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Hepatitis C: Beyond the Basics

2.5 Contact Hours including 2.5 Pharmacology Hours
This peer reviewed course is applicable for the following professions:
Advanced Registered Nurse Practitioner (ARNP), Certified Registered Nurse Anesthetist (CRNA), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Midwife (MW), Nursing Student, Registered Nurse (RN)
This course will be updated or discontinued on or before Wednesday, May 4, 2022
Outcomes

This module will discuss the epidemiology, pathophysiology, and transmission of the hepatitis C virus, and the clinical course and treatment of hepatitis C infection.

Objectives

After finishing this module, the learner will be able to:

  1. Identify how hepatitis C is transmitted.
  2. Identify risk factors for hepatitis C transmission.
  3. Identify screening parameters and testing for hepatitis C.
  4. Identify two extrahepatic complications of hepatitis C.
  5. Identify drug therapy and lifestyle modifications used to treat hepatitis C.

Note: This module will focus primarily on chronic infection.

CEUFast Inc. did not endorse any product, or receive any commercial support or sponsorship for this course. The Planning Committee and Authors do not have any conflict of interest.

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To earn of certificate of completion you have one of two options:
  1. Take test and pass with a score of at least 80%
  2. Reflect on practice impact by completing self-reflection, self-assessment and course evaluation.
    (NOTE: Some approval agencies and organizations require you to take a test and self reflection is NOT an option.)
Author:    Dana Bartlett (RN, BSN, MA, MA, CSPI)

Introduction

Hepatitis C is an RNA virus that infects the liver. The hepatitis C virus was isolated and identified in 19891. Since then, targeted screening and highly effective direct-acting antivirals have decreased the incidence of chronic hepatitis C infections and offered a cure rate of 95% to 100%.1 However, hepatitis C is still a major public health problem in the United States. There are approximately 2.4 million Americans who have a chronic hepatitis C infection.2 Chronic hepatitis C can cause cirrhosis and liver cancer,1 and it is an important reason for liver transplantation in the United States.1,2

Note: The term hepatitis means inflammation of the liver. The hepatitis viruses A, B, C, D, and E, can cause hepatitis. However, there are other viral causes of hepatitis, hepatitis can be an autoimmune disease, and drugs and toxins can cause hepatitis.

The hepatitis A virus was first identified in the 1970s and hepatitis B in the 1960s. There was clear evidence that another hepatitis virus existed as there were many cases of hepatitis and transfusion-associated hepatitis that were not caused by hepatitis A or B and at the time, these were referred to as non-A/non-B hepatitis.1

Case Study # 1

A 57-year-old male has made an appointment with his primary care physician. He is in good health, he has no major medical problems, he has no history of psychiatric illnesses, and he does not take any prescription medications. He is moderately overweight (BMI of 27.6), drinks alcohol (occasionally to excess), and smokes one pack of cigarettes a day. The patient has no specific complaints or problems. However, he will be starting a new job that requires strenuous activity, and his employer has requested that he be examined by a physician to determine if he can tolerate this level of physical stress.

During the interview, the man admits to the physician that as a young man, he had experimented with IV drugs for a brief period but has not used any illicit substances for over 35 years. Laboratory tests reveal that his serum AST is 115 IU/L, and his serum ALT is 190 IU/L; these levels are considered moderate elevations, and there are no previous tests for comparison. A test for hepatitis C antibodies is positive, and hepatitis C RNA is detected, as well, genotype 1a. A Fibroscan of his liver reveals a mild level of fibrosis but no cirrhosis. He does not have an infection with HIV, hepatitis A, or hepatitis B, and his CBC, INR, prothrombin time, vitamin D level, thyroid studies, and renal function tests were normal. His serum cholesterol is mildly elevated. The office screening test does not reveal the presence of or risk for depression.

The physician tells the patient that because he is male, because he has probably had the infection for a long time and because he is overweight, occasionally drinks to excess, and smokes, he is at risk for progression to cirrhosis and possibly liver cancer. The physician recommends treatment with antiviral therapy, and the patient agrees he should receive treatment for the hepatitis C infection. She prescribes ledipasvir/sofosbuvir (Trade name Harvoni®), one tablet a day for 12 weeks. The patient is advised that he may experience minor side effects such as diarrhea, fatigue, headache, insomnia, and nausea, but that most patients tolerate the drug very well, and discontinuation because of adverse effects is very uncommon. He is enrolled in a smoking cessation program, provided with a weight reduction diet and an exercise program, and advised to stop drinking alcohol. He is also counseled on safe sex practices, given information on how hepatitis C is transmitted, and he is instructed on how to avoid transmission of the virus. The physician stresses the importance of adherence to the drug regimen. The patient is instructed to contact the physician if he has any intolerable and/or unusual signs or symptoms of if he develops signs and symptoms that are indicative of liver damage, e.g., jaundice.

After four weeks of drug therapy, there is no detectable hepatitis C RNA, and the liver transaminases are within normal limits. Aside from occasional episodes of nausea, the patient has no somatic complaints, and his mood is good. Twelve weeks after finishing the drug regimen, there is no detectable hepatitis C RNA, and his liver transaminases and all other blood tests are within normal limits. The patient has a sustained virologic response (SVR), and because his risk profile is low, the physician informs the patient that he is effectively cured; the risk of a relapse is very, very low. He is encouraged to continue with lifestyle modifications, continue safe sex practices, and continue to avoid behaviors that may put him at risk for reinfection. Because he had only mild fibrosis and no evidence of cirrhosis, no specific follow-up testing is needed.

Transmission Of The Hepatitis C Virus

Transmission of the hepatitis C virus is caused by exposure to infected blood, sexual contact, and mother-to-child transmission.2-4 In approximately one-third of all cases of hepatitis C, the cause of the infection cannot be identified.3

Exposure to Infected Blood

The primary mode of transmission of hepatitis C is by exposure to infected blood,2-4 and in the United States, injection drug use and the sharing of injection equipment is the most common way that hepatitis C is transmitted.2

Transmission of hepatitis C by IV drug use is very efficient.4-7 It has been estimated that within one year of beginning IV drug use, one-third of all users will be infected, and the lifetime prevalence of hepatitis C infection in this population has consistently been found to be > 50% and often much higher.4,6,7 A study published in 2017 reported that in the United States the prevalence of hepatitis C infection in people who inject drugs was 38.1%-68.0%.8 Hepatitis C is more easily transmitted by IV drug use than is HIV,7,9 and recent increases in the incidence of hepatitis C infection have been directly linked to IV drug use and the opioid epidemic.7,9

The risk of hepatitis C transmission and infection from a needle stick injury or other types of healthcare occupational exposure appears to be quite low.9-11 Naggie et al. (2017) reviewed 12 studies (1992 to 2012) that described 3,929 healthcare occupational exposures to hepatitis C.9 Most of the cases were needlestick injuries, and the transmission rate of hepatitis C was 0-10%. In three of the studies, there were no incidents of hepatitis C transmission, and in 11 of the 12, the rate of transmission was in single digits.8 Egro et al. (2017) retrospectively reviewed 1,361 healthcare exposures to hepatitis C contaminated blood (72.7%) or other body fluids.11 There were 885 percutaneous and 476 mucous membrane exposures and two employees seroconverted, a transmission rate of 0.1%.11

The risk of hepatitis C transmission from a blood transfusion has been estimated to be 1 case per 2 million units of transfused blood.2

Hepatitis C can be transmitted by exposure to contaminated blood during tattooing, body piercing, and dental and medical procedures.2,4 The level of risk for hepatitis C transmission during hemodialysis is not known. Studies performed before 2006 reported that the seroconversion rate in hemodialysis patients was 0.34% to 0.97%.12,13 From 2008 to 2018 there were 22 outbreaks of hepatitis C in hemodialysis units that were reported to the Centers for Disease Control and Prevention (CDC) and 104 patients who became infected.14 All of the outbreaks were caused by failure to adhere to standard precautions and infection control techniques.14

Horizontal, non-sexual transmission of hepatitis C can happen,2,4,15 perhaps when blood-contaminated personal care items like nail clippers or razors are shared. However, given that hepatitis C has been isolated in other body fluids and that it can survive in the environment outside of a host, determining how and how often this type of transmission occurs is very difficult.15

Sexual Transmission

Hepatitis C has been found in cervical secretions, menstrual blood, semen, and vaginal secretions,3,9,17 but sexual transmission of hepatitis C between monogamous heterosexual partners who are not IV drug users appears to be very uncommon.4,16-19 Terrault et al. (2013) reported that in monogamous heterosexual adults who were not IV drug users - and of whom 83% reported that they did not use condoms - the incidence of sexual transmission of hepatitis C was 0.07% per year or approximately one transmission of the virus per 190,000 sexual contacts.16

The risk of sexual transmission of hepatitis C is increased for people who have multiple sex partners or who have sexually transmitted infections.5

The incidence of hepatitis C in men who have sex with men (MSM) has been reported to be three times that of the general population20 and hepatitis C is a commonly occurring disease in MSM who are, and who are not co-infected with HIV.20-22 Infection with HIV, the presence of ulcerative sexually transmitted diseases, and sexual behaviors that increase the risk for hepatitis C transmission are the likely causes for this difference.20-22

Mother to Child Transmission

Mother to child transmission of hepatitis C occurs in 3%-15% of all pregnancies23 and 3% to 5% of the infections will become chronic.23 The risk of mother to child transmission is increased if the mother is infected with HIV.23 Each year there are approximately 10,000-20,000 births to mothers who are infected with hepatitis C.24

Possible Modes of Transmission

Infectious levels of hepatitis C RNA have been detected in cerebrospinal fluid, saliva, sweat, tears, urine, and other body fluids.3,9,15 There are no documented cases of hepatitis C transmission after contact with these fluids; this may be because the fluids contain a relatively the low viral load in comparison to blood.9 However, the possibility of transmission after contact with these fluids cannot be ruled out.3

The hepatitis C virus can survive and remain infectious on environmental surfaces for weeks,25 and it can survive and remain infectious in a syringe for weeks, as well.25

Hepatitis C is not transmitted by coughing, casual physical contact like holding hands or hugging, by sharing eating and/or drinking utensils, or through food or water.2

Risk Factors For Developing Hepatitis C

Factors that increase the risk of developing hepatitis C are listed in Table 1.

Table 1: Risk Factors for Hepatitis C Infection26-30
Alcohol abuse, past or present
Children born to a mother infected with hepatitis C
Chronic liver disease or chronic hepatitis for which there is no clear cause
Healthcare, emergency medical services, and public service personnel who had a needle stick, a sharps injury, or mucosal exposure to hepatitis C infected blood
HIV infection
Injection drug use, past, present, including a one-time use
Intranasal illicit drug use
Long term hemodialysis, even if the patient is no longer being dialyzed
Men who have sex with men
People who are or have ever been incarcerated
People who have had a percutaneous or parenteral exposure to blood in an unregulated setting, e.g., unregulated tattooing
Prior recipients of blood transfusion(s) or an organ transplant, including persons who were notified that they received blood from a donor who later tested positive for HCV, or received a transfusion of blood or blood components, or underwent an organ transplant before July 1992, or received clotting factor concentrates produced before 1987
Sexually active persons about to start pre-exposure prophylaxis for HIV
Solid-organ donors (deceased and living) and solid organ transplant recipients

Infection with hepatitis C is much more common in people who abuse alcohol or who were heavy drinkers.27-28 The prevalence of hepatitis C infection in people who abuse alcohol has been estimated to be 14%-36%,29 and alcohol use in patients infected with hepatitis C increases the risk for cirrhosis, the progression of fibrosis, and liver cancer.27-29

Birthdate of 1945 to 1965 had been considered a risk factor for hepatitis C because, for many years, ~ three-fourths of chronic hepatitis C cases occurred in people born during that time. However, in the past decade, the epidemiologic characteristics of hepatitis C in the United States have changed, and currently, most cases are caused by illicit drug use and/or the opioid epidemic and occur in people born after 1965.26

Natural History Of Hepatitis C Infections

A hepatitis C infection begins with acute exposure, and acute exposure is followed by one of three outcomes.

  1. Acute infection and spontaneous viral clearance: 15%-25%% of acute infections will be spontaneously cleared.2,31
  2. Chronic infection, uncomplicated: 75% to 85% of people who have an acute hepatitis C infection will not clear the virus, and the infection becomes chronic.2,31,32 Approximately 30% of these patients will not develop fibrosis, significant liver damage, or other complications.
  3. Chronic infections, complicated: 70% of patients who have chronic hepatitis C infection will develop fibrosis of the liver.32 The infection is dormant for many years before fibrosis begins, and the progression of fibrosis is variable. In some patients, the fibrosis progresses over several decades, and for others, it will develop more quickly, i.e., in < 20 years.32 In either situation, cirrhosis happens to ~ 20% of patients who have liver fibrosis, and 1%-4% of patients will develop decompensated liver damage or hepatocellular cancer.31 For most patients who have chronic hepatitis C, the infection does not increase the risk of death, and it is not a significant cause of mortality.31,32

Acute Hepatitis C Infection

The signs and symptoms of acute hepatitis C begin several weeks after exposure; the reported range of the time of onset is 2 to 26 weeks.2 Most patients who have an acute infection are asymptomatic, but 20%-30% will develop non-specific signs and symptoms like abdominal pain, anorexia, fatigue, fever, nausea, and vomiting2; signs, like jaundice, that indicate liver damage can occur, as well.2 Serum aminotransferase levels can be very elevated, 10-20 times the upper limit of normal. However, the aminotransferase levels can also decrease, increase, and vary considerably during an acute hepatitis C infection, from very low to very high.33,34 Antibodies that have been formed against the virus are usually detectable 8-11 weeks after infection.2 Hepatitis C RNA can be detected as early as two weeks after an infection.2

Clinical and biochemical recovery from an acute hepatitis C infection is usually complete within 3 to 6 months.5,33

There are likely multiple causes and /or mechanisms by which a hepatitis C infection can be spontaneously cleared,2,33,35,36 including but not limited to:

  1. Host factors like female gender, patients who have a chronic or resolved hepatitis B infection, variations in immune system response, specific genetic polymorphisms of the virus, and the young age of the patient when first infected.
  2. Viral factors, e.g., infection with genotype 1.
  3. Other factors like a recent surgery or treatment of an HIV infection with highly active antiretroviral therapy (HAART).2,33,35,36

Spontaneous clearance of hepatitis C virus will not prevent re-infection with the same genotype or with other genotypes of the virus.2,33

Chronic Hepatitis Infection

A hepatitis infection that has not been spontaneously cleared by six months is considered chronic. Most patients who have a chronic hepatitis C infection, even those with fibrosis and cirrhosis, are asymptomatic.2,31,32 The symptoms that do occur are non-specific or are caused by an extrahepatic complication (The latter will be discussed later),2,31,32 and serum transaminase levels in these patients are usually normal or mildly elevated.31,32 Cirrhosis develops in ~ 20% of patients, usually over 20-30 years; factors that increase the risk of developing cirrhosis are listed in Table 2.

Table 2: Risk Factors for Cirrhosis and Extrahepatic Complications27-29,31,32
Age > 40 years when the infection occurred
Alcohol abuse
Diabetes mellitus with insulin resistance
Duration of the infection; the longer the duration, the greater the risk
Hepatitis B infection
HIV infection
High level of fibrosis and inflammation
Male gender
Obesity
Pre-existing liver disease

Hepatic decompensation with ascites, bleeding, and encephalopathy32,36 is an uncommon complication of hepatitis C, occurring in ~ 4% of patients per year who have cirrhosis.31,32 Hepatocellular cancer occurs in ~ 1% of patients per year,37 and the risk is for cancer is much higher for patients who have cirrhosis.37

Screening For and Diagnosing Hepatitis C

Screening

The American Association for the Study of Liver Diseases (AASLD) and The Infectious Diseases Society of America (IDSA) state that screening for hepatitis C based only on the birth cohort (1945 to 1965) or on the presence of certain risk factors is inadequate.26 The AASLD/ISDA recommendations for screening for hepatitis C are in Table 3.26

Table 3: AASLD/ISDA Recommendations for Hepatitis C Screening
All adults 18 years of age and older: One time, opt-out screening
One-time screening on all persons < age 18 who have behaviors, conditions, circumstances, or exposures that are associated with an increased risk of hepatitis C infection
Annual screening for hepatitis C is recommended for anyone who injects drugs and for men who are infected with HIV and who have unprotected sex with other men

Testing

Tests for hepatitis C are the anti-hepatitis C antibody test, measurement of hepatitis C RNA, and determining the hepatitis genotype.

Testing for hepatitis C begins with an anti-hepatitis C antibody test.26,38 The test can be done using blood, a dried blood spot, plasma, serum, a finger stick, or oral fluids.

If the antibody test is negative, the patient does not have chronic hepatitis C, or the test result could be a false negative; a false negative can occur if the patient is infected with HIV, on hemodialysis, or is immunocompromised.26, 28 The antibody test can also be negative if the patient was recently exposed - within the past six months - and anti-hepatitis C antibodies have not yet formed.

For patients who could have been exposed in the past six months, another antibody test can be done in 6 months, or a test for hepatitis C RNA can be done.

If the antibody test and the RNA test are negative, the patient does not have hepatitis C.26

If the antibody test is positive, but the RNA test is negative, the patient does not have acute or chronic hepatitis C infection. However, he/she could be reinfected.26 In this situation, the positive antibody test likely represents prior infection that has been spontaneously cleared or cleared by drug therapy, but a false-positive antibody test can occur, as well.38 If it is suspected that the positive antibody tests are a false positive, a different type of antibody test can be done.26

If the antibody test is positive, and the RNA test is positive, the patient has hepatitis C.

There are at least six hepatitis C genotypes and dozens of subspecies.

Treatments that are effective against multiple genotypes are now available, but genotype testing is not needed unless the patient has been treated before and the virus was not cleared.26

Quantitative measurement of hepatitis C RNA, commonly called the viral load, should be done before drug therapy.26

Chronic Hepatitis C: Initial Evaluation

Evaluation for Fibrosis

Chronic hepatitis C infection causes inflammation of and damage to liver cells,39 resulting in hepatic fibrosis.39 Fibrosis is, essentially, the replacement of functional liver cells by scar tissue. Untreated fibrosis can be mild and reversible, but stage 3 bridging fibrosis and stage 4 fibrosis (the latter is also called cirrhosis) may not be reversible, and bridging fibrosis and cirrhosis are risk factors for liver decompensation and hepatocellular cancer. Note: Hepatic decompensation refers to the signs, symptoms and clinical conditions that can occur when liver damage is severe and hepatic function is compromised, e.g., ascites, bleeding, esophageal varices, and hepatic encephalopathy.

Cirrhosis is the last stage of fibrosis, and it is characterized by a specific pattern of liver tissue damage and by decreased liver size and function. Cirrhosis can be reversed, but it can also progress and cause serious complications like hepatic encephalopathy, esophageal varices, and hepatocellular cancer.

Accurately staging a patient’s level of fibrosis and determining if she/he has cirrhosis identifies patients at risk for serious complications, and staging can be used to predict outcomes.39 Liver fibrosis in patients who are infected with hepatitis C can be detected and evaluated with invasive or non-invasive techniques.40

Invasive Technique

Liver biopsy was long considered the gold standard test for detecting liver fibrosis. However, liver biopsy is invasive. Pain, bleeding, and significant complications like punctured gall bladder and pneumothorax can occur, and the procedure is associated with a mortality rate of 0.33%.40-42 Also, the amount of tissue that is sampled and examined is very small, approximately 1/50,000 of the liver’s mass, thus sampling errors can occur, and there can be significant variability in intra and inter-observer assessment of the degree of fibrosis.40,43 The usefulness of liver biopsy is also limited because liver tissue is examined at one point in time, fibrosis is a dynamic, ongoing process, and repeating the liver biopsy is not practical.41 A liver biopsy may be needed if the results of noninvasive testing are equivocal or if the patient may have another liver disease, as well.26,39

Non-invasive Techniques

Non-invasive techniques for detecting and determining the degree of fibrosis are:

  1. Blood tests that provide an indirect or direct measurement of fibrosis, and
  2. imaging tests

These are the preferred methods for detecting liver fibrosis and for determining the level of fibrosis in patients who have hepatitis C.

Blood tests-indirect measurement: Indirect measurements of fibrosis use patient data, e.g., age and weight, and laboratory tests. The laboratory tests may be routine tests like measurements of albumin, AST and ALT, and platelets, or they may be measurements of enzymes, proteins, and other compounds like α2-macroglobulin, gamma-glutamyl transferase (GGT), and haptoglobin that are produced by the liver.40,41,44

In either case, the patient information and test results are combined to provide a score that reflects the degree of liver fibrosis. Examples of tests that provide an indirect measurement of fibrosis include the AST to platelet ratio (APRI), the non-alcoholic fatty liver disease (NAFLD) fibrosis score, FIB-4, ActiTest, Fibrosure, Fibro Test, and Hepascore.40,44

Blood tests-direct measurement: Blood tests that provide a direct assessment of liver fibrosis combine measurement of compounds that are involved in the buildup and breakdown of the hepatic matrix, measurement of enzymes, measurement of cytokines and chemokines that are associated with fibrogenesis, and measurement of proteins and other compounds like α2-macroglobulin, gamma-glutamyl transferase (GGT), haptoglobin that are produced by the liver.40,44 Examples include FibroSpect II and the European Liver Fibrosis panel (ELF).44

Imaging tests: The primary imaging technique used to detect the presence and degree of liver fibrosis in patients who have hepatitis C is shear wave elastography.44,45 Shear wave elastography uses different modes of impulse formation that generate shear waves in the liver.44,45 Healthy liver tissue and fibrotic liver tissue respond to the shear waves in different ways, and shear wave elastography is a safe and accurate way of detecting and grading liver fibrosis in patients who have hepatitis C.42,44,45 There are different ways in which shear waves can be generated. In the United States, the most commonly used method is vibration-controlled transient elastography.42 A hand-held probe is placed on the abdominal wall, and the shear waves are displayed on a monitor; the procedure takes little time to complete, and it can be done at the bedside or in an office.

Each of the indirect and direct blood tests for detecting and evaluating fibrosis has advantages and disadvantages, e.g., specificity, positive predictive value, and none of the specific tests is universally considered to be part of the standard of care.44 As for imaging tests, the American Gastroenterology Association recommends using vibration-controlled transient elastography.42 However, their review (2017) did not compare this technique with other imaging techniques and other techniques, i.e., point shear wave elasticity (Point-SWE), and 2D-SWE have been found to compare favorably with transient elastography.46

Laboratory Tests

If the presence of a chronic hepatitis C infection has been confirmed, and treatment is planned, the laboratory tests listed in Table 4 should be done.26,38,47 The need for blood glucose, BUN, and creatinine will be explained in the sections on extrahepatic complications and drug therapy. Vitamin D deficiency may be a contributing cause of hepatitis C infection or a result of the infection, and vitamin D deficiency may cause hepatic damage in infected patients.48

Table 4: Hepatitis C Pre-Treatment Laboratory Studies
Albumin
Anti-hepatitis A antibodies
Bilirubin
Blood glucose
BUN and creatinine
Estimated glomerular filtration rate (eGFR)
Hepatitis B surface antigen, hepatitis B surface antibody, and hepatitis B core antibody
Hepatitis C genome and hepatitis C viral load
HIV
INR
Pregnancy test
Serum transaminases
25-hydroxy vitamin D

Extrahepatic Complications of Hepatitis C Infection

Extrahepatic complications are common in patients infected with hepatitis C, and essentially every organ system can be adversely affected by the virus. Some complications are rare, some are common, and the relationship of the hepatitis C infection to an organ system dysfunction or a specific complication:

  1. Might be a clear cause and effect.
  2. Might be an association but with no evidence that the virus is the direct cause of harm.
  3. Might be in the form of an aggravating factor, i.e., hepatitis C may increase the risk of developing complications like type 2 diabetes mellitus (DM) in patients who have risk factors for that disease.

Cognitive and Psychiatric

Depression, fatigue, mood disorders, memory deficits, and cognitive impairment are common in patients who have chronic hepatitis C infection49-52; for example, the prevalence of depression in people who have hepatitis C is higher than in the general population.49,53 These cognitive and psychiatric complications can occur in patients who are infected but who do not have liver dysfunction,52 and their cause is likely multi-factorial. They may be caused by a preexisting psychiatric illness, they may be an expected emotional and psychological consequence of having a chronic infection, and there is evidence that the hepatitis C virus itself and the inflammatory state caused by the infection can directly injure the brain and CNS.49-51 Viral clearance after treatment with direct-acting antiviral drugs has been shown to improve the psychological complications of the disease,54 but these cognitive and psychiatric problems may persist after a cure, as well.49

Diabetes

Chronic hepatitis C infection has been consistently associated with type 2 diabetes mellitus (DM).52,55-59 The prevalence of DM is higher in people infected with hepatitis C, and infection with hepatitis C may increase the risk of developing type 2 DM,56 especially in patients who have risk factors for type 2 DM.55 How and when hepatitis C causes and/or increases the risk for type 2 DM is not known.52 Insulin resistance is quite common in hepatitis C infected patients - a prevalence as high as 62% has been reported60 - and insulin resistance can occur in infected patients who do not have significant fibrosis or cirrhosis.61

Mixed Cryoglobulinemia

Mixed cryoglobulinemia is one of the most common extrahepatic complications of hepatitis C infection. Mixed cryoglobulinemia is an immune system-mediated process that causes the formation of specific immunoglobulins called cryoglobulins.62 The cryoglobulins are deposited in small and medium-sized blood vessels,62 causing obstruction and/or vasculitis,62,63 arthralgia, skin disorders like necrotic ulcers and purpura, renal complications like glomerulonephritis, and neurologic complications like peripheral neuropathy.52,62-66 The skin, joints, kidneys, and peripheral nervous system are affected most often, but cardiovascular, gastrointestinal, and pulmonary complications can occur.64

Between 40-60% of patients who have chronic hepatitis C infection have mixed cryoglobulinemia.67

Renal

The prevalence of hepatitis C infection in patients who have chronic kidney disease (CKD) and end-stage renal disease is very high,68,69 much higher than in the general population.69 Hepatitis C infection has been associated with an increased progression of CKD69,70 and increased morbidity and mortality in hemodialysis patients.70 Hepatitis C can also cause renal damage, usually by cryoglobulinemia, or possibly by a direct effect on the kidneys.69,70

Cancer and Hepatitis C

Hepatitis C is the leading cause of hepatocellular cancer in the United States,71 and hepatocellular cancer is an important cause of mortality in patients who have chronic hepatitis C infection.32,72 Between 1%-4% of chronically infected patients will develop hepatocellular cancer,31 and the risk of hepatocellular cancer is much higher for patients who have advanced fibrosis or cirrhosis.32,73

Hepatitis C has also been proven to cause B-cell non-Hodgkin lymphomas,74,75 and hepatitis C has been associated with an increased risk of other cancers, as well.74,75

Hepatitis C and HIV Co-Infection

Co-infection with hepatitis C and HIV is common; estimates of the prevalence of co-infection range from 6.2% to 37% and 80% to 90%, in people who are injection drug users.76

An HIV infection in patients who have chronic hepatitis C contributes to a poor prognosis. An HIV infection increases replication of the hepatitis C virus, it increases the progression of fibrosis, it increases the risk of developing cirrhosis, and it diminishes the response to the direct-acting antivirals.77-80 Co-infection with hepatitis C and HIV also increases the risk of developing hepatocellular cancer,77,78 and hepatitis C infection is a common cause of death in people who have an HIV infection.79

Hepatitis C infection does not appear to affect the clinical course of HIV infection adversely.79,80

Treatment: Drug Therapy

Treatment with direct-acting antiviral drugs is the standard of care, and it is recommended for all adults who have acute or chronic hepatitis C infection.26,31 Exceptions are adults who have a short life expectancy, and for whom antiviral therapy, liver transplantation, or other treatments would not affect longevity.26,31

Interferon-based regimens are no longer used, and ribavirin, an antihepaciviral/nucleoside which was previously part of the standard treatment regimen for hepatitis C, is now only used in a few specific circumstances.

The direct-acting antivirals inhibit viral growth, viral replication, and viral maturation. There are three types of direct-acting antivirals used to treat hepatitis C: NS3/4A protease inhibitors, NS5B polymerase inhibitors, and NS5A protein inhibitors. Each type targets a specific enzyme or a protein that is essential for the virus’s life cycle and replication, and direct-acting antivirals from these different categories are used in combination, not as single agents.

The currently available direct-acting antiviral drugs are very effective. More than 95% of treated patients have a sustained viral response (SVR), the medications are simple to take, and the adverse effects are mild.26,31 Also, treatment with direct-acting antivirals can prevent, slow the progression of, and reverse cirrhosis and fibrosis; reduce the risk of hepatocellular cancer and reduces the mortality rate, and; have a positive effect on many of the extrahepatic complications of hepatitis C infection.26,32,52,54,60,71,82-84 Hepatitis C has been called the only chronic viral infection that can be cured.84

Note: Sustained viral response is defined as no hepatitis C RNA detected in the blood 12 weeks after antiviral therapy has been completed.

Basic Drug Therapy for Chronic Hepatitis C

The American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (ISDA) operate a website, HCV Guidance: Recommendations for Testing, Managing and Treating Hepatitis C (www.hcvguidelines.org/), and the website has basic clinical guidelines advice and hepatitis C treatment regimens. 

The regimens differ depending on factors including (but not limited to) the presence or absence of cirrhosis, previous treatment for hepatitis C and the genotype and subspecies of the virus. 

The AASLD/ISDA developed two simplified treatment plans for two specific patient populations.26 These two treatment plans (listed below) and the drugs they use are discussed here; treatment plans for other clinical situations of hepatitis C infection can be viewed on the AASLD/ISDA website. 

  1. Patients who have chronic hepatitis C infection, genotype 1-6, who are treatment naïve, and who do not have cirrhosis.
  2. Patients who have chronic hepatitis C infection, genotype 1-6, who are treatment naïve, and who have compensated cirrhosis.

These two plans should not be used in any of the clinical conditions/situations listed in Table 5.26 Specific treatment plans for these clinical conditions/situations are available, and they are discussed later in this section. 

The AASLD/ISDA website also developed regimens for many other patient populations, e.g., a patient who has genotype 3 with decompensated cirrhosis and has previously been treated with interferon and ribavirin. All the recommended treatment regimens can be viewed on the website, www.hcvguidelines.org/.

Table 5: Simplified Hepatitis C Treatment Regimens Contraindications
If the patient is hepatitis B surface antigen-positive
If the patient is HIV surface antigen positive
Women who are pregnant
Patients who have had a liver transplant
The patient has known or suspected hepatocellular cancer
Patients who have decompensated cirrhosis
The patient has end-stage renal disease, eGFR <30 mL/min/m2

Chronic Hepatitis C, Treatment Naïve, No Cirrhosis

Two drug regimens are recommended, glecaprevir mg/pibrentasvir or sofosbuvir/velpatasvir. Either one can be used, and both are effective for treating hepatitis genotypes 1-6.90,91

Before initiating treatment26:

  1. Calculate the FIB-4 score: The FIB-4 score uses the patient’s age and measurement of platelet count, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) to estimate the degree of liver fibrosis.26 The FIB-4 score is a reliable way to determine the presence and degree of liver fibrosis.85
  2. Determine the absence/presence of cirrhosis: A patient is presumed to have cirrhosis of the FIB-4 score is > 3.25 or if any of the following are present: Clinical evidence of cirrhosis, e.g., liver nodularity and/or splenomegaly seen by an imaging study; a platelet count < 150,000 mm3; cirrhosis detected by liver biopsy; cirrhosis detected by transient elastography, or; a non-invasive serologic test result, e.g., a Fibrosure score, that is above the cut-off point for cirrhosis.26
  3. Blood tests: Six months or less before starting treatment, these blood tests should be done: AST and ALT, CBC, eGFR, serum albumin, and total and direct bilirubin. Before starting treatment, measure the hepatitis C RNA level, check for HIV antibody and antigen and check for hepatitis B surface antigen.26 Do a serum pregnancy test.26
  4. Medication list: Determine what prescription and over-the-counter medications the patient is taking. Be sure to ask the patient if he/she is taking alternative medicine products, dietary supplements, or herbal products. Check for drug-drug interactions between the direct-acting antivirals that will be prescribed and the medications, supplements, etc. that the patient is taking.
    1. Patients who take medications for the treatment of diabetes mellitus should be advised that the direct-acting antivirals used in these protocols can affect glucose metabolism.26 Treatment with direct-acting antivirals can decrease insulin resistance86 and in patients who have an SVR in response to treatment, fasting plasma glucose and glycated hemoglobin level, HbA1c, can be significantly reduced.86,87 Because of this, patients who continue taking the same doses of the same anti-diabetic medications may develop symptomatic hypoglycemia.88
    2. Concomitant use of direct-acting anticoagulants and warfarin decreases the effectiveness of warfarin and can cause a sub-therapeutic INR.26,89
  5. Provide patient counseling: This will be discussed later in the module in the Patient Education section.

Glecaprevir 300 mg/pibrentasvir 120 mg (Mavyret™)

Glecaprevir/pibrentasvir is an NS3/4A protease inhibitor/NS5A protein inhibitor combination.

Dose: Three tablets taken once a day, with food, for eight weeks.90

Dosing/geriatric: No dosing adjustments are needed.90

Dosing/hepatic impairment: Mavyret can be used in patients who have compensated cirrhosis, Child-Pugh score A,26,90 and no dosing adjustment is required.90 See Contraindications and Warnings and precautions for other information about Mavyret and patients who have hepatic impairment.

Dosing/renal impairment: No dosing adjustments are needed.

Contraindications: Glecaprevir 300 mg/pibrentasvir should not be taken by patients for whom ribavirin is contraindicated.90

Mavyret is contraindicated in patients who have moderate to severe hepatic impairment, Child-Pugh score B or C and in patients who have evidence of previous episodes of hepatic decompensation.90

Child-Pugh Classification System
The Child-Pugh classification system measures albumin, bilirubin, and prothrombin time or INR. It assigns a point score to each test result based on the numerical value of the result, and the total score can be used to determine the one-year survival rate in patients who have cirrhosis. The scores are divided into 3 categories: 5-6, category A, mild hepatic impairment; 7-9, category B, moderate; > 9, category C, severe. Patients who are category B or C have decompensated cirrhosis.
This example illustrates how the system is used.
  • Total bilirubin is > 50 mg/dL = 3 points
  • Serum albumin is 2.8-3.5 g/dL = 2 points
  • Prothrombin time is > 6.0 = 3 points
  • Ascites is mild = 2 points
  • Hepatic encephalopathy is absent = 0 points
This patient has a Child-Pugh score of 10 and has category C, severe hepatic impairment

US Boxed Warning: Hepatitis B virus reactivation has been reported in hepatitis C/hepatitis B coinfected patients who were undergoing or had completed treatment with hepatitis C direct-acting antivirals, and who were not receiving hepatitis B antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death.90

Note: Treating patients who are infected with hepatitis B and C will be discussed later in the module.

Warnings and precautions: In August 2019, the FDA issued a safety warning about Mavyret and two other direct-acting antivirals.91

“The Food and Drug Administration (FDA) has received reports that the use of Mavyret, Zepatier, or Vosevi to treat chronic hepatitis C in patients with moderate to severe liver impairment has resulted in rare cases of worsening liver function or liver failure. In most patients, symptoms resolved, or the worsening of liver function improved after stopping the medicine. In most cases, liver failure or decompensation typically occurred within the first four weeks of starting treatment.91

The safety warning notes that the majority of the patients who had severe outcomes had moderate or severe hepatic impairment (Child-Pugh B or C) before they took these drugs; some patients with mild hepatic impairment (Child-Pugh A) before antiviral therapy had had prior episodes of hepatic decompensation, and; there were rare cases of patients who did not have any degree of hepatic impairment but who had evidence of portal hypertension and who developed hepatic decompensation/liver failure.91 Also, some patients had risk factors for hepatic decompensation/liver failure like alcohol abuse or liver cancer.91

The FDA recommended that healthcare professionals should continue to use Mavyret, Zepatier, or Vosevi as indicated by the prescribing information, do a baseline assessment of liver function before starting antiviral therapy, and to closely monitor patients for signs and symptoms of liver failure.92

Adverse effects: During clinical trials, > 5% of patients had headache (13%), fatigue (11%) and nausea (8%).90

Drug interactions: The Lexicomp® Drug Interaction database lists 92 drug-drug interactions involving glecaprevir and pibrentasvir, and many of these involve commonly used drugs like antidiabetics, antiepileptics, statin drugs, and warfarin.

Drug-drug interactions can be checked by using the University of Liverpool, drug interaction checker.26 The website address is www.hep-druginteractions.org/checker. The AASLD/ISDA website has drug-drug interaction information, as well.

Monitoring: If there are no signs and symptoms of liver damage, there is no need to do laboratory testing during the treatment.

Twelve weeks or later, after the last dose, obtain a quantitative measurement of hepatitis C RNA and do a hepatic function panel: A hepatic panel should measure albumin, alkaline phosphatase, ALT, AST, and total and direct bilirubin.

If SVR has been attained and the AST and ALT are normal, no further treatment or follow-up is needed.26

If an SVR has been attained, but the AST and ALT are elevated, the patient should be assessed for other causes of liver damage.26

If an SVR has not been attained, the patient should be referred to a specialist.26

Treatment failure will be discussed later in the module.

During clinical trials of glecaprevir/pibrentasvir, 99% of patients who had genotype 1 had an SVR. The SVR for the other genotypes was 98% (genotype 2), 93% (genotype 4), 95% (genotype 5), and 100% (genotype 6).90 Patients who had genotype three were not included in these clinical trials.

Sofosbuvir 100 mg/velpatasvir 100 mg (Epclusa™)

Sofosbuvir/velpatasvir is an NS5A protein inhibitor/NS5B polymerase inhibitor.

The package insert for Epclusa, the brand name form of sofosbuvir/velpatasvir, recommends one dosing regimen for genotypes 1-6 in patients who are treatment naïve and who do not have cirrhosis or who have compensated cirrhosis.92

However, the AASLD/ISDA algorithm states that if the patient has genotype 3, drug resistance testing should be done.26 If drug resistance testing reveals that the patient has a specific hepatitis C genetic polymorphism, the Y93H polymorphism, a lower SVR may occur, and the AASLD/ISDA recommends that the patient should be treated with sofosbuvir/velpatasvir and weight-based ribavirin or with another drug, e.g., sofosbuvir/velpatasvir/voxilaprevir.26,93,94

Dosing: Once tablet, once a day, for 12 weeks.92

Dosing/geriatric: No dosing adjustments needed.92

Hepatic impairment: Patients who have a mild, moderate, or severe hepatic impairment, Child-Pugh A, B, or C, no dosing adjustment needed.92

Renal impairment: Patients who have mild, moderate, or severe renal impairment, including patients who have ESRD and require hemodialysis, no dosing adjustments needed.92

Contraindications: Epclusa is contraindicated in patients for whom ribavirin is contraindicated.92

US Boxed Warning: Hepatitis B virus reactivation has been reported in hepatitis C and hepatitis B coinfected patients who were undergoing or had completed treatment with hepatitis C direct-acting antivirals, and who were not receiving hepatitis B antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death.92

Warnings and precautions: Concurrent use of sofosbuvir/velpatasvir and amiodarone can cause serious, symptomatic bradycardia. This is especially likely if the patient is also taking a beta-blocker or if she/he has cardiac disease and/or advanced liver disease.92

P-glycoprotein (P-GP) is a transport protein, and one of its primary functions is to move xenobiotics out of cells. P-glycoprotein inducing drugs like carbamazepine and phenytoin can lower the plasma level of sofosbuvir/velpatasvir and reduce its therapeutic effectiveness.92,93 Drugs that are moderate to strong inducers of CYP2B6, CYP2C8, and CYP3A4 can have this effect, as well.92

Adverse effects: Adverse effects occurring in > 5% of patients are asthenia (lack of energy, weakness), fatigue, headache, insomnia, and nausea.91

Drug interactions: The Lexicomp® Drug Interactions database lists 93 drug-drug interactions involving sofosbuvir/velpatasvir, and many involve commonly used medications like anti-diabetic medications, e.g., glipizide and metformin, and warfarin.95

Drug-drug interactions can be checked by using the University of Liverpool, drug interaction checker.26 The website address is www.hep-druginteractions.org/checker. The AASLD/ISDA website has drug-drug interaction information, as well.

Monitoring: If there are no signs and symptoms of liver damage, there is no need to do laboratory testing during the treatment.

Twelve weeks or later, after the last dose, obtain a quantitative measurement of hepatitis C RNA and do a hepatic function panel. If SVR has been attained and the AST and ALT are normal, no further treatment or follow-up is needed.26

If an SVR has been attained, but the AST and ALT are elevated, the patient should be assessed for other causes of liver damage.26

If an SVR has not been attained, the patient should be referred to a specialist.26

Treatment failure will be discussed later in the module.

During clinical trials, the SVR for all patients, with or without compensated cirrhosis, genotypes 1,2, 4,5, and 6, was 99%.9

Chronic Hepatitis C, Treatment Naïve, Compensated Cirrhosis

Perform the same pretreatment assessment as for patients without compensated cirrhosis, and in addition26:

  1. Calculate CTP score: If the Child-Turcotte-Pugh (CTP) score is ≥ 7, CTP-B or CTP-C, the patient has decompensated cirrhosis and should not be treated with these regimens. (Note: The CTP and the Child-Pugh are the same).
  2. Do an ultrasound of the liver within six months or less of starting treatment; this is done to exclude the presence of hepatocellular cancer and subclinical ascites.26

Either glecaprevir 300 mg/pibrentasvir 120 mg, or sofosbuvir 100 mg/velpatasvir 100 mg can be used.26

During treatment with these specific drugs, it may be prudent to do laboratory testing for liver damage. Some patients who have cirrhosis and take direct-acting antivirals can develop hepatic decompensation. If the patient has physical or laboratory evidence of liver damage, she/he should be referred to a specialist.

Twelve weeks or later, after the last dose, obtain a quantitative measurement of hepatitis C RNA and do a hepatic function panel. If SVR has been attained and the AST and ALT are normal, no further treatment or follow-up is needed.26

If an SVR has been attained, but the AST and ALT are elevated, the patient should be assessed for other causes of liver damage.26

If an SVR has not been attained, the patient should be referred to a specialist.26

Hepatitis C and Hepatitis B Co-Infection

The AASLD/ISDA simplified treatment guidelines state that if the patient is positive for hepatitis B surface antigen (Acutely or chronically infected), direct-acting antivirals are contraindicated.26 The prescribing information of the direct-acting antivirals advises that use of these drugs in patients who have, or who had hepatitis B infection can cause worsening of hepatitis B (a flare) or a reactivation, i.e., loss of immune control, and increased hepatitis B viral replication, during and after drug therapy.

Hepatitis B flare and/or reactivation does occur during direct-acting antiviral therapy,96-99 primarily in patients who are hepatitis B surface antigen positive97,99,100 but also in patients who have hepatitis B antibodies or who have an occult infection, i.e., hepatitis B surface antigen-negative but detectable hepatitis B DNA.97,100 The risk for reactivation has been reported to be 2%-57%,97 but serious liver damage in these cases is rare.97,99

There is very little information about the use of direct-acting antivirals to treat chronic hepatitis C in patients who were, or currently are infected with hepatitis B.96 Chopra et al. (2019) and Abdelaal et al. (2019) recommend that if treatment for chronic hepatitis is planned, patients who meet the criteria for treatment of hepatitis B should be treated, either before or during the hepatitis C treatment.100,101 The AASLD/ISDA website states that for patients who are on direct-acting antiviral therapy, who are hepatitis B surface antigen-positive but are not going to be treated because the hepatitis B DNA level is low, one of two approaches can be used:

  1. Monitor the hepatitis B DNA level once a month during and after direct-acting antiviral treatment. (Note: It is not mentioned how long after drug therapy has finished the monitoring should be continued) If the level increases by 10-fold above the baseline or if it becomes > 1000 IU/mL, start hepatitis B antiviral therapy.
  2. Start hepatitis B antiviral therapy and continue it for 12 weeks after the last dose of direct-acting antiviral treatment.

Hepatitis C and HIV Co-Infection

The rate of adverse effects from and the efficacy of the direct-acting antivirals are similar in patients co-infected with hepatitis C and HIV and patients infected only with hepatitis C,102 and the direct-acting antiviral treatment protocols for co-infected patients are essentially no different. However, there are many potentially serious drug-drug interactions between the direct-acting antivirals and the antiretroviral drugs used to treat HIV infection.102 The AASLD/ISDA recommends that clinicians consult a drug interaction database when planning to treat patients for hepatitis C and HIV, and for this purpose, the AASLD/ISDA website mentions two drug interaction resources.102

  1. The University of Liverpool drug interactions website, www.hep-druginteractions.org/.
  2. The US Department of Health and Human Services HIV treatment guidelines aidsinfo.nih.gov/guidelines

Hepatitis C and Pregnancy

Pregnant women should be tested for hepatitis C.103

Treatment with direct-acting antivirals is beneficial for the health of hepatitis C infected women of reproductive age, and it can eliminate the risk of mother to child transmission of the virus.103 Women who are infected should be advised to delay pregnancy until after treatment has ended, and an SVR has been attained.103

Treating hepatitis C infected women who are pregnant is problematic. The prescribing information for these drugs states that no adequate human data are available to establish if the direct-acting antivirals have an adverse effect on pregnancy outcome, and the AASLD/ISDA website states “. . . there are no available data on the use of pangenotypic regimens during pregnancy.”103

The AASLD/ISDA recommends that direct-acting antiviral therapy can be considered (Italics added) for pregnant women on a case by case basis after the patient has been informed about benefits and risks.103 Women who become pregnant while taking direct-acting antivirals should consult with a healthcare practitioner about the benefits and risk of continuing treatment.103

Ribavirin is contraindicated for pregnant women.103

Elective cesarean delivery is not recommended.103

During perinatal care and delivery, diagnostic testing should be done by amniocentesis, not chorionic villus sampling, and episiotomies, internal fetal monitoring, and prolonged membrane rupture should be avoided.103

Hepatitis C infection is not a contraindication for breastfeeding unless the woman’s nipples are bleeding, cracked, or damaged.103 The direct-acting antivirals have not been studied in nursing women.

Hepatitis C and Decompensated Cirrhosis

Direct-acting antiviral therapy can improve the clinical status of patients who have hepatitis C and decompensated cirrhosis,104 but the response rate, i.e., the SVR, is lower than for patients without cirrhosis.104-107

The ASSLD/ISDA recommendations for patients who have decompensated cirrhosis, genotype 1-6, who can take ribavirin, and are treatment naïve are104:

  1. Genotype 1,4,5, or 6 only: Ledipasvir 90 mg/sofosbuvir 400 mg and a low initial dose of ribavirin, 600 mg. The ribavirin dose can be increased to a weight-based dose as tolerated. Once a day dosing, 12 weeks duration.
  2. Sofosbuvir 400 mg/velpatasvir 100 mg with a weight-based dose of ribavirin. Once a day dosing, 12 weeks duration.

If the patient has a Child-Pugh score of C, i.e., severe hepatic impairment, a low initial 600 mg dose of ribavirin is recommended, and the dose can be increased to a weight-based dose as tolerated.

The ASSLD/ISDA recommendations for patients who have decompensated cirrhosis, genotype 1-6, who cannot ribavirin, and are treatment naïve are104:

  1. Genotype 1,4,5, or 6 only: Ledipasvir 90 mg/sofosbuvir 400 mg. Once a day dosing, 24 weeks duration.
  2. Sofosbuvir 400 mg/velpatasvir 100 mg. Once a day dosing, 24 weeks duration.

Hepatitis C and Renal Impairment: Treatment

Elbasvir/grazoprevir, glecaprevir/pibrentasvir, and sofosbuvir-based regimens have been successful in treating patients who have severe renal impairment and patients who have ESRD and require hemodialysis.108-112 These direct-acting antivirals improve mortality rates, reduce the risk of developing extrahepatic complications, and they are well tolerated and appear to be safe for this patient population.108-112

No dosing adjustments of the direct-acting antivirals are required, but if the patient has CKD stage 3, 4, or 5, a dosing adjustment of ribavirin may be needed.108

Hepatitis C and Hepatocellular Cancer: Treatment

Direct-acting antiviral therapy has been shown to reduce the risk of developing hepatocellular cancer.113 However, in treatment naïve infected patients who have hepatocellular cancer, there is a small but statistically significant decrease in the SVR attained by direct-acting antivirals.113 Also, the American Gastroenterological Association (AGA) expert review on direct-acting antivirals and hepatocellular cancer stated:

  1. “There is no conclusive data that DAA therapy is associated with increased or decreased risk, differential time to recurrence, or aggressiveness of recurrent HCC in patients with complete response to HCC therapy. Although data have demonstrated a decreased risk of incident HCC after DAA therapy in patients with HCV cirrhosis, there continues to be debate about the risk and aggressiveness of HCC recurrence after DAA therapy in patients with a history of HCC.”113
  2. Clinicians and patients must consider the possibility of recurrent hepatocellular cancer versus the long-term benefits of direct-acting antiviral therapy. The AGA believes that for most patients, the benefits outweigh the risks.113
  3. It appears that the shorter the interval between successful response to treatment of hepatocellular cancer and initiation of treatment of hepatitis C, the greater the risk that the cancer will recur. The AGA believes that it is prudent to wait for at least 4 to 6 months after the successful treatment of hepatocellular cancer before starting antiviral therapy.113

Patient Monitoring During Direct Acting Antiviral Treatment

Patients and providers should maintain close contact during the treatment.

All patients who have hepatitis C should receive vaccination against hepatitis A and B.113

Invasive pneumococcal infection is more likely in people who have hepatitis C, and co-infected people are more likely to develop serious complications from pneumonia.113,114 The AASLD/ISDA recommends that anyone who has hepatitis C and cirrhosis should be vaccinated against pneumococcal pneumonia.113

If the patient is taking elbasvir/grazoprevir, a hepatic function panel should be done at eight weeks and again at 12 weeks if the therapy course will be 16 weeks. A hepatic panel should measure albumin, alkaline phosphatase, ALT, AST, and total and direct bilirubin.115 If there is a 10-fold increase in ALT, direct-acting antiviral therapy should be stopped, especially if the patient has signs or symptoms of liver damage or an increase in alkaline phosphatase, conjugated bilirubin, or INR.115 If the ALT increase is < 10-fold, the direct-acting antiviral therapy should be stopped if the patient also has nausea, jaundice, weakness, or vomiting, or a significant increase in alkaline phosphatase, bilirubin, or INR.115

If the increase in ALT is < 10-fold and the patient is asymptomatic, repeat the test every two weeks. If the ALT is persistently elevated, consider stopping antiviral therapy.115

In patients who are taking glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, hepatic function should be monitored during therapy, and drug therapy should be stopped if the patient develops signs and symptoms of hepatic decompensation.

If the patient is on one of the simplified treatment plans, the AASLD/ISDA does not recommend laboratory testing during the treatment. In other circumstances, laboratory monitoring may be needed and should be done if the patient has signs/symptoms of liver damage.115 Ribavirin can cause anemia, and if the patient is taking ribavirin, a complete blood count should be done at week 4, 8, and 12.116

Measuring the viral level during direct-acting antiviral therapy is not needed or recommended.116

After Care

The AASLD/ISDA recommends measuring hepatitis C RNA 12 weeks or later after the directing acting antiviral treatment has been completed. Less than 1% of patients will have a relapse after the 12-week point, and some of these cases may be reinfection.116 A relapse 24 weeks after the end of treatment is very rare.117

If an SVR has been attained and the patient does not have cirrhosis, no further assessment for hepatitis C infection or liver damage is needed unless the patient has signs/symptoms of liver damage or if reinfection occurs or might have occurred.115

If an SVR has been attained and the patient has cirrhosis, the patient should be screened for hepatocellular cancer,115 and the AASLD recommends an ultrasound examination, with or without alpha-fetoprotein testing, every six months.115 Also, the AASLD recommends that an endoscopic examination for the detection of esophageal varices should be periodically done, as well.115

Treatment failures do occur, caused by viral and host issues like drug-resistant viral sub-species, immune system factors, co-morbidities, and lifestyle.106,118,119

Patients who did not respond to direct-acting antiviral therapy can develop fibrosis, if they have fibrosis, it may worsen, and they can transmit the virus.115

A patient who did not attain an SVR should be reevaluated by a specialist and considered for retreatment. The AASLD/ISDA website has treatment recommendations for patients who had a treatment failure. In these patients, the AASLD recommends an ultrasound examination, with or without alpha-fetoprotein testing, every six months, and periodic endoscopic examination for the detection of esophageal varices should be periodically done, as well.115 Also, a CBC, hepatic function panel and an INR should be done every 6 to 12 months.115

A cure does not provide immunity against infection from the same genotype or other genotypes, and re-infection can occur. Injection drug users, MSM and who are infected with HIV, and MSM and are taking pre-exposure HIV prophylaxis have a relatively high risk of re-infection.115 These patients and anyone else who is at risk for reinfection should be screened annually for hepatitis C.26,116

Patient Education

Transmission of the virus: Patients should be instructed not to share personal care items like toothbrushes and razors that may be contaminated with blood.

Sexual transmission of hepatitis C between monogamous heterosexual partners who are not IV drug users appears to be very uncommon. The CDC does not have a recommendation about the use of barrier protection in this patient population. The AASLD/ISDA states that since patients who are infected with hepatitis C are more likely to have hepatitis B and/or HIV, both of which are sexually transmitted, the use of barrier protection should at least be considered, even for people in a stable, monogamous relationship.115 Patients should be counseled on safe sex practices, and they should be given information on how hepatitis C is transmitted and instructed on how to avoid transmission of the virus.

People who have multiple sexual partners and MSM should be encouraged to use condoms.26

Injection drug users should be advised not to share needles or injection drug equipment.

Hepatitis C is not transmitted by casual physical contact, coughing, by food or water, sneezing, or by sharing eating utensils.

Alcohol: There is no amount of alcohol that has been established as safe for patients who have hepatitis C.26,117 Excess alcohol consumption can cause cirrhosis, and it has been strongly associated with the development and progression of fibrosis and with hepatocellular cancer.113 Patients should be advised to abstain from drinking alcohol 26,113,117 and patients who have an alcohol use disorder should be referred for treatment.113

Drug-drug interactions: Patients should be told that drug-drug interactions can negatively influence the effectiveness of direct-acting antivirals, and potentially significant interactions can occur between over-the-counter medications and dietary/herbal supplements and the direct-acting antivirals. Do not take a new medication or supplement without first informing the provider or another healthcare professional.

Patients who take antidiabetic medications and/or warfarin should be instructed that the antiviral medications may cause hypoglycemia and can reduce the anticoagulant effects of warfarin.

Employment: People who have hepatitis C should not be restricted from any form of employment.2 Infected healthcare workers must simply follow infection control procedures and use Standard Precautions.

Marijuana: Research studies have found an association between chronic/daily use of marijuana in patients infected with hepatitis C and increased severity of fibrosis and steatosis (Abnormal accumulation of fat in the liver), the progression of the disease, and a higher level of hepatitis C RNA.117,120,121 Patients should be advised to abstain from using marijuana.

Medications: Patients should not take an over-the-counter medication, dietary supplement, or herbal product unless their provider or another healthcare professional has determined that doing so is safe. This is especially true for patients who have advanced fibrosis or cirrhosis, and these patients may need to avoid and/or use lower doses of medications like acetaminophen (potentially hepatotoxic and non-steroidal anti-inflammatories (potentially nephrotoxic).113

Obesity: Patients who are obese should be advised to lose weight. Obesity has been identified as a risk factor for the progression of liver fibrosis and liver damage.122,123

Reinfection: An SVR does not provide immunity against reinfection with hepatitis C, either from the same genotype or from the other genotypes. Patients should be instructed to contact their provider or another healthcare professional if they may have been re-infected.

Smoking: Smoking may increase the progression of fibrosis,124 and smoking cessation should be encouraged.

Substance use: Patients who have a substance use disorder should be referred to a treatment program.113 Current drug use is not a contraindication for direct-acting antiviral therapy.

Treatment adherence: Patients should be advised that non-compliance with the treatment regimen can cause treatment failure and/or allow a drug-resistant strain of the virus to develop.

Treatment - Adverse effects: The adverse effects of the direct-acting antivirals are mild and usually well tolerated. Patients should be instructed to contact their provider or another healthcare professional if they have any signs or symptoms that are new, unusual, severe, intolerable, or that interfere with activities of daily living. They should contact their healthcare provider or another healthcare professional if they develop any signs or symptoms that are indicative of liver damage.

Acute Exposure to Hepatitis C

There is no vaccine that can prevent hepatitis C infection, and prophylactic treatment after a known or suspected exposure to hepatitis C is not recommended.125 After an acute exposure to hepatitis C, the patient should be tested for hepatitis C RNA and anti-hepatitis C antibody and, if needed, tested for hepatitis B and HIV. The hepatitis C tests should be repeated six weeks later125 and treatment started if necessary.

Nursing Care

Nursing care of patients who have hepatitis C has been greatly simplified using the second-generation direct-acting antivirals. The course of therapy has been reduced from 44 weeks to 12 weeks, the risk of serious drug-induced complications has been dramatically reduced, and unlike interferon-based regimens, the side effects of these drugs are mild and well-tolerated.

These changes mean that the focus of nursing care for patients who have hepatitis C has, to a large degree, shifted from physical care to education and support: education about lifestyle issues relevant to hepatitis C, and support that helps and encourages patients to make the changes that are necessary for continued good health.

Nursing care for a patient who has hepatitis C will involve:

  • Knowledge of the extrahepatic complications of hepatitis C.
  • Knowledge of the medications and their potential side effects.
  • Patient education, specifically about extrahepatic complications of hepatitis C and safe and effective use of the antiviral drugs.
  • Patient education, specifically about the risks of alcohol use/abuse, diabetes, obesity, and smoking in relation to hepatitis C.
  • Support and education, specifically about the beneficial effects of alcohol abstinence, exercise, smoking cessation, and weight loss in relation to hepatitis C.
  • Assess the patient’s level of knowledge regarding hepatitis C transmission and behaviors that can put him/her at risk for reinfection.

Conclusion

Hepatitis C is a chronic infection of the liver that can cause liver damage, cirrhosis, and liver cancer, and hepatitis C can also cause serious extra-hepatic complications in essentially every organ system. Hepatitis C is one of the most common blood-borne diseases in the United States. Hepatitis C is an important cause of liver cancer, it may be a contributing cause of many common, chronic diseases, and hepatitis C can harm the progression of common chronic diseases like DM.

The hepatitis C virus was first isolated and identified in 1989, and for many years the available treatments were lengthy in duration, i.e., almost one year of drug therapy, not highly effective, and they caused very unpleasant and occasionally very serious adverse effects. The direct-acting antivirals have decreased the incidence of chronic hepatitis C infections and offered a cure rate of 95% to 100%, the treatment regimens are much shorter, and the drugs are well tolerated.

However, hepatitis C is still a major public health problem, and the continued use of illicit drugs and the opioid epidemic have contributed to the persistence of a disease that can be cured. Another issue that contributes to the failure to eliminate hepatitis C is the nature of the disease. Chronic hepatitis C seldom causes signs and symptoms, and the disease progresses silently for decades, so many infected people do not know they have hepatitis C. Also, the progression of liver fibrosis and liver damage caused by hepatitis C is negatively affected by co-morbidities and by common lifestyle issues like alcohol abuse, obesity, and smoking.

Fortunately, the treatment of hepatitis C has been greatly simplified. The currently available direct-acting antivirals are highly effective. The treatment regimens typically use oral medications that are taken once a day for 12 weeks, and serious adverse effects are uncommon. Simplified treatment plans that can be initiated and monitored by physicians, advanced practice RNs, and nurse practitioners are easily available. In most cases, hepatitis C can be cured, liver damage can be prevented, or if it is present, it can be reversed, and extrahepatic complications can be prevented and reversed.

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References

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