Wednesday, August 2, 2017

Persistent Neuropsychiatric Impairment in HCV Patients Despite Clearance of the Virus?!

In Case You Missed It - Persistent Neuropsychiatric Impairment in HCV Patients Despite Clearance of the Virus?!

If you have not read the full text article published 9 February 2017 in Journal of Viral Hepatitis, the study is now available over at Medscape , commentary on this article published at Infectious Disease Advisor, discussion only provided below.

Many patients with HCV infection report disabling chronic fatigue--even after viral clearance. Might HCV be implicated in a virus infection-associated chronic fatigue syndrome?

Persistent Neuropsychiatric Impairment in HCV Patients Despite Clearance of the Virus?!
M. Dirks; H. Pflugrad; K. Haag; H. L. Tillmann; H. Wedemeyer; D. Arvanitis; H. Hecker; A. Tountopoulou; A. Goldbecker; H. Worthmann; K. Weissenborn
J Viral Hepat. 2017;24(7):541-550. 

Discussion Only
Full text article published @ Medscape 
To our knowledge the present study is the largest study concerning neuropsychiatric symptoms in PCR-positive and PCR-negative HCV-afflicted patients with only mild liver disease that combined the assessment of health-related quality of life with the assessment of chronic fatigue, mood disturbances and cognition.

The results of our study can be summarized as follows: (i) PCR+ and PCR− HCV-afflicted patients with only mild liver disease but neuropsychiatric symptoms do not differ with regard to the features and extent of these symptoms, (ii) chronic fatigue is the most frequent neuropsychiatric symptom and has the most significant impact on the patients' health-related quality of life, (iii) significant cognitive dysfunction is present in about one-third of the patients with neuropsychiatric symptoms and (iv) is not feigned by the presence of depression.

So far, the largest population sample related to cognitive function in HCV-afflicted patients was published by Fontana et al.[31] They analysed cognitive function in PCR−positive patients with advanced liver fibrosis (Ishak fibrosis score 3–6), who took part in the HALT-C trial—a prospective, randomized, controlled study of long-term pegylated interferon for chronic hepatitis C patients with advanced fibrosis who were nonresponders to prior interferon therapy. Two hundred and one patients were included of whom 38% had developed liver cirrhosis. Fifty-two per cent of their patients met DSM-IV criteria for a lifetime diagnosis of an alcohol use disorder, and 39% of subjects met DSM-IV criteria for a lifetime diagnosis of a drug use disorder. In analogy to our findings Fontana and co-workers reported that about 33% of their patients showed evidence of mild cognitive dysfunction. Domains predominantly affected were verbal recall and working memory. Of note and in line with our data, they did not find evidence for a significant effect of neither liver function nor grade of liver fibrosis or of former alcohol or drug abuse upon their neuropsychological results. Interestingly, the domains affected were congruent with those described in other studies upon cognitive dysfunction in HCV-afflicted patients but incongruent with the characteristic neuropsychological pattern of hepatic encephalopathy associated with liver cirrhosis.[32] Thus, there was clear evidence that cognitive dysfunction in the patients in Fontana's study was not due to hepatic encephalopathy, but instead probably due to HCV infection.

Our study included patients with mild liver disease, exclusively, thereby even further eliminating the confounding of advanced liver disease on brain function. Nevertheless, we found deficits in the recognition of words or figures in 45% and attention deficits in 30% of the patients. About 77% showed chronic fatigue, and 50%-60% mild to moderate anxiety and depression. Health-related quality of life correlated negatively with fatigue, as did the patients' attention ability. Of note, the patients' cognitive function was independent from their mood status. The significant correlation between attention test sum score and the fatigue and depression scores would indicate otherwise on the first view, multiple regression analysis, however, identified the extent of fatigue as the main and single independent predictor of attention deficit. The positive correlation between the attention test sum score and the LLW sum score relates to the fact that LLW tests working memory and learning ability and thus attentional function. Memory function in our patients did not show a correlation with either fatigue or depression scores and was even independent from the attention test performance, thus also indicating that cognitive dysfunction in the patients is independent from mood alterations.

Of note, we did not find a fundamental difference in the neuropsychiatric symptom profile considering the PCR status or treatment history.

Chronic fatigue has been identified as the most frequent complication of HCV infection years ago.[2] For a long time, however, the patients' complaints about disabling fatigue have not directly been linked to the virus. Symptoms were classified as reaction to the knowledge of being infected or as a consequence of advanced liver disease. Patients showing sustained response to antiviral therapy were and are still in general considered to be cured. Our data, however, show that the neuropsychiatric symptoms, if present, feature identical in PCR-positive and PCR-negative HCV-afflicted patients. Former studies showed similar alterations of brain metabolite levels, cerebral glucose utilization and dopaminergic neurotransmission in PCR-positive and PCR-negative patients, as well as a relationship between these parameters and the patients' cerebral function.[33–35] This indicates that clearance of the virus in the periphery is not equivalent to cure from neuropsychiatric sequelae of HCV infection. It has still to be clarified, for example, if quasispecies of the virus are able to persist within the brain after successful clearance in the periphery, or if the virus induces a neuroinflammatory response that carries on independent of the presence or absence of the virus. Recently, HCV RNA was detected in peripheral blood mononuclear cells (PBMCs) in patients with sustained viral response (SVR) 52–66 months after pegylated IFN and ribavirin therapy.[36] In addition, it has been shown that cure of HCV infection does not lead to complete restoration of the altered cytokine and chemokine milieu. According to a recent paper by Hengst and colleagues, several soluble inflammatory mediators that are suppressed in HCV patients before successful antiviral therapy remain suppressed thereafter.[37]

Patients in both PCR-negative groups were more impaired than those in the PCR-positive groups in this study. This, however, can reflect a selection bias, because PCR-negative patients without any further symptoms are less likely to present in a hepatitis outpatient clinic or to seek support in a patient support group and to take part in a study upon neuropsychiatric symptoms than PCR-negative patients with symptoms. The same aspect holds true of course also for PCR-positive patients and might lead to an overestimation of the frequency of neuropsychiatric symptoms in HCV patients.

Recent therapeutic studies were able to show that virus eradication results in clinically meaningful improvements in several HRQoL domains.[11–14] These studies also showed that improvement was likely to be achieved in physical but not in mental health scores. Based on these findings Bonkovsky et al.[14] suggested that HCV infection per se has an effect on emotional states. Accompanying cognitive deficits in HCV-infected patients, however, was suggested to result from underlying conditions such as anxiety and depression or use of psychotropic medications rather than from HCV infection itself.[14] This explanation is disproved by our findings as we did not observe a significant correlation between cognitive function and anxiety or depression and had excluded patients on psychotropic drugs. Comparing the results of patients who had been interferon/ribavirin exposed to those who had never been treated, we were able to show that the neuropsychiatric symptoms in formerly treated HCV-afflicted patients cannot be ascribed to interferon/ribavirin therapy.

Today we have growing evidence for HCV invasion into and replication within the brain.[38–42] Interestingly, evidence for virus replication was found in about 50% of the samples studied. That is nearly identical with the percentage of HCV patients with neuropsychiatric symptoms in population studies.[2,18,43] In a recent autopsy study, microglia and astrocytes were identified as host cells for the virus.[42] The alterations of magnetic resonance spectra of the brain of HCV patients suggested a neuroinflammatory response to the virus.[8–10,35] This assumption was supported by the finding of an activation of brain microglia cells in autopsy brain tissue from HCV-positive patients.[44] Therefore, evidence for microglia activation in patients with HCV−associated encephalopathy was searched using 11C- PK11195 positron emission tomography. 11C-PK11195 binds to the translocator protein (TSPO) which is located amongst others on the outer mitochondrial membrane of microglia, and which is expressed especially in activated microglia.[45,46] Indeed, microglia activation was observed compared to controls both in PCR-positive and in PCR-negative patients.[47,48] Differences in 11C-PK11195 binding, however, were found between patients with and without cognitive dysfunction. Preserved cognitive function was associated with significantly increased microglia activation indicating a neuroprotective role of microglia activation in the HCV−exposed patients.[48]

In our study, PCR+ and PCR− patients scored similarly in all assessed domains, while both patient groups scored significantly worse than the healthy controls. The data clearly show that neither the HRQOL, nor the extent of fatigue, nor cognitive or mental function in HCV-exposed patients depend on their PCR status. This finding is in line with earlier studies including large and representative cohorts of women infected through anti-D prophylaxis. In both cohorts, from Ireland[49] and from Germany,[43] fatigue was a frequently observed phenomenon, but unrelated to liver disease and virological status.

The observation that the neuropsychiatric syndrome in HCV-exposed patients is independent of the virus replication state as measured in the patients' blood is in favour of the hypothesis that the symptoms are unrelated to HCV infection. However, the development of an HCV infection triggered autoimmune process, which continues after clearance of the virus, or—alternatively—the possibility of a virus variant persisting in the brain should seriously be discussed. Considering the data upon virus infection-associated chronic fatigue syndrome HCV just appears to be more capable to induce this disorder than other viruses, while the clinical features are similar irrespective of the underlying cause.[50] It will be of outmost interest to observe whether sustained response to the new direct acting antivirals will be more effective with regard to neuropsychiatric manifestations of HCV than the interferon/ribavirin combination therapy.

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