Combination therapy is superior to lamivudine monotherapy in reducing the rate of
resistance in patients. However, there is no such role for combination therapy for
those agents (entecavir, tenofovir DF) associated with low resistance as
monotherapy. Therefore, combination therapy is not appropriate for C.R. at this time.
his chronic HBV infection, what nonpharmacologic interventions are available?
PegIFN alfa-2a Nucleos(t)ide Analogues
Lack or very little resistance
seroconversion within 12 months
Disadvantages Moderate antiviral effect
PegIFN: pegylated interferon; ROA: route of administration.
One-year survival rates for patients with cholestatic or alcoholic liver disease
who undergo liver transplantation are greater than 90% in most liver transplant
117 Historical data for liver transplants in patients with chronic HBV infection
indicated that the spontaneous risk for allograft reinfection was approximately
117–120 This reinfection rate was associated with the initial liver disease and the
hepatitis B viral load at the time of transplantation, and with allograft failure,
retransplantation, or death. However, with appropriate post-transplant HBV
prophylactic management, overall survival rates of patients who received a liver
transplant for HBV-related cirrhosis have exceeded 85% at 1 year and 75% at 5
years, making liver transplantation a viable alternative for C.R.
CASE 80-12, QUESTION 13: What are the current recommendations for prevention of recurrent HBV
infection after liver transplantation?
The most efficacious approach to preventing HBV recurrence after transplantation
historically was with high-dose IV HBIG given in the anhepatic and postoperative
periods. Daily IV HBIG in the early postoperative period with maintenance of serum
anti-HBs levels of 100 IU/L or more had an overall survival (84%) that approached
that observed in other transplant recipients without HBV infection.
patients receiving long-term HBIG administration (>6 months) compared with
patients receiving short-term HBIG (<6 months) had a lower risk for recurrent HBV
infection (35% vs. 75%) and longer 3-year actuarial survival (78% vs. 48%).
Hepatitis B Immunoglobulin Dosage, Administration, and Adverse Effects
Over the years, many liver transplant centers routinely administered
immunoprophylaxis with IV HBIG 10,000 IU (10 vials, 50 mL in 250 mL of saline)
given in the anhepatic (recipient liver excised) phase, then gave 10,000 IU (50 mL
infused for 4–6 hours) for the next 6 days postoperatively. HBIG (10,000 IU) was
generally administered on a monthly basis for life, or discontinued if HBsAg
becomes positive, indicating treatment failure.
119,120 This regimen was able to achieve
trough anti-HBs titers of approximately 500 IU/L and up to 2,000 IU/L, which
provided protection from HBV recurrence in the majority of transplanted patients.
Patients who received HBIG oftentimes experienced a serum sickness-like syndrome
(fever, myalgias) and were managed by receiving premedication (i.e.,
acetaminophen, diphenhydramine), thus prolonging the HBIG infusion (up to 6 hours),
or discontinuing HBIG therapy altogether.
Long-term concerns associated with HBIG administration included the potential
119,120 Some data suggested that pharmacokinetic modeling and use of
maintenance therapy with IM administration of HBIG (e.g., 2.5–10 mL every 2–3
weeks) after a reduced induction dose (e.g., 10,000 IU anhepatically, then 2,000 IU
intravenously for six doses) could achieve similar outcomes and reduce the cost
associated with IV administration of the drug.
The nucleoside and nucleotide analogs, such as lamivudine, adefovir, entecavir,
tenofovir DF and, more recently, TAF, potentially prevent recurrence of HBV in
patients who undergo transplants for chronic HBV infection.
monotherapy was proven successful in converting HBV DNA-positive patients to
negative status before and after liver transplantation. Resistance in transplant and
nontransplant recipients also has been observed.
Nucleoside analogs are not FDA-approved for this prophylaxis in the United
States. Several transplant centers, however, have implemented clinical protocols that
administer adefovir, entecavir, or tenofovir DF before transplantation to achieve
undetectable HBV DNA viral loads at the time of transplant, then combine one of
these agents with HBIG in the postoperative setting.
management strategies have emerged as a clinical standard in the preoperative and
early postoperative period because they are effective and have low rates of
resistance. Future considerations for preventing recurrent HBV infection after
transplantation include combining oral nucleoside (adefovir, entecavir) with
nucleotide (tenofovir DF) analogs, thus avoiding HBIG altogether.
safety and efficacy data are very limited for TAF in liver transplant recipients.
HCV is recognized now as the most common cause of chronic NANB transfusionassociated hepatitis.
122,123 HCV is a positive-sense, single-stranded RNA virus in the
Flaviviridae family that is 50 to 65 nm in diameter (see Table 80-1). It causes acute
and chronic HCV infection in humans and chimpanzees. If untreated, chronic HCV
can progress to cirrhosis and HCC in a subset of patients.
structure is comprised of envelope glycoproteins in a lipid bilayer that contain the
125 After entry into the hepatocyte, the viral RNA is
translated through host machinery into a polyprotein, which is cleaved during and
after translation by both host- and viral-encoded proteases into mature viral proteins
and nonstructural (NS) proteins (Fig. 80-6).
The worldwide prevalence estimated that up to 180 million people are infected with
chronic hepatitis C. This estimate included high-risk populations, such as people who
inject drugs, hemodialysis patients, cancer patients, and paid blood donors.
Excluding the high-risk populations, the global prevalence of HCV infection, based
on anti-HCV, was 1.6% (1.3%–2.1%) corresponding to 115 (92–149) million past
126–128 The estimated prevalence is conservative as it did not
include high-risk populations (e.g., hemodialysis patients, cancer patients, paid blood
donors, and injection drug users). The majority of these infections, 104 million, were
among adults with an anti-HCV infection rate of 2.0%. There are six genotypes
reported for HCV worldwide. Globally, the genotype 1 distribution is most common,
accounting for 46% of all infections, followed by genotype 3 (22%), genotypes 2 and
4 (13% each). Subtype 1b accounted for 22% of all infections.
of the genotype distribution across the global regions shows that genotype 1 is
prevalent in Australia, Europe, Latin America, and North America (53%–71% of all
cases), and genotype 3 accounting for 40% of all infections in Asia.
is the most common (71%) in North America, Egypt, and the Middle East.
HCV infection occurs among persons of all ages, but the highest incidence is
among persons aged 20 to 39 years, with a male predominance. Blacks and whites
have similar incidence rates of acute disease, whereas persons of Hispanic ethnicity
have higher rates. In the general population, the highest prevalence rates of chronic
HCV infection are found among persons aged 30 to 49 years and among
124,134,135 Unlike the racial or ethnic pattern of acute disease, blacks have a
substantially higher prevalence of chronic HCV infection than do whites. In the
United States, the predominant HCV genotype is type 1, with subtypes 1a and 1b
regarding therapy. Once the genotype is identified, it need not to be tested again;
genotypes do not change during the course of infection. Because HCV has a high
mutation rate during replication, several so-called quasi-species, a heterogeneous
population of HCV isolates that are closely related, may, however, exist in an
134,136 The number of quasi-species increases during the course of
infection, which allows HCV to escape the host’s immune system, leading to
persistent infection. In 2012, the CDC issued a new recommendation that all adults
specific cohort is selected based on data reporting HCV prevalence, disease burden,
and cost-effectiveness analysis of routine screening.
138 The prevalence of anti-HCV
found in this cohort is approximately 3.5%.
138,139 Furthermore, an estimated 70% of
all hepatitis C-related deaths are attributed to this cohort. Birth cohort screening
linked with effective hepatitis C treatment is presumed to significantly reduce future
cases of decompensated cirrhosis, HCC, liver transplantation, and HCV-related
deaths. The CDC screening recommendation for this cohort is also supported by the
United States Preventive Services Task Force (USPSTF) and the American
Association for the Study of Liver Disease, particularly for those with high-risk
behaviors, risk exposure, and medical conditions associated with HCV
in HCV therapy. Nat Rev Gastroenterol Hepatol. 2011;8(2):69–71.)
Similar to other hepatitis virus infections, acute HCV infection is defined as
having an infection <6 months following acquisition of HCV. Acute HCV infection
could occur whether or not the person develops clinical signs or symptoms of acute
hepatitis. Six months is usually the time period to define an acute infection based on
evidence that most individuals who clear HCV will do so by 6 months. Oftentimes,
patients with acute HCV infection do not have a distinct symptomatic illness and
most are not aware of their recent exposure to hepatitis C. If symptoms from acute
infection develop, they usually develop within the first 4-12 weeks after infection
and may persist between 2 and 12 weeks.
142,143 The clinical manifestations of acute
HCV infection are similar to other types of viral hepatitis (e.g., jaundice, flu-like
symptoms, dark urine and white stool, nausea, abdominal pain and malaise).
Approximately 15-20% of symptomatic acute liver disease in the United States is
reported as resulting from acute HCV.
145 There are many potential sources of
exposure to HCV, such as percutaneous transmission (e.g., blood transfusion,
high-risk sexual practices and exposure to nosocomial exposure to contaminated
The incidence of HCV infection is 48% to 90% among injection drug users, and the
risk of acquiring the infection in these persons is as high as 90%.
drug users with acute NANB hepatitis, 75% are anti-HCV positive and, unlike
transfusion-related hepatitis, the incidence of HCV infection associated with
injection drug use has not declined.
124,125,134 Additional risk factors for HCV infection
include the presence of HBV or HIV infection. Other populations at risk for acquiring
HCV include patients receiving chronic hemodialysis (up to 45%) and healthcare
workers (0%–4% seroconversion after needlestick).
NONPERCUTANEOUS AND SPORADIC TRANSMISSION
Nonpercutaneous transmission includes transmission between sexual partners and
from mother to child. This route of transmission is less efficient compared with the
percutaneous route, and is supported by data assessing sexual transmission of HCV.
The risk of sexual transmission appears to be highest with male-to-male exposures,
particularly with physically traumatic or rough sex.
QUESTION 1: A 30-year-old woman presents to the clinic 3 months after having a diagnosis of chronic
hepatitis C infection. Her past medical history shows that she was injecting crystal methamphetamine
transmitting hepatitis C to her boyfriend?
The couple do not need to alter their sexual practices. The CDC has issued
recommendations regarding counseling recommendations for persons infected with
hepatitis C. Patients should be counseled not to share needles or any of the injection
materials, such as cookers, cottons, water, or the actual drug. The risk of HCV
transmission among long-term, monogamous, discordant couples is very low.
Therefore, the CDC recommends couples in that setting do not need to alter their
sexual practices. The risk of HCV transmission among men who have sex with men is
likely significant, especially with rough sexual activity. Household transmission of
HCV can potentially occur via razors or toothbrushes, but it is not considered a risk
to share food, water, or eating utensils.
Compared with the high incidence of perinatal transmission of HBV from mothers
to infants, perinatal transmission of HCV infection is relatively low. In general, it is
considered safe for HCV-infected women to breastfeed their infants, with the
exception that most experts recommend stopping breastfeeding if the mother’s nipples
(or surrounding area) are cracked and bleeding. The mother can temporarily pump
her breast milk (and discard it) and then resume breastfeeding after the nipple region
and the natural history of perinatally acquired infection.
Natural History and Pathogenesis
Between 75% and 85% of persons who acquire HCV will develop chronic
146 The rate of viral production is high, between 10
and the lack of proofreading by the viral polymerase leads to a broad genetic
diversity. Among those who develop chronic HCV infection, approximately 20% to
25% will develop cirrhosis 20 to 30 years after HCV acquisition.
the host immune system has a major challenge in its mechanisms to eradicate the
150 Nevertheless, a small percentage of persons infected with HCV infection
have spontaneously cleared the infection. The following host factors or
characteristics that have been associated with a lower rate of chronicity include the
following: younger age (<20 years old), female gender, nonblack race, competent
immune status, and IL28B CC genotype.
151,152 Of note, individuals with the CC allele
of IL28B genotype are more likely to spontaneously clear HCV than those with CT or
The pathogenesis of liver damage from HCV infection most likely results from
both direct and indirect immune-mediated responses instigated by the virus. In some
studies, having genotype 3a has been associated with a higher prevalence of
steatosis, which is associated with fibrosis progression.
147,153,154 Hepatic fibrosis is a
dynamic scarring process in which chronic inflammation stimulates production and
accumulation of collagen and extracellular matrix proteins. Over time, with chronic
HCV infection, the total collagen content increases and fibrosis can develop, with
potential progression to cirrhosis. Fibrosis is a precursor to cirrhosis.
persons infected with HCV infection, factors that can influence
an increased rate of progression of liver fibrosis include acquisition of HCV at an
older age (>40 years old), male sex, heavy alcohol use, heavy marijuana use,
coinfection with HIV or HBV, and metabolic factors (e.g., steatosis and insulin
155–160 For persons who develop hepatitis C-related cirrhosis, there is an
estimated 1% to 4% risk per year of developing HCC.
Two classes of assays are used in the diagnosis and management of HCV. These
include serologic assays that detect specific antibody to HCV (anti-HCV) and
molecular assays that detect viral nucleic acid. These assays are not used to assess
the severity of disease or predict prognosis in patients infected with HCV.
Screening for additional causes and contributors of liver disease and abnormal
liver function tests should be part of the diagnosis process of liver disease. There are
nonviral causes of hepatic inflammation, hereditary, and acquired conditions.
Secondary causes of liver disease may include alcoholic liver disease, nonalcoholic
fatty liver disease (NAFLD), α-1 antitrypsin (AAT) deficiency, hemochromatosis
(excessive accumulation of iron in the liver), and autoimmune hepatitis.
LABORATORY STUDIES AND SEROLOGIC ASSAYS
The laboratory studies that are commonly used to evaluate HCV infection are HCV
RNA, antibodies to HCV (anti-HCV), and ALT. Persons who become infected with
HCV may develop abnormal laboratory findings in the following order: detectable
HCV RNA, elevation in ALT, and anti-HCV.
Recent laboratory tests reveal the following results:
HCV RNA level: 1,100,000 IU/mL
What are the clinical and serologic features of acute HCV infection in N.P.?
N.P. clearly presents with a clinical picture consistent with acute HCV infection,
including symptoms of fatigue, headache, and dark urine color. His laboratory tests
show elevated ALT, positive anti-HCV, and detectable HCV RNA levels.
HCV RNA is usually detected in blood within 1 to 2 weeks after infection by a
nucleic acid test (NAT). Qualitative, quantitative, and genotype test results are also
performed for the HCV RNA. The period from infection until HCV RNA is
detectable in plasma (by a commercially available assay) is referred to as the
“eclipse phase,” or “previremic phase.” During this phase, the probability of
establishment of HCV infection in susceptible hepatocytes is most likely. The eclipse
phase is followed by an 8- to 10-day “ramp-up” phase in which HCV replication
increases exponentially and readily becomes detectable in plasma. The “plateau
phase” follows afterward with the HCV RNA viral load levels peaking 6 to 10
weeks after injection, and remains near these peak levels for approximately 40 to 60
163,164 During an acute infection, detection of HCV RNA is not very reliable
because RNA levels could fluctuate significantly. However, detectable HCV RNA
levels are more uniform and present at the onset of symptoms.
Between 4 and 12 weeks after infection, patients may have liver cell injury
resulting in an elevation in serum ALT levels. Increases in ALT occur 1 to 2 weeks
range. The CDC uses an ALT >200 IU/L during the period of acute illness as part of
The last of the three abnormal laboratory findings associated with HCV infection
is the presence of antibodies to HCV in the blood. Anti-HCV is usually detectable
between 8 and 12 weeks after infection. Approximately after 12 weeks, >90% of
patients will have positive anti-HCV. This is referred to as the “serologic window
period,” which describes the time period from initial infection until
143 Having detectable anti-HCV does not clearly differentiate acute
from chronic HCV infection. Moreover, anti-HCV is not a reliable marker to
diagnose acute HCV because only approximately 50% to 70% of patients have
detectable anti-HCV at the onset of symptoms.
CASE 80-14, QUESTION 2: After N.P. or any other person becomes infected with HCV, what is the
typicalsequence of laboratory findings?
Detectable HCV RNA, then increased aminotransferase levels, then anti-HCV
The gold standard for the laboratory diagnosis of acute HCV infection is anti-HCV
However, because no many patients are unaware of their exposure or risk of
infection, they may not present to their healthcare providers early enough to be
evaluated and diagnosed. Oftentimes, acute HCV is diagnosed based on the first-time
detection of HCV RNA and newly elevated ALT compared to negative laboratory
results at baseline. Close follow-up of patients who have encountered high-risk
exposures is recommended to establish the diagnosis and their treatment care. The
laboratory testing for a known exposure to HCV is recommended as follows
At initial presentation: anti-HCV, HCV RNA and ALT
At 4 weeks from time of suspected exposure: anti-HCV, HCV RNA, and ALT
At 12 weeks from time of suspected exposure: anti-HCV, HCV RNA, and ALT
increased ALT is required as part of the clinical description?
An ALT >200 IU/L. N.P.’s ALT result is 350 IU/L.
Acute HCV infection rarely causes a life-threatening illness. The CDC 2016 case
definition for acute hepatitis C includes clinical and laboratory criteria, case
classification as probable or confirmed, and criteria to distinguish a new case from
162 Clinical criteria of acute hepatitis C is described as an illness
with an onset of any sign or symptom consistent with acute viral hepatitis (e.g., fever,
headache, abdominal pain, malaise, anorexia, nausea, vomiting, and diarrhea)
combined with jaundice, or a peak-elevated serumALT level >200 units/Lduring the
As part of the comprehensive patient work-up, a complete laboratory evaluation of
the patient with chronic HCV infection includes the following
General: CBC, platelet count, serum creatinine, and thyroid function tests (TSH).
Because some studies have shown that persons with vitamin D deficiency have
hepatitis C treatment, some experts recommend obtaining baseline vitamin D
Hepatic inflammation and function: ALT or aspartate aminotransferase (AST), total
and direct bilirubin, alkaline phosphatase, serum albumin, INR.
Assays to detect coinfections: hepatitis A antibody, hepatitis B surface antigen,
hepatitis B core antibody, hepatitis B surface antibody, HIV antibody.
HCV RNA level (viral load): a quantitative HCV RNA viral load to confirm that
the patient has chronic HCV infection, and to establish a pretreatment baseline
level. In the absence of treatment, it is not necessary to repeatedly assess the HCV
RNA levels because monitoring values over time does not provide useful
HCV genotype: HCV exists as one of six distinct genotypes with significantly
different clinical characteristics, mostly with respect to treatment response rates.
In the United States, HCV genotype 1 is the most common, accounting for between
70% and 74% of prevalent cases. Knowing the HCV genotype is very important
because response to antiviral therapy is very different among different genotypes
and treatment protocols differ substantially.
IL-28B testing: This is a single-nucleotide polymorphism (SNP) at the IL-28B locus
that codes for interferon lambda and strongly correlates with HCV treatment
response, especially with interferon-based therapies. Since the emergence and
recommended for chronic HCV treatment. This test is now optional.
Serologic assays in terms of noninvasive, serum markers have clinical utility in
predicting the presence or absence of significant fibrosis or cirrhosis and, however,
are not useful in differentiating between intermediate stages of fibrosis. The indirect
markers include the aspartate aminotransferase-to-platelet ratio index (APRI), FIB-4,
FibroIndex, Forns Index, HepaScore (FibroScore), FibroSure, and FibroTestActiTest.
The APRI model is an easily calculated method to predict significant, severe
fibrosis or cirrhosis. It is calculated using the patient’s aspartate aminotransferase
an estimated sensitivity (77%) and specificity (72%) for detection of significant
hepatic fibrosis (greater than or equal to F2 by METAVIR). A cut-off score of a least
1.0 has an estimated sensitivity (61%–76%) and specificity (64%–72%) for
detection of severe fibrosis/cirrhosis (F3–F4 by METAVIR). For detection of
cirrhosis, a cut-off score of at least 2.0 was more specific (91%), but less sensitive
168–171 APRI has good diagnostic utility for predicting severe fibrosis or
cirrhosis, but does not accurately differentiate intermediate fibrosis from mild or
severe fibrosis. The liver guidelines recommend using APRI with other noninvasive
The FIB-4 is a simple, quick, and inexpensive test that provides results
significant fibrosis. A cut-off value >3.25 has a specificity (98%) in confirming
cirrhosis. FIB-4 has valid utility in excluding or confirming cirrhosis; however,
values between 1.45 and 3.25 do not clearly discriminate fibrosis.
methods to predict liver fibrosis are recommended.
The FibroIndex is a simple scoring method comprised of three biochemical
markers: AST, platelet count, and gamma globulin. A cut-off value ≤ 1.25 has a
sensitivity (40%) and specificity (94%) for mild fibrosis (F0 or F1 by METAVIR).
In contrast, a cut-off value ≥ 2.25 has a sensitivity (36%) and specificity (97%) for
significant fibrosis (F2 or F3 by METAVIR). Patients with F4 fibrosis were not
The Forns Index uses a complicated calculation method. It incorporates
parameters, such as age, gamma glutamyltransferase (GGT), cholesterol, and platelet
count. A cut-off value of <4.25 has a negative predictive value of 96% for excluding
significant fibrosis (F2, F3, or F4). On the other hand, a cut-off of >6.9 has a positive
predictive value of 66% for significant fibrosis (F2, F3, or F4). The Forns Index is
useful and has good predictive value in selecting those with low risk of significant
fibrosis, but does not reliably predict more advanced fibrosis or cirrhosis.
with genotype 3 HCV infection may have varying cholesterol levels; thus, the Forns
Index should not be used in these patients.
The HepaScore or FibroScore algorithm is more complex than other indirect
markers. Additional fibrosis markers (i.e., age, sex, total bilirubin, GGT, α-2-
macroglobulin, and hyaluronic acid levels) are included in the equation. Cut-off
value ≤0.2 has a negative predictive value of 98% to exclude fibrosis. In contrast,
cut-off value ≥0.8 has a positive predictive value of 62% for predicting cirrhosis.
The HepaScore has good utility at excluding significant fibrosis, but not as good at
The FibroSure and FibroTest-ActiTest are identical tests marketed in the United
States and Europe. FibroSure is the test available in the United States. These tests are
utilized to assess liver inflammation and fibrosis. The FibroSure provides estimates
of grade and stage of fibrosis. It includes patient age and gender along with a
composite of six biochemical markers associated with hepatic fibrosis: α-2-
macroglobulin, haptoglobulin, GGT, apolipoprotein A1, total bilirubin, and ALT.
The cut-off value <0.31 has a negative predictive value of 91% for the absence of
clinical significant fibrosis. The positive predictive value for presence of significant
fibrosis at a cut-off value >0.48 was 61% and cut-off of 0.72 was 76%.
contraindications to using the FibroSure test (e.g., Gilbert disease, acute hemolysis,
extrahepatic cholestasis, post-transplantation, or renal insufficiency), which may
result in inaccurate quantitative calculations and predictions.
Aside from the invasive, indirect markers for predicting liver fibrosis or cirrhosis,
there are direct markers of fibrosis. Direct markers of fibrosis include procollagen
type (II, III, IV), matrix metalloproteinases, cytokines, and chemokines. These
markers exhibit variable effectiveness in predicting liver fibrosis. The FIBROSpect
II is the only commercially available test that combines hyaluronic acid, tissue
inhibitor of a metalloproteinase-1 (TIMP-1), and α-1-macroglobulin to predict
fibrosis stages (F2–F4). An index score of >0.42 indicates the presence of stage F2
to F4 fibrosis. The cut-off values for sensitivity and specificity are 80.6% and
176,177 The FIBROSpect II test is a good tool to use to determine
the presence of absence of cirrhosis in patients who have contraindications to liver
biopsy, or those who refuse it. These markers may serve as reliable clinical
alternatives in patients who are not candidates for liver biopsy. If noninvasive
methods provide a clear assessment of hepatic fibrosis, then a liver biopsy may not
Radiologic imaging of the liver has been effective noninvasive, diagnostic
techniques for identifying cirrhosis and stratifying the stages of liver fibrosis. Several
techniques that are currently been used include hepatic ultrasound, transient
ultrasound elastography, and magnetic resonance elastography.
Liver biopsy with histologic analysis continues to be the gold standard for diagnosing
other causes of liver disease and establishing severity of fibrosis. It provides
information on both the grade (degree of inflammation associated with ongoing liver
injury) and the stage (amount of currently established fibrosis). Some factors (e.g.,
alcohol consumption, increased hepatic iron concentration, and steatosis) are
associated with accelerated fibrosis progression and may elicit concern for advanced
178–180 Some limitations of a liver biopsy include its invasive technique,
associated risks of bleeding and complications, and the probability of incorrectly
staging fibrosis in about 20% of patients.
178–180 Because of these limitations and the
development of noninvasive tests that estimate hepatic fibrosis, liver biopsy is now
Kidney transplant recipients also have a high incidence of HCV infection (6%–28%),
which may be acquired through dialysis before transplant or from the allograft or
blood products after transplantation.
181,182 After kidney transplantation, elevation in
Clinical and Extrahepatic Manifestations
Most patients with acute HCV infection are asymptomatic.
approximately 40% of patients with chronic HCV infection will develop at least one
extrahepatic manifestation. Specific extrahepatic conditions may vary, and their
prevalence is estimates derived from observational studies. Extrahepatic
manifestations and conditions include cryoglobulinemic vasculitis, renal disorders
with or without cryoglobulinemia, dermatologic manifestations including cutaneous
leukocytoclastic vasculitis and porphyria cutanea tarda, diabetes mellitus and
metabolic syndrome, and lymphomas.
183–190 Successful eradication of HCV may
reduce the risk of some extrahepatic manifestations (i.e., lymphoma and diabetes) and
conditions (i.e., cryoglobulinemic vasculitis and renal disease).
No vaccines are effective against HCV, and current measures to prevent hepatitis C
infection have largely focused on identifying high-risk uninfected persons and
counseling them on risk-reducing strategies to prevent infection. The CDC and the
National Institutes of Health have published recommendations that address these
126,162 Suggested primary preventive measures are that in healthcare settings,
adherence to universal (standard) precautions for the protection of medical personnel
and patients be implemented and that HCV-positive individuals should refrain from
donating blood, organs, tissues, or semen. In some situations, the use of organs and
tissues from HCV-positive individuals may be considered. For example, in
emergency situations, the use of a donor organ in which the HCV status is either
positive or unknown may be considered in an HCV-negative recipient after full
disclosure and informed consent. Strategies should be developed to identify
prospective blood donors with any history of injection drug use. Such individuals
must be deterred from donating blood.
Furthermore, safer sexual practices, including the use of latex condoms, should be
126–128 Although HCV-positive individuals and
their partners should be informed of the potential for transmission, insufficient data
exist to recommend changes in current sexual practice in persons with a steady
partner. It is recommended that sexual partners of infected patients should be tested
In households with an HCV-positive member, sharing razors and toothbrushes
126–128 Covering open wounds is recommended. Injection needles
should be carefully disposed of using universal precaution techniques. It is not
necessary to avoid close contact with family members or to avoid sharing meals or
utensils. No evidence justifies exclusion of HCV-positive children or adults from
participation in social, educational, and employment activities.
Additionally, pregnancy is not contraindicated in HCV-infected individuals.
Perinatal transmission from mother to baby occurs in less than 6% of instances.
No evidence indicates that breast-feeding transmits HCV from mother to baby;
therefore, it is considered safe. Babies born to HCV-positive mothers should be
tested for anti-HCV at 1 year.
Finally, needle exchange and other safer injection drug-use programs may be
beneficial in reducing parenterally transmitted diseases.
programs should be considered in an effort to reduce the rate of transmission of
hepatitis C. It is important that clear and evidence-based information be provided to
both patients and physicians regarding the natural history, means of prevention,
management, and therapy of hepatitis C.
(about a year ago) for HCV and HIV by her physician. The laboratory results were both negative.
stigmata of liver disease), ascites, nor jaundice. Abdominal ultrasound is normal.
HCV RNA level: 6.1 million IU/mL
FibroSure: F1 (mild form of fibrosis; no cirrhosis)
definition of a sustained virologic response 12 (SVR12)?
K.C. clearly has a clinical picture consistent with chronic HCV infection,
including symptoms of flu-like symptoms, an elevated ALT, positive anti-HCV, and
detectable HCV RNA levels. A SVR12 is defined as the HCV RNA level remaining
undetectable for 12 weeks after completing therapy. The primary goal of HCV
therapy is achieving virologic cure, or a SVR24 which is defined as the HCV RNA
level remaining undetectable 24 weeks after completion of therapy. A negative HCV
RNA level is <25 IU/mL, below the level of detection by sensitive test assays.
The primary goal of HCV therapy is to achieve SVR, which is an undetectable
HCV RNA level using a sensitive assay (<25 IU/mL)
12 weeks after completion of therapy for hepatitis C.
SVR12. Among persons who achieve a SVR12, more than 99% proceed to achieve
191 A long-term follow-up of patients who achieve a SVR24 has demonstrated
nearly 100% remain HCV RNA-negative years after therapy.
achieving SVR24 is comparable to achieving virologic cure or total eradication of
The impact of a SVR is remarkably positive because patients have an improvement
in liver inflammation and fibrosis compared to those who do not achieve a SVR.
Study data from pooled analysis of paired liver biopsies before and 1 month to 6
years after treatment with standard interferon monotherapy, PegIFN monotherapy, or
PegIFN with ribavirin showed those patients who had a SVR were twice likely to
have lower necroinflammatory scores after treatment versus patients who relapsed
195 Other studies have also confirmed the long-term histologic
In a study involving the general population, patients with advanced
fibrosis who underwent antiviral therapy and achieved a SVR had reduction in
overall mortality, liver-related death, liver failure, and HCC when compared with
those who did not achieve a SVR.
197 Most of this survival benefit from successful
treatment response was associated with improved clinical outcomes, primarily
because of lower rates of liver failure. In a meta-analysis of 35 studies, investigators
showed a clear benefit in the 5-year overall survival with HCV treatment, including
patients with cirrhosis and with HIV coinfection.
198 With regard to the extrahepatic
manifestations, successful treatment of HCV is associated with improvement or
remission of insulin resistance and diabetes mellitus.
associated with reversal of hepatic inflammation and fibrosis, and can reduce the
chance of dying from hepatitis C by at least 60%.
FACTORS THAT PREDICT RESPONSE TO THERAPY
CASE 80-15, QUESTION 2: K.C.’s parents have read about HCV infection and how treatment response
In the DAA therapy era, K.C.’s genotype should not really affect her response to
treatment. Treatment responses are high across all genotypes if a DAA-based
combination appropriate for the genotype is used. There are viral and host factors
that predict a person’s response to therapy, such as the HCV genotype, HCV RNA
level, IL28B genotype, race, age, gender, and degree of hepatic fibrosis. The HCV
has six major genotypes, numbered 1 through 6. During the interferon era of treatment
and prior to the emergence of the potent DAA drugs, the genotype was the predictor
In contrast, the role of HCV genotype in predicting
treatment response has lessened in its influence as the DAAs are highly efficacious in
their treatment of all genotypes.
The HCV RNA level had an influence in the successful treatment outcome in the
interferon era. Patients with high RNA levels and genotype 1 infection had
approximately 27% lower chance of achieving a SVR.
however, the baseline HCV RNA has little impact on achieving a SVR. Of note, in a
post hoc analysis, a very high baseline RNA level of >6 million IU/mL is associated
with reduced likelihood of SVR with shorter duration (8 weeks) of therapy with
The polymorphisms in the IL28B gene is associated with a difference in treatment
response rates for persons receiving interferon-based therapies. The CT or TT
alleles were associated with a 40% lower SVR rate compared to patients with the
207 The majority of African-Americans have either the less favorable
genotypes (CT or TT). On the other hand, Asians have the highest proportion of the
CC genotype that may lead to better response to interferon-based therapy. In the DAA
era, IL28B genotype does not seem to influence treatment response. Similarly, in the
DAA era, a person’s race, age, and gender do not appear to have a significant
influence on treatment response for HCV infection.
The degree of hepatic fibrosis may still influence the SVR rates for persons
receiving DAA therapies. Advanced fibrosis, defined as F3 (precirrhosis or bridging
fibrosis), and F4 (cirrhosis) were associated with a much lower virologic cure rate
across all genotypes (between 10% and 20% lower) during the interferon era.
This is similarly observed in patients receiving DAA therapies. Patients with
decompensated cirrhosis (Child-Pugh class B or C) had lower SVR rates (86%–
87%) with 12-week treatment of ledipasvir/sofosbuvir compared with SVR rates of
>95% in similarly treated noncirrhotic patients.
208 Current strategies to improve the
SVR rates for patients with cirrhosis include adding ribavirin to the DAA
combination therapies and lengthening the duration of therapy.
CURRENT TREATMENT STRATEGIES OF CHRONIC HEPATITIS C
Historically, genotype 1 hepatitis C was considered the most difficult to treat
hepatitis C genotype. From 1998 to 2013, therapy evolved from interferon
monotherapy, to PegIFN monotherapy, to PegIFN plus ribavirin, to triple therapy
with PegIFN plus ribavirin plus an NS3/4A protease inhibitor (boceprevir or
telaprevir), the first-generation DAA serine protease inhibitors. Research
methodologies for enhancing the effectiveness of HCV treatments and improving
virologic cure rates, or SVR, primarily focused on genotype 1. The most promising
of these explorations has been the development of the DAA agents. These oral
compounds are developed to directly target the specific steps within the viral
replication genome of hepatitis C. In late 2013 and most of 2014, the standard of care
(SOC) for initial therapy of genotype 1 comprised of PegIFN plus ribavirin plus
either sofosbuvir or simeprevir. Since 2015, the SOC for genotype 1 including the
rest of the six genotypes consists of all-oral, interferon-free therapy with DAA
combination regimens because of their significant high SVR rates and better
tolerability profile. With the SOC changed from PegIFN to the DAAs, the treatment
duration was also shortened from the traditional 48 weeks to 24 and then to 12
weeks. These oral compounds are developed to directly target the specific steps
within the viral replication genome of hepatitis C. The four classes of DAAs are
defined by their mechanism of action and therapeutic target, such as the NS proteins
3/4A (NS3/4A) serine protease inhibitors, NS5B nucleoside polymerase inhibitors,
NS5B non-nucleoside polymerase inhibitors, and NS5A inhibitors.
According to the AASLD/IDSA HCV guidance, treatment should be offered to all
persons with chronic HCV infection because the DAAs are safer, better tolerated,
and more effective in achieving virologic cure.
contraindications for DAA treatment: persons with short life expectancies (<12
months); the use of ribavirin in pregnant women, women who may become pregnant,
or men whose female partners are pregnant.
211,212 Persons with chronic HCV infection
who are of reproductive age and are to receive treatment that includes ribavirin
should be strongly advised to use two forms of contraception during treatment and for
at least 6 months following the end of treatment. Similarly, there are relative
contraindications to considerations for initiating HCV treatment. They include active
severe substance abuse, psychiatric issues not controlled or stabilized, and social
issues that may negatively affect a person’s adherence to treatment, laboratory, and
CASE 80-15, QUESTION 3: Genotyping of K.C.’s HCV infection shows that she has genotype 1a. What
pharmacologic agents are effective treatments for patients with chronic HCV infection genotype 1a?
K.C. has a lot of treatment options with the DAA combination therapies. She has
no signs of cirrhosis, or decompensated disease with splenomegaly, ascites,
coagulopathy, and esophageal varices. Furthermore, she does not have HIV or HBV
coinfections that could accelerate the progression of hepatitis C. The DAA
combination therapies are highly potent and successful in achieving >90% SVR rates
for persons with genotype 1 (1a and 1b) HCV infection (Table 80-8).
The NS3/4A protease inhibitors function through two mechanisms. They block the
NS3/4A serine protease, an enzyme involved in post-translational processing and
replication of HCV. They disrupt the virus replication process by blocking the NS3
catalytic site or the NS3/NS4A interaction.
213 The NS3/NS4A protease inhibitors
also block the TRIF-mediated Toll-like receptor signaling and Cardif-mediated
retinoic acid-inducible gene 1 (RIG-1) signaling, which result in impaired induction
of interferons and blocking viral elimination (see Table 80-8).
Telaprevir and boceprevir were the first-generation NS3/4A protease inhibitors
for HCV treatment. They were used in combination with PegIFN-α2a plus ribavirin
for the treatment of genotype 1 infection. The clinical importance of telaprevir and
boceprevir substantially diminished because of their cumbersome administration,
substantial adverse effects, drug–drug interactions, and low barrier to resistance. As
more-potent and better-tolerated protease inhibitors were developed and approved
for HCV treatment without PegIFN-α2a and ribavirin, telaprevir and boceprevir
eventually became clinically obsolete. The newer protease inhibitors have fewer
drug–drug interactions, improved dosing schedules, and fewer severe adverse
effects. In spite of their improved efficacy against genotype 1 infection, the newer
protease inhibitors have limited efficacy against other genotypes and lower barrier to
214 The subsequent-generation protease inhibitors available in the United
States include simeprevir, grazoprevir, and paritaprevir. Asunaprevir is available in
Simeprevir is the first second-generation, macrocyclic protease inhibitor. It is
approved as 150-mg capsule for the use in combination with PegIFN-α2a plus
ribavirin, or in combination with sofosbuvir with or without ribavirin for chronic
215 Simeprevir is administered orally once daily with food
and should not be used as monotherapy. No dose adjustment is required in patients
fivefold increases in drug exposure. Higher simeprevir exposure was reported in
patients of East Asian ancestry; thus, simeprevir should be used with caution for this
Comparison of Direct-Acting Antiviral Agents for HCV Treatment
Inhibitors NNPI NS5A Inhibitors
Sofosbuvir Dasabuvir Daclatasvir
Potency High (varies by GT) Moderate-to-high
Barrier to resistance Low (GT 1a < GT
High (1a = 1b) Very low (1a < 1b) Low (1a < 1b)
High Low Variable Low-to-moderate
Dosing Daily to 3 times daily Daily to 2 times daily Daily to 3 times daily Daily
Simeprevir is overall well tolerated although pruritus and nausea have been
reported. In clinical trials, treatment discontinuations from adverse effects were
217,218 However, photosensitivity and rash have occurred that led to
serious reactions requiring hospitalization for some patients in the trials. Patients
taking simeprevir should be cautioned about the risk of photosensitivity and rash, and
to use sun-protective measures and/or limit sun exposure while on treatment. If a
severe rash or photosensitivity reaction occurs, simeprevir should be discontinued.
Transient, mild elevations in bilirubin have been reported, which may result from
decreased bilirubin elimination related to inhibition of the hepatic transporters
OATP1B1 and MRP2. This does not suggest worsening of hepatic function.
With regard to drug interactions, simeprevir is oxidatively metabolized by CYP3A
isoenzyme, primarily the hepatic and intestinal CYP3A4.
potent inducers and inhibitors of CYP3A4 will affect the serum levels of simeprevir.
It is observed to inhibit the OATP1B1/3 transporter; therefore, serum levels of
substrates of OATP1B1/3 (atorvastatin and rosuvastatin) could increase.
The efficacy of simeprevir is affected by the presence of resistance mutations or
polymorphisms of the NS3/4A protease. In particular, the presence of Q80K
polymorphism was associated with a lower SVR rate (58% vs. 84% if the Q80K
216 However, data suggest that the Q80K mutation does not
significantly affect SVR rates when simeprevir is coadministered with sofosbuvir, an
220 The emergence of other resistance mutations during
unsuccessful treatment with either telaprevir or boceprevir, such as R155K and
A156T/V, has been reported to affect the clinical response to simeprevir.
Grazoprevir is a potent, second-generation protease inhibitor that is only
available in combination with an NS5A inhibitor, elbasvir. Grazoprevir has activity
against HCV genotypes 1, 4, and 6 and, however, is only FDA-approved for
genotypes 1 and 4. (See elbasvir/grazoprevir section.)
Paritaprevir is the third, second-generation protease inhibitor FDA-approved for
the treatment of HCV genotype 1 infection. It is coadministered with low-dose
ritonavir, an HIV protease inhibitor, for pharmacokinetic enhancing effects via
inhibition of CYP3A-mediated metabolism. Ritonavir does not have any anti-HCV
activity. Paritaprevir and ritonavir are coformulated as a fixed-dose combination
with ombitasvir, an NS5A inhibitor. (See
paritaprevir/ritonavir/ombitasvir/dasabuvir section.)
The NS5A inhibitors block the protein that has a role in viral replication and the
assembly of the HCV (see Table 80-8).
221–222 The NS5A class is relatively potent and
effective across all genotypes; however, it has a low barrier to resistance and
variable toxicity profile. When coadministered with PegIFN and ribavirin, NS5A
inhibitors can substantially reduce HCV RNA levels and improve SVR.
NS5A inhibitors in fixed-dose combinations with other DAAs comprise of
ledipasvir, ombitasvir, and elbasvir. Daclatasvir is the only available, stand-alone
Daclatasvir (Daklinza) is a NS5A inhibitor mainly used in combination with
sofosbuvir, a NS5B polymerase inhibitor. It has activity against HCV genotypes 1, 2,
and 3. It is dosed as 60 mg orally once daily with or without food. It cannot be used
as monotherapy and approved to be coadministered with sofosbuvir with or without
ribavirin. If sofosbuvir is discontinued, daclatasvir should also be discontinued.
Dose adjustments for patients with renal or hepatic impairment are not required.
Daclatasvir is well tolerated with commonly reported adverse effects of headache,
fatigue, and nausea from clinical trial data.
Daclatasvir is metabolized via the CYP3A pathway and should not be
coadministered with potent inducers, such as rifampin, phenytoin, carbamazepine,
and Saint-John’s-wort. The serum levels of daclatasvir will be significantly reduced
to suboptimal efficacy. When coadministered with moderate CYP3A inducers (e.g.,
efavirenz, etravirine, dexamethasone, and nafcillin), the dose of daclatasvir should
be increased to 90 mg once daily. On the other hand, when given with potent CYP3A
inhibitors (e.g., HIV protease inhibitors, some azole agents, and clarithromycin), the
dose of daclatasvir should be reduced to 30 mg once daily. Aside from the CYP450
system, daclatasvir also inhibits P-glycoprotein (P-gp), organic anion transporting
polypeptide (OATP) 1B1 and 1B3, and the BCRP. Digoxin dose may need to be
adjusted when coadministered with daclatasvir.
In vitro resistance mutations associated with daclatasvir include polymorphisms at
M28, A30, L31, and Y93, which is the most clinically relevant. Based on the clinical
trial data, the emergence of Y93H polymorphism was associated with lower SVR
rates and responsible for several virologic failures.
Elbasvir is a NS5A inhibitor only available as a fixed-dose combination with
grazoprevir, a NS3/4A serine protease inhibitor. (See elbasvir/grazoprevir section.)
Ledipasvir is a NS5A inhibitor only available as a fixed-dose combination with
sofosbuvir, a NS5B polymerase inhibitor. (See ledipasvir/sofosbuvir section.)
Ombitasvir is a NS5A inhibitor only available as a fixed-dose combination with
the protease inhibitors paritaprevir and ritonavir, and administered in combination
with dasabuvir, a NS5B non-nucleotide inhibitor. (See
paritaprevir/ritonavir/ombitasvir with or without dasabuvir section.)
Velpatasvir is a NS5A inhibitor that has pangenotypic antiviral activity against
genotypes 1 to 6. It is only available as a fixed-dose combination with sofosbuvir, a
NS5B polymerase inhibitor. (See sofosbuvir/velpatasvir section.)
NS5B RNA-Dependent RNA Polymerase Inhibitors
NS5B is an RNA-dependent RNA polymerase involved in post-translational
processing that is necessary for replication of HCV. The polymerase has a catalytic
site for nucleoside binding and four other sites for non-nucleoside binding to cause
an allosteric alteration. The enzyme structure is highly conserved across all six
genotypes. Two classes of NS5B polymerase inhibitors include the
nucleoside/nucleotide analogues (NPIs) and non-nucleoside analogues (NNPIs). The
NPIs bind to the catalytic site of NS5B, whereas NNPIs function as allosteric
Sofosbuvir (Sovaldi) is the first NS5B NPI available for HCV treatment. It should
not be used as monotherapy and most effective when used in many combinations with
other antivirals to treat different genotypes. Sofosbuvir is available as a 400-mg
tablet and given orally once daily with or without food. It is primarily renally
eliminated, however, pharmacokinetic studies suggest no dose adjustments are
required for patients with mild or moderate renal impairment (eGFR >30
226 Nevertheless, serum levels of sofosbuvir are increased in
patients with severe renal impairment and receiving hemodialysis. There is
insufficient data for dose-adjustment recommendations in these patients. Sofosbuvir
can be given in patients with moderate (Child-Pugh class B) or severe (Child-Pugh
class C) hepatic impairment and cirrhosis without dose adjustments.
Sofosbuvir is generally well tolerated. When given with PegIFN and ribavirin, the
commonly reported adverse effects of sofosbuvir and ribavirin (with or without
PegIFN) were fatigue, headache, nausea, insomnia, and anemia.
use of sofosbuvir and sofosbuvir-containing regimens with amiodarone is
contraindicated due to episodes of severe bradycardia and fatal cardiac arrest.
As a substrate of the P-gp drug transporter, sofosbuvir has significant drug
interactions with potent intestinal P-gp inducers
that could decrease its serum levels. The coadministration of sofosbuvir with the
contraindicated. Of note, the coadministration of sofosbuvir and amiodarone is also
In vitro resistance polymorphisms have been reported for
sofosbuvir; however, their clinical significance is unclear.
Dasabuvir, unlike sofosbuvir, is a NS5B NNPI that is administered and packaged
with paritaprevir/ritonavir/ombitasvir. (See paritaprevir/ritonavir/ombitasvir with
or without dasabuvir section.) As a class, the NNPI class is less potent than the NPI
class, is more specific for genotype 1, has a low-to-moderate barrier to resistance
and a variable toxicity profile.
CASE 80-15, QUESTION 4: According to the 2016 AASLD Guidelines, what fixed-dose DAA combination
therapies could K.C. benefit from and for what duration length of treatment?
There are currently four FDA-approved fixed-dose combinations that are effective
against HCV genotype 1 (and other genotypes). K.C. could benefit from either of the
elbasvir 50 mg/grazoprevir 100 mg (Zepatier) 1 tablet orally once daily for 12
ledipasvir 90 mg/sofosbuvir 400 mg (Harvoni) 1 tablet orally once daily for 12
sofosbuvir 400 mg/velpatasvir 100 mg (Epclusa) 1 tablet orally once daily for 12
paritaprevir 50 mg/ritonavir 33.33 mg/ombitasvir 8.33 mg plus dasabuvir 200 mg
As a coformulated single tablet, elbasvir 50 mg plus grazoprevir 100 mg (Zepatier)
is administered orally once daily for either 12 or 16 weeks.
administered with or without weight-based ribavirin, depending on certain patient
characteristics. Elbasvir/grazoprevir has been studied and approved for treatment of
HCV and HIV coinfection. Patients should have documentation of baseline
aminotransferases and be tested for current or previous HBV infection (HBsAg and
anti-HBc) to ensure that there is no risk of HBV flares during HCV treatment. The
regimen is the first of the newer DAA therapies that could be used in patients with
renal impairment, including hemodialysis, without the need for dose adjustments.
However, the regimen is contraindicated in patients with Child-Pugh class B or C
cirrhosis. Prior to administering elbasvir/grazoprevir, patients with genotype 1a
infection should be tested for the presence of NS5A resistance-associated
substitutions (RASs) and NS3 protein polymorphisms. Preexisting NS5A
polymorphisms that are associated with elbasvir resistance and lower SVR rates
with the regimen in genotype 1a patients are found at positions M28, Q30, L31, and
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