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Interferon Stops Parkinson Disease: Association of Antiviral Therapy With Risk of Parkinson Disease in Patients With Chronic Hepatitis C Virus Infection
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Original Investigation & Editorial
June 5, 2019
"This study found that PD incidence appeared to be lower in patients who were receiving interferon-based antiviral therapy for chronic HCV infection. The results seem to support the theory that HCV infection is a risk factor for developing PD. Antiviral therapy has shown potential in lowering this risk.......The incidence of PD is statistically significantly lower in patients with HCV infection who are treated with antiviral therapy, but a proportion of patients in this group still develop PD every year.....These researches support the epidemiologic finding of the association between HCV infection and PD occurrence.....it has been confirmed that interferon is capable of passing the blood-brain and blood-spinal cord barriers. antiviral therapy may, therefore, reduce the opportunity of central nervous system damage caused by HCV.....Protection from antiviral therapy may be possible only when patients with HCV infection received antiviral therapy before the premotor stage."
JAMA Neurol. Published online June 5, 2019
Several epidemiologic studies found an association between HCV infection and Parkinson disease (PD),6-9 and HCV infection has been suggested as a risk factor for PD. However, inconsistent results showing no association between HCV infection and PD have also been reported.10
To our knowledge, this is the first cohort study to investigate the association between antiviral therapy and risk of PD in patients with chronic HCV infection. The results demonstrated a reduced incidence of PD in patients who received interferon-based antiviral treatment. The reduction appeared obvious at 5 years after antiviral therapy and became more statistically significant at the end of follow-up. The lower rate of PD occurrence in the treated patients may suggest that HCV infection is a risk factor for PD development, and antiviral therapy lowers the risk. It cannot be fully excluded that interferon-based antiviral therapy had a direct protective quality against the development of PD. However, the short exposure of antiviral agent, 16 to 48 weeks in most treated participants, makes protecting against PD development in 5 years less likely.
Key Points
Question Is interferon-based antiviral therapy associated with Parkinson disease incidence in patients with chronic hepatitis C virus infection?
Findings In this cohort study of 188 152 patients with hepatitis C virus infection, the group treated with antiviral therapy had lower incidence density and risk of developing PD compared with the untreated group.
Meaning Results of treatment with interferon-based antiviral therapy appeared to support the hypothesis that hepatitis C virus may be a probable risk factor for Parkinson disease.
Results A total of 188 152 patients were included in the analysis. An equal number (n = 39 936) and comparable characteristics of participants were retained in the treated group (with 17 970 female [45.0%] and a mean [SD] age of 52.8 [11.4] years) and untreated group (with 17 725 female [44.4%] and a mean [SD] age of 52.5 [12.9] years) after matching. The incidence density of PD was 1.00 (95% CI, 0.85-1.15) in the treated group and 1.39 (95% CI, 1.21-1.57) per 1000 person-years in the untreated group. The advantage of antiviral therapy reached statistical significance at the 5-year follow-up (HR, 0.75; 95% CI, 0.59-0.96), and this advantage continued to increase until the end of follow-up (HR, 0.71; 95% CI, 0.58-0.87).
The event number and incidence density increased gradually over the years in both groups. The event rate in the treated group increased statistically significantly slower (3.03 per thousand to 4.06 per thousand) than in the untreated group (3.93 per thousand to 5.51 per thousand) (Figure 2).
Conclusions and Relevance Evidence suggested that the PD incidence was lower in patients with chronic HCV infection who received interferon-based antiviral therapy; this finding may support the hypothesis that HCV could be a risk factor for PD.
Discussion
To our knowledge, this is the first cohort study to investigate the association between antiviral therapy and risk of PD in patients with chronic HCV infection. The results demonstrated a reduced incidence of PD in patients who received interferon-based antiviral treatment. The reduction appeared obvious at 5 years after antiviral therapy and became more statistically significant at the end of follow-up. The lower rate of PD occurrence in the treated patients may suggest that HCV infection is a risk factor for PD development, and antiviral therapy lowers the risk. It cannot be fully excluded that interferon-based antiviral therapy had a direct protective quality against the development of PD. However, the short exposure of antiviral agent, 16 to 48 weeks in most treated participants, makes protecting against PD development in 5 years less likely.
Neuroinflammation has been suggested as a characteristic finding in the PD pathologic condition, and some studies suggest that an innate immune reaction may result in neuronal loss in PD.34 The HCV infection and PD also share elevated inflammatory biomarkers, such as interleukin 6 (IL-6), tumor necrosis factor, IL-1β, and IL-2, in peripheral blood.35,36 However, we do not fully comprehend the causality between the PD, peripheral inflammation, and neuroinflammation. In magnetic resonance imaging studies, chronic HCV infection was associated with cerebral inflammatory response, cognitive impairment, and neuropsychiatric symptoms, even when the liver disease was mild and the hepatic encephalopathy was absent.37,38 In another iodine 123–labeled β-carboxymethyoxy-3-β-(4-iodophenyl) tropane single-photon emission computed tomography study, serotonin and dopamine transmission were disrupted in patients with HCV infection, including those whose virus had been cleared.39 The underlying mechanism of the protective potential of interferon-based antiviral therapy could be complicated and may involve the modulation of anti-inflammatory cytokines.40
In contrast, the reduced incidence of PD by antiviral therapy could be associated with the reduction or clearance of HCV in patients. Hepatitis C virus, but not hepatitis B virus, particles were found to induce loss of tyrosine hydroxylase(+) neurons in midbrain neuron-glia cocultures, suggesting a neurotoxic effect of HCV on the dopamine cells.7 Microvascular endothelial cells of the human brain express receptors as the entries for HCV, and the viral replication in the endothelial cells may subsequently disrupt the blood-brain barrier.41 Concurrent HCV-related systemic inflammation, exposure of neurotoxin, and a disrupted blood-brain barrier could exert a greater detrimental power on the neuron.36,42 In addition, a few postmortem studies provide the evidence that viral replication happens in a human’s brain. The genotype of HCV in the brain, blood cells, and liver is diverse, and the virus with a brain-specific mutation may survive in the brain.43-45 These researches support the epidemiologic finding of the association between HCV infection and PD occurrence. Moreover, it has been confirmed that interferon is capable of passing the blood-brain and blood-spinal cord barriers.46 The antiviral therapy may, therefore, reduce the opportunity of central nervous system damage caused by HCV.
The incidence of PD is statistically significantly lower in patients with HCV infection who are treated with antiviral therapy, but a proportion of patients in this group still develop PD every year. The origins of PD are complex and largely unclear. An HCV infection could be only 1 source. Hence, the advantage of antiviral therapy is restricted. However, some participants in this study could be enrolled at the premotor stage of PD, when diagnosis as PD was not possible.47-49
Participants at the premotor stage had pathologically developed PD and inevitably presented PD motor symptoms (clinically diagnosed as PD) somewhere during the follow-up period. Protection from antiviral therapy may be possible only when patients with HCV infection received antiviral therapy before the premotor stage. Although interferon can enter the brain,46 ribavirin, included in the regimen of antiviral therapy, is a water-soluble molecule that can hardly penetrate the blood-brain barrier.50 Once the HCV enters the neuron or glia cell, the advantage of antiviral therapy may be dampened. Some studies reported cases of HCV infection who developed parkinsonian symptoms during or after interferon-based antiviral therapy and suspected that interferon-based antiviral therapy could be the origin of PD.14,51 However, the conclusion of this study refutes the conclusions of observational studies. The discrepancy could be explained by patients who received antiviral therapy at the premotor stage of PD but eventually developed PD.
In the subgroup analysis, the advantage of antiviral therapy was not observed in patients with nonliver cancers; any advantage was probably associated with the short lifespan of patients. The mean follow-up duration in patients with nonliver cancers was 3.36 (2.3) years and in patients without nonliver cancers was 4.05 (2.6) years. The mortality of patients with nonliver cancers was statistically significantly higher than that of patients without nonliver cancers (15.1% vs 5.6%; P < .001). Accordingly, the advantage of antiviral therapy did not emerge from the cohort in this subgroup. On the contrary, the protective potential of antiviral therapy against PD was most statistically significant in the subgroup of patients treated with dCCBs. This finding corresponds to study results, which concluded that dCCBs may be associated with reduced risk of PD.52-54 In patients with HCV infection who used dCCBs, antiviral therapy may provide an added advantage of reducing PD development.
Although the interaction in the age subgroup (21-50, 51-75, or >75 years) was not statistically significant (HR, 0.56 vs 0.67 vs 1.89; P for interaction = .11), the trend of association in the participants older than 75 years was different from that in the other groups. However, only a small number of patients received antiviral therapy in this age range. Hence, the results may be less conclusive. Moreover, considering age as a strong risk factor for PD, patients older than 75 years may be too advanced in age to find antiviral therapy advantageous.
Limitations
This study has some limitations. First, the hepatic function profile, serum virologic response, viral genotype, and HCV RNA-level data were unavailable in the NHIRD. However, the TNHI has strict regulations. All of the laboratory data of patients with HCV infection, including serum alanine aminotransferase level, HCV RNA, HCV antibody, and liver biopsy, have to be reviewed by experts before approval of the antiviral therapy. This requirement strengthens the authenticity of the data in our work. However, lack of the viral profiles made it impossible to associate PD incidence with severity of HCV infection. Second, the NHIRD lacked patients’ lifestyle information (eg, smoking status, consumption of coffee and alcohol), which may have affected the incidence of PD.24
Third, ascertaining the diagnosis of PD according to the ICD-9-CM code and anti-PD medications in the NHIRD may not be the ideal method, although the method used here was validated and shown to have a diagnostic accuracy of 94.8%.30 Differentiating PD from other similar parkinsonian syndromes is sometimes challenging in clinical practice. Long-term medical records and pathological diagnoses for PD are helpful in the accurate diagnosis of the disorder but were unavailable in the NHIRD. However, diagnostic bias was not relevant to the decision making of antiviral therapy and may have equally distributed to the treated and untreated groups and thus may not have confounded the estimate of treatment association.
Fourth, PD is a slow, progressive neurodegenerative disorder. A maximum 11-year follow-up period limited by the availability of antiviral therapy was not a long enough period in which to observe the full course of infection, inflammation, or treatment. A cohort study with a longer follow-up period may give a better answer in the future. In addition, prospective studies would be required for assessing the association between PD, viral genotype, RNA level, and severity of hepatic disease in patients with HCV infection and, if possible, the association between interferon, antiviral regimen, and PD development in participants without HCV infection.
Conclusions
This study found that PD incidence appeared to be lower in patients who were receiving interferon-based antiviral therapy for chronic HCV infection. The results seem to support the theory that HCV infection is a risk factor for developing PD. Antiviral therapy has shown potential in lowering this risk.
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Editorial
June 5, 2019
Is Interferon Therapy for Hepatitis C Infection a Treatable Risk Factor for Parkinson Disease?
JAMA Neurol. Published online June 5, 2019
Adolfo Ramirez-Zamora, MD; ChristopherW. Hess, MD; David R. Nelson, MD
Author Affiliations: Department of Neurology, Fixel Center for Neurological Diseases, University of Florida, Gainesville (Ramirez-Zamora, Hess); Clinical and Translational Science Institute, Department of Medicine, University of Florida, Gainesville (Nelson). Corresponding Author: Adolfo Ramirez Zamora, MD, Department of Neurology, Fixel Center for Neurological Diseases, University of Florida, 3450 Hull Rd, 4th Floor, Gainesville, FL 32607 (adolfo.ramirez-zamora-at-neurology.ufl.edu).
The authors found that although no early differences were noted, a statistically significant difference was found between the 2 groups in the fifth year. There was a slower rate of developing PD in patients treated with antiviral therapy. Lin and colleagues8 concluded that HCV infection was a risk factor for PD and that interferon-based antiviral therapy could lower that risk. They noted that the incidence of PD was reduced but was not eliminated by antiviral therapy, acknowledging that other factors also were present in the mechanisms of a complex disease such as PD. In addition, the authors did not observe transient parkinsonism in patients treated with interferon-based antiviral therapy as previously reported in small observational studies.9
Interferon has extensive immunomodulatory effects13 and has modest viral eradication rates of HCV infection14; thus, future analyses should evaluate the association between PD and those who cleared the virus as well as those who did not. This analysis will help provide insight into potential mechanisms of treatment response (immunomodulation of interferon vs direct clearance of virus). In addition, the newer direct-acting antiviral therapies (targeting specific nonstructural proteins of HCV and thus disrupting viral replication and infection) for HCV infection,15 with cure rates in excess of 90%, were not assessed in the present study along with other well-established lifestyle and demographic risk factors for developing the disease
The results of this study are relevant to both the fields of neurology and hepatology, as they reveal a potentially treatable hepatological risk factor for the development of PD. The findings also add to the evolving knowledge about the association between immunological and infectious factors in PD and related disorders. Furthermore, they suggest mechanisms that may be responsible for this association, including neuroinflammation and clearance of HCV infection. Although pathogenic mechanisms between HCV infection and PD remain unconfirmed, it is possible that HCV infection enters the brain through the microvasculature and then induces microglial and macrophages inflammatory changes, with damage associated with the release of neurotoxins such as nitric oxide and proinflammatory cytokines, including tumor necrosis factor, IL-1, and IL-6.10 Other potential mechanisms include immune cross-reactivity between HCV peptides and brain tissue antigens that leads to neurodegeneration.11
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Editorial
June 5, 2019
Is Interferon Therapy for Hepatitis C Infection a Treatable Risk Factor for Parkinson Disease?
Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms such as bradykinesia, tremor, and gait and postural abnormalities as well as neuropsychiatric and other nonmotor symptoms. It is more common in older adults and increases in prevalence with age, although it can also affect younger individuals. Worldwide, approximately 7.5 million people are estimated to be living with PD, and by 2040 this number is expected to double over the next 2 decades.
The pathophysiological mechanisms behind PD are unclear; however, a variety of immunological, inflammatory, toxic, and potentially infectious etiologies have been considered in the pathogenesis of the disease. Multiple individual characteristics have been identified that can increase the risk of developing PD, but only a few of the risk factors identified to date might actually be treatable.
One potential association that has generated recent interest is that between hepatitis C virus (HCV) infection and the risk of developing PD.1 The infection is a major cause of hepatic disease worldwide and is highly associated with the later occurrence of hepatocellular carcinoma, liver failure, and cirrhosis. It also increases the risk of developing other systemic medical complications.2 Experiments have shown that HCV infection can induce dopaminergic neuron death.3 Abnormal markers of neuroinflammation, brain viral replicative RNA, and impairment of striatal dopaminergic neurotransmission have all been reported in patients with HCV infection.4-6 Several epidemiologic studies have also suggested a possible association between HCV infection and PD.1,7 One of the main questions raised by observational studies has been the possible role of antiviral therapy in delaying or preventing the later development of PD.
In this issue of JAMA Neurology, Lin and colleagues8 report on a retrospective cohort study they conducted using the Taiwan National Health Insurance Research Database to assess the risk of developing PD in patients with HCV infection treated with antiviral therapy. The authors identified 242 568 patients with HCV infection using International Classification of Diseases, Ninth Revision, Clinical Modification codes from January 2003 to December 2013. Patients with an established history of severe liver disease, stroke, dementia, or PD were excluded. A total of 188 152 individuals were included in the final analysis and divided into 2 groups: those who received interferon alfa-2b and ribavirin, and those who did not receive antiviral treatment. After correcting for multiple variables, the main outcome of the study was the development of PD.
Lin and colleagues8 performed propensity score matching with covariate adjustment to match the characteristics of patients between groups. Each treated patient was paired with a corresponding untreated patient to minimize treatment selection bias. Faced with the wide ranges and variability of age, demographics, and comorbidities, the authors decided to use propensity score matching to balance the covariates between the exposed and unexposed groups. The authors found that although no early differences were noted, a statistically significant difference was found between the 2 groups in the fifth year. There was a slower rate of developing PD in patients treated with antiviral therapy. Lin and colleagues8 concluded that HCV infection was a risk factor for PD and that interferon-based antiviral therapy could lower that risk. They noted that the incidence of PD was reduced but was not eliminated by antiviral therapy, acknowledging that other factors also were present in the mechanisms of a complex disease such as PD. In addition, the authors did not observe transient parkinsonism in patients treated with interferon-based antiviral therapy as previously reported in small observational studies.9
The results of this study are relevant to both the fields of neurology and hepatology, as they reveal a potentially treatable hepatological risk factor for the development of PD. The findings also add to the evolving knowledge about the association between immunological and infectious factors in PD and related disorders. Furthermore, they suggest mechanisms that may be responsible for this association, including neuroinflammation and clearance of HCV infection. Although pathogenic mechanisms between HCV infection and PD remain unconfirmed, it is possible that HCV infection enters the brain through the microvasculature and then induces microglial and macrophages inflammatory changes, with damage associated with the release of neurotoxins such as nitric oxide and proinflammatory cytokines, including tumor necrosis factor, IL-1, and IL-6.10 Other potential mechanisms include immune cross-reactivity between HCV peptides and brain tissue antigens that leads to neurodegeneration.11
Although Lin and colleagues8 estimated a high diagnostic accuracy for PD, the diagnosis was based on International Classification of Diseases, Ninth Revision, Clinical Modification codes and medication records but lacked clinical, neuroimaging, or pathological confirmation, which is a limitation of the study. The diagnosis of PD in early stages can be challenging as other related conditions can mimic PD, including cirrhosis-related parkinsonism. Moreover, using record-linkage systems excludes patients who did not seek medical advice or those who were misdiagnosed by symptoms alone, which may also underestimate the prevalence of PD. Using population-based studies would be a more accurate method.12 It was also unclear if patients with PD and HCV infection represented a different subgroup of the PD population or if incident PD was also present. The authors speculated that the advantage of antiviral therapy might require early intervention during prodromal disease prior to HCV entering the brain. However, prodromal symptoms of PD could possibly occur for decades prior to the diagnosis, and additional research will be needed to confirm these theories and risks.
Serum virologic response, viral genotype, and HCV RNA levels were unavailable in the current study. Lin and colleagues8 assumed that patients fulfilled standard criteria for therapy, although the low percentage of patients who received antiviral therapy suggests that some selection bias was likely. It was, therefore, unclear if the specific contributions of these factors added to the risk of PD. The results did not include confirmatory evidence of viral clearance or viral profiles, which precludes analysis of causal relationship of HCV infection to treatment response.
Interferon has extensive immunomodulatory effects13 and has modest viral eradication rates of HCV infection14; thus, future analyses should evaluate the association between PD and those who cleared the virus as well as those who did not. This analysis will help provide insight into potential mechanisms of treatment response (immunomodulation of interferon vs direct clearance of virus). In addition, the newer direct-acting antiviral therapies (targeting specific nonstructural proteins of HCV and thus disrupting viral replication and infection) for HCV infection,15 with cure rates in excess of 90%, were not assessed in the present study along with other well-established lifestyle and demographic risk factors for developing the disease. Despite noting the consequences of the intervention and balancing the study cohorts, the authors could not generalize the results to those aged 75 years or older because of the substantially smaller number of patients in this age group. It is possible that treatment has different implications for different age groups.
While the search for a disease-modifying or neurorestorative therapies for PD continues, identification of potentially treatable PD risk factors presents a unique opportunity for treatment. Additional studies with detailed viral analysis and exposure are needed, including in other geographic and ethnic distributions.
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