Managing Neurologic Complications of Chronic HCV Infection

US Pharm. 2018;43(1):18-22.

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.

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