Article Author: Hajira Basit

Article Author: Isha Tyagi

Article Editor: Janak Koirala
Updated: 1/6/2020 9:10:43 PM
Hepatitis C

Introduction
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.[1][2][3]

Etiology
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."[4][5][6]

Epidemiology
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.[7]
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)

Pathophysiology
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.[8]

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

Evaluation
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.[9][10][11]
Other studies include:

 INR, prothrombin time

 Complete blood count
 Liver function tests
 GFR
 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.[6][12][13]
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.

Prognosis
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.

Complications
End-stage liver disease
Liver cancer

Consultations
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]