subsequent cataract development.

Even after adjusting for major confounding variables such as age and diabetes, HCV infection remained independently associated with cataract. The effects of HCV on ocular manifestations have been seldom studied. We hypothesized that the pathogenic mechanism connecting HCV infection and cataract is oxidative stress. Evidence has increasingly indicated that HCV infection-induced oxidative stress is systemic and not limited to the liver [1821]. HCV-infected patients have high insulin resistance and oxidative stress, which increases their risk of coronary artery disease [22], chronic kidney disease [23], glucose metabolism derangements, and diabetes [24]. Similarly, HCV may induce high oxidative stress within the lens, initiating a cascade of free radial formation, oxidized material accumulation, and ultimately, cataract development. Because we have adjusted our data for diabetes, a major risk factor for cataract and a recognized sequela of HCV infection, our results clearly demonstrated an independent association between HCV infection and cataract.

In this study, we observed a positive association between pegylated interferon and ribavirin therapy for HCV infection and risk of cataract. Our data showed that HCV patients receiving interferon alpha-only regimen had 1.29-fold higher risk of cataract, interferon alpha-ribavirin regimen had 1.83-fold higher risk of cataract, compared with non-HCV patients. Thus, the regimen combining Interferon alpha and ribavirin would have addictive and synergistic effects on the risk of developing cataract. Few case reports and studies with small sample sizes have reported similar findings [25, 26]. This current large-scale cohort study clearly demonstrated that pegylated interferon and ribavirin therapy for HCV infection is associated with a 1.83 times higher risk of cataract. Interferon-associated retinopathy has been described in the literature [27, 28], interferon alfa–ribavirin-associated cataract has seldom been mentioned. There are several possible explanations accounting for the association between HCV therapy and cataract. One supposed pathway would be direct effects of interferon/ribavirin treatment or to HCV itself. It has been reported that about 0.5% patients taking ribavirin have cataract, with the incidence being up to 55.36% during the initial 6 months of ribavirin use, and the most co-used medication in these cataract patients was interferon alfa-2a [29]. The sample size of our HCV patients receiving ribavirin only was too small to determine whether ribavirin would be direct related to the risk of cataract. Further prospective randomized control study would be needed to classify the association between ribavirin and cataract.

Our HCV cohort had significantly higher prevalence of comorbidities compared with non-HCV cohort. Our interaction analysis showed that HCV interacted with diabetes, hyperlipidemia, and alcohol-related illness on the increasing risk of cataract. HCV patients had diabetes had highest risk of cataract, among those with or without HCV or diabetes. Our data demonstrated that clinical relevance of HCV infection is not equal to those of the other confounding factors of high oxidative stress, including diabetes and aging.

The other possible explanations would be competing risk between HCV-related mortality and cataract. It would be reasonable to speculate that systemic oxidative stress would be positively associated with the degree of HCV infection. However, in our stratified analysis, there was no significant difference in developing cataract between cirrhosis and non-cirrhosis. Thus, we suppose that there are competing risk between cataract and HCV- related morbidity and mortality in those HCV decompensation patients. On the other hand, current guideline indicated therapy should be considered for all compensated treatment—na├»ve HCV patients [30]. Thus, possible bias resulting from competing risk would be minimized in those HCV patients receiving interferon–ribavirin therapy since those who receiving therapy all had compensated liver function. However, possible selection bias would exist since viral load of HCV, genotype of HCV, status of liver reserve, and mounted immune response to therapy, these possible predisposing factors of cataract, of whom receiving interferon/ribavirin would be different at baseline from those HCV patients not receiving interferon/ribavirin. Further large scale prospective study would be required to investigate the association between HCV treatment and cataract.

This study has several limitations. First, information regarding the cataract subtype and family history of each cataract patient was unavailable. Second, details regarding smoking habit, vitamin supplement use, ultraviolet exposure, and sun protection were not available from the ICD-9-CM codes. Third, because the NHIRD encrypts patient personal information to protect privacy, no records regarding HCV genotype, viral load of HCV, serological response to HCV treatment, and severity of cataract were available; therefore, a direct and substantial dose–response relationship between HCV infection and cataract could not be established. Nevertheless, we controlled for possible confounding variables such as frequency of clinical visits, diabetes, coronary artery disease, hypertension, hyperlipidemia, COPD, asthma, and alcohol-related illness; thereafter, HCV infection was found to be independently associated with risk of cataract. Finally, treatment outcome, i.e. response to HCV therapy was unavailable in NHIRD. However, lack of treatment outcome of HCV therapy would not have effects on our conclusion that HCV infection is associated with an increased risk of cataract especially undergoing interferon–ribavirin therapy.

In conclusion, the current nationwide cohort study revealed that HCV-infected patients have an increased risk of cataract. Furthermore, HCV-infected patients receiving interferon–ribavirin therapy have a 1.83 times higher prevalence of cataract than those without HCV infection. Considering the surgical curability of cataract and serious HCV infection-related morbidity, we do not discourage the use of anti-HCV therapy for HCV-infected patients. Instead, we recommend routine screening of these HCV patients for ocular problems, especially those received interferon alpha–ribavirin therapy.
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