CYPRESS COLLEGE DIVISION OF HEALTH SCIENCE HS 147 Hi.docx

CYPRESS COLLEGE
DIVISION OF HEALTH SCIENCE
HS 147
Hints for writing your final disease report: (not in any order)
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June 15, 2015 ◆ Volume 91, Number 12 www.aafp.org/afp

American Family Physician 835
Diagnosis and Management of Hepatitis C
THAD WILKINS, MD; MARIAM AKHTAR, MD; and EUNICE
GITITU, MD, Georgia Regents University, Augusta, Georgia
CHRISTINE JALLURI, MD, and JASON RAMIREZ, MD,
University of Maryland, Baltimore, Maryland
H
epatitis C virus (HCV) infec-
tion is a major cause of chronic
liver disease and cirrhosis.1
The World Health Organi-
zation reports that there are at least 185
million persons worldwide with the infec-
tion, causing 350,000 deaths annually.1 In
the United States, an estimated 2.7 mil-
lion individuals are chronically infected
with HCV.2 The burden of HCV infection
in the United States is expected to increase
because of the high proportion of persons
who were infected in the 1960s and 1970s.3
In 2013, the total cost of HCV infection in
the United States was estimated at $6.5 bil-
lion.4 Chronic HCV infection leads to sig-
nificantly more lost days of work, decreased
productivity, and increased health care
costs.5 This article focuses on chronic HCV
infection in adults and excludes special
groups, such as children, pregnant women,
transplant recipients, and persons coin-
fected with hepatitis B virus or human
immunodeficiency virus (HIV).

Modes of Transmission
HCV is predominantly transmitted through
blood or body fluids.1,6 It can also be trans-
mitted from mother to infant, through organ
transplantation that occurred before July 1992,
and through unprotected sex in HIV-infected
men who have sex with men.6 Any sexual con-
tact where blood-to-blood transmission may
occur (e.g., anal sex, sex during menses, shar-
ing of sexual paraphernalia, sex with partners
with open lesions) may also pose transmission
risk. Intravenous drug use is the most impor-
tant risk factor for HCV infection, accounting
for approximately 60% of acute infections in
the United States.6 Since 1992 when univer-
sal screening was instituted for blood donors,
blood transfusion has become a rare mode of
transmission, with an estimated risk of one in
1 million units of blood transfused.5,7 Table 1
lists risk factors for HCV infection.8
Pathophysiology and Natural History
There are six known genotypes of HCV.
The most common genotypes in the United
Hepatitis C virus (HCV) infection, a major cause of chronic
liver disease and cirrhosis, is predominantly transmit-
ted by exposure to blood or body fluids. The infection
progresses to a chronic state in 80% of patients, whereas the
virus clears completely after the acute infection in 20% of
patients. Screening for HCV with an anti-HCV antibody
test is recommended for all adults at high risk of infection, and
one-time screening is recommended in adults born
between 1945 and 1965. If the anti-HCV antibody test result is
positive, current infection should be confirmed with
a qualitative HCV RNA test. In patients with confirmed HCV

infec-
tion, quantitative HCV RNA testing and testing for HCV
genotype is
recommended. An assessment of the degree of liver fibrosis
with liver
biopsy or noninvasive testing is necessary to determine the
urgency
of treatment. Treatment of patients with chronic HCV infection
should be considered based on genotype, extent of fibrosis or
cirrho-
sis, prior treatment, comorbidities, and potential adverse
effects. The
goal of therapy is to reduce all-cause mortality and liver-
associated
complications. Although interferon-based regimens have been
the
mainstay of treatment for HCV infection, the U.S. Food and
Drug
Administration recently approved two combination-pill
interferon-
free treatments (ledipasvir plus sofosbuvir, and ombitasvir/pari-
taprevir/ritonavir plus dasabuvir) for chronic HCV genotype 1.
(Am Fam Physician. 2015;91(12):835-842. Copyright © 2015
Ameri-
can Academy of Family Physicians.)
CME This clinical content
conforms to AAFP criteria
for continuing medical
education (CME). See
CME Quiz Questions on
page 826.
Author disclosure: No rel-
evant financial affiliations.

▲
Patient information:
A handout on this topic,
written by the authors of
this article, is available at
http://www.aafp.org/afp/
2015/0615/p835-s1.html.
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Hepatitis C
836 American Family Physician www.aafp.org/afp Volume 91,
Number 12 ◆ June 15, 2015
States, comprising 97% of all U.S. HCV infections, are
1 (subtypes 1a and 1b), 2, and 3.9
The mechanism of hepatocyte damage induced by
HCV infection is not completely understood but may
involve direct cell injury and a local immune-mediated
mechanism that causes a chronic inflammatory state.10,11
Acute HCV infection progresses to chronic disease
(detectable virus after six months) in 50% to 80% of
patients and clears spontaneously in 20% to 50% of
patients.10 Of persons with chronic disease, 20% will
develop cirrhosis, end-stage liver disease, and/or hepato-
cellular carcinoma.12 Figure 1 illustrates the natural his-

tory of HCV infection.10
Screening and Diagnosis
The U.S. Preventive Services Task Force and the Centers
for Disease Control and Prevention recommend peri-
odic HCV screening for all adults at high risk of infec-
tion and one-time screening in adults born between 1945
and 1965.6,13,14 The American Association for the Study of
Liver Diseases recommends annual screening for intra-
venous drug users and for men who are HIV seroposi-
tive and have unprotected sex with men.6
An anti-HCV antibody test is recommended to
screen for HCV infection (sensitivity of 95%, specific-
ity of 99%, positive likelihood ratio of 95, and negative
likelihood ratio of 0.05).6 If the anti-HCV antibody
test result is positive, current infection should be con-
firmed with a qualitative measurement of HCV RNA
(Figure 2).1,6 If the anti-HCV antibody test result is
negative in a patient who may have been exposed
to HCV within the previous six months, HCV RNA
should be measured every four to eight weeks for at
least six months or follow-up anti-HCV antibody test-
ing should be performed in 12 weeks.6 Patients with a
positive anti-HCV antibody test result but a negative
HCV RNA test result are not considered to have HCV
infection.6 Quantitative HCV RNA testing is recom-
mended before initiating therapy to determine the
baseline viral load, and testing for HCV genotype is
recommended to help guide treatment decisions.1,6
Acute HCV Infection
Acute HCV infection refers to signs and symptoms
that occur within six months of presumed exposure.
An acute infection can be documented with a posi-

SORT: KEY RECOMMENDATIONS FOR PRACTICE
Clinical recommendation
Evidence
rating References
Periodic HCV screening is recommended in all adults at high
risk of infection, and one-time screening
is recommended in adults born between 1945 and 1965.
B 6, 13
Confirmation of chronic HCV infection is recommended using
qualitative HCV RNA measurement. C 1, 6
Patients should be assessed for quantitative HCV RNA and
genotype before initiating antiviral therapy. A 1, 6
All patients with chronic HCV infection should be assessed for
the degree of liver fibrosis and cirrhosis. C 1, 6
Ledipasvir/sofosbuvir (Harvoni);
ombitasvir/paritaprevir/ritonavir plus dasabuvir (Viekira Pak)
with or
without weight-based ribavirin (Rebetol); or sofosbuvir
(Sovaldi) plus simeprevir (Olysio) with or
without weight-based ribavirin is recommended for the
treatment of chronic HCV genotype 1.
C 6
All patients with chronic HCV infection should be assessed for
alcohol use. C 1, 6
Vaccination against hepatitis A and B is recommended for

susceptible patients with HCV infection. C 6
HCV = hepatitis C virus.
A = consistent, good-quality patient-oriented evidence; B =
inconsistent or limited-quality patient-oriented evidence; C =
consensus, disease-oriented
evidence, usual practice, expert opinion, or case series. For
information about the SORT evidence rating system, go to
http://www.aafp.org/afpsort.
Table 1. Risk Factors for Chronic HCV Infection
Most common
Blood transfusion before July 1992
History of illicit injection drug use
Less common
Born to a mother infected with HCV
History of chronic hemodialysis
History of illicit intranasal drug use
History of needlestick or other sharp or mucosal exposure
Incarceration
Men with human immunodeficiency virus infection who
have sex with men
Organ transplantation before July 1992

Persistently elevated alanine transaminase levels
Receipt of clotting factor concentrate before 1987
Sex with a partner infected with HCV
Sexual contact in which blood-to-blood contact may occur
Tattoo from an unregulated establishment
Adapted with permission from Campos-Outcalt D. Hepatitis C:
new
CDC screening recommendations. J Fam Pract.
2012;61(12):744.
Hepatitis C
tive HCV RNA test result in the setting of a negative
anti-HCV antibody test result that subsequently sero-
converts to a positive anti-HCV antibody test result
over eight to 12 weeks.15 Postexposure prophylaxis with
antiviral therapy is not recommended for patients with
acute HCV infection.6 The American Association for
the Study of Liver Diseases recommends either delay-
ing treatment for a minimum of six months to moni-
tor for spontaneous clearance of HCV RNA and then
following treatment recommendations for chronic HCV
infection, or treating the acute infection after monitor-
ing HCV RNA for a minimum of 12 to 16 weeks to allow

for spontaneous clearance.6,16 Decreased transmission
is a potential but unproven benefit of treatment during
acute HCV infection.6
Assessment
Assessing the degree of liver fibrosis and cirrhosis is
necessary in patients with confirmed HCV infection to
determine the urgency of treatment because the degree
of liver fibrosis predicts disease progression and clini-
cal outcomes.1,6,17 The Metavir scoring system (Table 2)
grades fibrosis from 0 to 4, and treatment should be con-
sidered in patients with substantial fibrosis (score of 2 or
greater).6,18
Liver biopsy is the preferred method to assess degree of
fibrosis. However, noninvasive tests, such as direct bio-
markers and liver elastography, may be used.19 Patients
with chronic HCV infection should be assessed for hep-
atitis B and HIV infections, which may accelerate liver
fibrosis.6
Treatment
All patients with chronic HCV infection
should be considered for treatment based
on genotype, extent of fibrosis or cirrhosis,
prior treatment, comorbidities, and poten-
tial adverse effects. The goal of therapy is
to reduce all-cause mortality and liver-
associated complications.6,20 Monitoring
of treatment effectiveness is assessed by
repeated measurement of HCV RNA.21 A
sustained viral response (SVR), defined by
the absence of HCV RNA on polymerase
chain reaction testing 24 weeks after cessa-
tion of treatment, is associated with a 99%
chance of being HCV RNA negative dur-

ing long-term follow-up.22,23 SVR 12 weeks
after treatment is a new primary end point
in many recent drug trials. A small post
hoc analysis of patients with HCV geno-
type 1 found that the SVR at 12 weeks has a
100% positive predictive value for SVR at 24
weeks.24 Table 3 shows predictors of SVR.25-31
Candidates for treatment are 18 years or
older, are willing to adhere to treatment,
and have elevated serum alanine transami-
nase levels and a Metavir score of 2 or more.6
Figure 1. Natural history of hepatitis C virus (HCV) infection.
Reprinted with permission from Pawlotsky JM. Pathophysiology
of hepatitis C virus infection and related liver disease. Trends
Microbiol. 2004;12(2):97.
Acute infection
Recovery
Chronic HCV
Stable
Cirrhosis
20 to 30 years
50% to 80%
20% to 50%

Mortality (cirrhosis,
hepatocellular carcinoma)
75%
20%
Stable
25%
80%
Diagnosis of HCV Infection
Figure 2. Algorithm for the diagnosis of hepatitis C virus
(HCV) infection.
Information from references 1 and 6.
Screen with anti-HCV antibody testing
Nonreactive
Acute HCV infection suspected?
Reactive
No further workup required
No
Perform HCV RNA testing
Detected
Current HCV infection

Use Metavir score to determine
the need for treatment (Table 2)
Not detected
No current HCV infection
Yes
Hepatitis C
Therapy is complex and rapidly changing, and should
be supervised by a physician experienced in treating
HCV infection. Although interferon-based regimens
have been the mainstay of treatment for HCV infec-
tion, new interferon-free regimens have recently been
approved.32 Table 4 summarizes treatment regimens for
HCV infection.6
RIBAVIRIN
Ribavirin (RBV; Rebetol) inhibits viral RNA polymerase,
thereby inhibiting protein synthesis. A 2010 Cochrane
review of randomized controlled trials involving 12,707
patients found that RBV combined with interferon ther-
apy improved the likelihood of SVR in treatment-naive
patients (relative risk = 0.72; 95% confidence interval,
0.68 to 0.75), compared with interferon alone.33 The
U.S. Food and Drug Administration (FDA) has issued
a boxed warning for RBV because of the risk of hemo-

lytic anemia. The medication also may worsen cardiac
disease, leading to myocardial infarction. Because RBV
has significant teratogenic and embryocidal effects,
two forms of reliable contraception should be used by
women taking the drug and by female partners of men
taking the drug, during therapy and for six months after
therapy.34,35
PEGYLATED INTERFERON
Pegylated interferon inhibits viral replication by antivi-
ral, antiproliferative, and immunomodulatory effects.
There are two FDA-approved formulations: pegin-
terferon alfa-2a (Pegasys) and peginterferon alfa-2b
(PEG-Intron). Two meta-analyses and one Cochrane
review found that the SVR was significantly
higher for peginterferon alfa-2a than for
peginterferon alfa-2b for all genotypes.36-38
Interferon-based therapy can cause serious
adverse effects, including development or
aggravation of life-threatening neuropsychi-
atric, autoimmune, ischemic, and infectious
disorders.39
NS3/4A INHIBITORS
Telaprevir (Incivek) and boceprevir (Vic-
trelis) were FDA approved in 2011 for the
treatment of chronic HCV infection when
used in combination with RBV and/or
pegylated interferon. However, the manufac-
turer discontinued telaprevir in the United
States because of alternative treatments and
diminishing market demands. Boceprevir
also will be discontinued in the United States

by the end of 2015.40 Regimens including tel-
aprevir and boceprevir are less effective than
the preferred regimens and are associated
with higher rates of serious adverse events.6
Figure 3 illustrates the HCV polyprotein
structure and selected targets.41
Simeprevir (Olysio) is effective for geno-
types 1, 4, 5, and 6.20 The most common
Table 2. Metavir Scoring System for the
Assessment of Liver Fibrosis and Cirrhosis
Level of fibrosis Score
No fibrosis 0
Minimal scarring 1
Positive scarring with extension beyond area
containing blood vessels
2
Bridging fibrosis with connection to other areas
of fibrosis
3
Cirrhosis or advanced liver scarring 4
NOTE: Treatment should be considered in patients with a score
≥ 2.6
Information from references 6 and 18.

Table 3. Predictors of SVR in Treatment of HCV Infection
Factor Comment
Age Rates of SVR are higher in patients younger than
40 to 45 years25
Fibrosis Advanced fibrosis and cirrhosis are associated with
lower SVR25
Hepatitis C
genotype
Strongest baseline predictor for SVR; SVR is highest
for genotypes 2 and 3 and lowest for genotype 126
IL28B
polymorphisms
IL28B gene is involved in viral resistance and is
upregulated by interferons; genotypes CC and TT
are strong SVR predictors for HCV genotype 1;
TT is associated with slightly increased SVR in
Asians with genotypes 2 and 327
Insulin resistance Patients with normal insulin sensitivity have
higher
SVR compared with patients with insulin resistance
(odds ratio = 2.86)28
Lower baseline
viral load
≤ 600,000 to 800,000 IU per mL is associated with
higher SVR25,29

Race Blacks have lower SVR rates than nonblacks25
Statin use Patients treated with statins have higher SVR
compared with patients not treated with statins30,31
HCV = hepatitis C virus; SVR = sustained viral response.
Information from references 25 through 31.
Hepatitis C
adverse effects include anemia, fatigue, flulike symp-
toms, pruritus, headache, and nausea.20 Two random-
ized controlled trials involving patients with genotypes 1
to 3 reported a superior SVR at 12 weeks with simeprevir
combined with pegylated interferon and RBV (80% to
92%) vs. pegylated interferon and RBV alone (40% to
50%).42,43
NS5B INHIBITOR
Sofosbuvir (Sovaldi) inhibits HCV viral assembly and
RNA polymerase, thus inhibiting viral replication. It is
effective for all HCV genotypes.20 The most commonly
reported adverse events are headache, anemia, fatigue,
and nausea.20 A randomized controlled trial involving
122 patients with HCV genotypes 1 to 3 found an SVR of
90% at 12 weeks with sofosbuvir, 200 mg, plus pegylated
interferon and RBV, compared with an SVR of 91% for
sofosbuvir, 400 mg, plus pegylated interferon and RBV,
and an SVR of 58% for pegylated interferon and RBV.44

Two randomized controlled trials involving patients
with chronic HCV genotype 2 or 3 found that the SVR at 12
weeks was superior for sofosbuvir and RBV (78% to 93%)
compared with placebo (0%).45,46 An open-label study of 82
patients with chronic HCV genotype 1 found that the SVR
at 12 weeks was superior for a combination of simeprevir
and sofosbuvir (93%), compared with a combination
of sofosbuvir, pegylated interferon, and RBV (75%).47
Regimens containing either sofosbuvir or simeprevir are
preferable over telaprevir or boceprevir because of fewer
adverse effects and greater ease of administration.6
INTERFERON-FREE REGIMENS
In October 2014, the FDA approved the first combina-
tion pill containing ledipasvir and sofosbuvir (Harvoni),
which is taken once daily to treat chronic HCV genotype 1
infection. Ledipasvir is an NS5A inhibitor that acts in
combination with sofosbuvir to interfere with viral
replication. A phase-3, randomized, open-label study
involving 647 treatment-experienced patients with HCV
genotype 1 infection concluded that treatment with eight
weeks of ledipasvir/sofosbuvir was noninferior to treat-
ment with 12 weeks of ledipasvir/sofosbuvir plus RBV.48
The most commonly reported adverse effects included
headache and fatigue.
In December 2014, the FDA approved Viekira Pak,
which consists of ombitasvir (NS5A inhibitor), parita-
previr (NS3/4A inhibitor), and ritonavir (HIV-1 protease
inhibitor) tablets copackaged with dasabuvir tablets
(NS5B inhibitor) for adults with chronic HCV genotype 1
infection. These drugs work together to inhibit the growth

Table 4. Treatment Regimens for Chronic Hepatitis C Virus
Infection in Treatment-Naive Patients
Genotype AASLD recommendations Cost estimate†
1a* Ledipasvir/sofosbuvir (Harvoni) for 12 weeks $93,000
Ombitasvir/paritaprevir/ritonavir plus dasabuvir (Viekira Pak)
and weight-
based RBV (Rebetol) for 12 weeks (no cirrhosis) or 24 weeks
(cirrhosis)
12 weeks: $94,000 ($90,400 if generic
RBV is used)
Sofosbuvir (Sovaldi) plus simeprevir (Olysio) with or without
weight-
based RBV for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis)
12 weeks with RBV: $156,000 ($152,400
if generic RBV is used)
12 weeks without RBV: $152,000
1b* Ledipasvir/sofosbuvir for 12 weeks $93,000
Ombitasvir/paritaprevir/ritonavir plus dasabuvir for 12 weeks
(no cirrhosis)
or with the addition of weight-based RBV for 24 weeks
(cirrhosis)
12 weeks: $94,000 ($90,400 if generic
RBV is used)
Sofosbuvir plus simeprevir for 12 weeks (no cirrhosis) or 24
weeks

(cirrhosis)
12 weeks: $152,000
2 Sofosbuvir plus weight-based RBV for 12 weeks (no
cirrhosis) or for
16 weeks (cirrhosis)
12 weeks: $86,000 ($82,400 if generic
RBV is used)
3 Sofosbuvir plus weight-based RBV for 24 weeks $86,000
($82,400 if generic RBV is used)
4* Ledipasvir/sofosbuvir for 12 weeks $93,000
Ombitasvir/paritaprevir/ritonavir plus dasabuvir and weight-
based RBV
for 12 weeks
$94,000 ($90,400 if generic RBV is used)
Sofosbuvir plus weight-based RBV for 24 weeks $188,000
($180,800 if generic RBV is used)
5 Sofosbuvir plus pegylated interferon plus weight-based RBV
for 12 weeks $97,000 ($93,400 if generic RBV is used)
6 Ledipasvir/sofosbuvir for 12 weeks $93,000
AASLD = American Association for the Study of Liver
Diseases; RBV = ribavirin.
*—Three options with similar effectiveness.
†—Estimated retail price of treatment based on information
obtained at http://www.goodrx.com (accessed April 27, 2015).

Information from reference 6.
of HCV and may be used with or without RBV. A mul-
ticenter, randomized, double-blind, placebo-controlled
trial evaluating 631 patients found an SVR of 96.2%, with
a 0.6% discontinuation rate because of adverse events.49
The most common adverse effects included fatigue,
weakness, decreased energy, nausea, and insomnia. The
cost of 12 weeks of Viekira Pak is similar to 12 weeks of
sofosbuvir and less than ledipasvir/sofosbuvir.
Monitoring
At every visit, patients being treated for HCV infec-
tion should be assessed for adherence to therapy and
adverse effects, monitored for new or worsening psy-
chiatric illness, and screened for alcohol and substance
abuse.1,6 Baseline tests include thyroid-stimulating hor-
mone level if pegylated interferon will be used; complete
blood count; creatinine level with glomerular filtration
rate; aspartate and alanine transaminase levels; alkaline
phosphatase levels; and pregnancy testing in women of
childbearing age.1,6 Complete blood count, creatinine
level, and aspartate and alanine transaminase levels
should be measured at week 4 of treatment and as clini-
cally indicated.6 Quantitative HCV viral load is recom-
mended at week 4 of treatment, and at 12 and 24 weeks
after completion of therapy.6
Complications

In a 17-year cohort study of 214 patients with chronic
Figure 3. Hepatitis C polyprotein structure and selected targets.
The HCV viral particle contains roughly 9,600 nucleo-
tides, which are translated into a 3,000 amino acid polypeptide
using host machinery. The polypeptide consists of both
structural and nonstructural components. The N-terminal (5′
end) of the polyprotein contains structural proteins C
(the core), E1 and E2 (envelope glycoproteins), and p7 (a
membrane protein that serves as an ion channel). The non-
structural proteins are towards the 3′ end: NS2, NS3–NS4A,
NS4B, NS5A, and NS5B. The NS2/3 cysteine protease starts
a cascade of enzymatic reactions leading to the release of all
subsequent proteins: NS3 serine protease and RNA heli-
case, NS3–4A serine protease, NS4B and NS5A RNA-binding
proteins, and NS5B RNA-dependent RNA polymerase. The
majority of these viral components have been investigated as
targets for anti-HCV antibody therapy, primarily NS3/4A
and NS5B inhibitors and more recently NS5A and p7.
Additionally, the envelope and core proteins are being utilized
as
potential targets for both prophylactic and therapeutic vaccines.
Reprinted with permission from Belousova V, Abd-Rabou AA,
Mousa SA. Recent advances and future directions in the
management of hepatitis C infec-
tions. Pharmacol Ther. 2015;145:94.
P7
protein
NS5A
protein
5’ 3’

C E1 E2 P7 NS2 NS3 NS4A NS4B NS5A NS5B
HCV RNA genome
NS3
protein
NS4A
protein
NS5B
protein
P7 inhibitor
BIT225
NS5A inhibitors
Daclatasvir (BMS-790052)
Ledipasvir (GS-5885)
ABT-267
MK-8742
ACH-3102
PPI-668
NS5B Inhibitors
Nucleoside
Sofosbuvir (PSI-7851)

Mercitabine (RG7128,
ROS024048)
Valopicitabine (NM283)
R7128
R1626
Nonnucleoside
ABT-333
ABT-072
BMS-791325
Setrobuvir (ANA-598,
RG-7790)
GS-9669
VX-222
NS3/4A inhibitors
Telaprevir
Boceprevir
ABT-450
Simeprevir (TMC 435)
Faldaprevir (BI 201335)

Asunaprevir (BMS-650032)
Vaniprevir (MK-7009)
Danoprevir (RG-7227)
GS-9541
Hepatitis C
HCV infection, the annual incidence of hepatocellular
carcinoma was 3.9%; decompensated cirrhosis, 3.9%;
ascites, 2.9%; upper gastrointestinal tract bleeding,
0.7%; and encephalopathy, 0.1%.50 The annual mortal-
ity rate in this cohort was 4%; hepatocellular carcinoma
was the main cause of death in 44% of patients who died
and was the first complication to develop in 27% of all
patients.50 Patients with HCV-related cirrhosis should
be assessed for hepatocellular carcinoma every six to 12
months using ultrasonography and α-fetoprotein mea-
surement.1,51 Patients with cirrhosis or advanced fibrosis
should be screened for varices using upper endoscopy
every one to two years.19 Referral for possible liver trans-
plantation should be considered for patients with HCV-
related cirrhosis.6
Prevention
Alcohol consumption should be assessed and quanti-
fied in patients with HCV infection.21 Patients should be
advised to decrease or abstain from alcohol, which can

accelerate the progression of liver fibrosis and cirrhosis.1
Antiviral therapy should not be withheld because of pre-
vious alcohol use. Vaccination against hepatitis A and B
is recommended for susceptible patients with HCV infec-
tion.6 Patients with chronic HCV infection and their fami-
lies should be educated on preventing HCV transmission.6
Data Sources: A PubMed search was completed in Clinical
Queries
using the key terms hepatitis C, pathogenesis, diagnosis, and
treatment.
The search included meta-analyses, randomized controlled
trials, clinical
trials, and reviews. We also searched the Agency for Healthcare
Research
and Quality evidence reports, Clinical Evidence, the Cochrane
database,
Essential Evidence Plus, the National Guideline Clearinghouse
database,
and DynaMed. Search dates: October 29, 2014, and March 1,
2015.
The Authors
THAD WILKINS, MD, is director of academic development and
a professor
in the Department of Family Medicine at Georgia Regents
University in
Augusta.
MARIAM AKHTAR, MD, is a second-year resident in the
Department of
Family Medicine at Georgia Regents University.
EUNICE GITITU, MD, is a third-year resident in the
Department of Family
Medicine at Georgia Regents University.

CHRISTINE JALLURI, MD, is a third-year resident in the
Department of
Family Medicine at the University of Maryland in Baltimore.
JASON RAMIREZ, MD, is an assistant professor in the
Department of Fam-
ily Medicine at the University of Maryland.
Address correspondence to Thad Wilkins, MD, Georgia Regents
Univer-
sity, 1120 15th Street, Augusta, GA 30912 (e-mail:
[email protected]).
Reprints are not available from the authors.
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Journal of Pakistan Association of Dermatologists. 2015;25
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285
Address for correspondence
Dr. Shagufta Anwar,
Department of Dermatology,

Bahawal-Victoria Hospital,
Quaid-e-Azam Medical College, Bahawalpur.
Email: [email protected]
Original Article
Frequency of cutaneous manifestations in
patients of hepatitis C infection
Introduction
The hepatitis C virus (HCV) is an RNA virus
that belongs to the family flaviviridae.1 HCV
replicates in the cytoplasm of hepatocytes, but
is not directly cytopathic. Persistent infection
appears to rely on rapid production of virus
and continuous cell-to-cell spread, along with
a lack of vigorous T-cell immune response to
HCV antigens. The HCV turnover rate can be
quite high with replication ranging between
10
10
to 10
12

virions per day and a predicted
viral half-life of 2 to 3 hours.2 The rapid viral
replication and lack of error proofreading by
the viral RNA polymerase are reasons why the
HCV RNA genome mutates frequently.3
There
are six known genotypes (numbered 1 through
6) and more than 50 subtypes (e.g., 1a, 1b,
2a...).4 Frequent HCV mutations and numerous
subtypes have made the search for an HCV
vaccine challenging. Chronic hepatitis C is the
most common cause of chronic liver disease
and cirrhosis, and the most common indication
for liver transplantation in the United States
(U.S.), Australia, and most of Europe.5,6
Approximately 170 million people are affected
with HCV worldwide, comprising ~3% of the
global population.4 Hepatitis C virus (HCV) is

the most common chronic blood borne
infection in the U.S., and is involved in 40%
of chronic liver disease.4,5
Shagufta Anwar, Muhammad Khalid, Jamil Ahmad Shaheen
Department of Dermatology, Quaid-e-Azam Medical College,
Bahawal-Victoria Hospital,
Bahawalpur
Abstract Objective To determine the frequency of cutaneous
manifestations in patients suffering from
hepatitis C infection.
Methods In this cross-sectional study, one hundred diagnosed
patients of hepatitis C, admitted
in medical units of Bahawal-Victoria Hospital, Bahawalpur,
Quaid-e-Azam Medical College,
Bahawalpur were registered over a period of six months.
Cutaneous manifestations in these
patients were recorded and analyzed.
Results Out of 100 patients, 51 (51%) were males and 49 (49%)
were females. Majority of the
patients (73%) were 20 to 59 years old. Most of the patients had
more than one cutaneous
manifestation. These included generalized pruritus 30%, lichen
planus 30%, urticaria 26%,
leukocytoclastic vasculitis 25%, necrolytic acral erythema 20%

and porphyria cutanea tarda
4%.
Conclusion Cutaneous manifestations of hepatitis are not
uncommon. These may be the first
clinical sign of chronic hepatitis C infection. Generalized
pruritus, lichen planus, urticaria,
leukocytoclastic vasculitis, necrolytic acral erythema and
porphyria cutanea tarda were the
important cutaneous manifestations recorded. Screening such
patients on the basis of these
dermatoses and investigating accordingly may help in early
diagnosis and prevention of
complications of this grave disease.
Key words
Hepatitis C, HCV, cutaneous manifestations.
(4):285-290.
286
Hepatitis C virus infection is one of the
commonest chronic
viral infections in the
world, with about 300 million people

chronically
infected worldwide. Chronic HCV
infection leads to cirrhosis of liver if not
treated properly.
8
Physicians know hepatic
cirrhosis and its complication since the time of
Hippocrates. W.H.O. has estimated that
cirrhosis is responsible for 1.1% of all deaths
worldwide. About 175 million people in the
world have cirrhosis of liver. Cirrhosis
comprises 10
th
most common cause of death in
USA. About 30% patients of cirrhosis die in
hepatic coma.
Hepatitis C infection is very common in this
southern area of Punjab. It is associated with
many cutaneous manifestations. These skin
manifestations may lead to screening and early

diagnosis of this chronic disease. To determine
the frequency of these skin changes among
hepatitis C patients was the objective of this
study.
Methods
Patients of both genders having positive anti-
HCV antibodies on the basis of BIOTEC
Latex Kit method® and presence of HCV
RNA by polymerase chain reaction (PCR)
(Qualitative), were included in the study.
Patients having age less than 15 years, known
alcoholics, patients of primary biliary cirrhosis
and patients with HBsAg-positive test were
excluded from the study.
Cases of hepatitis C with positive HCV
evidence, according to inclusion criteria,
admitted in medical units of Bahawal-Victoria
Hospital, Bahawalpur were considered. One

hundred cases of positive HCV were
registered in the study. Informed consent was
taken from the patients and all the information
was collected on pre-designed proforma, with
two parts, part-I comprising sociodemographic
details like age, sex, occupation and
educational status while part-II consisting
study variables. The cutaneous manifestations
were observed in each patient and
dermatological diagnosis was re-confirmed by
senior consultant dermatologist (MK and JAS)
and investigated where needed. The patients
who had anti-HCV antibodies in their serum
were subjected to HCV RNA by PCR
(Qualitative). Cryoglobulins and the levels of
complement were analyzed in patients who
had positive serologic tests for rheumatoid
factor (RF). Patients with co-existent liver

diseases (co-infection with hepatitis B virus),
alcoholic liver disease and primary biliary
cirrhosis were excluded.
All the information collected on the proforma
was analyzed using statistical package for
social sciences (SPSS) version 10.0.
Frequencies for individual cutaneous
manifestations and their percentages were
calculated in hepatitis C patients in general, as
well as, with respect to sex and age. Account
was also taken of the cutaneous features with
or without history of antiviral therapy. Mean
and standard deviation was calculated for age.
Results
One hundred diagnosed patients of hepatitis C,
on the basis of positive anti-HCV antibodies
and PCR, were included in this study. Out of
these, 51 (51%) were male and 49 (49%) were

female, with male to female ratio of 1.04:1.00.
The age ranged from 15 years to above 70
years. Majority of the patients (73%) were 20
to 59 years old while only 8% were less than
20 years and 19% were older than 59 years.
Most of the patients were relatively in middle
age i.e. 80% of patients were of the ages 54
years (range 23-76 years). Among these 100
patients, 17 had a history of previous surgery,
11 had received blood transfusions, four
patients had dental procedures, two underwent
hemodialysis for chronic renal failure, and one
patient had a history of intravenous drug
abuse. In 65 of 100 cases, the route of
transmission was not ascertained.
(4):285-290.

287
Figure 1 Frequency of different cutaneous manifestations in 100
HCV patients.
Figure 1 shows the frequency of different
cutaneous manifestations seen in the study
population. Out of 100 patients, generalized
pruritus was seen in 30% (18 male and 12
female), lichen planus in 30% (17 male and 13
female), urticaria in 26% (13 male and 13
female), leukocytoclastic vasculitis in 25% (14
male and 11 female), necrolytic acral erythema
in 20% (12 male and 8 female) and porphyria
cutanea tarda in 40% (3 male and 1 female),
Generalized pruritus was seen in 30 (30%)
cases. On examination, 6 had dry skin, and 2
excoriated papules, the skin in the remaining
was normal. In 5 of 30 patients with pruritus, a

moderate cholestasis was present.
Cutaneous and mucosal lichen planus (LP),
confirmed by histopathological examination,
were noted in 30 (30%) patients, 17 males and
13 females. These patients presented with
cutaneous lesions of various sized pruritic
papules and plaques mostly over the
extremities. 14 patients had cutaneous lesions
only and 4 patients had cutaneous, as well as,
oral lesions and oral lichen planus alone was
present in 12 patients. In some cases there
were whitish streaks over the oral mucosa,
while in others painful erosive lesions were
seen over the tongue. The LP lasted more than
one year.
25 patients of leukocytoclastic vasculitis,
presented with palpable purpura, erythematous
plaques, erosions and ulcers over the feet and

lower legs. Histopathology revealed a
cutaneous leukocytoclastic vasculitis. In 5 of
these, RF was positive, the complement levels
were low and cryoglobulinemia was detected.
Necrolytic acral erythema was reported in 20%
patients as erythematous, scaly plaques on
hands and feet. Histopathology was suggestive
of the disease. In 4 patients of PCT, there was
history of photosensitivity and blistering on
face and hands, hyperpigmentation,
hypertrichosis and scarring but the
biochemical diagnosis could not be confirmed
due to unavailability of laboratory tests.
The serum levels of ALT and AST were
normal in 22 of the 100 chronic HCV infected
patients (22%). Fifty-five patients (55%)
showed mild to severe elevations of the serum
transaminases. RF was positive (>20 IU/ml) in

44 of 100 patients (44%). In 5 serum samples
from the RF positive patients,
cryoglobulinemia and altered complement
levels were detected. Forty patients (40%) had
received or were on antiviral therapy, which
was a combination of interferon and ribavirin.
None of the patients were on interferon
therapy alone or on ribavirin therapy only. All
30 30
26 25
20
4
0
5
10
15
20
25

30
35
40
Gen. pruritus Lichen planus Ch urticaria Leucocytoclastic
vasculitis
Necrolytic acral
erythema
Porphyria cutanea
tarda
(4):285-290.
288
the patients were on supportive/symptomatic
therapy.
Discussion
In the present study, total one hundred patients
were included. 51 (51%) were male and 49

(49%) were female. The male predominance
has been observed in various studies
conducted in Pakistan, as well as,
internationally previously, so is the case in this
study. This male to female difference may be
due to delayed consultation by female patients
and gender inequality in utilization of health
care facilities in Pakistan. The other factor
may be that, as compared to females, males are
relatively more exposed to the risk factor for
the transmission of HCV i.e. transmission
through barbers and intravenous drug abuse.
Fifty seven percent patients were illiterate.
Epidemiological studies have revealed that
HCV infection is uncommon in age groups
younger than 20 years and prevalent in persons
older than 40 years.
5

Our results show only 8
patients of less than 20 years with a frequency
of 8%, hence an almost similar scenario but
we found the infection also common in the age
range of 40-49 years. This may indicate that in
our region younger persons are becoming a
victim to the disease.
Pruritus was found more often in patients with
severe fibrosis and cirrhosis. Pruritus with
non-specific excoriations was a common
finding with a frequency of 30%. Several
etiologies can be considered. Pruritus could be
a direct effect of HCV infection or related to
IFN therapy. Cholestasis alone could be
another cause.10 The prevalence of pruritus in
HCV infected patients varies from one country
to another, and the epidemiology of HCV
differs substantially between countries. It is,

therefore, difficult to compare the results. For
example, the HCV rate in patients with
pruritus was 0.7% in a study from France11
while in another French study, pruritus was
found in 15% of HCV positive patients.12
The relationship between LP and HCV is
debatable and several studies have been
conducted. A retrospective study by Beaird et
al.
13
reported 70% frequency of HCV in
patients of LP. Another case-control study on
340 LP patients revealed 55% frequency.
14
Epidemiological study by Tameez-ud-Deen et
al.
15
on patients of LP have reported an
association of 32.7% while Mahboob et al.
16

reported a frequency of 23.5%. All these
studies were conducted on patients of LP
while in our study HCV positive patients were
examined for features of LP. We found a
frequency of 30%. This difference in
frequency could be due to our detection of LP
in HCV patients rather than HCV detection in
LP patients.
In several studies, a possible link between
urticaria and HCV infection was mentioned. A
Japanese study by Kanazawa et al.17 in 1996,
showed a statistically significant association
between urticaria and hepatitis C. A study, in
Pakistan, on patients of chronic urticaria by
Ahmed et al.18 showed a frequency of 13.16%
cases positive for anti-HCV antibodies.
The

demographic data revealed an almost equal
gender distribution. A study carried out by
Umar et al.19 in Pakistan showed a similar
male to female ratio.
Cutaneous vasculitis has been associated with
HCV infection. Karlsberg et al.20
did a
systematic dermatological evaluation of 408
patients with hepatitis C and vasculitis was
found in 10 (3%) patients. In a comparative
study on essential mixed cryoglobulinemia in
HCV infected vs. noninfected patients, 21% of
HCV infected patients presented with
cutaneous features of palpable purpura.21
Our
findings of 25% vasculitis are almost similar.
Palpable purpura was a feature seen in all our

cases of cutaneous vasculitis. Cryoglobulins
are immunoglobulins that undergo reversible
precipitation at low temperatures. These
consist of IgG and IgM polyclonal rheumatoid
factors. There is a strong association between
(4):285-290.
289
type II and type III mixed cryoglobulinemia
and HCV infection. The initial observation
was by Pascual et al.21 in 1990 who found anti-
HCV antibodies in patients with type II
cryoglobulinemia.
Porphyria cutanea tarda was
seen in 4 (4%) of our cases and it is frequently
associated with HCV infection.22

Chronic HCV is a leading cause of cirrhosis in
Bahawalpur. As there is no vaccine yet
available against hepatitis C virus and it is the
commonest cause of cirrhosis in this part of
world hence needs more meticulous approach
to prevent its transmission, through avoidance
of risk factors and early detection, if a patient
presents with cutaneous manifestation. Even if
the cirrhosis develops, early detection and
prompt treatment of these viral infections
improve the overall outcome of the patients
and prevent from development of
hepatocellular carcinoma. Once the cirrhotic
process has begun, the incidence of
hepatocellular carcinoma ranges from 1% to
4%. Hepatitis C is reaching epidemic
proportions and is a significant cause of
morbidity worldwide. Timely intervention can

stabilize the disease and positively impact
morbidity and mortality. This underscores the
importance of detecting individuals infected
with HCV. Since dermatologic manifestations
may be the only and most apparent sign of
chronic HCV, it is important that health care
professionals be aware of these dermatologic
manifestations. The cutaneous features are not
only themselves a cause of morbidity, but they
can also provide an indirect clue for the
underlying disease. Such an observation leads
to early detection and initiation of therapy.
Accurate and timely diagnosis of HCV is
critical to prevent the life threatening
complications. Antiviral therapy for HCV may
also be effective in curing the cutaneous
disease for example, cryoglobulinemia.
Moreover, such identification can help to

prevent further transmission of the disease.
Conclusion
Cutaneous manifestations may be the first
clinical sign of chronic HCV infection.
Screening for HCV infection in certain
dermatological conditions may lead to
antiviral treatment being effective in curing
cutaneous diseases. Moreover, such
identification will help prevent further
transmission of HCV.
References
1. Lauer GM, Walker BD. Hepatitis C virus
infection. N Engl J Med. 2001;345:41-52.
2. Neumann AU, Lam NP, Dahari H et al.
Hepatitis C viral dynamics in vivo and the
antiviral efficacy of interferon-alpha
therapy. Science. 1998;282:103-7.
3. Bukh J, Miller RH, Purcell RH. Genetic
heterogeneity of hepatitis C virus:
Quasispecies and genotypes. Semin Liver
Dis. 1995;15:41-63.

4. National Institutes of Health Consensus
Development Conference Statement:
Management of hepatitis C 2002 (June 10-
12, 2002). Gastrenterology.
2002;123:2082-99.
5. Wasley A, Alter MJ. Epidemiology of
hepatitis C: geographic differences and
temporal trends. Semin Liver Dis.
2000;20:1-16.
6. Centers for Disease Control and
Prevention. Recommendations for
prevention and control of hepatitis C virus
(HCV) infection and HCV-related chronic
disease. MMWR Recomm Rep. 1998;47:1-
39.
7. Charlton M. Hepatitis C infection in liver
transplantation. Am J Transplant.
2001;1:197-203.
8. Shah NH, Shabbier G. A review of
published literature on hepatitis C and B
virus prevalence in Pakistan. J Coll
Physicians Surg Pak. 2002;12:368-71.
9. Cribier B, Santinelli F, Schmitt C et al.
Should patients with pruritus be tested for
hepatitis C virus infection? A case-
controlled study. Br J Dermatol.
2000;142:1234-64.
10. Dega H, Frances C, Dupin N et al.
Pruritus and the hepatitis C virus. Ann

Dermatol Venereol. 1998;125:9-12.
11. Khokhar N, Gill ML, Malik GJ. General
seroprevalence of hepatitis C and hepatitis
B virus infections in population. J Coll
(4):285-290.
290
12. Dervis E, Serez K. The prevalence of
dermatologic manifestations related to
chronic hepatitis C virus infection in a
study from a single center in Turkey. Acta
Dermatovenerol Alp Panonica Adriat.
2005;14:93-8.
13. Beaird LM, Kabloon N, Franco J, Fairley
JA. Screening of HCV in lichen planus
patients. J Am Acad Dermatol.
2001;44:311-2.
14. Chuang TY, Stitle L, Brashear R, Lewis
C. Hepatitis C virus and lichen planus: A
case control study of 340 patients. J Am
Acad Dermatol. 1999;41:787-9.
15. Tameez-ud-Deen, Naqqash S, Butt AQ.
Lichen planus and hepatitis C virus
infection: An epidemiologic study. J Pak
Assoc Dermatol. 2003;13:127-9.

16. Mahboob A, Haroon TS, Iqbal Z et al.
Frequency of anti-HCV antibodies in
patients with lichen planus. J Coll
17. Paoletti V, Mammarella A, Basili S et al.
Prevalence and clinical features of skin
disease in chronic hepatitis C infections. A
prospective study in 96 patients.
Panminerva Med. 2002;44:349-52.
18. Ahmed I, Wahid Z, Ahmed Z. Chronic
urticaria: frequency of anti-HCV
antibodies. J Pak Assoc Dermatol.
2003;13:179-83.
19. Umar M, Bushra HT, Shuaib A et al.
Spectrum of chronic liver disease due to
hepatitis C virus infection. J Coll
20. Karlisberg PL, Le WM, Casey DL et al.
Cutaneous vasculitis and rheumatoid
factor positivity as presenting signs of
hepatitis C virus induced mixed
cryoglobulinemia. Arch Dermatol.
1995;131:1119-23.
21. Ito A, Kazama T, Ito K et al. Purpura with
cold urticaria in a patient with hepatitis C
virus infection-associated mixed
cryoglobulinemia type III: Successful
treatment with interferon beta. J
Dermatol. 2003;30:321-5.

22. 22Chuang TY, Stitle L, Brashear R, Lewis
C. Porphyria cutanea tarda and hepatitis C
virus: A case control study and meta-
analysis of the literature. J Am Acad
Dermatol. 1999;41:31-6.
23. Gisbert JP, Garcia-Buey L, Pajares JM,
Moreno-Otero R. Prevalence of hepatitis
C virus infection in porphyria cutanea
tarda: systematic review and meta-
analysis. J Hepatol. 2003; 39: 620-627
24. Poynard T, Yuen MF, Ratziu V, Lai CL.
Viral hepatitis C. Lancet. 2003;362:2095-
2100.
25. Dupin N, Chosidow O, Lunel F et al.
Essential mixed cryoglobulinemia-
comparative study of dermatological
manifestations in patients infected or
noninfected with hepatitis C virus. Arch
Dermatol. 1995;131:1424-7.
Copyright of Journal of Pakistan Association of Dermatologists
is the property of Pakistan
Association of Dermatologists and its content may not be copied
or emailed to multiple sites
or posted to a listserv without the copyright holder's express

written permission. However,
users may print, download, or email articles for individual use.
October 1, 2018 ◆ Volume 98, Number 7 www.aafp.org/afp
Editorials
Family Physicians Can Manage
Adults with Hepatitis C
Richard R. Andrews, MD, MPH
HOPE Clinic, Houston, Texas
Hepatitis C virus (HCV) causes the only chronic
viral disease that is consistently curable with
medication. However, it causes more deaths in
the United States than the next 60 reportable
infections combined, including human immuno-
deficiency virus (HIV), tuberculosis, and pneu-
mococcal disease.1
The epidemiology of HCV infection is complex
and differs in key ways from hepatitis B and HIV
infections. HCV is not commonly transmitted
through sex, but it is far more infectious than
hepatitis B virus and HIV when transmitted via
injection and intranasal drug use.2 Despite effec-
tive treatments, the incidence of HCV infection is
increasing in the United States. High-risk groups
include persons born between 1945 and 1965,
those who use certain illicit drugs, and those who
are incarcerated.2

Sustained viral response (SVR), defined as
the persistent absence of detectable virus in the
blood, is the goal of hepatitis C treatment. The
term SVR12 is used when SVR occurs 12 weeks
or more after completion of antiviral treatment.
SVR12 is widely accepted as reflecting the eradi-
cation of HCV from the body, as opposed to mere
suppression. Medications can eliminate HCV
because the virus does not have a hidden reser-
voir in the body, unlike hepatitis B virus.3
SVR was first achieved in 1986 using interferon;
ribavirin (Virazole) was added in later regimens.
Complex treatment protocols often caused severe
adverse effects and were less effective against cer-
tain viral genotypes.4 Currently recommended
treatments use direct-acting antivirals. When
used for the specified durations, these medica-
tions consistently achieve SVR12 rates at or above
90%, and the newest agents are effective against
all HCV genotypes 5-10 (Table 111).
SVR can reverse liver fibrosis, and even cir-
rhosis can start to reverse after viral hepatitis is
cured.12 It is not known whether SVR achieved
with direct-acting antivirals reduces the occur-
rence of hepatocellular carcinoma, but recent
evidence is encouraging.13,14 Reflecting the sys-
temic nature of chronic hepatitis C, persons who
achieve SVR have a lower incidence of diabetes
mellitus, glomerulonephritis, non-Hodgkin lym-
phoma, stroke, and other conditions.15
It is not clear whether the high cost of direct-
acting antivirals is offset by long-term savings

related to reduced morbidity and mortality from
hepatitis C. Economic estimates vary by health
system and by type of study analysis (e.g., whether
the study end point is focused on achieving SVR
or on post-SVR improvements in HCV-related
extrahepatic disease).16-19 A typical treatment
course is one to three pills per day for eight to 12
weeks, and is usually well tolerated. Viral counts
are obtained at four weeks to assess effectiveness.
A final test is performed 12 weeks or more after
the last pill is taken. Guidelines recommend that
patients with pretreatment evidence of cirrhosis
have lifelong surveillance for hepatocellular car-
cinoma using liver imaging and α-fetoprotein
testing at six-month intervals.20 Prior HCV infec-
tion and treatment do not confer immunity, so
patients at high risk of reinfection (e.g., those
with active injection or intranasal drug use, sex
partners of infected persons) should be screened
periodically.21
The Centers for Disease Control and Preven-
tion encourages family physicians to treat hepa-
titis C.22 Outcomes when primary care physicians
prescribe direct-acting antivirals to patients with
uncomplicated hepatitis C are comparable to
those of subspecialists.23 Patients with hepatitis C
who do not have cirrhosis, or who have compen-
sated cirrhosis, typically respond well to man-
agement by primary care physicians. Treatment
in patients with decompensated cirrhosis (char-
acterized by the presence of ascites, esophageal
varices, or hepatic encephalopathy) is complex.
Family physicians should be able to identify these
patients and refer them to a gastroenterologist or
hepatologist.

Additional content at https://
www.aafp.org/afp/2018/1001/p413.html.
Author disclosure: In 2016, Dr. Andrews received
compensation for travel expenses to attend a meet-
ing on hepatitis B from Gilead Sciences, Inc., which
manufactures drugs used to treat hepatitis C. Dr.
Andrews declined an honorarium from Gilead.
Number 7 ◆ October 1, 2018
EDITORIALS
Training and support are available for family
physicians who wish to treat patients with hep-
atitis C. A reasonable initial approach would be
to complete one or more self-paced online study
courses (eTable A). Because some insurers require

consultation with a subspecialist before they will
cover a direct-acting antiviral, use of a telehealth
program such as Project ECHO (Extension for
Community Healthcare Outcomes) can be help-
ful. These resources provide real-time affordable
access to subspecialist consultation using a case
presentation format.
By reducing the prevalence of HCV infec-
tion, direct-acting antivirals are a key tool in the
treatment-as-prevention approach.24 They are
a necessary—but not sufficient—component of
any worldwide program to eliminate HCV. As
with many treatments, these medications are
most effective when combined with evidence-
based public health measures, such as accessibil-
ity of clean needles in exchange for used needles
among persons who inject drugs.25
Although the new direct-acting antivirals to
treat hepatitis C are expensive, especially in the
United States, there are multiple pharmaceutical
assistance programs to ensure access to ther-
apy for all patients, regardless of their ability
to pay (eTable B). By participating in treatment
programs and advocating for effective policy
decisions, such as needle exchanges, family phy-
sicians can have a major impact on the hepatitis C
epidemic.
Address correspondence to Richard R. Andrews, MD,
MPH, at [email protected] hopechc.org. Reprints are not
available from the author.
References
1. Ly KN, Hughes EM, Jiles RB, Holmberg SD. Rising mortal-

ity associated with hepatitis C virus in the United States,
2003-2013. Clin Infect Dis. 2016; 62(10): 1287-1288.
2. Hall EW, Rosenberg ES, Sullivan PS. Estimates of state-
level chronic hepatitis C virus infection, stratified by race
and sex, United States, 2010. BMC Infect Dis. 2018; 18(1):
224.
3. Kim CW, Chang KM. Hepatitis C virus: virology and life
cycle. Clin Mol Hepatol. 2013; 19(1): 17-25.
4. Strader DB, Seeff LB. A brief history of the treatment of
viral hepatitis C. Clin Liver Dis. 2012; 1(1): 6-11.
5. Geddawy A, Ibrahim YF, Elbahie NM, Ibrahim MA. Direct
acting anti-hepatitis C virus drugs: clinical pharmacology
and future direction. J Transl Int Med. 2017; 5(1): 8-17.
TABLE 1
Direct-Acting Antiviral Agents for Hepatitis C Treatment–Naive
Patients Without Cirrhosis
Drug HCV genotypes Dosage Treatment duration Cost*†
Elbasvir/grazoprevir
(Zepatier)
1 and 4 One 50-mg/100-mg
tablet daily with or
without food
12 weeks $54,000
Glecaprevir/pibrentasvir

(Mavyret)
All Three 100-mg/40-mg
tablets once daily with
food
Eight weeks $26,000
Ledipasvir/sofosbuvir
(Harvoni)
1a, 1b, 4, 5,
and 6
One 90-mg/400-mg
without food
Genotype 1a or 1b: eight weeks
in nonblack patients who do
not have human immunode-
ficiency virus infection if HCV
RNA < 6 million IU per mL; 12
weeks in black patients or if
HCV RNA ≥ 6 million IU per mL
Genotypes 4 to 6: 12 weeks
$62,000 to $93,000
depending on treat-
ment duration
Sofosbuvir/velpatasvir
(Epclusa)
All One 400-mg/100-mg

without food
12 weeks $74,000
*—Estimated retail price for full treatment course based on
information obtained at http:// www.goodrx.com (accessed June
12, 2018).
†—See eTable B for information about pharmaceutical
assistance programs for uninsured and underinsured patients.
Information from reference 11.
Number 7 ◆ October 1, 2018
EDITORIALS
6. Sulejmani N, Jafri SM. Grazoprevir/elbasvir for the treat-
ment of adults with chronic hepatitis C: a short review
on the clinical evidence and place in therapy. Hepat Med.
2018; 10: 33-42.
7. Kwo PY, Poordad F, Asatryan A, et al. Glecaprevir and
pibrentasvir yield high response rates in patients with HCV
genotype 1-6 without cirrhosis. J Hepatol. 2017; 67(2):
263-271.
8. Kowdley KV, Sundaram V, Jeon CY, et al. Eight weeks of
ledipasvir/sofosbuvir is effective for selected patients with
genotype 1 hepatitis C virus infection. Hepatology. 2017;
65(4): 1094-1103.

9. Gayam V, Khalid M, Mandal AK, et al. Direct-acting antivi-
rals in chronic hepatitis C genotype 4 infection in com-
munity care setting. Gastroenterology Res. 2018; 11(2):
130-137.
10. Liu CH, Sun HY, Liu CJ, et al. Generic velpatasvir plus
sofosbuvir for hepatitis C virus infection in patients with
or without human immunodeficiency virus coinfection.
Aliment Pharmacol Ther. 2018; 47(12): 1690-1698.
11. American Association for the Study of Liver Diseases;
Infectious Diseases Society of America. Testing, evalua-
tion, and monitoring of hepatitis C. September 21, 2017.
http:// www.hcvguidance.org. Accessed June 11, 2018.
12. Hytiroglou P, Theise ND. Regression of human cirrhosis:
an update, 18 years after the pioneering article by Wan-
less et al. [published online ahead of print March 27, 2018].
Virchows Arch. https:// link.springer.com/article/10.1007%
2Fs00428-018-2340-2. Accessed June 12, 2018.
13. Calvaruso V, Cabibbo G, Cacciola I, et al. Incidence of
hepatocellular carcinoma in patients with HCV-associated
cirrhosis treated with direct-acting antiviral agents
[published online ahead of print April 12, 2018]. Gastro-
enterology. https:// www.gastrojournal.org/article/S0016-
5085(18)30441-4/pdf. Accessed June 12, 2018.
14. Konjeti VR, John BV. Interaction between hepatocellular
carcinoma and hepatitis C eradication with direct-acting
antiviral therapy. Curr Treat Options Gastroenterol. 2018;
16(2): 203-214.
15. Mahale P, Engels EA, Li R, et al. The effect of sustained
virological response on the risk of extrahepatic mani-

festations of hepatitis C virus infection. Gut. 2018; 67(3):
553-561.
16. Linas BP, Nolen S. A guide to the economics of hepatitis
C virus cure in 2017. Infect Dis Clin North Am. 2018; 32(2):
447-459.
17. Maier MM, Zhou XH, Chapko M, Leipertz SL, Wang X,
Beste
LA. Hepatitis C cure is associated with decreased health-
care costs in cirrhotics in retrospective Veterans Affairs
cohort. Dig Dis Sci. 2018; 63(6): 1454-1462.
18. Younossi ZM, Park H, Dieterich D, Saab S, Ahmed A,
Gordon SC. The value of cure associated with treating
treatment-naïve chronic hepatitis C genotype 1: are the
new all-oral regimens good value to society? Liver Int.
2017; 37(5): 662-668.
19. Cacoub P, Buggisch P, Carrión JA, et al. Direct medical
costs associated with the extrahepatic manifestations of
hepatitis C infection in Europe [published online ahead of
print February 24, 2018]. J Viral Hepat. https:// onlinelibrary.
wiley.com/doi/abs/10.1111/jvh.12881. Accessed June 12,
2018.
20. Costentin C, Layese R, Bourcier V, et al.; ANRS CO12
Cir-
Vir group. Compliance with hepatocellular carcinoma
surveillance guidelines associated with increased lead-
time adjusted survival of patients with compensated viral
cirrhosis [published online ahead of print May 2, 2018].
Gastroenterology. https:// www.gastrojournal.org/article/
S0016-5085(18)30488-8/pdf. Accessed June 12, 2018.
21. Falade-Nwulia O, Sulkowski MS, Merkow A, Latkin C,

Mehta SH. Understanding and addressing hepatitis C rein-
fection in the oral direct-acting antiviral era. J Viral Hepat.
2018; 25(3): 220-227.
22. Mitruka K, Thornton K, Cusick S, et al.; Centers for
Disease
Control and Prevention. Expanding primary care capacity
to treat hepatitis C virus infection through an evidence-
based model – Arizona and Utah, 2012-2014. MMWR Morb
Mortal Wkly Rep. 2014; 63(18): 393-398.
23. Tran TT. Hepatitis C: who should treat hepatitis C virus?
The role of the primary care provider. Clin Liver Dis. 2018;
11(3): 66-68.
24. Olafsson S, Tyrfingsson T, Runarsdottir V, et al.
Treatment
as prevention for hepatitis C (TraP Hep C) - a nationwide
elimination programme in Iceland using direct-acting anti-
viral agents. J Intern Med. 2018; 283(5): 500-507.
25. Bixler D, Corby-Lee G, Proescholdbell S, et al. Access to
syringe services programs - Kentucky, North Carolina, and
West Virginia, 2013-2017. MMWR Morb Mortal Wkly Rep.
2018; 67(18): 529-532. ■
October 1, 2018 ◆ Volume 98, Number 7 www.aafp.org/afp
American Family Physician 416A
EDITORIALS
eTABLE A
Selected Hepatitis C Resources for Physicians

Website Comments
HCVGuidelines.org (https:// www.
hcvguidelines.org)
Online, free, self-paced guidance from the American
Association for the Study of Liver Diseases and the
Infectious Diseases Society of America
Hepatitis C Online (https:// www.hepatitisc.
uw.edu/go/evaluation-treatment/
cost-access-medications/core-concept/all)
Free, self-paced online courses with available con-
tinuing medical education from the University of
Washington and University of Alabama–Birmingham,
funded by a grant from the Centers for Disease Control
and Prevention
Project ECHO (Extension for Community
Healthcare Outcomes; https:// echo.unm.
edu/)
Free scheduled videoconferences and optional case
presentations with subspecialist feedback and con-
tinuing medical education from the University of New
Mexico, funded by multiple federal, state, and private
entities, including the Centers for Disease Control and
Prevention
UpToDate (https:// www.uptodate.com/
home)
Online subscription service with continuing medical
education

eTABLE B
Selected Resources for Improving Access to Hepatitis C
Medications
for Uninsured and Underinsured Patients
AbbVie Patient Support (patient assistance program for
Mavyret)
https:// www.mavyret.com/hcp/patient-support or (877) 628-
9738
Gilead Sciences Support Path (patient assistance program for
Epclusa and Harvoni)
http:// gilead.com/responsibility/us-patient-access
HepMag: Paying for Hepatitis Treatment (overview and contact
information for multiple patient
assistance programs)
https:// www.hepmag.com/basics/hepatitis-c-basics/paying-
hepatitis-c-treatment
Merck Access and Support (patient assistance program for
Zepatier)
https:// www.merckaccessprogram-zepatier.com
Specialty pharmacies (staff members are familiar with patient
assistance programs for acquiring
direct-acting antivirals and typically will do most of the
required paperwork on behalf of the patient
and physician, and arrange delivery and tracking)

Note: One or more office staff members can be assigned to
process applications for the programs listed above. Approval
can take several weeks, but the paperwork is less cumbersome
than might be expected, especially for pharmaceutical
patient assistance programs.
CLINICAL ASPECTS
AMT, vol. 20, no. 3, 2015, p. 76
EXTRAHEPATIC MANIFESTATIONS IN
CHRONIC HEPATITIS C
LILIANA COLDEA1
1“Lucian Blaga” University of Sibiu
Keywords: chronic
hepatitis C,
extrahepatic
manifestations
Abstract: Chronic hepatitis C is a frequently encountered
problem worldwide, the number of infected
individuals is high and continues to be, becoming a public
health problem. In Romania, there are nearly
1 million persons infected with hepatitis C virus, the magnitude
of its spread being related to specific
risk factors. Among the hepatic manifestations, in chronic

hepatitis C, there also occur other
extrahepatic manifestations, such as mixed cryoglobulinemia
(sometimes, associated with
membranoproliferative glomerulo-nephritis), as well as other
endocrine manifestations (diabetes
mellitus, hypothyroidism), haematological manifestations –
aplastic anemia, thrombocytopenia purpura,
lymphomas. In accordance with recent studies, lichen planus,
chronic urticaria, corneal ulceration,
uveitis and lung fibrosis represent other extrahepatic
manifestations. These manifestations are rare.
1Corresponding author: Liliana Coldea, B-dul. Victoriei, Nr.
10, Sibiu, România, E-mail: [email protected], Phone: +40745
635662
Article received on 12.05.2015 and accepted for publication on
10.08.2015
ACTA MEDICA TRANSILVANICA September 2015;20(3):76-
79
INTRODUCTION
An important number of infections with hepatitis C
virus (HCV) present simultaneous extrahepatic manifestations
proved to be the single manifestation and its detection is
important for diagnosis and treatment.
The association between infection with hepatitis C
virus and extrahepatic manifestations is important to be
recognized for adequate diagnosis tests.
Knowing extrahepatic manifestations of hepatitis C
virus infection and the confirmation of the simultaneous

presence of hepatitis C virus allow applying a medical treatment
which often determines the improvement of extrahepatic
manifestations.
PURPOSE
I analyzed the distribution of chronic hepatitis C virus
in the General Hospital of Sibiu, between 1 January 2009 and 1
January 2012, the aim of study being to establish the
characteristics and the frequency of extrahepatic manifestations.
At the same time, I aimed at establishing the
correlations between age, gender, residence, the possible
infection moment and extrahepatic manifestations.
MATERIALS AND METHODS
The study is a retrospective one based on 162 cases of
chronic hepatitis with positive HCV antibodies hospitalized in
the General Hospital of Sibiu. 78 cases with chronic hepatitis C
were followed up prospectively during hospitalization.
Each patient had a clinical observation sheet with
personal data, personal pathological and heredity history,
anamnesis and clinical data, the results of lab tests and
paraclinical investigations.
The test which was used for evidence of the HCV
antibodies was generation II or III ELISA (Murex anti-HCV-
versions III, Menolisa (R) anti-HCV PLUS, ORTHO (R) HCV
3.0 ELISA). There were recorded the onset of the clinical
manifestations, the moment of diagnosis, the way of tracing out
the infection with hepatitis C virus, epidemiological inquiry in
order to establish the possible infection moment. All

information
was based on personal assertions.
For each patient, there was made a short case
presentation in order to highlight the particular aspects of
diagnostic, evolution and treatment.
The inclusion criteria were the following:
• patients with hepatitis C infection confirmation by ELISA
(II or III generation), with hepatic and extrahepatic
manifestations.
The exclusion criteria were the following:
• patients with simultaneous infection with hepatitis B virus
and HIV;
• patients with alcoholic hepatitis;
• patients with autoimmune hepatitis or with autoimmune
manifestations;
• patients with liver cirrhosis and hepatocellular carcinoma,
with hepatitis C virus infections confirmed by ELISA
generation II or III.
The diagnosis of chronic hepatitis C virus was
established by:
• anamnesis criteria (epidemiological inquiry);
• clinical criteria;
• laboratory criteria (hepatic functional test and aetiological
confirmation);
• hystopathological criteria.

RESULTS
The group of 162 cases with chronic hepatitis with
positive HCV antibodies included 102 females (63%) and 60
males (37%).
In this study, I noticed that the affection tended to be
preponderant in the age group of 60 – 69 years old (27.16%),
followed by the age group of 50 – 59 years old (25.92 %), with
a
p value of 0.0668.
The average age was 54.46±13.15 years. Of the group,
132 patients came from the urban environment (81%) and 30
patients from the rural environment (19%).
53 patients (33%) had hepatic manifestations and
extrahepatic manifestations, and 109 patients presented only
hepatic manifestations – figure no 1.
CLINICAL ASPECTS
AMT, vol. 20, no. 3, 2015, p. 77
Figure no. 1. Distribution of the group of patients according
to hepatic and extrahepatic manifestations
The distribution of cases with extrahepatic
manifestations was the following: 16 patients had endocrine
manifestations (30.18%), p value = 0.008; Odds ratio = 0.43 and

the Relative risk = 0.58; 22 patients had cryoglobulinemia
(41.53%), p value = 0.085; Odds ratio = 0.62 and Relative risk
=
0.73; 5 patients presented skin manifestations (9.43%), p value
=
0.0000044; Odds ratio = 0.14 and Relative risk = 0.21; 8
patients had hematological manifestations (15.09%), p value =
0.00006; Odds ratio = 0.22 and Relative risk = 0.33; and 2
patients had other manifestations (3.77%), p value = 0.0000002;
Odds ratio = 0.06 and Relative risk = 0.09 – figure no. 2.
Figure no. 2. Patients’ distribution depending on the type of
extrahepatic manifestations
One third of patients presented extrahepatic
manifestations which showed the high frequency of extrahepatic
manifestations – table no. 1.
Table no. 1. Patients’ distribution depending on the type of
extrahepatic manifestations
Extrahepatic manifestations Number of cases Percentage
ENDOCRINE MANIFESTATIONS
Diabetes mellitus without insulin 11 20.75 %
Diabetes mellitus with insulin 2 3.77 %
Thyroiditis 1 1.88 %
Hypothyroidism 2 3.77 %
p value = 0.008; Odds ratio = 0.43; 0.23<OR<0.86 and Relative

risk = 0.58; 0.37<RR<0.91
CRYOGLOBULINEMIA
Mixed crioglobulinemia 17 32.17 %
Chronic glomerulonephritis
associated with impure nephrotic
syndrome
1 1.88 %
Chronic glomerulonephritis 2 3.77 %
membranoproliferative
Vascular purpura 2 3.77 %
p value = 0.085; Odds ratio = 0.62; 0.34<OR<1.11 and Relative
risk = 0.73; 0,5<RR<1.07
CUTANEOUS MANIFESTATIONS
Chronic urticaria 1 1.88 %
Porphyria cutanea tarda 1 1.88 %
Vitiligo 1 1.88 %
Lichen planus 2 3.77 %
p value = 0.0000044; Odds ratio = 0.14; 0.05<OR<0.38 and
Relative risk = 0.21; 0,09<RR<0.5
HAEMATOLOGICAL MANIFESTATIONS
Immunoblastic lymphoma 1 1.88 %
Malignant lymphoma nonhodgkinian 3 5.66 %
Acute lymphoblastic leukosis (ALL2) 1 1.88 %

Acute myeloid leukemia (AML2) 1 1.88 %
Chronic lymphoproliferative
syndrome
2 3.77 %
Relative
risk = 0.33; 0.17<RR<0.63
OTHER MANIFESTATIONS
Pulmonary fibrosis 1 1.88 %
Rheumatoid arthritis 1 1.88 %
Relative risk = 0.09; 0.02<RR<0.36
In accordance with specialized literature, vascular
purpura, chronic glomerulo-nephritis with impure nephrotic
syndrome, membranoproliferative glomerulo-nephritis and
manifestation of mixed cryoglobulinemia were present in 22
cases (41.53%), p value = 0.085.
The most frequent extrahepatic manifestations in the
study group was mixed cryoglobulinemia, both symptomatic – 5
cases (9.43%) and asymptomatic – 17 cases (32.17%), followed
by diabetes mellitus without insulin – 11 cases (20.75%).
Analyzing alanine aminotransferase (ALAT) level, in
the most cases with extrahepatic manifestations, ALAT level
was in normal limits – 19 cases (35.84%) and to twice normal
limits in 20 cases (37.74%) and over twice normal limits – 14
cases (26.42%) – figure no. 3.

Figure no. 3. Group distribution depending on the value of
ALAT
Analyzing aspartate transaminase (ASAT) level, the
most cases with extrahepatic manifestations had ASAT in
normal limits – 14 cases (26.42%) and to twice normal limits 29
cases (54.72%) and over twice normal limits – 10 cases
(18.86%) – figure no. 4.
CLINICAL ASPECTS
AMT, vol. 20, no. 3, 2015, p. 78
Figure no. 4. Distribution of the group of patients depending
on the value of ASAT
normal
limits
twice
normal
limits
ove r twice
normal
limits
14
29

10
49
33
27
0
10
20
30
40
50
without manifestations
with manifestations
Analyzing the transfusion history, 9 cases (6%)
received blood transfusion and 90 patients (56%) had surgery
history. Analyzing the viral load in the cases with hepatic and
extrahepatic manifestations, it was shown that the viral load
below 800 000 UI/ml was registered in 68 patients (62.38%)
with hepatic manifestations versus 26 patients (49%) with extra-
hepatic manifestations and viral load above 800 000 UI/ml was
registered in 41 patients (37.62%) with hepatic manifestations
versus 27 patients (51%) with extrahepatic manifestations, p
value = 0.1; Odds ratio = 0.58 and Relative risk = 0.83 – figure
no. 5.

Figure no. 5. Patients’ distribution according to viral load
68
41
26
27
0
20
40
60
80
100
120
hepatic
manifestations
extrahepatic
manifestations
up 800 000 UI/ml
down 800 000 UI/ml
In this study, there were no significant statistical

differences in fibrosis stage in the patients with hepatic
manifestations and extrahepatic manifestations. Also, there was
no correlation between viral load and extrahepatic
manifestations, meaning that a high viral load to be correlated
with lesions other than the hepatic ones.
By comparing the results of therapy in the patients
with hepatic and extrahepatic manifestations, it was shown that
30 patients (58.83%) with hepatic manifestations had
incomplete response versus 10 patients (26.32%) with
extrahepatic manifestations; 11 patients (21.54%) with hepatic
manifestations presented a complete response versus 3 patients
(7.89%) with extrahepatic manifestations and 10 patients
(19.63%) with hepatic manifestations had no response versus 25
patients (65.79%) with extrahepatic manifestations – table no.
2.
Table no. 2. Group distribution depending on the response
to treatment in patients with hepatic and extrahepatic
manifestations
Type of
response
Hepatic
manifestations
Extrahepatic
manifestations
Incomplete 30 (58.83 %) 10 (26.32%)
Complete 11 (21.54 %) 3 (7.89%)
Lack of response 10 (19.63 %) 25 (65.79%)
The most patients had rebound in the first 6 months,

subsequently, until the end of the follow-up period of time, the
number of relapses was very low. The clinical response was in
parallel with the immunological response, the values being
compatible.
DISCUSSIONS
An important aspect of chronic infection with hepatitis
C represents its association with a number of extrahepatic
manifestations.(1) Almost 40% of patients infected with HCV
develop at least one extrahepatic manifestation during the
disease.(2)
Extrahepatic manifestations are diseases or conditions
that affect other organs besides the liver. Extrahepatic
manifestations of HCV can be found in the skin, eyes, joints,
immune system, nervous system and kidneys. Among them, the
most important, but the most common, is mixed
cryoglobulinemia.
Pascual et al. (3), for the first time in 1990, suggested
an association between HCV and extrahepatic syndromes when
they presented two patients with HCV infection and mixed
cryoglobulinemia. In some of these, such as mixed
cryoglobulinemia, it was established that there is a direct
involvement of HCV in the disease, in other cases, this relation
cannot be established.(4)
In the study conduced by Alan Franciscus, it was
determined that 74% of patients with chronic hepatitis C
showed
extrahepatic manifestations. Some of the reported events were:
arthralgia (74%); tingling in limbs (17%); myalgia (15%);
pruritus (15%), and sicca syndrome (11%).(5)

Extrahepatic manifestations in the studied group of
patients with chronic hepatitis C were present in one third of
them, which indicates that extrahepatic manifestations occur
with increased frequency. According to the literature, the study
shows that vascular purpura, chronic glomerulonephritis
associated with nephrotic syndrome impure, chronic
membranoproliferative glomerulonephritis and mixed
cryoglobulinemia manifestations were present in 22 cases
(41.53%), the data obtained were statistically significant (p
value = 0.085; Odds ratio = 0.62; 0.34<OR<1.11 and Relative
risk = 0.73; 0.5<RR<1.07).
The most common extrahepatic manifestations in the
studied group was mixed cryoglobulinemia, both symptomatic
form – 5 cases (9.43%) and asymptomatic – 17 cases (32.17%),
followed by type 2 diabetes without insulin – 11 cases
(20.75%).
The literature reported two cases of tongue carcinoma
and HCV infection known for 6 and 10 years with oral cancers
detected in tissues of RNA chains + and - of HCV in 100% and
71%.
In the present study, I have not encountered any cases
of tongue cancer, but there were 4 cases of tumours of other
location: vaginal tumour – 1 case (1.88%); lung cancer – 1 case
(1.88%); rectal tumour – 1 case (1.88%); a tumour of the
bladder – 1 case (1.88 %). In the literature, there were not
reported cancers with these locations associated to chronic
infection with hepatitis C virus.
Also, the data in the literature show that sialadenitis
occurs in 57% of patients infected with hepatitis C virus (6,7),
but in this study, there was not detected any event, although
clinical symptoms occurred in 8 cases, but without establishing
the diagnosis, probably due to the lack of necessary

examinations (biopsy, sialography and scintigraphy of the
salivary glands).
My observation is that antiviral treatment may
improve the clinical picture of vasculitis, even in the absence of
sustained virologic response. The disappearance of
CLINICAL ASPECTS
AMT, vol. 20, no. 3, 2015, p. 79
cryoglobulins in patients who have not achieved virologic
response may be due to their marked quantitative reduction to
undetectable levels by ordinary means.
CONCLUSIONS
ÿ The extrahepatic manifestations were present in one third
of patients, meaning that extrahepatic manifestations
appear with a high frequency.
ÿ The most frequent extrahepatic manifestations was: mixed
cryoglobulinemia, both symptomatic (9.43%) and
asymptomatic (32.17%), followed by diabetes mellitus
without insulin (20.75%). In accordance with specialized
data, mixed cryoglobulinemia is the most frequent
extrahepatic manifestations, which is also confirmed in this
study.
ÿ Chronic hepatitis C is frequently associated with
extrahepatic manifestations, the most frequent extrahepatic
manifestation is mixed cryoglobulinemia. If in some of

extrahepatic manifestations, the role of HCV is well
established, in others, it is still speculative. The number of
extrahepatic manifestations in chronic hepatitis C continues
growing and has become an open field of research.
REFERENCES
1. Conjeevaram HS, Wahed AS, Afdhal N, et al. Changes in
insulin sensitivity and body weight during and after
peginterferon and ribavirin therapy for hepatitis C.
Gastroenterology. 2011;140:469.
2. Lo Re V 3rd, Volk J, Newcomb CW, et al. Risk of hip
fracture associated with hepatitis C virus infection and
hepatitis C/human immunodeficiency virus coinfection.
Hepatology. 2012;56:1688
3. Ennishi D, Maeda Y, Niitsu N, et al. Hepatic toxicity and
prognosis in hepatitis C virus-infected patients with diffuse
large B-cell lymphoma treated with rituximab-containing
chemotherapy regimens: a Japanese multicenter analysis.
Blood. 2010;116:5119.
4. Ramos – Casals M, Font J. Extrahepatic manifestations in
patients with chronic virus infection. Current Opinions on
Rheumatology. 2005;17(4):447-55.
5. Franciscus A. A guide to extrahepatic manifestations of
hepatitis C. HCSP FACTsheet. 2005;1-3.
6. Liu SQ, Dong MG, Men CH, Yang MJ, Liu W. Relation
research between chronic hepatitis C and type 2 diabetes
(in Chinese). J Pract Diagn Ther. 2011;25:83-84.
7. Zheng YY, Fan XH, Wang LF, Tian D, Huo N, Lu HY.

Efficacy of pegylated interferon – alpha – 2a plus
ribavirinum for patients aged at least 60 years with chronic
hepatitis C. Chin Med J. 2012;125:1852-56.
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HS 147 Disease Report Outline Rubric
Attach to your report and your references
Student: Disease Topic: .
Disease Report Required
Components
Points
Possible
Points
Earned
Comments/Suggestions
Name, Title, Short Introduction 0.5

Definition 0.5
Etiology 0.5
Pathogenesis 0.5
Manifestations 0.5
Lab Findings 0.5
Diagnosis 0.5
Treatment 0.5
Prognosis 0.5
Resource page: APA format 0.5
Outline total points 5
Attached Resource hard copy;
Scholarly and current (2015-2018)
20
Total points possible with resources 25
(student name and ID)
Report Title
Introduction: (a brief description of the disease you’ll be
covering)

This report will review and discuss non-alcoholic-fatty-liver
(NAFD), it’s
causes, detection, prevention and the latest treatment will be
covered in this
report.
Report: Two or three sentences that will cover each required
component is all
you need.
1. Definition: Non-alcoholic-fatty-liver (NAFL) is described
as.........
2. Etiology: There are a variety of causes that include......
3. Pathogenesis: Initially the changes in the liver may be subtle
starting
with ....... and progresses to......
4. Manifestations: One of the first complaints is malaise with a
dark
urine......
5. Lab findings: Lab findings include a blood bilirubin level of
15
mgs/cmm of blood, the normal level is 0-1.5 mgs/cmm of blood.
6. Diagnosis: The clinician’s final diagnosis is NAFL due to
chronic
alcoholism.
7. Treatment: Stop drinking immediately to prevent further
liver
damage. Prescribe Tetracycline 250 mgs. four times a day with
Ambian at bedtime.

8. Prognosis: NAFL is a precursor to cirrhosis of the liver.
9. Resources: Cornell University Medical School (n.d.) Non-
alcoholic-
fatty-liver Disease. Retrieved December 12, 2011, from Cornell
School
of Medicine information institute:
http://www.law.cornell.edu/constitution/amendmentxix .
(minimum of three, scholarly sources and their hardcopy
attached)
http://www.law.cornell.edu/constitution/amendmentxix
Scholarly Source Examples: These are just a few, there are
others on your
syllabus. When in doubt, check with instructor before you
begin your outline.
Journal of American Medical Association (JAMA.org),
New England Journal of Medicine ( NEJM.org),
Annal of Internal Medicine,
(Assoc.) American Family Physician (AAFP.ORG),
Journal of Psychiatric Research,
Canadian Medical Association (CMAJ.org)
Journal of Rheumatology
British Medical Journal
The Lancet Medical Journal
Journal of Clinical Investigation
Journal of Infectious Diseases (JID.org)
DO NOT USE THESE RESOURCES: Remember, you’re
talking to another medical
professional. Don’t use sources that are designed for the

general public. Don’t
review information that the reader already knows. i.e. “the
lungs are the organs
in the chest where the exchange of gasses takes place”.
Wikipedia
Webmd
Medline
CDC
NIH
Encyclopedias
Dictionaries
Textbooks
Pamphlets
Nursing, or other ancillary professional journals without the
actual research
included.
http://jama.org
http://nejm.org
http://aafp.org
http://cmaj.org
http://jid.org

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