Hepatitis C; Reversible autonomic dysfunction during antiviral treatment

Reversible autonomic dysfunction during antiviral treatment in patients with chronic hepatitis C virus infection

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Abstract:

Background:
The first clinical sign of chronic hepatitis C virus (HCV) infection can be one of the various extrahepatic manifestations. During antiviral treatment, symptoms of HCV-associated neuropathies usually improve, but can also worsen and lead to discontinuation of anti-HCV therapy. Recently, we have reported autonomic dysfunction in patients with HCV infection.

Objectives: In the present prospective study, we analyzed the changes of autonomic function during anti-HCV treatment.

Patients and Methods:
Cardiovagal autonomic function was assessed in 22 HCV RNA-positive, treatment-naive patients by determining heart rate variability (HRV) and baroreflex sensitivity (BRS), at the beginning of treatment and 12, 24 and 48 weeks of antiviral therapy. interferon alfa-2 and ribavirin were given according to the guidelines.

Results:
Both HRV and BRS time and frequency domain indices decreased after 12 weeks of therapy compared to the pre-treatment values; then the mean±SD values increased significantly by week 24 and continued to improve by week 48 of therapy-253.0±156.1 ms before therapy vs 111.6±81.9 at week 12, and 183.4±169.6 at week 24 vs 211.6±149.1 ms at week 48 for low-frequency HRV index; p<0.05 for all comparisons). These changes were independent from the presence of cryoglobulins and from virologic response.

Conclusions:
The first rise followed by reversible autonomic dysfunction during antiviral therapy may be caused by the immunomodulatory actions of interferon alfa-2.Keywords: Autonomic dysfunction; Antiviral treatment; Hepatitis C virus

DiscussionOnly :
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Following our previous study of autonomic dysfunction in patients with chronic hepatitis C (13), we investigated the changes of autonomic function in patients with chronic HCV infection during antiviral therapy. Interestingly, a significant decrease in autonomic function occurred by week 12 of the treatment to be followed by a significant improvement by week 24 and a return to pre-treatment values by week 48 of antiviral therapy.
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Neurological symptoms in patients with chronic hepatitis C usually improve during antiviral therapy. However, exacerbations or even the first onset of neurological manifestations have also been observed during antiviral treatment. Ribavirin has no known neurological side effects; neither ribavirin monotherapy trials (20, 21) nor randomized trials comparing the combination of IFN-α and ribavirin with IFN-ß monotherapy showed significant neurological complications (22, 23). A direct neurotoxic effect of IFN-α in our study is unlikely because autonomic dysfunction improved after three months despite the continuation of therapy. However, IFN-α may induce vasculitis with or without cryoglobulinemia, and can increase preexisting ischemia, leading to purpura, skin ulcerations, arthritis or ischemic polyneuropathy (24, 25). None of these manifestations was observed in our patients with chronic HCV infection during antiviral therapy. Presence of cryoglobulins was not associated with the changes of autonomic function. Further manifestations related to neuropathies in HCV infection may be the HCV and IFN-α treatment-related insulin resistance (26, 27).
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Diabetic peripheral and autonomic neuropathies are well known complications of persistent hyperglycemia (28). Similarly, impaired cardiovagal autonomic indices are early, subclinical signs of glucose neurotoxicity in patients with diabetes (29). In our study, patients with diabetes were excluded and fasting glucose levels did not change during antiviral therapy. Therefore, an impaired carbohydrate metabolism does not underlie the changes of autonomic dysfunction in our patients. However, the determination of the fasting glucose level only is a limitation of our study, as this method is insufficient to assess insulin resistance and glucose metabolism and possible effects of HCV-related insulin resistance on the development of cardiovagal autonomic dysfunction. Therefore, in further studies more sophisticated techniques (glucose clamp technique, homeostasis model assessment score) should be used.
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The immunomodulatory effect of IFN-α suggests that the immune status correlates with autonomic dysfunction.
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Cohort studies in HIV-positive and AIDS patients indicate that autonomic dysfunction parallels the HIV disease progression-i.e., heart rate variability indices correlate with the CD4 cell count (30, 31). The degree of autonomic dysfunction remains mild and subclinical in patients with HIV infection/AIDS in all stages of the disease, just as it was observed in our patients with chronic HCV infection. In addition, abnormal heart rate and baroreflex responses have been documented in patients with multiple sclerosis (MS) (32). In a 24-month follow-up of 26 patients with clinically active remitting-relapsing MS, autonomic dysfunction assessed by heart rate responses correlated with the clinical activity of MS and disease progression (33). These results are consistent with data from molecular and immunological analyses that addressed links between dysfunction of the immune regulation and the autonomic nervous system. These studies suggest that the balance between sympathic/parasympathic system plays a major role as an integrative interface between the brain and the immune system (34, 35). Consistent with this hypothesis, IFN-α in human brain physiologically affects not only the immune but also the central nervous system (36, 37).
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These findings suggest that the autonomic dysfunction in our patients with chronic HCV infection may be associated with changes of the immune status and IFN-α modulated immune responses. Further studies should address these interactions.
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In summary, the increase of cardiovagal autonomic dysfunction during the first 12 weeks of antiviral therapy is no reason to modify the treatment strategy in patients with chronic HCV infection because autonomic dysfunction remains mild and subclinical, and improves during continued antiviral therapy.

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