Hepatitis C - Adverse events from DAAs can persist for months after treatment

Of Interest
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Side effects associated with different hepatitis C direct-acting antiviral drugs 

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Patient-Reported Outcomes After HCV Treatment With Sofosbuvir and Velpatasvir, With or Without Voxilaprevir 

May 30, 2018

Prospective Study: No psychiatric side effects with new IFN-free treatment for HCV 

Article

Adverse events from DAAs can persist for months after treatment, study finds

Liz Meszaros, MDLinx | August 21, 2018
Adverse events (AEs) related to treatment with direct-acting antivirals (DAAs) may persist after treatment in a significant number of patients with chronic hepatitis C, according to results from a study published in the European Journal of Gastroenterology and Hepatology. Clinicians and patients should be aware of this possibility.

Abstract: Outcome and adverse events in patients with chronic hepatitis C treated with direct-acting antivirals: a clinical randomized study

“This real-life study is to the best of our knowledge the first to examine the rate of AEs in patients with hepatitis C virus (HCV) genotype (GT) 1 infection, randomized to one of two different DAA regimens in a real-world setting,” noted these authors, led by Christina Sølund, MD, PhD, Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.

Recently, the development of DAA agents has revolutionized the treatment of chronic hepatitis C, which is estimated to affect more than 70 million people worldwide. Before the advent of DAAs, the standard of care for these patients consisted of treatment with pegylated-interferon and ribavirin (RBV), lasting for 24 to 48 weeks, which not only had significantly lower cure rates and tolerability, but also carried a high incidence of severe AEs.

Now in their second iteration, DAAs have changed the playing field in the treatment of chronic hepatitis C by directly targeting the proteins responsible for viral replication. Improved sustained virologic responses (SVR) of 90% or more and good tolerability and efficacy in patients who have historically been difficult to treat—such as those with liver cirrhosis, liver transplantation, or previous treatment failures—have characterized the second-generation DAAs.

Few studies, however, have compared different DAA regimens. For this reason, Dr. Sølund and colleagues conducted their investigation. They included 96 patients with chronic hepatitis C with either GT1 or GT3, who were randomized to two different treatment arms. The first was comprised of 72 patients infected with GT1, who were treated for 12 weeks with ledipasvir/sofosbuvir/RBV vs paritaprevir/ombitasvir/ritonavir/dasabuvir/RBV. The second group consisted of 24 patients infected with GT3, who were treated with daclatasvir/sofosbuvir/RBV for 12 weeks vs a 24-week course of sofosbuvir/RBV.

Unfortunately, due to a change in national treatment guidelines, the GT3 treatment arm was prematurely terminated. Therefore, efficacy data are available from both GT3 and GT1 patients, but the incidence of AEs is available only for GT1 patients.

Cure was achieved by 97% of GT1 patients and 83% of GT3 patients, with SVR at 12 months. Virologic failure occurred in only one G3 patient.

Adverse events occurred in 97% of GT1 patients with the most common being anemia, fatigue, and headache.

“We found no statistically significant difference in AEs, neither between treatment groups nor in relation to anemia or cirrhosis. The overall rate of AEs was comparable to other real-world studies, but the frequency of the most common AEs, such as anemia (78%), fatigue (74%), headache (74%), pruritus/eczema (46%), and heartburn/abdominal discomfort (38%), was higher in our study,” they added.

Only 3% of GT1 patients discontinued treatment due to AEs. Notably, 45% of patients with AEs thought to be related to a DAA regimen still manifested the AEs at 4 weeks after treatment. At 12 weeks this was still the case in 11% of patients.

“We consider this an important finding that can be used when informing the patient about AEs that might be caused by the DAA regimen, despite the number of patients included in our study being relatively small,” noted the authors. “The low discontinuation rate reflects that AEs possibly induced by DAA treatment are rarely treatment limiting, even when DAA treatment is given in combination with RBV,” they concluded.

This study received support from the Faculty of Health and Medical Sciences, University of Copenhagen and from Hvidovre Hospital Research Foundation, the Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, the Capital Region of Denmark’s Research Foundation, the Innovation Fund Denmark project 060-2009-3, the Novo Nordisk Foundation, and the Danish Research Council.

https://www.mdlinx.com/infectious-disease/article/2470

Managing Neurologic Complications of Chronic HCV Infection

In case you missed it
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.

What causes chronic fatigue? What we know, don’t know and suspect

Recommended Reading

February 2017
Persistent Neuropsychiatric Impairment in HCV Patients Despite Clearance of the Virus?!
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?

Link To Article: 2017 full-text article is open access over at Medscape (free registration required), discussion only, here (no registration). Patients can also read an overview with commentary at Infectious Disease Advisor. Original article was published 9 February 2017 in Journal of Viral Hepatitis.

May 16, 2018
Do fatigue and quality of life improve after hepatitis C is cured?
Keith Alcorn
Published: 16 May 2018
Patient-reported outcomes such as fatigue, vitality and mental health improve substantially in the two years following hepatitis C cure for people with cirrhosis, but people with cirrhosis are less likely than others to experience rapid resolution of severe fatigue after successful hepatitis C treatment, according to two studies from the Center for Outcomes Research in Liver Diseases reported last month at the 2018 International Liver Congress in Paris.

Today's Article

What causes chronic fatigue? What we know, don’t know and suspect

Mark Guthridge 

Senior Research Fellow, Monash University 

Source: The Conversation

Around 200,000 people in Australia suffer from a debilitating illness often branded with the unfortunate name of chronic fatigue syndrome (CFS). I say “unfortunate” because this implies patients are simply tired, run-down, burnt-out or overly stressed.

But myalgic encephalomyelitis, or ME/CFS as it is now more commonly called, is a serious and incapacitating disease that can have a devastating impact on a patient’s life. Symptoms include:

profound and unexplained fatigue for more than six months
memory or concentration difficulties
muscle pain (myalgia) and weakness
joint pain
sleep disturbances
flu-like symptoms
light headedness, palpitations, breathlessness
headaches
heightened sensitivity to light and sound
tender lymph nodes, sore throats
new sensitivities to food, medicines or chemicals.

Initially bewildered by their incapacitating fatigue, many ME/CFS patients continue trying to go about their daily lives. But such efforts come at a severe cost. Even small amounts of activity can trigger “crashes” called post-exertional malaise that worsen symptoms, sometimes for many days.

Simple activities such as showering, grocery shopping or meeting a friend for coffee become difficult, if not impossible. Sadly, for around 25% of patients, symptoms are so severe they remain bed-bound or house-bound, and suicide risk is elevated.

Most patients face a major challenge getting a diagnosis. One UK study found less than half of doctors were confident with the diagnosis or treatment of ME/CFS and more than 85% of patients go from doctor to doctor for over two years without a diagnosis.

What we know

The underlying causes of ME/CFS have proved difficult to pinpoint. For many patients, blood and pathology testing are entirely normal.

This has led some to suggest ME/CFS is a psychological condition. In 2011, the findings of a clinical trial suggested patients could recover through psychological therapy (cognitive behavioural therapy or CBT) and graded exercise therapy. These findings have fuelled debate as to whether ME/CFS might be a disease of the mind.

But a landmark US study examining nearly 10,000 research publications suggested otherwise, concluding that ME/CFS is a serious, chronic, complex and systemic disease.

Criticisms of psychological and exercise therapy for ME/CFS have been widespread, with over 50 published letters in leading scientific journals (BMJ, Journal of Health Psychology, Nature, Lancet) raising serious concerns about the robustness of the claims.

Australian guidelines continue to recommend exercise and CBT therapies despite the US Centers for Disease Control and Prevention discontinuing these recommendations.

While exercise can clearly benefit patients with a wide range of illnesses, physical activity can cause a rapid deterioration of symptoms in patients with ME/CFS.

What we don’t know

There are no laboratory tests available to categorically diagnose someone with ME/CFS. But Australian research is playing a leading role in the discovery of possible diagnostic markers. For example, inflammatory blood proteins such as activin B and interferon are increased in ME/CFS. Other studies have shown metabolic waste products from some gut bacteria accumulate in ME/CFS patients and so may also provide diagnostic information in the future.

Women are four times more likely to be diagnosed with ME/CFS than men, but the reason for this is unclear. Also, having a first-degree relative with ME/CFS more than doubles the risk of developing the disease, but the role of genetics is not known.

For some, the onset of symptoms is slow. In others, ME/CFS begins with infections causing glandular fever (infectious mononucleosis), respiratory or gastrointestinal illnesses.

While ME/CFS patients have immune disruptions and abnormal inflammatory responses, the underlying causes remain elusive. The vicious cycles of tissue damage typical of autoimmune diseases such as multiple sclerosis or lupus don’t seem to occur in ME/CFS.

One theory is that ME/CFS patients have a “chink” in their immunological armour, possibly leading to persistent “smouldering” infections and chronic inflammation.

But it’s remarkably difficult to find direct evidence for such ongoing infections in most ME/CFS patients. And antiviral drugs or antibiotics seem to have very modest activity in ME/CFS despite their life-saving activities in many other infectious diseases.

ME/CFS patients also have metabolic defects in the way energy is generated in their bodies - pointing to one reason why they rapidly succumb to muscle fatigue during exercise. But whether this metabolic defect is due to immune attack, chronic infection or some other cause is unknown.

With no approved treatments or cures for ME/CFS, more research is urgently needed. So far, clinical trials examining the effects of immunosuppressive drugs, antibody therapies, anti-viral drugs, attention deficit hyperactivity disorder therapies and anti-depressants have not led to major improvements.

Diets and nutritional supplements also seem to provide little help. While some dietary supplements involved in generating metabolic energy seem to improve some ME/CFS symptoms, larger and better studies are required.

A reboot of ME/CFS research is now underway. Sufferers are hopeful the recent establishment of a National Health and Medical Research Council ME/CFS Advisory Committee will reinvigorate Australian biomedical ME/CFS research to find new treatments and possibly a cure.

Read the original article.

Do fatigue and quality of life improve after hepatitis C is cured?

Do fatigue and quality of life improve after hepatitis C is cured?

Keith Alcorn
Published: 16 May 2018

Patient-reported outcomes such as fatigue, vitality and mental health improve substantially in the two years following hepatitis C cure for people with cirrhosis, but people with cirrhosis are less likely than others to experience rapid resolution of severe fatigue after successful hepatitis C treatment, according to two studies from the Center for Outcomes Research in Liver Diseases reported last month at the 2018 International Liver Congress in Paris.

Quality of life can be severely impaired in people with chronic hepatitis C, especially in people with cirrhosis. Fatigue, insomnia, problems in physical functioning, depression, anxiety and mood disorders are reported by a substantial proportion of people with hepatitis C....

Continue reading: http://www.aidsmap.com/Do-fatigue-and-quality-of-life-improve-after-hepatitis-C-is-cured/page/3266466/

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aidsmap news from EASL 2018

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The Liver Meeting® 2017 - Hepatitis C cure leads to improved quality of life

Hepatitis C cure leads to improved quality of life
Liz Highleyman
Published:23 October 2017

Produced in collaboration with hivandhepatitis.com

People who were cured of hepatitis C with direct-acting antivirals (DAAs) had sustained improvements in their health-related quality of life, including both physical and mental health measures, according to study results presented at the AASLD Liver Meeting this week in Washington, DC.

These findings have important policy implications, showing that "treatment is not only about clinical benefit, but also about the patient experience," said presenter Zobair Younossi of Inova Fairfax Hospital in Virginia.

Read the article @infohep, here - http://www.infohep.org/page/3182893/

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Hepatitis C Patients Delay Treatment Due to Cost Concerns

In Case You Missed It

Hepatitis C In America 2017 was conducted online May 3, 2017 – June 26, 2017 and released through Health Union’s online community, HepatitisC.net. 

If you missed the following survey, I highly suggest you read the results over at  HepatitisC.net.

Published August 28, 2017 

The Physical and Emotional Toll of Hep C: Results from the Hepatitis C In America Survey

A diagnosis of hepatitis C affects more than just the body. Many don’t realize the full impact hepatitis C can have on someone’s life. We conducted a survey to better understand the symptoms and experiences of people living with hep C. The Hepatitis C In America 2017 online survey gathered insights from 609 individuals who tested positive for hepatitis C infection and have been diagnosed with chronic hepatitis C infection. Of the 609 survey-takers, 49% were reported to be cured of hep C and 51% were not yet cured at the time of the survey.

Read it here..........

Published Oct 4, 2017

Survey: Hepatitis C Patients Delay Treatment Due to Cost Concerns

— Most Uncured Respondents Not Actively Treating the Disease —

October 4, 2017
“Hepatitis C In America,” a new Health Union national survey of 609 individuals diagnosed with chronic hepatitis C infection, shows that more than one-third of uncured respondents were not currently under the care of a healthcare provider (HCP), typically due to financial concerns.

While new Hepatitis C treatment options are revolutionizing care, many patients report financial challenges (53 percent) and insurance denial/lack of insurance coverage (25 percent), along with apprehension about treatment and side effects, as common barriers to accessing treatments. The survey also found most (86 percent) respondents with current chronic Hepatitis C infection were not actively treating their condition at the time of the survey.

Hepatitis C is the most common blood-borne infection in the United States and can lead to serious complications including cirrhosis and liver cancer. According to the Centers for Disease Control and Prevention (CDC), Hepatitis C is the leading cause of liver transplants in the U.S.

In this year’s survey, 49 percent of respondents reported they were cured of Hepatitis C and 51 percent were not yet cured at the time of the survey. Seventy-three percent of all respondents had received treatment for Hepatitis C from their healthcare professional; however, 21 percent of treated patients did not achieve a sustained viral response – considered “cured.”

Of those who had been treated, 38 percent reported waiting more than five years from diagnosis to begin treatment. Additionally, one out of four treated patients reported they had to stop a treatment early, often due to medication side effects.

The survey also found a desire to know more about the condition, with most respondents wishing they had more information at the time of diagnosis, particularly about Hepatitis C’s impact on their bodies and long-term complications of the virus. Prior to their diagnosis, one-third of respondents were not aware of Hepatitis C.

“Typing in those words, ‘Hep C,’ causes a lot of trauma,” said Karen Hoyt, a HepatitisC.net patient advocate. “But we also want to find out what’s going on in our own bodies. An online support network like HepatitisC.net helps us know we’re not alone and provides a sense of connection for us.”

The survey also showed many people living with Hepatitis C make lifestyle changes following their diagnosis. Some of these changes include staying hydrated, avoiding alcohol, maintaining a healthy diet, getting more sleep, and managing stress.

“There’s nothing like the fear of a serious health condition to motivate you,” Hoyt added, “and making lifestyle changes can fight feelings of powerlessness and lack of control.”

“The findings from ‘Hepatitis C In America’ reflect opportunity for the pharmaceutical industry and patients alike,” said Health Union Senior Vice President, Insights, Anna McClafferty. “Among respondents who aren’t cured, more than half have never been treated. For these patients, financial concerns, lack of health insurance, and worries about the treatments themselves are primary barriers to starting therapy. Given these findings, it’s not surprising to see so many people with Hepatitis C interested in clinical trials and aware of new treatments in development.”

More details about the survey may be available upon request; email Insights@health-union.com.
https://health-union.com/news/hepatitis-c-patients-delay-treatment-due-to-cost-concerns/

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

Persistent Neuropsychiatric Impairment in HCV Patients Despite Clearance of the Virus?!
Original article was published 9 February 2017 in Journal of Viral Hepatitis, the research article is open access over at Medscape, patient-friendly commentary 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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Extrahepatic manifestations of HCV & Treatment

Found On This Blog
A collection of research articles on ailments related to HCV

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If you are interested in reading full text articles about the treatment and management of HCV I highly suggest you follow Henry E. Chang on Twitter.

Latest Tweets By @HenryEChang on the extrahepatic manifestations of HCV.

July 14, 2017

Extrahepatic manifestations of HCV: The role of direct acting antivirals

María Laura Polo and *Natalia Laufer
Expert Review of Anti-infective Therapy DOI: 10.1080/14787210.2017.1354697

Introduction:

Hepatitis C virus (HCV) represents a major health concern, as nearly 3 million people become newly infected by this pathogen annually. The majority of infected individuals fail to clear the virus, and chronicity is established. Chronic HCV patients are at high risk for liver disease, ranging from mild fibrosis to cirrhosis and severe hepatocellular carcinoma. Over the last few years, the development of multiple direct acting antivirals (DAA) have revolutionized the HCV infection treatment, demonstrating cure rates higher than 90%, and showing less side effects than previous interferon-based regimens. Areas covered: Besides liver, HCV infection affects a variety of organs, therefore inducing diverse extrahepatic manifestations.

This review covers clinical, experimental, and epidemiological publications regarding systemic manifestations of HCV, as well as recent studies focused on the effect of DAA in such conditions.  Expert commentary: Though further research is needed; available data suggest that HCV eradication is often associated with the improvement of extrahepatic symptoms. Therefore, the emergence of DAA would offer the opportunity to treat both HCV infection and its systemic manifestations, requiring shorter treatment duration and driving minor adverse effects.
Link - Download Full Text Article.......

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Clinics in Liver Disease, Volume 21, Issue 3

Chronic Hepatitis C Virus Infection and Depression
Luigi Elio Adinolfi, Riccardo Nevola, Luca Rinaldi, Ciro Romano, Mauro Giordano

KEYWORDS
HCV Depression Quality of life

KEY POINTS
Depression is an extrahepatic manifestation of chronic hepatitis C virus (HCV) infection reported in one-third of patients.

The prevalence of depression in patients with HCV has been estimated to be 1.5 to 4.0 times higher than that observed in the general population.

Direct HCV neuro-invasion, induction of local and systemic inflammation, neurotransmission, and metabolic derangements are the hypothesized pathogenic mechanisms of depression.

Depression considerably impacts health-related quality of life of HCV-positive patients.

Clearance of HCV by antiviral treatments is associated with an improvement of both depression and quality of life.
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Metabolic Manifestations of Hepatitis C Virus
Lawrence Serfaty

KEYWORDS
Hepatitis C Steatosis Hypobetalipoproteinemia Microsomal triglyceride transfer protein Insulin resistance. Tumor necrosis factor

KEY POINTS
Out of excessive alcohol consumption, steatosis should be classified into 2 types according to hepatitis C virus (HCV) genotypes: metabolic steatosis, which is associated with features of metabolic syndrome and insulin resistance in patients infected with nongenotype 3, and viral steatosis, which is correlated with viral load and hyperlipemia in patients infected with genotype 3.

HCV interacts with host lipid metabolism by several mechanisms, such as promotion of lipogenesis, reduction of fatty acid oxidation, and decreases of lipids export, leading to hepatic steatosis and hypolipidemia.

A strong link between HCV infection and diabetes mellitus has been found in subjectbased studies and, to a lesser degree, in population-based studies.

HCV-mediated insulin resistance may be promoted through multiple pathogenic mechanisms, such as direct inhibition of insulin signaling pathway by HCV core protein in the liver, overproduction of tumor necrosis factor-alpha, oxidative stress, modulation of incretins, or pancreatic ß-cells dysfunction.
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Neurologic manifestations of hepatitis C virus infection
Sentia Iriana, MD, Michael P. Curry, MD, Nezam H. Afdhal, MD, DSc

KEYWORDS
Hepatitis C Fatigue Neurocognition MR spectroscopy Interferon Ledipasvir/sofosbuvir Cerebrovascular disease

KEY POINTS
The extrahepatic manifestations of hepatitis C virus (HCV) in the brain include neurocognitive dysfunction, which is manifested by subtle changes in memory, attention, and processing speed.

Neurocognitive defects are independent of the histologic stage of disease and may be induced by a direct effect of HCV on microglial cells or mediated by systemic cytokines crossing the blood-brain barrier.

Magnetic resonance spectroscopy demonstrates abnormal metabolism in basal ganglia and prefrontal and frontal cortex, which has been associated with fatigue and abnormal neurocognitive testing. Interferon and direct-acting antiviral therapy can improve cerebral metabolism and neurocognition if a sustained virologic response is obtained.

Cerebrovascular events and mortality are increased in patients with HCV and may be through an increased risk of carotid artery disease and plaque formation.
Link - Full Text PDF Article
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Rheumatologic manifestations of hepatitis C virus

Patrice Cacoub, Cloé Comarmond, Anne Claire Desbois, David Saadoun

KEYWORDS
Hepatitis C (HCV) Rheumatic disorders Arthritis Vasculitis Arthralgia Sicca syndrome

KEY POINTS
Main rheumatologic manifestations reported with hepatitis C virus (HCV) chronic infection include arthralgia, myalgia, cryoglobulinemia vasculitis, and sicca syndrome.

Immunologic factors predisposing to developsuch manifestations include stimulation of B cells, expansion of B-cell–producing immunoglobulin M with rheumatoid factor activity and of clonal marginal zone, like B cells, and a decrease of regulatory T cells.

The treatment of HCV infection with interferon alpha has been contraindicated for a long time in many rheumatologic autoimmune/inflammatory disorders.

New oral interferon-free combinations now offer an opportunity for patients with HCV extrahepatic manifestations, including rheumatologic autoimmune/inflammatory disorders, to be cured with a high efficacy rate and a low risk of side effects.

Link - Full Text PDF Download
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Other EHM of HCV infection (pulmonary, idiopathic thrombocytopenic purpura, nondiabetes endocrine disorders

Daniel Segna, Jean-François DuFour

KEYWORDS
Hepatitis C Extrahepatic manifestations Pulmonary Endocrine Idiopathic thrombocytopenic purpura

KEY POINTS
Hepatitis C Virus (HCV) infection may increase the risk for obstructive, interstitial, and vascular lung disease, lung cancer, and mortality in HCV-infected lung transplant recipients.

HCV infection may increase the risk of idiopathic thrombocytopenic purpura, nonresponse to corticosteroids during the treatment, and higher rates of splenectomy.

HCV infection may increase the risk of autoimmune thyroiditis, infertility, growth hormone and adrenal deficiency, osteoporosis, and low-trauma fractures.

Targeted prospective cohorts may confirm these results mostly obtained from small casecontrol studies with different study populations and low level of evidence.

Link - Full Text PDF Download
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Hepatitis C Virus–Associated Non-Hodgkin Lymphomas
Gabriele Pozzato, Cesare Mazzaro, Valter Gattei

KEYWORDS
Hepatitis C virus Marginal zone lymphoma Non-Hodgkin lymphoma Direct antiviral agents

KEY POINTS
Eradication of hepatitis C virus (HCV) in indolent non-Hodgkin lymphomas (NHLs), especially in marginal zone lymphomas(MZLs), determines the regression of the hematological disorder in a significant fraction of cases.

Because direct antiviral agents (DAAs) show an excellent profile in terms of efficacy, safety, and rapid onset of action, these drugs can be used in any clinical situation and the presence of any comorbidities.

To avoid the progression of the NHL, despite HCV eradication, antiviral therapy should be provided as soon as the viral infection is discovered; before that, the chronic antigenic stimulation determines the irreversible proliferation of neoplastic B cells.
Link - Full Text PDF Download
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Dermatologic manifestations of chronic hepatitis C
Mehmet Sayiner, Pegah Golabi, Freba Farhat, Zobair M. Younossi

KEYWORDS
Hepatitis C Extrahepatic manifestation Dermatologic manifestation Cryoglobulinemia Porphyria Lichen planus

KEY POINTS
HCV infection is associated with several dermatologic diseases, such as symptomatic mixed cryoglobulinemia, lichen planus, porphyria cutanea tarda, and necrolytic acral erythema.

Most of the dermatologic manifestations may be caused by immune complexes. In the interferon and ribavirin era, treatment was associated with dermatologic side effects.

The new generation of interferon-free and ribavirin-free anti-HCV regimens is devoid of dermatologic side effects.
Link - Full Text PDF Download
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Hepatitis C Infection - A systematic disease
Zobair M. Younossi
KEYWORDS
Hepatitis C virus Hepatic complications Extrahepatic complications

KEY POINTS
It is critical to recognize that hepatitis C virus (HCV) infection is a multifaceted systemic disease with both hepatic and extrahepatic complications.

The comprehensive burden of HCV should not only include its clinical burden, but also its burden on the economic and patient-reported outcomes.

It is only through this comprehensive approach to HCV infection that we can fully appreciate its true burden, and understand the full benefit of curing HCV for the patient and the society.
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Thank you Henry E. Chang

Hepatitis C Fatigue - What's that all about?

Hepatitis C Fatigue - What's that all about?
Fatigue is the most commonly experienced symptom in people with liver disease, and it has a significant impact on their quality of life.  Hepatitis C is a major cause of chronic liver disease in the United States, with fatigue reported as the most frequent disabling symptom - in over one-half of all people diagnosed with the virus.

In this post we look at available research and possible related conditions that may contribute to that all too familiar symptom.

Research
Let's start with a recent study which examined whether HCV fatigue, depression and health-related quality of life improves after successful HCV therapy. The result?  Well, not always.

Persistent neuropsychiatric impairment in HCV patients despite clearance of the virus?
Previous research has shown that fatigue from chronic hepatitis C usually decreases after achieving a sustained virologic response (SVR), however, occasionally fatigue may still persist after patients clear the hepatitis C virus. In a study published in Journal of Viral Hepatitis February 2017, researchers evaluated chronic fatigue after successful virus eradication. In the study researchers enrolled 159 individuals with HCV, without advanced liver disease. Patients answered a series of questions about fatigue, depression, coupled with various attention and memory tests. The patients were divided into 4 groups according to their viremia (presence of HCV virus in the blood) and interferon treatment history. Eighty-five per cent of the patients had chronic fatigue, 50-60% mild depression or anxiety, 45% memory deficits and 30% attention deficits, irrespective of their HCV viremia status or treatment history. The results suggest that HCV infection may cause long-standing cerebral dysfunction that significantly impairs health-related quality of life that may persist even after virus clearance. Commentary on the study written by Stephanie Finucane, MS, CMPP summed up the results nicely, the author wrote;

Disabling chronic fatigue is reported in approximately 60% of patients with confirmed hepatitis C virus (HCV) infection, as well as decreased quality of life and cognitive dysfunction (eg, deficits in attention and verbal learning). While these neuropsychiatric symptoms may be expected in patients with ongoing HCV infection, it is questionable whether these effects are also present in HCV-exposed patients who currently are cured of the infection.

A study recently published in the Journal of Viral Hepatitis found no evidence linking the presence of HCV infection with these neuropsychiatric symptoms. Instead, researchers suggest that the fatigue and impairment in health-related quality of life (HRQoL) and cognitive and mental function commonly found in HCV-exposed patients may be explained by either an HCV infection-triggered autoimmune response persisting beyond virus clearance or the development of a virus variant in the brain.  

Commentary here, full text article here.

Other Contributing Factors
Other contributing factors may include lifestyle, pre-existing conditions, coping with the diagnosis, loss of employment, medical coverage, and the cost of expensive HCV medications, all of which can cause depression and anxiety leading to fatigue, yet these conditions are frequently overlooked when patients seek out medical care.

Extrahepatic Manifestations

Fatigue can be caused by other conditions related to the virus, although hepatitis C infection primarily affects the liver, 40% of patients with HCV will develop at least one extrahepatic manifestation (conditions that affect organs other than the liver) during the course of their disease.

The most prevalent and most closely linked extrahepatic manifestation found in hepatitis C patients is essential mixed cryoglobulins causing dermatologic, neurologic, renal, and rheumatologic complications. Cryoglobulinemia happens when abnormal proteins in the blood solidify in cold conditions. In patients with mixed cryoglobulins, 35 to 54% reported various symptoms that include but not limited to fatigue, joint pain, muscle pain, itching, rashes, tingling in hands and feet. Non-cryoglobulin diseases with a less definite relationship to HCV include systemic vasculitis, splenic lymphoma, porphyria cutanea tarda, and the sicca syndromes.

Review
International therapeutic guidelines for patients with HCV-related extrahepatic disorders. A multidisciplinary expert statement
A paper published in Autoimmunity Reviews March 2017, set out to investigate what effects new HCV interferon-free and old interferon-based antiviral therapy may have on different HCV-extrahepatic manifestations (HCV-EHMs). The effect of Non-viral therapies on HCV-extrahepatic manifestations were also included in the article. In summary the article reported that compared to interferon-based therapy, interferon-free antiviral therapy caused minimal reduction in patient-reported outcomes during therapy and improvement of vitality and fatigue at SVR12. As stated in the abstract: In the era of interferon-free anti-HCV treatments, international recommendations for the therapeutic management of HCV-EHMs are needed. This implies the need to define the best criteria to use antivirals and/or other therapeutic approaches.
Full Text - Download PDF

Recommended Reading
Patient Reported Outcomes Critical in the Fight Against HCV
HCV Next, March 2017
Zobair M. Younossi, MD, MPH
When you look at the consequences of any chronic liver disease such as hepatitis C, three different types of impact emerge. The first impact is the clinical consequences of HCV infection. The clinical impacts of HCV can further be divided into hepatic manifestations like cirrhosis and liver cancer and extrahepatic manifestations of HCV infection such as cryoglobulinemia, chronic fatigue and diabetes. Both the hepatic and extrahepatic complications of HCV infection can lead to excess mortality and ultimately impact patient’s survival. In this context, clinical outcomes of HCV can be surrogates for survival.

The second type of impact of HCV infection is captured by patient reported outcomes, or PROs. PROs are reported directly by the patient without any changes or modifications by the physician or caregiver. PRO is an umbrella term that includes everything from health-related quality of life (HRQoL), functional status and even stigma associated with HCV infection. PROs are surrogates for the patients’ experience with their disease and its treatment. If you improve PRO scores, you are improving the patient experience with their disease.

The third type of impact of HCV infection is related to its economic consequences, which can include direct, indirect or intangible costs of the disease and its treatment. In this context, the economic impact represents a surrogate for resource utilization.

When you consider these three impacts of HCV infection together, you get a complete and comprehensive picture of HCV infection and its impact on the individual patient and the society.
Continue reading...

Links
An Overview of Extrahepatic Manifestations of Hepatitis
A patient friendly fact sheet explaining conditions associated with HCV including symptoms.
Direct-acting Antivirals Effective for HCV-related Mixed Cryoglobulinemia

Recently published in Journal of Advanced Research is a nice collection of review articles on the extrahepatic manifestations of HCV.

Volume 8, Issue 2, March 2017, Pages 85–87

Thyroid Disease

According to the American Thyroid Association (ATA). About 20 million Americans—more of them women than men—are affected by a thyroid disease or disorder. In fact, an estimated one in eight women will develop a thyroid disorder at some time in her life.

Hypothyroidism & Hyperthyroidism: Symptoms
Hyperthyroidism - When your thyroid gland makes more thyroid hormones than your body needs.
Symptoms of Hyperthyroidism include nervousness, irritability, increased perspiration, heart racing, hand tremors, anxiety, difficulty sleeping, thinning of your skin, fine brittle hair and weakness in your muscles—especially in the upper arms and thighs.
Hypothyroidism - When your thyroid gland does not make enough thyroid hormones
Symptoms of Hypothyroidism may include feeling cold, fatigued, dry skin and forgetfulness.

Thyroid Disease And HCV

Before approved interferon-free medicines were available in the U.S. to treat HCV, thyroid dysfunction (interferon induced thyroiditis) was a common side-effect of interferon-based therapies. However, hepatitis C itself can cause thyroid changes, even in people that have never treated with interferon.

Chronic HCV infection is associated with several endocrine disorders (diseases related to the endocrine glands), for example the most frequent is thyroid disorders and type 2 diabetes. Thyroid imbalance and thyroid anti-bodies are much more common in patients with Hepatitis C virus infection than in people without the virus.  According to a 2016 study the hepatitis C virus shares some molecular similarities with the thyroid and this may make the immune system mistakenly attack the thyroid gland in response to the presence of foreign molecules coming from the virus. The virus could also be infecting the thyroid cells and that could trigger the attack of the immune system on the thyroid gland.

Thyroid Disturbance in Patients with Chronic Hepatitis C Infection: A Systematic Review and Meta-analysis
In a review article published in Journal of Gastrointestinal and Liver Diseases June 2016, researchers looked at literature dated up to August 2015 to identify observational studies which compared thyroid dysfunction in interferon naïve HCV-infected and non-HCV infected subjects. The study confirmed HCV infection may be an independent risk factor for thyroid disturbance independent of administration of interferon therapy. Download the article, here.

Recommended Reading
Hyperthyroidism
Hypothyroidism
Hashimoto’s disease

Depression
Depression and anxiety is often associated with a diagnosis of a chronic illness, especially with a serious chronic disease like hepatitis C. As a result of having HCV, symptoms may already exist, for example disturbed sleep, impaired appetite, and joint pain, these ongoing symptoms decrease quality of life and increase fatigue.

A Warning
Experts warn, if depression was present before being diagnosed with HCV a distinction between an adjustment reaction and a depressive illness should be determined by your health care provider.

Moving Forward

The phrase “knowledge is power” is a profound one to be sure, especially when applied to hepatitis C. Acquiring knowledge about hepatitis C can lead to an early diagnosis, a cure, and important management strategies to treat complications of this sometimes life-threatening virus.

Educating yourself about the virus will put control back into your life, test results become easier to understand, discussions with your health care professional about managing or treating the virus will be more productive, this is turn may elevate anxiety. Once all this is in place a plan of action begins. If treatment is considered, the next hurtle can prove to be difficult, many insurance companies and state Medicaid programs limit treatment to those with the most severe cases of HCV, the good news is that this is improving, but it's taking far too long.

Recommended Reading

Delayed HCV treatment can increase risk for mortality

Anxiety And Trump

At the moment possible changes in regard to the proposed replacement for the Affordable Care Act under the current administration is enough to cause a healthy person extreme anxiety, to say the least, here is the latest on the subject.

Recently, TAG-Treatment Action Group launched their spring issue of TAGline, with this informative article; Wrangling Affordable Drug Pricing and HCV Elimination Under the New White House Administration.

Baby Boomers
Personally, I consider age an important factor in relation to stress and fatigue, baby boomers, people born between 1945 (age 72) and 1965 (age 52) account for about 80 percent of chronic hepatitis C cases in the U.S.  This segment of the population are sandwiched between raising children and taking care of loved ones, including aging parents, the latter can be at times overwhelming, plagued with grave depression and severe anxiety. In addition, other health issues arise as we age; diabetes, arthritis and heart disease, to name a few.

Identifying Contributing Factors Associated With Fatigue
Depression can drain your energy, leading to lack of sleep which may start a vicious unhealthy cycle. As for anxiety, well that is just exhausting. By first identifying these possible contributing factors, you can then begin to use coping tools that help relax or even energize you. Setting limits on what you’re able to handle is probably the best advice - learn to say no. Eventually, try doing little things like going for a walk, or reading about ways to manage stress, these small steps go a long way on the road back to wellness and may improve fatigue.

Links
Education
Support

Until next time, wishing you all a safe and healthy journey.

Photo Credit - Created by Freepik

Persistent neuropsychiatric impairment in HCV patients despite clearance of the virus?!

Original Paper
J Viral Hepat. 2017

Persistent neuropsychiatric impairment in HCV patients despite clearance of the virus?!
Meike Dirks, Henning Pflugrad, Kim Haag, Hans L. Tillmann, Heiner Wedemeyer, Dimitrios Arvanitis, Hartmut Hecker, Argyro Tountopoulou, Annemarie Goldbecker, Hans Worthmann, Karin Weissenborn

Accepted manuscript online: 24 January 2017
DOI: 10.1111/jvh.12674

Abstract
Background
One of the most disabling symptoms of hepatitis C virus (HCV)-infection is chronic fatigue. While this is accepted for HCV-polymerase chain reaction (PCR)-positive patients a relationship between HCV-infection and chronic fatigue is questioned after successful virus eradication.

Aims
As fatigue is a subjective criterion we aimed to evaluate in addition mood alterations and cognitive function in HCV-exposed patients with only mild liver disease and to assess a) possible interrelationships between these factors and health related quality of life, and b) the impact of viremia and former interferon treatment.

Methods
159 anti-HCV-positive individuals without advanced liver disease answered health related quality of life (HRQoL), fatigue and depression questionnaires and underwent a battery of attention and memory tests. Accompanying diseases which could distort the results of the study such as HIV-co-infection or drug addiction were exclusion criteria. The patients were subdivided into four groups according to their viremia-status and interferon treatment history. Patients’ data were evaluated with respect to norms given in the respective test manuals and in addition compared to those of 33 age-matched healthy controls.

Results
Eighty-five percent of the patients had chronic fatigue, 50-60% mild depression or anxiety, 45% memory deficits and 30% attention deficits, irrespective of their HCV-viremia-status or treatment history. HRQoL correlated negatively with chronic fatigue (p<0.001), while cognitive deficits – especially memory function were independent from fatigue and depression.

Conclusions
HCV-infection may cause long-standing cerebral dysfunction that significantly impairs HRQoL and may even persist after clearance of the virus.

This article is protected by copyright. All rights reserved.

Of Interest

Article - Interferon-Free Treatment May Slow Cognitive Decline in Hepatitis C

Study - “Effect of Interferon-Free Therapy on Cognition in HCV and HCV/HIV Infection: A Pilot Study”

Effective Antiviral Treatment Reduces Fatigue in People with Hepatitis C

INHSU 2016 - the 5th International Symposium on Hepatitis Care in Substance Users - the only international, scientific conference dedicated to hepatitis C in people who use drugs.

Wednesday 7 September - Friday 9 September
Oslo, Norway

Coverage - HIV and Hepatitis

INHSU 2016: Effective Antiviral Treatment Reduces Fatigue in People with Hepatitis C 

Written by Liz Highleyman

Fatigue -- a common symptom among people living with hepatitis C virus (HCV) infection -- is associated with liver inflammation and fibrosis, but antiviral therapy that leads to a cure significantly reduces the likelihood of fatigue, according to a Danish study presented at the 5th International Symposium on Hepatitis Care in Substance Users (INHSU 2016) this week in Oslo

Continue reading...

Fatigue in chronic hepatitis C infection: Understanding patients' experience from a cognitive-behavioural perspective

Fatigue in chronic hepatitis C infection: Understanding patients' experience from a cognitive-behavioural perspective

This study captured the common and unique aspects of fatigue from a cognitive-behavioural perspective in individuals with HCV infection and clinically significant fatigue. 

Interviews were gathered from fourteen participants with HCV, (64% women; age >18 years)  

Interview excerpts:

The fatigue definitely is: How do I feel at this moment? It's a day to day thing. I do make the plans and of course when that time comes if I can't do it, I just don't do it. 

(Female, age 48, living with HCV infection for 8 years) 

I'm not overweight. I have no blood pressure problems, I'm not diabetic. I have nothing. I have no illnesses whatsoever other than hep C. That's the only problem I have and that's the only thing that's doing this to my body.

(Female, age 61, living with HCV for 20 years)

I think I can regulate it in the sense that I know I'm limited with what I can do so I don't try to push myself before I get started. I say I'm going to do this much, this much I feel like I accomplish and I can. And so it allows me to be in control rather than let the situation control me. 

(Male, age 57, living with HCV infection for 3 years)

Abstract with Discussion provided below, view original full text article, here. 

British Journal of Health Psychology

View issue TOC
Volume 21, Issue 1
February 2016
Pages 157–172

Dora Zalai1,*, Colleen E. Carney1, Morris Sherman2, Colin M. Shapiro3,4 andKelly McShane

Article first published online: 6 AUG 2015 DOI: 10.1111/bjhp.12155 © 2015 The British Psychological Society

Abstract
Objectives
Fatigue is a leading concern of patients with chronic hepatitis C virus (HCV) infection. Despite its clinical significance, fatigue in HCV is poorly understood and therefore invariably under-treated. A cognitive-behavioural approach offers a framework to understand and treat fatigue, but the characteristics of fatigue in chronic HCV infection have not been documented from a cognitive-behavioural perspective. This study captured the common and unique aspects of fatigue from a cognitive-behavioural perspective in individuals with HCV infection and clinically significant fatigue.

Design

Cross-sectional, qualitative using a critical realism approach.

Methods
Fourteen individuals (64% women; age >18 years) participated in semi-structured interviews. The interviews documented the features, course, and perceived antecedents of fatigue; fatigue-specific cognitions; fatigue management behaviours; and the functional impact of fatigue.

Results
Participants' descriptions included the aspects of fatigue that have been targets of cognitive-behavioural therapy in other medical conditions, including attributing fatigue to the illness; expectation of chronicity; low control; and fatigue-driven coping. There were also components of fatigue experience that appear to be unique characteristics of fatigue related to HCV, including predominantly physical fatigue; high acceptance of fatigue; and liver-protective diet as a fatigue management behaviour.

Conclusions
This was the first study to document the experience of fatigue in chronic HCV infection in a cognitive-behavioural framework. The findings suggest that the cognitive-behavioural approach can be applied to fatigue in chronic HCV infection. This would open an avenue to alleviate fatigue and thus improve the primary patient-reported outcome of the disease.

Discussion ONLY

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This is the first study documenting the experience of fatigue in chronic HCV infection from a cognitive-behavioural perspective. Patients' descriptions revealed clinically important components of the fatigue experience which appear to overlap with that of other conditions and could be seen as specific treatment targets (Table 4). The patient interviews also highlighted the aspects of fatigue that appear to be unique to HCV infection compared to other health conditions, and this will need to be considered when designing interventions for patients with chronic HCV infection (Table 4). The results indicate that fatigue in HCV can be conceptualized within a cognitive-behavioural framework and suggest that CBT may be applied for the treatment of fatigue in chronic HCV infection.

A number of clinically important cognitions and behaviours were discussed in the interviews that have been shown to amplify fatigue and lead to adverse fatigue outcome in previous research. These include attributing fatigue to the infection; perception and expectations of chronicity; low control beliefs; excessive passive rest; and fatigue-driven coping.

The association between somatic fatigue attributions and intense fatigue is consistent with research in chronic fatigue syndrome, cancer, and multiple sclerosis (Bol, Duits, Hupperts, Vlaeyen, & Verhey, 2009; Servaes, Verhagen, & Bleijenberg, 2002; Sharpe, 1997). Attributing fatigue to the infection is a central issue because it fuels other non-adaptive fatigue cognitions. One of these cognitions is patients' expectations that their fatigue will be chronic and worsening, in parallel with the course of their disease. Indeed, expectations of chronicity of fatigue symptoms, even in a context of a benign virus infection, predict the development of chronic fatigue within 6 months (Moss-Morris, Spence, & Hou, 2011).

In addition to expectations about chronicity, attributing fatigue to the disease also increases fatigue via emotional pathways. A previous qualitative study in HCV, as well as evidence in cancer, multiple sclerosis, and chronic fatigue syndrome, has also shown that being fatigued may become emotionally threatening and distressing if patients believe fatigue is a sign of disease progression/recurrence/flare-up (Bol et al., 2009; Glacken, Coates, Kernohan, & Hegarty, 2003; Servaes et al., 2002; Sharpe, 1997). There is evidence to support the idea that negative emotions can amplify unpleasant physical sensations (e.g., fatigue) because they increase self-focused attention and monitoring (Mor & Winquist, 2002).

A further example of clinically important, non-adaptive cognitions was participants' beliefs that they had little control over their fatigue. Participants with low control beliefs preferred predominantly fatigue-driven, passive coping behaviours, including excessive rest and avoidance of activities. This behavioural adaptation to fatigue characterizes and amplifies other chronic fatigue conditions and has been the primary treatment target in CBT for chronic fatigue syndrome (Bol et al., 2010; Leeuw et al., 2007).

In addition to the fatigue-specific cognitive-behavioural factors that appear to be similar to what has been found in other disorders, patients' descriptions also revealed the following unique categories: Predominantly physical fatigue; high acceptance; cognitive avoidance; positive thinking; active rest; and engaging in physical and pleasurable activities.

In relation to describing fatigue as a physical sensation, this study is consistent with a previous qualitative study on HCV infection (Glackenet al., 2003). In contradistinction, patients with cancer and multiple sclerosis see physical and mental fatigue as equally salient (Ford, Trigwell, & Johnson, 1998; de Raaf, de Klerk, & van der Rijt, 2013). An adaptation of CBT for fatigue in chronic HCV infection will need to take this difference into consideration, perhaps by incorporating a treatment component that targets physical fatigue (e.g., graded exercise or muscle relaxation). It is important to be aware when implementing these interventions that a unique antecedent of fatigue was ‘bending’, which could be related to physical discomfort caused by an enlarged liver.

A second characteristic aspect of fatigue in this study was high acceptance. Acceptance of fatigue has been observed in some medical conditions in which patients accept fatigue as belonging to the illness, whereas acceptance is less typical in other medical conditions (e.g., chronic insomnia and chronic fatigue syndrome). Acceptance of unpleasant physical sensations is generally adaptive in chronic conditions that cannot be cured by routine medical interventions, for example in chronic pain conditions or in chronic fatigue syndrome (Brooks, Rimes, & Chalder, 2011; McCracken & Vowles, 2008; Van Damme, Grombez, Van Houdenhove, Mariman, & Michielsen, 2006). In the situation when fatigue is caused by treatable a condition, for example by an undiagnosed sleep disorder (which is common in chronic HCV infection), accepting chronic fatigue as an inevitable part of the infection is non-adaptive. Encouraging patients to adopt behaviours that promote sleep (e.g., avoiding excessive time in bed and stimulus control) should be a part of CBT for patients with poor sleep and high fatigue.

Finally, participants in this study described diet as a typical coping behaviour, which also appears to be specific for this illness. Being on a liver-protective or ‘anti-inflammatory’ diet in particular appears to be a logical attempt to fight fatigue in a condition that patients associate with accumulation of toxins in the body. From a behavioural perspective, however, this coping strategy was non-adaptive as it did not combat chronic fatigue; instead, it confirmed patients' beliefs that fatigue was uncontrollable. Instead of pursuing non-adaptive behaviours, for example ‘antitoxic diet’, CBT can help patients to acquire and practise new behaviours that are effective in reducing the sensation and the impact of fatigue.

A minority of participants indicated a self-discovery of such behaviours in the current study, for instance regular physical activity, engaging in pleasurable activities, and ‘active rest’. Indeed, physical activity (particularly graded exercise) has been successfully applied for the treatment of fatigue in cancer and in chronic fatigue syndrome (Jacobsen, Donovan, Vadaparampil, & Small, 2007; White et al., 2011). It remains to be evaluated whether gradually re-introducing pleasurable activities and scheduling active, instead of passive rest could be an active treatment component of HCV-related fatigue.

As the above findings indicate, there are a number of cognitions and behaviours that can be incorporated into a cognitive treatment of fatigue in chronic HCV infection. For example, fatigue attributions can be modified in a single session with a simple, cognitive intervention (Harris & Carney, 2012). Educating patients to recognize a range of modifiable contributors of fatigue (e.g., excessive rest, fatigue-driven coping, feeling upset and guilty when being tired, giving up pleasurable activities) allows them to actively take steps to successfully control their fatigue, instead of accepting it as an inevitable, uncontrollable ‘symptom’ of the illness. Planning activities and following through with the plan, instead of making decisions based on momentary fatigue level, has been the central component of the cognitive-behavioural treatment for fatigue and could be recommended for patients with fatigue-driven coping. Focusing on the physical aspects of fatigue and planning physical activities that do not require bending should be disease-specific themes in CBT for fatigue in patients with HCV infection.

It is noteworthy that some patients attributed their fatigue to comorbid medical conditions (including sleep problems) in addition to the hepatitis infection. These attributions and the contribution of comorbidities to the fatigue experience of patients should be taken into account in fatigue assessment and treatment. There was a variability in the daytime course of fatigue in this study, with some individuals reported that fatigue started early, while for others fatigue became noticable later, during the day. Participants describing that their fatigue started in the morning also experienced sleep problems in this study. Sleep problems, in particular insomnia and obstructive sleep apnoea, are common in chronic medical conditions and cause non-restorative sleep, which patients may describe as morning fatigue (Budhiraja, Roth, Hudgel, Budhiraja, & Drake, 2011; Young, Skatrud, & Peppard, 2004). It is therefore imperative to assess sleep disorders in individuals with chronic medical conditions and high fatigue. For patients with insomnia, CBT is the front-line treatment approach, and sleep-focused CBT for insomnia has been shown to reduce fatigue in medical populations, for example in patients with cancer (Espie et al.,2008; Ritterband et al., 2012). Sleep- and fatigue-focused CBT can also be combined to enhance fatigue outcomes.

The study has refined the CBT model of fatigue as it has captured features of fatigue, cognitions, and behaviours that has not been identified or related to the CBT model in previous research. Notwithstanding the value of using the CBT approach, the authors recognize that their orientation in behavioural medicine and in CBT made a mark on the research questions, the research objectives, and the research design, and by taking a CBT lens, they did not explore fatigue from other (e.g., cultural discourses, environmental, and social) perspectives. A limitation of the data collection was a possible selection bias, as only those willing to discuss their fatigue volunteered to participate. At the same time, these were the individuals for whom fatigue was a pressing issue, and therefore, they may be the ones who would benefit most from fatigue interventions. The inclusion of quotes that contradicted the main findings (e.g., patients' views that chronic fatigue does not always cause functional impairment) reflects the researchers' attempt to demonstrate the validity of the findings (Binderet al., 2012). Using an interview schedule and collecting data until saturation increased the probability that crucially important information relating specifically to the research questions was not missed. The unique strength of the qualitative approach was that it allowed the emergence of themes that could not have been captured with existing questionnaires. Future studies should expand these findings by developing the items identified into a quantitative format and applying it in larger samples.

In conclusion, this study documents for the first time the fatigue experience of patients with chronic HCV infection using a cognitive-behavioural framework. The findings suggest that a cognitive-behavioural conceptualization and treatment could be applied to fatigue in chronic HCV infection. However, the specific aspects of fatigue experience need to be taken into account in the CTB for fatigue in this condition. The key clinical implication of the findings is that CTB would open a new treatment avenue to alleviate fatigue and thus improve the primary patient-reported outcome of chronic HCV infection.

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