Managing Neurologic Complications of Chronic HCV Infection

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Managing Neurologic Complications of Chronic HCV Infection
Anushka Burde, PharmD; Rebecca Hoover, PharmD, MBA, BCPS
US Pharmacist. 2018;43(1):18-22.

Abstract and Introduction

Abstract

Chronic hepatitis C virus (HCV) infection can cause a multitude of extrahepatic complications, including neurologic manifestations. These complications can lead to substantial neuropsychiatric deficits, such as fatigue, cognitive impairment, restless legs syndrome, Parkinson's disease, and peripheral neuropathy. In addition to detecting and managing these neurologic complications, pharmacists in community settings can promote HCV screening, improve medication access and adherence, and recommend preventive strategies patients can use to avoid transmission of this widespread infection.

Hepatitis C virus (HCV) infection is widespread, and about one-half of the 3.5 million HCV-infected people in the United States are likely unaware of being infected.1 Community pharmacists, as the most accessible type of healthcare practitioner, are optimally positioned to detect and manage HCV. They can help HCV-infected patients by engaging in appropriate screening, ensuring proper management of the infection, and recognizing extrahepatic symptoms, including neurologic complications.

Screening
Pharmacists in community settings should identify those patients most in need of screening. For example, the pharmacist can run a listing of baby-boomer patients (i.e., born between 1945 and 1965) at the pharmacy and can recommend one-time HCV testing irrespective of prior risk factors discussed in the American Association for the Study of Liver Diseases guidelines.1 Factors for the pharmacist to keep in mind are that about 60% of acute HCV infections in the U.S. are a result of injection-drug use and that there is a substantial risk of HCV transmission in HIV-infected men who have unprotected sex with men. The pharmacist can also identify patients for screening by checking medication histories.

The pharmacist should counsel patients to get tested for HCV infection based on the recognition of risk factors, including poor adherence to HIV medications, which can be determined by checking refill history. Patients are more likely to disclose a history of drug use to their pharmacist after developing a sense of trust and confidence. Pharmacists should put patients at ease by assuring them that their information will not be used against them, but rather will be used appropriately to refer them for HCV testing. For example, women with active HCV infection or a history of it should be advised to get their children tested as well. Pharmacists can recommend HCV testing for patients with a history of incarceration by noting that data suggest the presence of anti-HCV antibodies in about 29% of incarcerated persons in North America.1 Other risk factors, such as history of organ transplant, receipt of transfusion, and piercings and tattoos obtained at unregulated settings, should be taken into consideration regarding HCV screening.

Community pharmacies can also engage in screening practices by testing for the presence of HCV antibodies. Multiple diagnostic tests for HCV are available that combine laboratory-based and point-of-care assays. One of these, the OraQuick HCV Rapid Antibody Test, is an FDA-approved Clinical Laboratory Improvement Amendments–waived test.1 This waiver enables patients to be tested at various locations, including community pharmacies. The test is straightforward and efficient, providing results in about 20 minutes. It can test for multiple HCV genotypes, and its accuracy exceeds 98%.2

Patient Education
Pharmacists can educate patients with HCV infection on how to prevent spread of the virus, such as to avoid sharing toothbrushes or shaving equipment. Patients should also be counseled to use barrier precautions to prevent sexual transmission and to stop using illicit drugs. The use of clean needles and syringes should be encouraged, as HCV reinfection is highly likely if the risk of drug use is ongoing.3 Persons infected with HCV should be encouraged to abstain from alcohol and smoking. Patients should be counseled to enter substance-abuse treatment facilities in order to prevent progression of liver disease. The pharmacist should also mention that definitive evidence supporting the use of complementary and alternative supplements is lacking. Other clinical pearls offered by the pharmacist could include possible benefits of coffee consumption, a diet low in fat and sodium, weight loss, and vitamin D testing. The pharmacist should also recommend limiting acetaminophen use to 2 g per day in noncirrhotic HCV-infected patients and 1 g per day in those who are cirrhotic.1 The pharmacist could also recommend a daily multivitamin without iron.

Pharmacists can also ensure that patients who are susceptible to HCV infection receive appropriate, routine CDC-recommended vaccines, including those for hepatitis A and B. Pneumococcal vaccine should be administered to patients with cirrhosis.1

Treatment
Significant side effects and profound laboratory abnormalities plagued older HCV treatments, making them unfavorable options for patients.4 Interferon-based regimens, historically the standard of care, were associated with substantial side effects, such as flulike symptoms, fatigue, neuropsychiatric symptoms, and hematologic effects. Newer interferon-free, direct-acting antiviral (DAA) oral regimens introduced since 2013 have successfully achieved sustained virologic response (SVR), a marker of virologic cure. A few commonly used DAAs include ledipasvir-sofosbuvir (Harvoni), sofosbuvir-velpatasvir (Epclusa), sofosbuvir (Sovaldi), daclatasvir (Daklinza), elbasvir-grazoprevir (Zepatier), and ombitasvir-paritaprevir-ritonavir plus dasabuvir (Viekira Pak). Glecaprevir-pibrentasvir (Mavyret) and sofosbuvir-velpatasvir-voxilaprevir (Vosevi) were approved in 2017. Epclusa, Mavyret, and Vosevi are pangenotypic and may be used to treat all HCV genotypes (i.e., types 1-6). Treatment with and duration of DAAs depend on HCV genotype, presence of cirrhosis, HCV RNA level, and history of prior treatment.

Reductions in all-cause mortality, liver-related adverse outcomes such as end-stage liver disease, and hepatocellular carcinoma are the goals of treatment in HCV-infected persons. Despite the availability of successful treatments, multiple barriers must be overcome. One such barrier is lack of access to treatment, reasons for which include high medication costs, lack of insurance, geographic distance, and lack of specialist availability. A treatment-naïve genotype 1a patient will require treatment that can cost up to $54,600 to $150,000, on average.3,4 Longer duration of treatment further increases these costs. Community pharmacists can help patients by identifying patient-assistance programs and providing appropriate navigation through insurance plans to alleviate some of the cost burden.

Medication Adherence
Educating patients with HCV on the importance of medication adherence is a critical component of HCV treatment and determines virologic cure. Adherent and immunologically competent treatment-naïve patients with compensated liver disease are 95% more likely to achieve SVR with direct-acting antivirals.1,4 Several methods for checking compliance may be implemented at a community pharmacy, including pharmacy-refill assessment, pill counts, and follow-up phone calls to patients. The pharmacist should advise patients that modification of certain risk factors—such as reducing alcohol intake, weight loss (in obese patients), and cessation of cigarette smoking and marijuana use—can reduce, and may also reverse, progression of liver disease. Pharmacists are also in a key position to identify drug-drug interactions, including prescription medications for comorbidities and OTC products.

Neurologic Extrahepatic Complications
Many community pharmacists go the extra mile for their patients by screening for HCV infection and overseeing therapy upon diagnosis. However, pharmacists should understand that HCV can impact health beyond liver dysfunction. A variety of extrahepatic issues are associated with chronic hepatitis C, including diabetes and dermatologic manifestations such as porphyria cutanea tarda and lichen planus.1 Fatigue, arthralgias, renal disease, and neurologic diseases such as peripheral neuropathy are manifestations of cryoglobulinemia, a lymphoproliferative disorder that causes local deposition of immune complexes.1

An increased prevalence of neuropsychiatric symptoms in HCV-infected patients, independent of any preexisting mental disorders or high-risk behaviors, is being reported in emerging literature. HCV likely has a direct biological effect on the central nervous system. Possible mechanisms include neuroinflammation, as noted on brain imaging, and peripheral inflammation across the blood-brain barrier that is induced by elevation of proinflammatory cytokines.5

Fatigue and Cognitive Impairment: Chronic HCV infection is associated with fatigue and cognitive impairment, which contribute to reduced quality of life. More than 50% of HCV-infected patients report that fatigue is the most common symptom. The occurrence of fatigue may be difficult to predict. HCV RNA, HCV genotype, and liver histology are not associated with fatigue.6 Numerous quality-of-life measures have shown that fatigue impairs the quality of life and activity level of HCV-infected patients. Cure of HCV infection results in a reduction in fatigue, as noted in some studies.1 The community pharmacist should recognize chronic HCV as a potential cause when a patient complains of chronic fatigue, low energy levels, and pain. Abnormal circulating levels of thyroid-stimulating hormone or thyroxine have been noted in HCV-infected patients, which might result in a high prevalence of fatigue.6 Pharmacists could suggest thyroid-function testing in these patients.

Deficits in measures of attention, higher executive functions like planning, decision making, judgment, or reasoning skills, verbal learning ability, recall, and working memory have been reported in literature examining HCV-associated cognitive impairment.7 Pharmacists should refer patients to their medical provider for complaints of brain fog or neuropsychiatric symptoms such as difficulty paying attention, concentrating, failing memory, and so on. Patients should be counseled that studies have shown that successful clearance of the virus is associated with improved attention, vigilance, and working memory.

Restless Legs Syndrome (RLS): Beyond cognitive manifestations, patients with HCV may also have motor-neuron problems. HCV infection may place patients at greater risk for RLS. This condition, which is characterized by an impulse to move the legs, typically manifests in the evening and at night. Cirrhosis and use of older agents, such as interferon-alpha, for drug therapy are associated with RLS and are of particular concern.8,9 Patients complaining of sleep difficulties or those using prescription or OTC sleep aids with or without RLS treatment may benefit from further education and evaluation regarding the possible relationship between RLS and HCV infection.

Parkinson’s Disease: Most evidence supports an association between Parkinson’s disease and HCV infection, but the cause is unclear.10-12 Parkinson’s disease could be a direct consequence of HCV infection or perhaps even its treatment. The relationship could also be due to similarities in the mechanisms of the diseases. The extent of the association is unclear as well. A recent analysis of data from Medicare patients failed to find an association between HCV infection and occurrence of Parkinson’s disease.12 However, in the same way that early detection is essential for HCV treatment, early detection of Parkinson’s disease is important for maintaining quality of life. Pharmacists should be alert to complaints of movement disorders in HCV-infected patients. Asking patients about movement problems or tremors is an important first step. Parkinson’s disease may have a gradual onset, and patients may not readily recognize early signs. Community pharmacists can counsel HCV patients to self-monitor parkinsonian symptoms by looking for shaking, slowed movement, or changes in speech. Patients reporting these problems are good candidates for further assessment by a specialist or primary care provider.

Peripheral Neuropathy: Peripheral neuropathy is a common complaint presented at community pharmacies. Although most pharmacists associate neuropathy with diabetes, thyroid disorder, or renal failure, it is important to also consider HCV. Neuropathy is caused by a breakdown of sensory and motor neurons, which prevents proper signals between the central and peripheral nervous systems. Mechanisms for neuropathy in HCV are likely due to indirect factors such as inflammation and cryoglobulinemia, in which immunoglobulins precipitate and clump together.13 About 10% of HCV patients report peripheral neuropathy, which is most likely to occur in those with cryoglobulinemia.14

Patients may complain of motor problems such as weakness or sensory impairment such as numbness, burning or prickling sensation, or intense pain.4 Neuropathy presents in various forms, and it may be hard to determine the cause. Because neuropathy in HCV patients may go unrecognized, it is important to ask patients about their pain status and refer them to their primary care provider as needed. It may be useful for patients to keep a pain journal to detect triggers or determine which therapy works best. Neuropathy can be difficult to alleviate, and it may be necessary to help the prescriber select the medication and titrate as appropriate.

Interrelatedness of Extrahepatic Complications: Beyond traditional neurologic implications, it is necessary for pharmacists to appreciate that extrahepatic manifestations of HCV infection are interrelated. For example, a stroke may be caused by cardiovascular risks related to HCV infection but may result in neurologic impairment. Literature shows that HCV promotes carotid plaque formation, a well-known predictor of cardiovascular disease. Other possible contributory mechanisms are cryoglobulinemia-associated vasculitis and autoimmune antibody development. Patients who have had a cryptogenic stroke should be screened for HCV and cryoglobulins.1 Being vigilant in monitoring a patient’s response and adherence to treatment can help prevent extrahepatic issues. HCV management should be gradually geared toward primary care through collaboration with specialists, and complicated cases should always be referred to HCV specialists.

Conclusion

Community pharmacists serve a vital function in the care of patients infected with HCV. The pharmacist can play an important role in HCV management by identifying patients who should be tested for HCV, providing extensive medication and disease-state counseling, recommending and administering appropriate vaccines, determining and managing extrahepatic complications, and collaborating with providers on care.

REFERENCES

1. AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology. 2015;62:932-954.
2. OraSure Technologies, Inc. OraQuick HCV Rapid Antibody Test product information. www.orasure.com/products-infectious/products-infectious-oraquick-hcv.asp. Accessed November 3, 2017.
3. CDC. Viral hepatitis surveillance—United States, 2014. www.cdc.gov/hepatitis/statistics/2014surveillance/pdfs/2014hepsurveillancerpt.pdf. Accessed December 5, 2017.
4. Deming P. Viral hepatitis. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. New York, NY: McGraw-Hill Education; 2017:561-578.
5. Negro F, Forton D, Craxì A, et al. Extrahepatic morbidity and mortality of chronic hepatitis C. Gastroenterology. 2015;149:1345-1360.
6. Poynard T, Cacoub P, Ratziu V, et al. Fatigue in patients with chronic hepatitis C. J Viral Hepat. 2002;9:295-303.
7. Gess M, Forton D. Effect of hepatitis C on the central nervous system of HIV-infected individuals. J Virus Adaptation Treat. 2012;4:93-106.
8. Anderson K, Jones DE, Wilton K, Newton JL. Restless leg syndrome is a treatable cause of sleep disturbance and fatigue in primary biliary cirrhosis. Liver Int. 2013;33:239-243.
9. Tembl JI, Ferrer JM, Sevilla MT, et al. Neurologic complications associated with hepatitis C virus infection. Neurology. 1999;53:861-864.
10. Abushouk AI, El-Husseny MW, Magdy M, et al. Evidence for association between hepatitis C virus and Parkinson’s disease. Neurol Sci. 2017;38:1913-1920.
11. Pakpoor J, Noyce A, Goldacre R, et al. Viral hepatitis and Parkinson disease: a national record-linkage study. Neurology. 2017;88:1630-1633.
12. Golabi P, Otgonsuren M, Sayiner M, et al. The prevalence of Parkinson disease among patients with hepatitis C infection. Ann Hepatol. 2017;16:342-348.
13. Nemni R, Sanvito L, Quattrini A, et al. Peripheral neuropathy in hepatitis C virus infection with and without cryoglobulinaemia. J Neurol Neurosurg Psychiatry. 2003;74:1267-1271.
14. Bonetti B, Scardoni M, Monaco S, et al. Hepatitis C virus infection of peripheral nerves in type II cryoglobulinaemia. Virchows Arch. 1999;434:533.535.

Symptom burden and comorbid medical conditions in patients with HCV initiating direct acting antiviral therapy

A comprehensive assessment of patient reported symptom burden, medical comorbidities, and functional well being in patients initiating direct acting antiviral therapy for chronic hepatitis C: Results from a large US multi-center observational study

A comprehensive understanding of baseline symptom burden in patients with HCV is necessary to lay the groundwork for subsequent real-world investigations of potential changes in symptoms during DAA therapy and after virologic cure. We aimed to characterize patient-reported symptoms, medical conditions, and functional well-being in a large multi-center US cohort who initiated DAA therapy in clinical practices in 2016-2017. Our secondary aim was to evaluate sociodemographic/SDoH, liver-related, and other clinical features associated with these health outcomes.

Published: August 1, 2018 

https://doi.org/10.1371/journal.pone.0196908 

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Abstract
Background
Symptom burden, medical comorbidities, and functional well-being of patients with chronic hepatitis C virus (HCV) initiating direct acting antiviral (DAA) therapy in real-world clinical settings are not known. We characterized these patient-reported outcomes (PROs) among HCV-infected patients and explored associations with sociodemographic, liver disease, and psychiatric/substance abuse variables.

Methods and findings
PROP UP is a large US multicenter observational study that enrolled 1,600 patients with chronic HCV in 2016–2017. Data collected prior to initiating DAA therapy assessed the following PROs: number of medical comorbidities; neuropsychiatric, somatic, gastrointestinal symptoms (PROMIS surveys); overall symptom burden (Memorial Symptom Assessment Scale); and functional well-being (HCV-PRO). Candidate predictors included liver disease markers and patient-reported sociodemographic, psychiatric, and alcohol/drug use features. Predictive models were explored using a random selection of 700 participants; models were then validated with data from the remaining 900 participants. The cohort was 55% male, 39% non-white, 48% had cirrhosis (12% with advanced cirrhosis); 52% were disabled or unemployed; 63% were on public health insurance or uninsured; and over 40% had markers of psychiatric illness. The median number of medical comorbidities was 4 (range: 0–15), with sleep disorders, chronic pain, diabetes, joint pain and muscle aches being present in 20–50%. Fatigue, sleep disturbance, pain and neuropsychiatric symptoms were present in over 60% and gastrointestinal symptoms in 40–50%. In multivariable validation models, the strongest and most frequent predictors of worse PROs were disability, unemployment, and use of psychiatric medications, while liver markers generally were not.

Conclusions

This large multi-center cohort study provides a comprehensive and contemporary assessment of the symptom burden and comorbid medical conditions in patients with HCV treated in real world settings. Pain, fatigue, and sleep disturbance were common and often severe. Sociodemographic and psychiatric markers were the most robust predictors of PROs. Future research that includes a rapidly changing population of HCV-infected individuals needs to evaluate how DAA therapy affects PROs and elucidate which symptoms resolve with viral eradication.

Continue to complete article: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196908

Neuroimaging abnormalities, neurocognitive function, and fatigue in patients with hepatitis C

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Neuroimaging abnormalities, neurocognitive function, and fatigue in patients with hepatitis C

April D. Thames, PhD, Steven A. Castellon, PhD, Elyse J. Singer, MD, Rajakumar Nagarajan, PhD, Manoj K. Sarma, PhD, Jason Smith, PharmD, Nicholas S. Thaler, PhD, Jonathan Hien Truong, MD, Daniel Schonfeld, BS, M. Albert Thomas, PhD and Charles H. Hinkin, PhD

Published online January 14, 2015 doi: 10.1212/NXI.0000000000000059Neurol Neuroimmunol Neuroinflamm February 2015 vol. 2 no. 1 e59

Abstract

Objective: This study examined neurologic abnormalities (as measured by proton magnetic resonance spectroscopy imaging and diffusion tensor imaging), neurocognitive performance, and fatigue among a sample of adults with hepatitis C virus (HCV). We hypothesized that HCV+ individuals would demonstrate structural brain abnormalities and neurocognitive compromise consistent with frontostriatal dysfunction as well as increased fatigue compared to controls.

Method: Participants were 76 individuals diagnosed with HCV and 20 controls who underwent a comprehensive neurocognitive evaluation and clinical assessments. A subset of the HCV+ participants (n = 29) and all controls underwent MRI.

Results: Individuals diagnosed with chronic HCV infection demonstrated greater fractional anisotropy in the striatum as well as greater mean diffusivity in the fronto-occiptal fasciculus and external capsule compared to HCV− controls. HCV+ participants also demonstrated lower levels of N-acetylaspartate in bilateral parietal white matter and elevations in myo-inosital (mI) in bilateral frontal white matter compared to HCV− controls (all p values < 0.05). HCV+ participants also demonstrated significantly poorer neuropsychological performance, particularly in processing speed and verbal fluency. HCV+ patients reported higher levels of fatigue than controls, and fatigue was significantly correlated with diffusivity in the superior fronto-occipital fasciculus, elevations in mI in frontal white matter, and overall cognitive performance.

Conclusions: Our results suggest that HCV-associated neurologic complications disrupt frontostriatal structures, which may result in increased fatigue and poorer cognitive performance, particularly in those cognitive domains regulated by frontostriatal regions.

DISCUSSION ONLY

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The current study examined the effects of chronic HCV infection on microstructural brain abnormalities, cerebral metabolites, fatigue, and neurocognitive performance. Major strengths of the current investigation include the use of DTI and MRSI in combination with measures of neurocognitive functioning and fatigue, and the use of a control group for comparison. As hypothesized based on prior literature, we observed microstructural abnormalities in such areas as the striatum, external capsule, and fronto-occipital fasciculus, which is consistent with previous DTI studies of HCV^9,10 and findings among individuals with HIV infection.^28,29

We observed greater FA in gray matter regions of the striatum in HCV+ patients compared to healthy volunteers. Higher FA in the striatum has been found among patients with Huntington disease³² and is thought to be due to degeneration of efferent pathways that increase the coherence of gray matter structures. In a study of patients with chronic subdural hematoma, increased FA was found in the striatum, which reduced following surgical intervention.³³ Therefore, our findings are consistent with other investigations of neuropathology in regions that are affected in HCV.

Increased diffusivity in the fronto-occipital tract and external capsule was also found in the HCV+ group compared to controls. The fronto-occipital tract has been suggested as modulating frontal lobe–related inhibitory control and occipital lobe–related sensory inputs.³⁴ Alterations of this tract may interfere with integrating sensory information and inhibiting control over impulses and emotion, which is problematic among drug abusers. The external capsule contains a variety of different nerve bundles and pathways connecting the cerebral cortex to subcortical nuclei as well as connecting different parts of the cortex to each other. Therefore, disruption to fibers of the external capsule may result in dysfunction of frontal-subcortical circuitry.

HCV+ participants demonstrated lower levels of NAA in bilateral parietal white matter and elevations of mI in bilateral frontal white matter compared to controls, which was associated with poorer performance in the cognitive domains of processing speed and verbal/language fluency. Further, there was a correspondence between our DTI and MRSI measures. Specifically, higher NAA in parietal white matter was significantly correlated with lower diffusivity in the fronto-occipital fasciculus, whereas greater frontal white matter mI was significantly correlated with higher diffusivity in the fronto-occipital fasciculus.

That stated, our MRSI results were generally consistent with previous MRSI studies of HCV+ cohorts,^8,12,35 although we did not observe abnormal cerebral metabolite levels in basal ganglia as was expected.

However, in the current study we were careful to exclude participants with medical (e.g., cirrhosis) and psychiatric conditions that potentially could have confounded interpretation of the neuroimaging findings. Through this process we may have excluded HCV+ individuals with more severe neurologic impairments and neuropathologic changes in subcortical structures that are detectable by H-MRS. Although HCV+ patients demonstrated poorer global neurocognitive performance than controls, examination of performance data suggests normal range of performance (i.e., T > 40). Again, because of the use of stringent inclusion/exclusion criteria, this group may not be fully representative of the general HCV+ population. Despite the potential recruitment of higher-functioning HCV+ individuals, we still found the poorer performance in the cognitive domains of processing speed and verbal fluency (relative to controls) that has been reported across other studies,^4,5,13,15,16 and this performance was independent of such factors as liver fibrosis and history of substance abuse.

HCV+ participants also reported greater fatigue than controls, which was associated with abnormalities in frontal white matter, whereas poorer cognitive performance was associated with abnormalities in both frontal white matter and subcortical structures. These results suggest that HCV-associated neurologic complications that are specific to changes in frontal-subcortical structures give rise to both reduced cognitive performance and fatigue. The specific cognitive deficits observed in verbal/language fluency and information processing speed are all regulated by frontal-striatal structures.³⁶ In our sample, verbal fluency demonstrated the greatest degree of performance difference between HCV+ and control groups and the strongest correlation with elevated levels of mI in frontal white matter.

There are limitations to the current study. First, while structural neuroimaging methods are helpful in identifying microstructural pathology that may not be detected on standard MRI, they do not provide a clear understanding about the functions of these neural circuits. Hence, existing disruptions in a neural circuit may make a patient more vulnerable to developing symptoms such as fatigue. Second, although we attempted to control for a number of demographic variables between HCV patients and controls, we recognize that there are a myriad of psychosocial differences (e.g., stress, past drug use) that may account for the reduced cognitive performance and structural brain differences that were observed in the current study. For instance, we were unable to examine past drug abuse differences between our HCV+ and control groups because information on past drug abuse was not collected from the controls. We recognize that in order to precisely rule out the effects of past drug abuse we would have needed to recruit a sample of past drug abusers who were HCV−. However, considering that 61% of our HCV+ patients reported a lifetime history of cocaine or opiate use, we attempted to address this concern by examining the effects of past drug abuse within this subgroup. While we did not find significant differences in our neuroimaging or neurocognitive data as a function of past drug abuse (all p values > 0.10), we cannot rule out the residual confounding effects of distant substance use on neurologic function.

Despite these limitations, the current study represents a significant extension of the extant literature on HCV's effects on neurologic and neurobehavioral functioning by demonstrating how abnormalities in frontal/parietal and subcortical structures have independent and overlapping relationships with cognitive performance and fatigue.

It has long been known that HCV is hepatotoxic; increasingly there is reason to believe that it is neurotoxic as well. While the precise pathophysiologic mechanism remains unclear, findings from the current study as well as others have demonstrated that HCV infection is associated with neurophysiologic and neurobehavioral abnormality. While advances in the pharmacologic treatment of HCV hold incredible promise, there remain millions of HCV-infected adults in the United States and approximately 100 million worldwide. Continued study of the neurologic effects of HCV is needed. 

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REFERENCES

Poster - "Fatigue, Cognitive Function, and Sleep Quality in Patients with Chronic Hepatitis C

Bailey Presents at 2012 State of the Science Congress on Nursing Research

September 30, 2012
Friday, September 28, 2012
Source

Chip Bailey presented a poster entitled "Fatigue, Cognitive Function, and Sleep Quality in Patients with Chronic Hepatitis C (CHC)" at the Council for the Advancement of Nursing Science 2012 State of the Science Congress on Nursing Research in Washington, D.C., September 13-15. He co-authored the abstract with Shelly Epps, Trina Walker, Justin Levens, Karin Weissenborn, Richard Keefe, and Hans L. Tillmann.

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Fatigue, Cognitive Function, and Sleep Quality in Patients with Chronic Hepatitis C (CHC)

Authors:
Donald E. Bailey, Jr. 1
Shelly Epps 2
Trina Walker 3
Justin Levens 2
Karin Weissenborn 4
Richard Keefe 3
Hans L. Tillmann 3

1 Duke University School of Nursing, Durham, NC;
2 Duke Office of Clinical Research, Durham, NC;
3 Duke University School of Medicine, Durham, NC;
4 Department of Neurology, Medizinische Hochschule, Hannover, Germany

Background
Fatigue is a frequent complaint in CHC patients. CHC patients also often experience problems with cognitive function: difficulties with attention, concentration, memory.

Study Aims
Describe cognitive processing difficulties in adults with CHC. Explore relationship of cognitive function in these patients with fatigue, sleep quality, and disease stage.

Sample (n=29)
Adult patients with CHC:
*18 with fatigue
*11with no fatigue
*Convenience sample
* Recruited at Duke University Medical Center, Gastroenterology Clinic
*Baseline data for sample demographic and clinical characteristics are shown in tables

Measures
Fatigue: Revised Piper Fatigue Scale (PFS).
*22-item scale (each item scaled 0-10); use summary score.
*Summary score scaled 0-10 (higher score indicates more fatigue).
*Administered only to patients reporting fatigue (n=18)

Sleep Quality:
*Sleep Timing & Sleep Quality Screening Questionnaire: 1 item
Disease Stage and Disease Grade :
*Clinical data abstracted from medical record

Measures of Cognitive Function
*Brief Assessment of Cognition (BAC) includes 6 tasks:
List Learning -- Verbal Memory
Digit Sequencing Task -- Working Memory
Token Motor Task – Motor Spped Verbal Fluency
Semantic/Letter Fluency Tower of London
Reasoning & Problem Solving / Executive Function Symbol Coding
Attention and Processing Speed

B. Continuous Phase Trials – Identical Pairs (CPT – IP)
Measures Sustained Attention and Vigilance

Analysis
* Standardized z-scores calculated for BAC cognitive function test (based on comparisons with normative healthy control sample). Separate z-scores for each of the 6 BAC measures; BAC composite z-score

*Means, 95% CI for BAC task & composite scores calculated for:
CHC patients with fatigue (n=18) vs. without fatigue (n=11) Patients at each disease grade (0-3; measures inflammation) Patients at each disease stage (I-IV; measures fibrosis)

*Mann-Whitney rank sum test used to compare z-scores on BAC and CPT-IP score for CHC patients with vs. without fatigue.

*Pearson correlation used to evaluate relationships between BAC z-scores and PFS fatigue scores, sleep quality ratings.

Results

HCV patients in this study showed significant impairment independent of fatigue for 3 of the 6 BAC tasks.

In the graphs below, z-score for healthy controls on each task = 0.0 (shown in graphs below as a red dotted line)

Mean z-scores for all HCV patients were significantly lower than healthy control scores (no overlap of 95% CI with control line) for the 3 tasks identified by red star

These findings suggest HCV-related impairment of cognitive function in the 3 domains of verbal memory, working memory, reasoning/problem solving.

 RESULTS

 

*No significant differences between HCV patients with fatigue vs. without fatigue on BAC composite scores (cognitive function) or CPT–IP (attention/vigilance).

*BAC composite scores of HCV patients lower than those of healthy controls.

*Disease stage (fibrosis) had no effect on BAC composite scores.

*Higher disease grade (liver inflammation) may be weakly associated with poorer cognitive function in patients with HCV.

Pearson correlation analysis of relationships between scores on 6 individual BAC tasks and: Level of Fatigue, Quality of Sleep:
 
Piper Fatigue Scale summary score (level of fatigue): No correlation with scores on any BAC cognitive task.

Sleep Quality Item: Poor sleep quality (high scores) was significantly correlated with impairment on three BAC tasks: Digit Sequencing, Symbol Coding, and Tower of London.

Examples below shows Pearson correlation analyses for symbol coding:

Conclusions
Findings of this study support previous reports of cognitive processing difficulty in patients with CHC. Differences in cognitive processing between CHC patients with vs. without fatigue at baseline were not significant in this sample, but merit further study in a larger sample.

Acknowledgements
This study was supported by a research grant from the National Institute of Nursing Research (NIH/NINR: 1 R15 NR 008794-01A1, Bailey, PI) and by a small grant from the Duke University School of Nursing Office of Research Affairs (Bailey, PI).

Chronic Fatigue Syndrome:ME/CFS

Digital Art / Photomanipulation

Hepatitis C has been associated with a wide spectrum of symptoms, with chronic fatigue being the most commonly reported. The symptom can be so devastating that sleep does not seem to solve the problem; with patients waking up feeling as if they have never gone to sleep. However, medical research connecting HCV with Chronic fatigue syndrome-CFS has yet to be proven. In this entry we revisit the studies over the last few years on CFS, including the 2009 discovery of the retrovirus XMRV.

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Chronic fatigue syndrome (CFS) is a disease characterized by fatigue and chronic inflammation that can last years and may affect ~1% of the world’s population.

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ME/CFS is the acronym for Myalgic Encephalomyelitis or Myalgic Encephalopathy / Chronic Fatigue Syndrome, a condition that has never been properly named. The disease has had many names, including: post-viral fatigue syndrome, low natural killer cell disease, chronic Epstein-Barr virus syndrome, chronic fatigue and immune dysfunction syndrome (CFIDS), and the insulting Yuppie flu. While all diagnosed ME/CFS patients are “functionally impaired by definition,” according to the Centers for Disease Control, the CDC studies indicate the illness can be as disabling as multiple sclerosis, lupus, rheumatoid arthritis, heart disease, chronic obstructive pulmonary disease, or end-stage (terminal) renal failure.

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ME/CFS is also a relapsing, remitting illness that often follows a cyclical course. Typically the ME/CFS patient’s fatigue is made worse by either physical or mental activity, so that giving in to the temptation to overdo is repaid by “post-exertional malaise” (extreme, prolonged exhaustion and a worsening of symptoms following physical or mental exertion). The worse the illness, the less activity is possible. Indeed, the first means of testing objectively for ME/CFS may be a “Two-day Exercise Test” demonstrating diminished cardiopulmonary capacity in patients on the day following an initial exercise test.

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Because of the difficulties surrounding the diagnosis of this condition, some physicians have suggested that the condition is imaginary or the result of depression or other mental disorder. Research, however, supports that ME/CFS is a real physiological condition that causes a substantial amount of suffering and is not a form of psychiatric illness or depression.

Source

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The XMRV debate

In December of 2010 you may recall the half page ad placed in the The Washington Post by patients bringing attention to HIV-like retroviruses, including XMRV. This new retrovirus has been linked to CFS and other diseases including aggressive prostate cancer. It was also detected in healthy blood donors suffering from chronic fatigue syndrome.

According to MCWPA

"A major scientific breakthrough occurred in October 2009 when the Whittemore Peterson Institute (WPI) at the University of Nevada, Reno, working with the National Cancer Institute and Cleveland Clinic, published the results of a landmark study. The seminal study, published in the leading scientific journal, Science, discovered the third human retrovirus, XMRV, in the blood of 67% of ME/CFS patients and in 3.7% of healthy controls. This suggests that up to 10 million US citizens could already be infected. This finding was later confirmed by the FDA, NIH and Harvard Medical School in a study published in the Proceedings of the National Academy of Sciences. Their results linked a family of human gamma retroviruses (to which XMRV belongs) to ME/CFS at a rate of 86.5% and 6.8% in the healthy population, bringing the total of Americans who may be infected up to 20 million people."

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With this new 2009 research from the Whittemore Peterson Institute patients felt finally there was proof; CFS was not all in their head. The scientific community had an interest in chronic fatigue syndrome, so did the media, help was on the way.

Then research in October of 2010 changed all that; Medscape reported online in October 2010 the latest from researchers; "In More Studies Find No XMRV in Chronic Fatigue Syndrome, HIV, or Hepatitis C"

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These are the three studies published at the same time in the Journal of Infectious Diseases.

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This information is from; XMRV in Chronic Fatigue Syndrome: More Studies, More Controversy

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1-J Infect Dis. 2010 Nov

Failure to Detect XMRV in Blood of Individuals at High Risk of Blood-Borne Viral Infections.

This study looked for the retrovirus somewhere you'd expect to find it -- the bodies of people with compromised immune systems. Examining the blood of 230 people with HIV and hepatitis C, they found nothing. This was a European study, and thus far, European studies have all come up empty handed, regardless of their collection and detection methods.

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2-J Infect Dis. 2010 Nov 15;202(10):1478-81. Epub 2010 Oct 11.

XMRV Prevalence in Patients with Chronic Fatigue Syndrome or Chronic Immunomodulatory Conditions

Researchers in Boston looked for XMRV in 293 people seen at academic hospitals in the city. Patients came from 1 of 5 groups -- chronic fatigue syndrome, HIV, rheumatoid arthritis, transplants, and general patients. They found no evidence of XMRV in any of them, in spite of using the same detection methods as the FDA/NIH study released over the summer, which did detect XMRV (and other related retroviruses) in similar numbers to the Whittemore Peterson research. The lead researcher brought up the possibility of geographical differences in the presence of XMRV.

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3-J Infect Dis. 2010 Nov 15;202(10):1470-7. Epub 2010 Oct 11.

Detection of XMRV in Normal and Tumor Tissue ... [in] Prostate Cancer is Dependent on Specific Polymerase Chain Reaction Conditions.

This study involved 144 prostate cancer patients from the southern United States, and researchers looked first at whether XMRV was present, and then whether it was linked to a abnormality in RNase L (an immune marker believed to be associated with some cases of both prostate cancer and chronic fatigue syndrome.) They found XMRV in 22% of patients, in normal tissue and in tumor tissue, suggesting that infection may precede cancer. They did not find a link with the RNase L polymorphism.

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Updates;

XMRV & Chronic Fatigue Syndrome: Where Do We Stand?
Wednesday January 5, 2011

It's been 15 months since the Whittemore Peterson Institute (WPI) published its study linking a retrovirus to chronic fatigue syndrome (ME/CFS) and a lot more research has been done, but if anything, the waters are only growing cloudier. The loudest voices right now are shouting "cross contamination."...continue reading...

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Hepatitis C Patients Understand All To Well How The Game Is Played

Patients and researchers know that medical science will continue to evolve with improved sophisticated means of testing, in time research will again come full circle. What was once medical evidence will be reversed, what was once reversed will become medical evidence. The revolving door of medical science is a proven dilemma, for us and for them. Until that time CFS patients go back to the holding tank, waiting for validation of a disease that medical researchers and even friends do not really understand.

This familiar scenario has played out over and over with other diseases. HCV patients were ignored for years, even with elevated LFTs. With some female patients feeling discriminated against as physicians attributed their symptoms to depression, environmental stress, or lifestyle. This female blogger/patient felt neurotic as I left numerous appointments ashamed and embarrassed, was I just lazy ? The irony is patients wait for medical validation knowing before the research comes out; what they have is real. When will the medical community put in place a system which will bring to light the fact "a patients dialogue" is the most valuable entry into research.

Now CFS patients will start all over , as the wait for medical validation continues............

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Symptoms / Diagnostic criteria

The most commonly used diagnostic criteria and definition of CFS for research and clinical purposes were published by the United States Centers for Disease Control and Prevention (CDC).

The CDC definition of CFS requires the following two criteria be fulfilled:
A new onset (not lifelong) of unexplained, persistent fatigue unrelated to exertion and not substantially relieved by rest, that causes a significant reduction in previous activity levels.
Four or more of the following symptoms that last six months or longer:

Impaired memory or concentration
Post-exertional malaise, where physical or mental exertions bring on "extreme, prolonged exhaustion and sickness"

Unrefreshing sleep
Muscle pain (myalgia)
Pain in multiple joints (arthralgia)
Headaches of a new kind or greater severity
Sore throat, frequent or recurring
Tender lymph nodes (cervical or axillary)
Other common symptoms include:
Irritable bowel, abdominal pain, nausea, diarrhea or bloating
Chills and night sweats
Brain fog
Chest pain
Shortness of breath
Chronic cough
Visual disturbances (blurring, sensitivity to light, eye pain or dry eyes)
Allergies or sensitivities to foods, alcohol, odors, chemicals, medications or noise
Difficulty maintaining upright position (orthostatic instability, irregular heartbeat, dizziness, balance problems or fainting)

Psychological problems (depression, irritability, mood swings, anxiety, panic attacks)

The CDC recommends that persons with symptoms resembling those of CFS consult a physician to rule out several treatable illnesses: "sleep disorders, depression, alcohol/substance abuse, diabetes, hypothyroidism, mononucleosis (mono), lupus, multiple sclerosis (MS), chronic hepatitis and various malignancies." Medications can also cause side effects that mimic symptoms of CFS.
Source


Top Five Myths

Misinformation can kill. Let’s put these myths to bed.

Myth: ME/CFS is when you are tired a lot
Fact: For the severe cases, a patient’s experience is more like a “living death,” much more than just being tired. Nausea, headaches, dizziness, cognitive problems, light sensitivity, vertigo, and pain, in addition to feeling like their body is made of lead, can be so debilitating that many sufferers are largely housebound or bedbound. Symptoms can be mild, medium or severe. It is also not uncommon for sufferers to make some recovery only to relapse later and become bedridden again, sometimes for years.

Myth: ME/CFS is a psychological problem
Fact: Most ME/CFS patients have immune system abnormalities, infection reactivation, abnormal brain scan readings and many other biological signs of an organic disease. Some of the symptoms, such as a sore throat, swollen lymph nodes, and low grade fevers are not associated with psychiatric problems but are associated with infections or immune system responses.

Myth: ME/CFS is a disease of middle-aged women
Fact: ME/CFS can strike anyone at any time. Children as young as four and people as old as 70 can develop the disease. Men of all ages also develop this disease. While middle-aged women make up a large percentage of cases, teenagers of both genders are also commonly seen within our patient community.

Myth: ME/CFS is not infectious
Fact: ME/CFS has occurred in outbreaks reported to the CDC in the 1980s. It also occurred in an outbreak at the Royal Free Hospital in the 1950s. Other outbreaks of illnesses with similar or matching symptoms go back to the early 1900s in numerous countries. Many experts now think these illness outbreaks were really what is now called ME/CFS, even though they were given other names, such as atypical poliomyelitis, encephalitis, abortive poliomyelitis, Akureyri disease, Iceland disease and epidemic neuromyasthenia. As research is now linking a retrovirus to this disease, which appears higher in family members of CFS patients, evidence is mounting that the disease is infectious.

Myth: ME/CFS is not fatal
Fact: An inquest into Sophia Mirza’s death showed she died from acute renal failure as a result of dehydration, caused by chronic fatigue syndrome. She died at age 33. Casey Fero was diagnosed with ME/CFS at the age of nine and died at age 23 from myocarditis, which means he had heart damage. A 2006 study of 166 deceased ME/CFS patients shows an increased risk of premature death from the following:
General population average age of death from cancer – 72, ME/CFS patients – 47.8
General population average age of death from heart failure – 83.1, ME/CFS patients – 58.7
General population average age of death from suicide – 48, ME/CFS patients – 39.3

Chronic fatigue syndrome patients address the CDC ,

Vague symptoms help to keep hepatitis C "hidden" inside the body for years

Radio Show

Experts at Europe's largest liver transplant unit - at King's College Hospital in London - explain how vague symptoms help to keep hepatitis C "hidden" inside the body for years. Dr Mark Porter looks at the latest ways to manage this condition.
Producer: Helen Sharp.

http://www.bbc.co.uk/i/xhh74/

Additional Information
Symptoms Of HCV
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