Continuing Education Activity
Hepatitis C virus (HCV) is a major public health problem affecting 185 million people worldwide. The percentage of people who are seropositive for anti-HCV antibodies worldwide is estimated to have increased from 2.3% to 2.8% between 1990 to 2005. Most patients (80% to 85%) who become acutely infected cannot clear the virus and progress to chronic infection. The effects of chronic infection include cirrhosis, portal hypertension, hepatic decompensation with encephalopathy, and hepatocellular carcinoma. The landscape of treatment has evolved substantially since the introduction of highly active direct-acting antivirals (DAAs) in 2011. This activity reviews the pathophysiology, evaluation, and management of hepatitis C and highlights the role of the interprofessional team in the management of affected patients.
- Identify the epidemiology of hepatitis C.
- Describe the typical presentation of a patient with hepatitis C.
- Outline the treatment and management options available for hepatitis C.
- Review interprofessional team strategies for improving care coordination and communication to advance the treatment of hepatitis C and improve patient outcomes.
First diagnosed in 1989, the hepatitis C virus (HCV) is a significant public health problem affecting 185 million people worldwide. The percentage of people who are seropositive for anti-HCV antibodies worldwide is estimated to have increased from 2.3% to 2.8% between 1990 to 2005. Most patients (80% to 85%) who become acutely infected cannot clear the virus and progress to chronic infection. The effects of chronic infection include cirrhosis, portal hypertension, hepatic decompensation with encephalopathy, and hepatocellular carcinoma.
HCV is the most common blood-borne pathogen and a leading cause of morbidity and mortality.
The landscape of treatment has evolved substantially since the introduction of highly active direct-acting antivirals (DAAs) in 2011. The goals of treatment aim at viral eradication, delay fibrosis progression, alleviate symptoms, prevent complications, minimize all-cause mortality, and ultimately maximize the quality-of-life.
HCV is a spherical, enveloped, positive-strand ribonucleic acid (RNA) virus that is approximately 55 nm in diameter. It is a member of the family Flaviviridae, yet distinct to be classified as a separate genus, Hepacivirus. The genome is approximately 9.6 kb in length. It encodes a polyprotein that then gets processed into at least ten proteins. These include three “structural” proteins, the nucleocapsid protein, core (C), and two envelope proteins (E1 and E2); two proteins that are essential for virion production (p7 and NS2); and five nonstructural proteins that are an essential part of the viral replication complex (NS3, NS4A, NS4B, NS5A, and NS5B). There is a very high level of virion turnover by the NS5B RNA polymerase with an absence of proofreading, resulting in the generation of viral mutants, also known as "quasispecies."
Globally, it is estimated that more than 185 million people are living with HCV. As per the Centers for Disease Control estimates from 2013, approximately 2.7 to 3.9 million people are living with HCV worldwide. In developed nations, the HCV prevalence is typically 1% to 2%. The number of acute cases of HCV reported in the United States increased each year from 2009 to 2013. After adjusting, an estimated 29,718 acute HCV cases occurred in 2013. Of the three types of viral hepatitis (hepatitis A, B, and C), HCV accounted for the greatest number of deaths and the highest mortality rate, 5.0 deaths/100,000 population in 2013. HCV transmission requires that infectious virions contact susceptible cells that allow replication. HCV RNA can be detected in blood (including serum and plasma), saliva, tears, seminal fluid, ascitic fluid, and cerebrospinal fluid. Available data suggest that HCV may get transmitted during sexual intercourse, but this rarely occurs. Perinatal transmission frequency ranges from 0% to 4% in more extensive studies. But for most patients with HCV in the United States and Europe, the infection is acquired via intravenous drug abuse or poor medical practices in resource-limited areas of the world.
As per the most updated classification, there are seven genotypes of HCV based on their nucleotide variability in HCV sequences recovered from multiple geographic regions.
- Genotype 1: the most widely dispersed worldwide, 60% to 70% of isolates from the United States are subtype 1a or 1b
- Genotype 2: widely dispersed but most diverse in central and west Africa
- Genotype 3: widely distributed but most diverse in Asia, linked to illicit drug use
- Genotype 4: Northern Africa and the Middle East.
- Genotype 5: South Africa
- Genotype 6: Southeast Asia.
- Genotype 7: Central Africa (Congo)
The hepatitis C RNA virus enters the hepatocyte via endocytosis mediated by at least four co-receptor molecules. Following internalization in the cytoplasm, its positive-stranded RNA is uncoated and translated into ten mature peptides. These are then cleaved by both host proteases and virally encoded proteases known as NS3-4a serine proteases. These mature peptides then go on to reside on the endoplasmic reticulum, forming a replication complex that contains an important enzyme, the NS5B RNA dependent RNA polymerase. This enzyme catalyzes the positive RNA strand into its negative-strand intermediate, which in turn serves as the template for new positive-strand synthesis. These are then packaged with core and envelop glycoprotein into mature virions, which then exit the cell via exocytosis. HCV cannot integrate into the host's genome.
Over the years, many genotypes of HCV have been identified. The dominant genotype globally is genotype 1, which is also associated with more severe liver disease and a much greater risk of developing liver cancer. In the US, genotype 1 accounts for about 60% of cases of HCV. Genotypes 2a, 3b, and 2c account for about 10% of cases in the USA and are most responsive to antiviral medications.
The virus is detectable in plasma within days of exposure, often 1 to 4 weeks. Viremia peaks in the first 8 to 12 weeks of infection, and then plateaus or drops to undetectable levels (viral clearance); in the majority, 50% to 85% it persists. Persistent infection appears to be due to weak CD4+ and CD8+ T-cell responses, which fail to control viral replication. When a chronic infection is established, HCV does not appear to be cytopathic; it is the local inflammatory response that triggers fibrogenesis. Multiple external factors, including alcohol consumption, HIV/HBV coinfections, Genotype 3 infection, insulin resistance, obesity, and non-alcoholic fatty liver disease, have links with accelerated fibrosis progression and cirrhosis. The severity of liver fibrosis tightly correlates with the increased risk of hepatocellular carcinoma via facilitating genetic aberrations and promoting neoplastic clones.
History and Physical
Although usually not associated with symptoms, acute HCV infection may cause malaise, nausea, and right upper quadrant pain, followed by dark urine and jaundice. This is clinically indistinguishable from any other acute viral hepatitis. Persistently infected individuals tend to be asymptomatic for the most part. Symptoms are nonspecific and include fatigue or malaise, intermittent right upper quadrant pain, and joint pain as well as a general feeling of being unwell with overall reduced quality of life. It is challenging to relate these symptoms to HCV alone, as there could be a potential psychological basis due to the knowledge of having an underlying chronic disease.
Ten percent to 20% of HCV-infected persons with cirrhosis will decompensate clinically within five years, as evidenced by the development of portal hypertension, esophageal varices, ascites, coagulopathy, encephalopathy, or hepatocellular carcinoma. At this stage, they could have physical signs indicating stigmata of chronic liver disease with caput-medusae, spider angiomas, palmar erythema, asterixis, anasarca, and fluid thrill. Moreover, they may have signs and symptoms of other extrahepatic manifestations like mixed cryoglobulinemia, membranoproliferative glomerulonephritis, porphyria cutanea tarda, lichen planus, neurocognitive changes, insulin resistance, and B cell lymphoproliferative disorders.
The physical exam may reveal signs of end-stage liver disease, which include:
- Temporal muscle wasting, cyanosis, icterus, enlarged parotid gland
- Palmar erythema, asterixis, clubbing, Dupuytren contracture
- Gynecomastia, small testes
- Fetor hepaticus
- Ankle edema, spider nevi, petechiae, scant body hair
- Caput medusae, paraumbilical hernia, hepatosplenomegaly
The diagnosis of HCV infection is based principally on the detection of antibodies to recombinant HCV polypeptides and by assays for HCV RNA. These are enzyme immunoassays that measure antibodies directed against NS4, core, NS3, and NS5 sequences. These cannot differentiate between past or current HCV infection. Direct testing for HCV RNA is necessary to distinguish between ongoing or prior infection in persons with HCV antibodies. HCV Rapid Antibody Test with rapid turnover can be an essential public health tool in nontraditional settings. There are three scenarios in which the HCV RNA test should be considered upfront: (1) exposure within the past six months, (2) an immunocompromised host, and (3) suspicion for reinfection.
Further evaluation consists of checking the viral genotype, which is still important in choosing the most optimal regimen and also for predicting the response to therapy. Other baseline evaluations include testing for HIV, hepatitis B surface antigen, susceptibility to hepatitis A and hepatitis B virus infections, and screening for other underlying causes of liver disease such as autoimmune liver disease, hemochromatosis, and Wilson disease. Before determining the HCV treatment strategy, the next step is to stage the disease, utilizing liver biopsy (gold standard) or approved imaging modalities with or without noninvasive biomarkers. Lastly, all of these patients should also undergo variceal screening and screening for hepatocellular carcinoma.
Other studies include:
- INR, prothrombin time
- Complete blood count
- Liver function tests
- Serology for other hepatic viruses
- Thyroid function
- Screening for drug abuse and alcohol
- Mental health assessment
A liver biopsy is not routine, but it may help determine the severity of the disease. Other indications for a liver biopsy include 1) uncertain diagnosis, 2) presence of another liver disorder, and 3) immunocompromised patient.
Treatment / Management
Treatment can permanently eradicate HCV infection such that HCV RNA is no longer detectable in blood or liver with a decline in antibody titers and improved liver pathology. Before the development of the all-oral DAAs, the mainstay of therapy was injectable pegylated interferon and ribavirin. In addition to only having a cure rate of 40% to 60%, this form of treatment led to numerous adverse effects, including flu-like illness, hematological effects like neutropenia, thrombocytopenia, and severe anemia; and neurocognitive effects. With the advent of DAAs, immense progress has been seen toward shortening the duration of treatment from 48 weeks to 12 weeks, improving the adverse effects, increasing cure rates to 90% to 97%, and eliminating the need for injectable agents. Currently, three classes of DAAs include (1) second-generation protease inhibitors that inhibit the NS3/4 serine proteases, (2) the NS5A inhibitors which interferes with the structural protein NS5A, a crucial element in the formation of the replication complex and (3) the NS5B polymerase inhibitor which inhibits the enzyme responsible for transcription of a negative-strand intermediate for future viral progeny. These three classes are used in different combinations to make a robust treatment regimen against the various genotypes of hepatitis C.
The standard regimens are anywhere from 12 weeks to 24 weeks with or without ribavirin based on the genotype, treatment experience, and presence or absence of cirrhosis. With the current DAAs, it is the Genotype 3 infection, which is the least responsive that is associated with rapid accelerated fibrosis progression and a higher incidence of hepatocellular carcinoma. Genotype 1, the most common genotype present in the United States, has four different treatments approved, two of these require only a single pill/day. For example, the combination of sofosbuvir and ledipasvir in a single pill and the combination of grazoprevir and elbasvir as a single pill. There are many more drugs in phase III and IV clinical trials that appear to have a pan-genotypic potential such that it will eliminate the need to check the hepatitis C genotype. Defining each regimen for the various genotypes is beyond the scope of this chapter.
- Drug-induced liver injury
Only 10-15% of patients infected with HCV have a self-limited infection; in all others, the infection is progressive. About 20% will develop cirrhosis within two decades, and another 1 to 5% will develop liver cancer within three decades. The progression of the disease is more common in alcoholic, cirrhotics, and those with a coexisting HBV infection. Individuals who have an undetectable viral load generally have a decreased risk of developing cirrhosis and death.
End-stage liver disease
Several other crucial issues are related to treating hepatitis C in special populations, for example, individuals who are co-infected with HIV and Hepatitis C. Many drug-drug interactions are encountered between the patient's antiretroviral therapy and the oral DAAs for Hepatitis C. With co-infected individuals with Hepatitis B, there have been case reports of Hepatitis B reactivation due to the phenomenon of viral interference. Treating Hepatitis C in patients with end-stage renal disease poses another challenge in itself, although progress has been made, and there are regimens for them. Numerous drug-drug interactions between Hepatitis C drugs and their immunosuppressive medications have been encountered in patients who are organ transplant recipients, requiring frequent blood level monitoring. Antiviral resistance is a new adverse event brought about by the use of DAA agents; it needs to be keyed in when selecting a regimen in previously treated individuals, and with some drugs (e.g., elbasvir), there is enough baseline resistance before exposure. The other challenging groups include the decompensated cirrhotics (CTP stage B or C) and the recurrent hepatitis C seen after liver transplantation. Details are beyond the scope of this summary.
Enhancing Healthcare Team Outcomes
Hepatitis C is a serious infection that has high morbidity and mortality. The management of HCV is prohibitively expensive, and newer antivirals offer a potential cure for the disorder. The infection is best managed by an interprofessional team that also includes nurses and pharmacists. All clinicians who see patients with HCV should educate them and advise them against the use of alcohol, which is known to accelerate the progression of the infection. Also, the infectious disease nurse should provide basic sex education and inform these patients that they may transmit the virus to their partners during sexual intercourse. Additionally, these patients should avoid sharing personal care products with others. The patients should be told not to donate blood or any organs as the risk of transmission is high.
The key is that many advances have taken place in the treatment of hepatitis C, which can eradicate the virus, shorten the duration of treatment, and hopefully prevent hepatocellular cancer. The board-certified infectious disease pharmacist should educate the patients about the newer antiviral drugs which are effective in eradicating the virus. Following treatment with the newer drugs, monitoring is still necessary to ensure compliance; here again is where nursing can step to the front, alerting the clinician of any issues. Current short term data indicate that the drugs can eliminate the virus from the bloodstream.
Only through open communication between members of the interprofessional team will the morbidity and mortality of this infection be reduced. [Level 5]