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Complete outline

Topic: Hepatitis C

Follow the instructions
 

Outline contains introduction and

1-2 sentences under “report”tab

Bibliography

Outline instructions and resources attached

Also attached full report instructions. DO NOT START THE FULL REPORT

(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)

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.

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

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 %

p value = 0.00006; Odds ratio = 0.22; 0.09<OR<0.51 and Relative
risk = 0.33; 0.17<RR<0.63

OTHER MANIFESTATIONS

Pulmonary fibrosis 1 1.88 %
Rheumatoid arthritis 1 1.88 %

p value = 0.0000002; Odds ratio = 0.06; 0.01<OR<0.24 and
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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October 1, 2018 ◆ Volume 98, Number 7 www.aafp.org/afp American Family Physician 413

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.

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414 American Family Physician www.aafp.org/afp Volume 98, 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
tablet daily with or
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
tablet daily with or
without food

12 weeks $74,000

HCV = hepatitis C virus.

*—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.

416 American Family Physician www.aafp.org/afp Volume 98, 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.

Journal of Pakistan Association of Dermatologists. 2015;25 (4):285-290.

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.

Journal of Pakistan Association of Dermatologists. 2015;25 (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.

Journal of Pakistan Association of Dermatologists. 2015;25 (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

Journal of Pakistan Association of Dermatologists. 2015;25 (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

Journal of Pakistan Association of Dermatologists. 2015;25 (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
Physicians Surg Pak. 2004;14:534-6.

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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.
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13. Beaird LM, Kabloon N, Franco J, Fairley
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14. Chuang TY, Stitle L, Brashear R, Lewis
C. Hepatitis C virus and lichen planus: A
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15. Tameez-ud-Deen, Naqqash S, Butt AQ.
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16. Mahboob A, Haroon TS, Iqbal Z et al.
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17. Paoletti V, Mammarella A, Basili S et al.
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18. Ahmed I, Wahid Z, Ahmed Z. Chronic
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19. Umar M, Bushra HT, Shuaib A et al.
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20. Karlisberg PL, Le WM, Casey DL et al.
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21. Ito A, Kazama T, Ito K et al. Purpura with
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22. 22Chuang TY, Stitle L, Brashear R, Lewis
C. Porphyria cutanea tarda and hepatitis C
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23. Gisbert JP, Garcia-Buey L, Pajares JM,
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25. Dupin N, Chosidow O, Lunel F et al.
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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
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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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Downloaded from the American Family Physician website at www.aafp.org/afp. Copyright © 2015 American Academy of Family Physicians. For the private, noncom-
mercial use of one individual user of the website. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests.

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

HCV = hepatitis C virus.

Adapted with permission from Campos-Outcalt D. Hepatitis C: new
CDC screening recommendations. J Fam Pract. 2012;61(12):744.

Hepatitis C

June 15, 2015 ◆ Volume 91, Number 12 www.aafp.org/afp American Family Physician 837

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

838 American Family Physician www.aafp.org/afp Volume 91, Number 12 ◆ June 15, 2015

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

June 15, 2015 ◆ Volume 91, Number 12 www.aafp.org/afp American Family Physician 839

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.

840 American Family Physician www.aafp.org/afp Volume 91, Number 12 ◆ June 15, 2015

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

June 15, 2015 ◆ Volume 91, Number 12 www.aafp.org/afp American Family Physician 841

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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3. El Khoury AC, Klimack WK, Wallace C, Razavi H. Economic burden
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6. American Association for the Study of Liver Diseases; Infectious Dis-
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treating hepatitis C. http://www.hcvguidelines.org/. Accessed March 1,
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7. Klevens RM, Hu DJ, Jiles R, Holmberg SD. Evolving epidemiology of
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8. Campos-Outcalt D. Hepatitis C: new CDC screening recommendations.
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9. Delwart E, Slikas E, Stramer SL, et al.; NHLBI-REDS-II Study Group.
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10. Pawlotsky JM. Pathophysiology of hepatitis C virus infection and related
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11. Bostan N, Mahmood T. An overview about hepatitis C: a devastating
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12. Maasoumy B, Wedemeyer H. Natural history of acute and chronic hepa-
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13. Chou R, Cottrell EB, Wasson N, Rahman B, Guise JM. Screening for
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14. Smith BD, Morgan RL, Beckett GA; Centers for Disease Control and
Prevention. Recommendations for the identification of chronic hepati-
tis C virus infection among persons born during 1945-1965 [published
correction appears in MMWR Recomm Rep. 2012;61(43):886]. MMWR
Recomm Rep. 2012;61(RR-4):1-32.

15. Cox AL, Netski DM, Mosbruger T, et al. Prospective evaluation of
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16. Deterding K, Grüner N, Buggisch P, et al.; Hep-Net Acute HCV-III Study

BEST PRACTICES IN GASTROENTEROLOGY:
RECOMMENDATIONS FROM THE CHOOSING
WISELY CAMPAIGN

Recommendation Sponsoring organization

Do not repeat hepatitis C
viral load testing outside
of antiviral therapy.

American Association for
the Study of Liver Diseases

Source: For more information on the Choosing Wisely Campaign,
see http://www.choosingwisely.org. For supporting citations and to
search Choosing Wisely recommendations relevant to primary care,
see http://www.aafp.org/afp/recommendations/search.htm.

Hepatitis C

842 American Family Physician www.aafp.org/afp Volume 91, Number 12 ◆ June 15, 2015

Group. Delayed versus immediate treatment for patients with acute hep-
atitis C: a randomised controlled non-inferiority trial. Lancet Infect Dis.
2013;13(6):497-506.

17. Everhart JE, Wright EC, Goodman ZD, et al.; HALT-C Trial Group.
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20. Miller MH, Agarwal K, Austin A, et al.; British Viral Hepatitis group;
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and direct-acting anti-viral therapy. Aliment Pharmacol Ther. 2014;
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21. European Association for Study of Liver. EASL Clinical Practice Guide-
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22. Swain MG, Lai MY, Shiffman ML, et al. A sustained virologic response is
durable in patients with chronic hepatitis C treated with peginterferon
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23. Manns MP, Pockros PJ, Norkrans G, et al. Long-term clearance of hepa-
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24. Zeuzem S, Mensa FJ. Concordance between sustained virologic
response week 12 (SVR12) and SVR24 in genotype 1 hepatitis C virus
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25. Kau A, Vermehren J, Sarrazin C. Treatment predictors of a sustained
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26. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB; American
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2011;54(4):1433-1444.

27. Chen Y, Xu HX, Wang LJ, et al. Meta-analysis: IL28B polymorphisms
predict sustained viral response in HCV patients treated with pegylated
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28. Eslam M, Aparcero R, Kawaguchi T, et al. Meta-analysis: insulin resis-
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29. Thomas DL. Predicting the response to the treatment of hepatitis C virus
infection. Clin Liver Dis. 2012;1(2):46-48.

30. Harrison SA, Rossaro L, Hu KQ, et al. Serum cholesterol and statin use
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31. Rao GA, Pandya PK. Statin therapy improves sustained virologic
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32. Schinazi R, Halfon P, Marcellin P, Asselah T. HCV direct-acting antivi-
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35. Brok J, Gluud LL, Gluud C. Ribavirin monotherapy for chronic hepatitis C.
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rin versus pegylated interferon-α2b and ribavirin in chronic hepatitis C:
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42. Hayashi N, Seto C, Kato M, Komada Y, Goto S. Once-daily simeprevir
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CYPRESS COLLEGE
DIVISION OF HEALTH SCIENCE

HS 147

Hints for writing your final disease report: (not in any order)

1. In your abstract, don’t give a history of your disorder. Give the reader a
short synopsis of what the research is going to cover. Don’t forget “key
words”. Research papers are not a “friendly format”, don’t add personal
comments or opinions or slang. Assume this will be printed in a journal.

2. Use 12 point, Geneva style font (or similar) for your paper, with a 1”
margin on all sides.

3. Number your pages in the upper right corner. Your report will be about 7-9
pages not counting the cover page and reference page. Remember to
print the “word count” on cover page (1500 minimum).

4. Do not list or use bullets. Write in complete sentences and paragraphs.

5. Section headings help the reader. Remember to only double space,
even between headings or paragraphs.

6. Don’t start a sentence with “according to……”. Instead start with the
information and use an in-text citation at the end of the sentence or
paragraph.

7. If you start a sentence with a number, you must write out the number.

8. For your report remember, you are writing as a professional to another
professional and not to a patient or “lay person”. Do not explain things
that you would expect that the reader would already know.

9. Have someone else read your report before you turn it in for grammar,
spelling and punctuations.

10. Do not use a separate page for each section or heading (double space
only).

11. Include the website that the information was retrieved from, not the
search engine the school used (EBSCO). Use the APA format in your
syllabus.

Good luck!

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