REVIEW

Role of the nurse practitioner in the management of patients

with chronic hepatitis C
Mary Olson, NP (Clinical Trials Program Director) & Ira M. Jacobson, MD (Vincent Astor Professor of Clinical
Medicine)
Weill Medical College of Cornell University, New York, New York

Correspondence
Mary Olson, NP, Clinical Trials Program Director,
Center for the Study of Hepatitis C, Weill
Medical College of Cornell University, 1305 York
Avenue, 4th Floor, New York, NY 10021.
Tel: 646-962-4742;
Fax: 646-962-0377;
E-mail: maa9041@med.cornell.edu
Received: June 2009;
accepted: January 2010
doi: 10.1111/j.1745-7599.2011.00603.x
Disclosure
No relationship exists between M.O. and any
commercial entity or product mentioned in this
article that might represent a conict of
interest. I.M.J. has been paid by ScheringPlough for grant/research support, as a
consultant/advisor, and for lectures on this
topic. No monetary or other inducement was
made to the authors to submit this article.
The authors wish to acknowledge Lynn Brown,
PhD, Tim Ibbotson, PhD, and Claudette Knight,
PharmD, for writing assistance. This assistance
was funded by Schering-Plough.

Abstract
Purpose: To inform nurse practitioners (NPs) of the vital role they play in
recognizing patients who may have hepatitis C.
Data sources: Selected review of scientific literature.
Conclusions: NPs involved in the management of patients with chronic hepatitis C are well positioned to provide supportive care and contribute to the
development of effective treatment strategies that maximize the opportunity
for successful treatment outcomes. Although peginterferon alfa plus ribavirin
therapy is associated with a well-described series of side effects, effective measures are available for the management of these events that permit the continuation of treatment and enhance the likelihood of attaining sustained virologic
response. NPs can play a pivotal role in ensuring that these measures are in
place in a preemptive manner. For example, growth factor supplementation
represents an alternative to dose reduction or treatment discontinuation in selected patients with neutropenia or anemia and may help to improve treatment
adherence.
Implications for practice: Hepatitis C is a widespread problem; approximately 3% of the global population is chronically infected with the virus.
Awareness of risk factors for hepatitis C will help the NP to recognize at-risk
patients, who should then be screened for the virus and referred for treatment
based on specific criteria.

Hepatitis C is a widespread healthcare problem, with

approximately 2.2%3% of the global population (or
130170 million persons) chronically infected with the
virus and an additional 34 million persons newly infected each year (Lavanchy, 2009). According to the Centers for Disease Control and Prevention (CDC, 2008),
an estimated 1.6% of the U.S. adult population is infected with the hepatitis C virus (HCV). Of those 4.1
million persons (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK], 2006), 3.2 million
have chronic infection (CDC, 2008). HCV infection accounts for about 15% of acute viral hepatitis, 60%70%
of chronic hepatitis, and up to 50% of cirrhosis, end-stage
liver disease, and liver cancer (NIDDK, 2006). Morbidity and mortality levels associated with chronic hepatitis

410

C (CHC) are expected to continue to increase between

2010 and 2019, resulting in 165,900 deaths from chronic
liver disease and 27,200 deaths from hepatocellular carcinoma (HCC) and costing $10.7 billion in direct medical
expenditure (Dienstag & McHutchison, 2006; Kim, 2002;
Wong, McQuillan, McHutchison, & Poynard, 2000).
Nurse practitioners (NPs) play a vital role in the management of hepatitis C. They are well placed to aid in
the recognition of patients who may have hepatitis C by
thoroughly reviewing past medical history and gaining
knowledge of previous and current social behaviors, such
as intravenous (IV) drug use. In addition, the provision of
effective supportive care strategies during treatment can
promote adherence and thus help maximize treatment
outcomes. The aim of this article is to review the role of

C 2011 The Author(s)

Journal of the American Academy of Nurse Practitioners 23 (2011) 410420 
C 2011 American Academy of Nurse Practitioners
Journal compilation 

Chronic hepatitis C management of side

M. Olson & I. M. Jacobson

Table 1 Risk factors for hepatitis C

r Illicit intravenous drug use

r Intranasal drug use
r Comorbid condition (e.g., HIV/HBV infection)
r Hemodialysis
r Birth to HCV-infected mother
r Organ transplantation
r Needlestick injury
r Military service
r Recipient of blood transfusion or blood product before June 1992

the NP in the management of CHC and to consider the

multiple ways in which NPs are able to influence disease
course and treatment outcomes.

Screening, diagnosis, expectations, and

referral
Risk factors
Transmission of HCV occurs primarily through contact with infected blood or blood products. The current primary risk factor for infection is IV drug use
(from sharing of needles); however, anyone who received a blood transfusion before June 1992 (when sensitive blood screening tests were introduced in most countries) is also at significant risk (NIDDK, 2006; Poynard,
Yuen, Ratziu, & Lai, 2003). NPs should be vigilant to the
fact that patients frequently disclose only a single previous experience with IV drugs, which nevertheless should
be considered as a significant risk factor for hepatitis C
infection. Awareness of risk factors for hepatitis C will
also help the NP to recognize at-risk patients, who should
then be screened for the virus (see Table 1).

Screening
CHC is diagnosed in clinical practice by testing for
antibodies to HCV (anti-HCV) and then by using HCV
RNA to document viremia (Chevaliez & Pawlotsky, 2006;
Strader, Wright, Thomas, & Seeff, 2004). Enzyme immunoassays are available that can detect antibodies with
high specificity (> 99%; Chevaliez & Pawlotsky, 2006).
If the HCV antibody test result is positive, an HCV polymerase chain reaction (PCR) assay should be performed
to confirm HCV viral replication. These PCR assays are
able to detect HCV RNA at very low levels (Chevaliez &
Pawlotsky, 2006).

Patient evaluation
Evaluation of the patient with newly diagnosed hepatitis C includes assessment of liver function tests (includ-

ing liver enzyme, albumin, and total protein levels) and

other markers that may reflect advanced hepatic fibrosis
(including platelet count, prothrombin time, and international normalized ratio [INR]). The status of immunity
to hepatitis A and B should be assessed, and seronegative persons should be vaccinated. Baseline abdominal
ultrasound helps to assess liver architecture, screen for
fatty liver disease, and establish whether any focal lesions
are present, which may signal the presence of progressive
liver disease. At present, liver biopsy is the most reliable
measure of liver disease. Screening for HCC with alpha
fetoprotein and abdominal imaging should be performed
every 6 months for patients with stage 3 or 4 fibrosis.
Patients should be educated about strategies to prevent
transmission of the virus, the disease course (which can
vary greatly), and lifestyle modifications (such as alcohol
abstinence) that will improve outcomes. In general, patients whose hepatitis C is diagnosed by a primary care
physician should be referred for care to a specialist in
gastroenterology, hepatology, or, in some areas, infectious diseases. This referral should be made immediately
upon diagnosis (HCV antibody positive and detectable
HCV RNA by PCR).

Therapy for CHC

All patients with HCV infection should be considered potential candidates for treatment; however, antiviral therapy is not recommended for patients with hepatic decompensation (those with ascites, varices, hepatic
encephalopathy, spontaneous bacterial peritonitis, jaundice, coagulopathy, or biochemical deterioration; Ghany,
Strader, Thomas, & Seeff, 2009; Hoffman La Roche, Inc.,
2008; Schering Corporation, 2009). Moreover, in patients
with absent or mild fibrosis, initiation of treatment is less
urgent and thus the decision to treat is based, in part, on
assessment of the degree of liver fibrosis.
All candidates for antiviral therapy should be tested
for HCV genotype by serologic immunoassay or molecular determination. Among the six major known HCV
genotypes (G), most patients in the United States have
G1 (approximately 70%80%) or G2 or G3 (20%30%;
Dienstag & McHutchison, 2006). Viral genotype is the basis for determining the planned duration of antiviral therapy and is a major factor in the likelihood of attaining
virologic response.
The primary goal of treatment is eradication of the
virus, as identified by a sustained virologic response
(SVR), which is defined as undetectable HCV RNA 24
weeks after the completion of treatment. Long-term
follow-up studies of patients who have attained SVR
have shown that SVR is durable and that the risk of late
relapse is very low (Maylin et al., 2008). The current
411

Chronic hepatitis C management of side

standard of care for patients with CHC is a combination of once-weekly subcutaneous pegylated interferon
(PEG-IFN) alfa plus daily oral ribavirin (Ghany et al.,
2009). Two types of PEG-IFN alfa have been approved
by the U.S. Food and Drug Administration (FDA) for
patients with hepatitis C infection. They are PEG-IFN
R
), which is administered as a fixed 180
alfa-2a (Pegasys
g/week dose (Hoffman La Roche, Inc., 2008), and PEGR
), which is administered accordIFN alfa-2b (PegIntron
ing to the patients body weight (1.5 g/kg/week; Schering Corporation, 2009).
Ribavirin doses vary according to patient body weight
and viral genotype (G16). When used in combination
with PEG-IFN alfa-2a, ribavirin doses of 1000 mg/day
or 1200 mg/day are recommended in G1 patients who
weigh less than 75 kg or who weigh 75 kg or more,
respectively; ribavirin doses of 800 mg/day are recommended in G2 and G3 patients (Hoffman La Roche, Inc.,
2008). When used in combination with PEG-IFN alfa-2b,
ribavirin doses between 800 and 1400 mg/day according
to patient body weight are recommended for all patients
regardless of genotype (Schering Corporation, 2009). Duration of treatment depends on genotype. Current treatment recommendations specify that G1 patients receive
treatment for 48 weeks and that G2 or G3 patients receive treatment for 24 weeks (Ghany et al., 2009). There
is also clinical evidence to support a reduced treatment
duration (24 weeks in G1 patients; Zeuzem et al., 2006
and 1216 weeks in G2/3 patients; Mangia et al., 2005;
Shiffman et al., 2007) in those who respond rapidly to
therapy (with undetectable HCV RNA at week 4 of treatment, referred to as a rapid virologic response [RVR]),
and an extended treatment duration in G1 patients who
are slow to respond (Pearlman, Ehleben, & Saifee, 2007).
Predictors of treatment response include a range of host
and viral characteristics. Host factors associated with improved treatment outcomes include younger age, nonAfrican American race, lack of extensive fibrosis, no
steatosis, and absence of comorbidities such as human
immunodeficiency virus (HIV) coinfection. In the IDEAL
study (Individualized Dosing Efficacy vs. Flat Dosing to
Assess Optimal PEG-IFN Therapy; McHutchison et al.,
2009b), SVR rates in patients receiving current standard
of care regimens were 53%56% in those 40 years
of age and 38% in those 40 years of age. Similarly,
SVR was 43% in patients with mild-to-moderate fibrosis
compared with 21%24% in those with bridging fibrosis or cirrhosis; SVR was 48%49% in patients with no
steatosis compared with 35%36% in those with steatosis (McHutchison et al., 2009b). Other recent studies indicated that SVR rates were significantly lower in Latino
compared with non-Latino patients (34% vs. 49%, p
.001; Rodriguez-Torres et al., 2009) and in African Amer412

M. Olson & I. M. Jacobson

ican compared with non-Hispanic white patients (19%

vs. 52%, p .001; Muir, Bornstein, Killenberg, & the Atlantic Coast Hepatitis Treatment Group, 2004). Finally,
several studies have reported that SVR rates among patients with HIV and HCV coinfection are 27%40% (Carrat et al., 2004; Chung et al., 2004; Torriani et al., 2004),
which is markedly lower than SVR rates of 54%56% reported in the PEG-IFN alfa-2a and -2b registration studies
(Fried et al., 2002; Manns et al., 2001).
Viral factors that can impact treatment outcomes include genotype and baseline viral load. There is generally less hesitation to treat patients with G2 or G3 infection because they have a greater likelihood of attaining
viral eradication and the duration of treatment is shorter.
The preferred approach for identifying patients at risk of
progressive disease is to assess the degree of fibrosis. The
presence of bridging fibrosis or cirrhosis on liver biopsy is
a sign of disease progression and should be viewed as an
indication for treatment. In contrast, minimal fibrosis is
associated with a low risk for liver-related complications
and current recommendations suggest that treatment of
patients with absent or mild fibrosis should be considered
on a case-by-case basis (Ghany et al., 2009).

Efcacy of CHC treatment

The clinical efficacy of PEG-IFN and ribavirin combination therapy in patients with CHC has been demonstrated
in two large phase 3 registration trials (see Figure 1; Fried
et al., 2002; Manns et al., 2001). In these studies, PEGIFN alfa-2a (180 g/week) plus ribavirin (10001200
mg/day) or PEG-IFN alfa-2b (1.5 g/kg/week) plus ribavirin (800 mg/day) was significantly more effective
than standard IFN (3 MIU three times daily) plus ribavirin (10001200 mg/day). Overall SVR rates were 54%
and 56% in patients treated for 48 weeks. Predictably,
SVR rates were higher (76%82%) among G2/3 patients
than among the more difficult-to-treat G1 population
(42%46%; Fried et al., 2002; Manns et al., 2001). These
studies demonstrated for the first time the benefits associated with pegylation of the interferon molecule in terms
of a once-weekly administration schedule (vs. three times
weekly with standard interferon), coupled with significantly improved treatment outcomes. Importantly, no
increase in frequency of discontinuations as a result of
adverse events with PEG-IFN alfa therapy compared with
standard IFN therapy was found in either study.
Subtle pharmacologic differences exist between the two
PEG-IFNs, primarily as a result of differences in molecular structures. PEG-IFN alfa-2a has a 40-kDa polyethylene
glycol moiety, whereas PEG-IFN alfa-2b has a 12-kDa
moiety. These structural differences appear to affect in
vitro properties such as antiviral activity (which is greater

Chronic hepatitis C management of side

M. Olson & I. M. Jacobson

All

90

G1

G2/3
82

Patients, % SVR

80

76

70
60
50

56

54
46
42

40
30
20
10
0

Fried, et al., 2002

Manns, et al., 2001

PEG-IFN alfa-2a

PEG-IFN alfa-2b

Figure 1 Summary of efcacy outcomes in PEG-IFN alfa registration trials. Sustained virologic response rate: all patients versus G1 versus G2/3. G =
genotype; PEG-IFN = pegylated interferon (Fried et al., 2002; Manns et al., 2001)

with 12-kDa PEG moiety) and pharmacokinetic parameters such as plasma half-life (which is longer with the 40kDa PEG moiety; Bordens, Xie, Wylie, Grace, & Schreiber,
2006; Grace et al., 2005; Silva et al., 2006). Until recently,
there has been a lack of prospective, randomized head-tohead clinical comparisons between these two agents. The
phase 3b IDEAL study was initially designed to compare
two doses of PEG-IFN alfa-2b (1.5 or 1.0 g/kg/week)
plus ribavirin (8001400 mg/day) in treatment-naive G1
patients. A PEG-IFN alfa-2a (180 g/week) plus ribavirin
(10001200 mg/day) treatment arm was subsequently
added (McHutchison et al., 2009b). SVR rates were similar across the three treatment groups (39.8%, 38.0%, and
40.9%, respectively). End-of-treatment response (EOTR)
occurred more frequently in recipients of PEG-IFN alfa2a (64.4% [PEG-IFN alfa-2a 180 g/week] vs. 53.2%
[PEG-IFN alfa-2b 1.5 g/kg/week] and 49.2% [PEG-IFN
alfa-2b 1.0 g/kg/week]), whereas relapse rates were
lower in recipients of PEG-IFN alfa-2b (23.5% [PEGIFN alfa-2b 1.5 g/kg/week] and 20.0% [PEG-IFN alfa2b 1.0 g/kg/week] vs. 31.5% [PEG-IFN alfa-2a 180 g/
week]; McHutchison et al., 2009b). Tolerability was similar across all three treatment groups.

Treatment milestones
Several treatment milestones have been identified that
can be used as early indicators of how well patients are
responding to treatment (see Table 2). They include RVR,
defined as undetectable HCV RNA at week 4 of therapy,

and early virologic response (EVR), defined as 2 log10

decrease in HCV RNA levels from baseline (partial EVR)
or as undetectable HCV RNA (complete EVR) at week
12. At the completion of therapy, patients with undetectable HCV RNA are considered to have attained EOTR,
and those who continue to have undetectable HCV RNA
for the 24-week follow-up period are considered to have
attained SVR. Relapse is defined as undetectable HCV
RNA at the end of treatment, with the reappearance of
serum HCV RNA during follow-up (Figure 2; Zeuzem &
Herrmann, 2002).
RVR and EVR can be used to predict the outcome of
treatment, to help tailor therapy to each patient, and to

Table 2 Summary of treatment milestones used to assess response to

antiviral therapy
RVR

Rapid virologic response: undetectable HCV RNA at

week 4
EVR
Early virologic response: 2 log10 decrease in HCV RNA
levels from baseline (partial EVR) or undetectable HCV
RNA (complete EVR) at week 12
EOTR
End-of-treatment response: undetectable HCV RNA at the
end of treatment
SVR
Sustained virologic response: undetectable HCV RNA
24 weeks after treatment cessation
Relapse
Undetectable HCV RNA at EOT that becomes detectable
during follow-up
Breakthrough Undetectable HCV RNA on treatment and then
subsequent detectable HCV RNA while still on
treatment

413

Chronic hepatitis C management of side

Rapid virologic response

Early virologic response*

Partial response

M. Olson & I. M. Jacobson

Null response

Sustained virologic response

HCV RNA log10, IU/mL

7
Breakthrough

Relapse

5
4

2-log10 decline

3
2

Limit of detection

1
0
0

12

Week 4 Week 12
(RVR)
(EVR)
*

Undetectable HCV RNA;

18

24

30

36

Weeks

42

48

54

60

Week 48
(EOT)

2-log10 decrease in HCV RNA from baseline.

motivate patients to continue therapy, especially early in

the course of treatment, when they frequently experience side effects. A few studies have suggested that G1 patients with low viral load at baseline who attain RVR can
be treated for 24 weeks rather than the standard 48-week
period, with no apparent decrease in efficacy (Ferenci
et al., 2008; Zeuzem et al., 2006). Similarly, some studies
have suggested that G2/3 patients who attain RVR can be
treated for 1216 weeks and still attain SVR rates similar
to those attained with the standard 24-week treatment
duration (Mangia et al., 2005; von Wagner et al., 2005).
However, the largest trial to date that evaluated shortened treatment duration in G2/3 patients still showed superiority with 24-week treatment (Shiffman et al., 2007).
Similarly, failure to attain EVR is associated with a very
low likelihood of attaining SVR. Current guidelines indicate that almost all patients with a < 2 log10 decrease in
HCV RNA at week 12 will not attain SVR (Ghany et al.,
2009). In these patients, therefore, treatment is generally stopped at week 12. G1 patients who attain > 2 log10
reduction in HCV RNA by week 12 with subsequent viral clearance (slow responders) have a high likelihood (>
50%) of experiencing relapse when treated for 48 weeks.
Recent studies suggest that these patients may derive additional benefit from extending treatment to 72 weeks
(Berg et al., 2006; Mangia et al., 2008; Pearlman et al.,
2007).
At this time, the practice of extended and shortened
treatment durations based on HCV RNA levels at week 4
or 12 does not fall within the FDA-approved guidance for
the treatment of patients with CHC.

66

72
Week 72
(SVR)

Figure 2 Summary of treatment milestones.

Rapid virologic response (RVR), undetectable
HCV RNA at week 4; early virologic response
(EVR), 2 log10 decrease in HCV RNA levels
from baseline (partial EVR) or undetectable HCV
RNA (complete EVR) at week 12; end of treatment (EOT), undetectable HCV RNA at EOT
(the graph depicts a 48-week treatment period); breakthrough, undetectable HCV RNA during treatment that become detectable before
EOT; sustained virologic response (SVR), undetectable HCV RNA 24 weeks after treatment cessation; relapse, undetectable HCV RNA at EOT
that becomes detectable during follow-up. Figure adapted with permission from Zeuzem &
Herrmann, 2002. Dynamics of hepatitis C virus
infection. Annals of Hepatology, 1, 5663.

work revealed elevated liver enzymes. In reviewing her

medical and behavioral history for risk factors for HCV infection, she reported brief intranasal cocaine use around
1995, while she was in college. Hepatitis serology test
results revealed detectable HCV antibodies. To confirm
HCV infection, HCV RNA level was measured (with use of
PCR) and determined to be 879,000 IU/mL. She had HCV
G1 infection. Liver biopsy revealed grade 1 inflammation
and stage 2 fibrosis score on a 5-point scale ranging from
0 to 4. The patient was contemplating pregnancy.

Treatment decision
Together, the patient and healthcare provider decided
to start treatment with PEG-IFN alfa plus ribavirin with
the aim of achieving HCV eradication before attempting conception and to prevent vertical transmission in
the event of pregnancy. The vertical transmission rate
for HCV is < 5% (Ferrero et al., 2003). Treatment initiation was supported by her moderate level of liver
fibrosis, which indicated that the fibrosis was progressing. She was advised to use two methods of contraception while on treatment and for 6 months after
treatment cessation. The potential side effects of PEGIFN alfa-based therapy, including fatigue and depression,
were discussed thoroughly with the patient before treatment. Finally, the close relationship between poor adherence and a reduced likelihood of SVR was discussed, and
the patient was counseled to adhere closely to her prescribed regimen.

Safety prole of PEG-IFN alfa

Clinical vignetteIntroduction
A 31-year-old white woman went to her primary care
provider for an annual physical examination. Her blood
414

Flulike symptoms, such as fever, myalgia, and rigors,

are commonly associated with IFN-based therapy occurring in approximately 35%56% of treated patients

M. Olson & I. M. Jacobson

(Fried, 2002). These symptoms typically occur several

hours to days after the first injection but may occur also
after subsequent injections. Strategies to reduce these
symptoms include treatment administration just before
bedtime, rest, healthy eating habits, and plenty of fluids
(eight 8-oz. glasses of water are recommended daily). In
addition, patients may take acetaminophen (maximum,
2 g/24 h) or nonsteroidal antiinflammatory drugs (allowed in patients with good synthetic liver function [including normal albumin levels and reduced clotting factors]) to alleviate symptoms.
Headaches are another common side effect of IFNbased treatment. They may occur throughout therapy in
approximately 60% of patients. Several strategies may be
used to minimize headaches, including limiting caffeine
intake, especially in the late afternoon or evening; maintaining adequate hydration; avoiding loud noises, bright
lights, and strong odors; and establishing regular eating
and sleeping routines. Acetaminophen may be taken to
alleviate pain as necessary. It is also important to be
aware that migraine headaches may be triggered by IFNbased therapy. Patients with suspected migraine should
be managed in the same manner as patients who do not
have HCV infection.
Bone marrow suppression caused by IFN-based therapy
can lead to decreased numbers of neutrophils (< 1500
cells/L). Rapid decreases in neutrophil count can
occur during the first 2 weeks of therapy but usually stabilize during the following 4 weeks as steady state PEGIFN concentrations are established. Clinical trials indicate that neutropenia (absolute neutrophil count [ANC]
< 750/mm3 ) develops in about 20% of patients with CHC
receiving PEG-IFN therapy (Fried et al., 2002; Manns
et al., 2001). Only a small number of patients (3%5%)
develop ANC levels < 500/mm3 (Hadziyannis et al.,
2004). The incidence of neutropenia is much higher in
patients with advanced liver disease (it can be as high
as 40% in patients with cirrhosis) and is accompanied
by a high incidence of thrombocytopenia (Everson et al.,
2006).
According to the prescribing information, IFN-induced
neutropenia may be managed by reducing the dose of
PEG-IFN alfa. Among patients receiving PEG-IFN alfa-2a,
a decrease in ANC to < 750 cells/mm3 should be managed
by a dose reduction from 180 g/week to 135 g/week.
If ANC falls to 500 cells/mm3 , PEG-IFN alfa-2a therapy should be suspended until ANC recovers to 1000
cells/mm3 (Hoffman La Roche, Inc., 2008). Among patients receiving PEG-IFN alfa-2b, doses should be reduced by 50% in patients whose ANC is < 750 cells/mm3
and should be permanently discontinued in patients
whose ANC reaches 500 cells/mm3 (Schering Corporation, 2009). Serious infections in patients with IFN-

Chronic hepatitis C management of side

induced neutropenia, however, are uncommon (Fried

et al., 2002; Manns et al., 2001), and many clinicians,
including the authors, do not always reduce the PEGIFN alfa dose when ANC levels are between 500 and
750/mm3 . Particular caution, however, is warranted in
patients with cirrhosis or with HIV and HCV coinfection.
An alternative strategy to manage neutropenia is the
use of recombinant growth factors. Cytokines, such as
granulocyte-colony stimulating factor (G-CSF; filgrastim), significantly increase white blood cell counts by interacting with receptors on the myeloid progenitor cells
in the bone marrow to induce cell proliferation, differentiation, and activation (Collantes & Younossi, 2005).
Small studies have indicated that recombinant G-CSF can
be used in place of dose reduction to improve neutrophil
counts in patients with CHC (Nader et al., 2007; Ong
& Younossi, 2004). Although several studies have considered the use of recombinant G-CSF and other studies are ongoing, at this time recombinant G-CSF is not
approved by the FDA for use in patients with hepatitis C. Furthermore, although recombinant G-CSF analogues have been shown to improve neutrophil counts
in patients with hepatitis C receiving IFN-based antiviral therapy, there are no data demonstrating that use of
these agents improves the likelihood of SVR (Collantes &
Younossi, 2005).
Depression is a well-known side effect of IFN-based
therapy. In the registration trials, 29%31% of patients
receiving PEG-IFN alfa plus ribavirin experienced clinical
depression during treatment (Fried et al., 2002; Manns
et al., 2001). These estimates are based on a general side
effects review rather than a validated diagnosis of major depressive disorders. A formal approach to estimating the incidence of depression using a validated rating
scale has suggested that 39% of patients with CHC receiving PEG-IFN alfa-2b plus ribavirin experience moderate to severe symptoms of depression (Raison et al.,
2005a).
Patients with a history of depression are generally considered more likely to develop depression during IFNbased therapy. Some studies suggest that baseline depression score is a significant predictor of depression
(Raison et al., 2005a); other studies have indicated that
the development of depression is unrelated to baseline
psychiatric status (Hauser et al., 2002; Schaefer et al.,
2003). Interestingly, it has been suggested that patients
with more severe symptoms of depression may be less
likely to attain SVR (Maddock et al., 2005; Raison et al.,
2005b). In one study, only 34% (10/29) of patients with a
major depressive episode (defined by a 20-point increase in Zung self-rating depression scale [SDS] Index
score) had undetectable HCV RNA at 24 weeks compared with 59% (24/41) of patients with 10- to 19-point
415

Chronic hepatitis C management of side

increases and 69% (22/32) of patients with < 10-point

increases (p < .05) (Raison et al., 2005b).
Thus, early recognition and appropriate management
of depression in patients with CHC receiving IFN-based
therapy is likely to result in improved patient outcomes.
Depression may be effectively managed with conventional antidepressant drugs such as citalopram or paroxetine, both of which have been shown to be effective
in patients in whom major depression develops during
IFN-based treatment (Hauser et al., 2002; Kraus, Schafer,
Faller, Csef, & Scheurlen, 2002; Maddock et al., 2004).
Furthermore, there is also evidence to support the prophylactic use of antidepressant medication in patients
who are considered at significant risk for developing IFNrelated depression (particularly those with preexisting
moderate to severe psychiatric conditions; Asnis & De La
Garza R II, 2006; Kraus, Schafer, Al-Taie, & Scheurlen,
2005).

Clinical vignetteCourse of treatment

Side effects
At treatment week 4, the patient visited the clinic
and reported flulike symptoms, which had resolved, and
ongoing symptoms of fatigue, depression, and difficulty
sleeping. She denied suicidal ideation but stated that she
had been tearful and had difficulty motivating herself.
R
; Forest Pharmaceuticals, St. Louis,
Citalopram (Celexa
MO) 20 mg/day by mouth was started for depression,
R
; Sanofi-Aventis, Bridgewaand zolpidem (Ambien CR
ter, NJ) 12.5 mg as needed (PRN) was prescribed at bedtime for sleep. Treatment week 4 laboratory test results
showed a hemoglobin (Hb) value of 9.5 g/dL. The patient had fatigue and shortness of breath but denied chest
pain. Her ribavirin dose was decreased by 200 mg/day,
and she was started on epoetin 40,000 U/week. Her CBC
was checked every 2 weeks, and her Hb improved to between 10.0 and 10.5 g/dL. The full ribavirin dose was reinstated, and she remained on epoetin 40,000 U/week.
Her ANC was 800 cells/mm3 , and she continued full-dose
PEG-IFN alfa.

Viral eradication
At treatment week 4, HCV RNA remained detectable;
at week 12, the patient had a > 2 log10 decrease from
baseline in viral load and treatment was continued. At
treatment week 24, she had undetectable HCV RNA, and
she was continued on treatment for 72 weeks because she
had partial EVR at week 12.

416

M. Olson & I. M. Jacobson

Safety prole of ribavirin

Anemia, defined as an Hb level < 12 g/dL or > 3 g/dL
decrease in Hb from baseline, is the most frequent reason
for dose reduction or discontinuation of ribavirin (Reddy
et al., 2007). In the PEG-IFN alfa registration studies,
9%22% of patients receiving doses of ribavirin between
800 and 1200 mg/day required dose modification because of anemia (Fried et al., 2002; Manns et al., 2001).
Pooled data from 569 patients enrolled in two phase 3 trials of 48 weeks duration with PEG-IFN alfa-2a and ribavirin showed that the development of anemia and subsequent modifications of ribavirin dosage can adversely
affect treatment outcomes (Reddy et al., 2007).
Patients with falls in Hb levels of 1.5 g/dL during
the first 2 weeks of ribavirin treatment are at significant risk for severe anemia (2.5 g/dL decline) by week
4. Other factors significantly related to the development
of anemia include the presence of cirrhosis, low baseline
Hb, non-African American or Asian race, and low creatinine clearance (Reau, Jensen, Hadziyannis, Messinger,
& Fried, 2006). Current prescribing information recommends reducing the ribavirin dose by 200 mg/day in patients with Hb levels < 10.0 g/dL and discontinuing ribavirin in those with Hb levels < 8.5 g/dL (Hoffman La
Roche, Inc., 2008; Schering Corporation, 2009).
Although they are not FDA-approved for the treatment of patients with CHC, erythropoietic growth factors are commonly used to manage anemia in this patient
group. Several studies have shown that erythropoietic
growth factors, such as epoetin alfa and darbepoetin alfa
R
R
and Aranesp
both from Amgen, Inc., Thou(Epogen
sand Oaks, CA) can be effectively used to manage anemia in patients with CHC, thereby avoiding the need for
ribavirin dose reductions (Afdhal et al., 2004; Dieterich
et al., 2003; Younossi et al., 2008), which can impact
SVR rates. In these studies, mean Hb levels in patients
receiving erythropoietic growth factors ranged from 12.6
to 13.8 g/dL compared with 10.5 to 11.4 g/dL in patients
receiving standard of care (dose reductions, discontinuations, blood transfusions; Afdhal et al., 2004; Dieterich
et al., 2003).
Thus, erythropoietic growth factors appear to be a
useful option for the management of anemia in selected patients with hepatitis C receiving antiviral therapy. The use of these agents can help maintain higher
doses of ribavirin and higher Hb levels and also improve health-related quality of life (Afdhal et al., 2004;
Dieterich et al., 2003). However, it should also be cautioned that use of these agents is known to substantially increase treatment costs (Del Rio, Post, & Singer,
2006) and has not been shown to increase SVR. In addition, based on recent observations from other patient

M. Olson & I. M. Jacobson

Chronic hepatitis C management of side

Figure 3 Recent recommendations for use of erythropoiesis-stimulating

agent (ESA) therapy in patients with hepatitis C receiving antiviral therapy. Adapted from Muir and McHutchison, 2006 (Muir et al., 2006) and
http://www.fda.gov/cder/drug/infopage/RHE/default.htm. The goal of ESA
therapy should be to maintain the lowest hemoglobin (Hb) level sufcient

to avoid red blood cell transfusion. a The dose of ESA should be reduced
as the Hb level approaches 12 g/dL or increases by >1 g/dL in any 2-week
R
period (Aranesp
prescribing information [revised], Amgen Inc., 2008a;

R
Epogen prescribing information [revised], Amgen Inc., 2008b). HCV =
hepatitis C virus; RBV = ribavirin; SC = subcutaneous.

populations, such as persons with cancer, the FDA issued

a black box warning stating that the aggressive use of
erythropoiesis-stimulating agents (ESAs) to raise Hb levels to 12 g/dL has been associated with serious and
life-threatening side-effects and/or death (http://www.
fda.gov/cder/drug/infopage/RHE/default.htm). These revised recommendations regarding target Hb levels for
erythropoietic growth factors should also be observed
when used to treat ribavirin-induced anemia (see
Figure 3; Muir & McHutchison, 2006).
Ribavirin also has known teratogenic properties, so extreme caution must be taken to avoid pregnancy both
during therapy and for a period of 6 months after completion of treatment (Schering Corporation, 2008). It
is advisable that at least two effective forms of contraception be used during ribavirin treatment and during the 6-month posttreatment period. Pregnancy should
be avoided both by women receiving ribavirin and by
women whose male partners are receiving ribavirin
(Schering Corporation, 2008).
Finally, ribavirin has also been associated with a pruritic papular rash on the trunk and extremities that can
be managed with topical steroid creams or oral antihistamines. Occasionally, the rash is severe enough to require dose reduction or even temporary discontinuation.
Both ribavirin and PEG-IFN can also cause cough. With

ribavirin this is a benign dry cough; however, PEG-IFN

has rarely been associated with interstitial lung disease.
Therefore, patients who develop a cough while receiving treatment should be evaluated with a chest x-ray
and possibly a computed tomography scan, as clinically
indicated.

Clinical vignetteResolution
Ongoing investigations
CBC and chemistry panels were conducted monthly,
and PCR analysis for HCV RNA levels was conducted at
weeks 4 and 12, and every 3 months thereafter while the
patient was receiving treatment. She was able to maintain full doses of PEG-IFN alfa-2b and ribavirin without
growth factor supplementation. Her mood and sleep disturbances improved with citalopram and zolpidem treatment, respectively, which were continued during therapy
and tapered 1 month after therapy ended.

End of treatment and follow-up

The patient stopped antiviral treatment after 48 weeks
(at which time she had undetectable HCV RNA levels)
and was followed for 6 months. HCV RNA remained
417

Chronic hepatitis C management of side

undetectable for 6 months after therapy end; therefore,

she attained SVR. She is scheduled to return in 6 months
to confirm that HCV RNA levels remain undetectable, after which it will be unnecessary to repeat further HCV
PCR testing (unless liver function test results become
abnormal), because SVR has been proven to be durable in
long-term follow-up studies. The patient was cautioned
to avoid pregnancy until 6 months after discontinuing
ribavirin therapy (Schering Corporation, 2008).

Management of side effects: The role of the

primary care NP
NPs can help reduce morbidity and improve outcomes
in patients with CHC receiving PEG-IFN alfa plus ribavirin therapy. They are well placed to provide education and information to patients and caregivers about
potential side effects of treatment and, importantly, provide reassurance that these events are manageable. This
encourages caregivers and patients to introduce precautionary measures that will also help limit the impact of
side effects. In addition to discussing the potential problems associated with therapy, NPs should educate patients regarding the benefits of therapy and especially to
persevere with therapy. The importance of adherence to
therapy cannot be overemphasized and is essential for optimizing treatment outcomes (McHutchison et al., 2002).
Adherence may be improved when patients understand
the consequences of not adhering to the optimal treatment regimen. Finally, it is important that NPs schedule
patients for appropriate follow-up visits and laboratory
tests to ensure that side effects are identified and managed as early as possible.

Future of hepatitis C treatment

Given the limitations of current standard of care, especially for patients with HCV G1 infection, intense
efforts to develop novel treatment approaches are ongoing. Recent research has focused on new IFN formulations, specifically targeted antiviral drugs, and immune
modulators.
An alternative IFN formulation in early clinical development is PEG-IFN lambda. PEG-IFN lambda is of
interest because it binds predominantly to hepatocytes, unlike the broader binding activity of PEG-IFN
alfa; therefore, it may be associated with less toxicity (Lawitz et al., 2008). Studies have also examined the efficacy and tolerability of a consensus INF
(CIFN) CIFN molecule in retreating patients who previously did not respond to PEG-IFN alfa plus ribavirin
(Bacon et al., 2009; Leevy, 2008).
418

M. Olson & I. M. Jacobson

Viral enzyme inhibition disrupts the viral replication

machinery by inhibiting key enzymes such as HCV
NS3/4A serine proteases, which are involved in the production of functional proteins necessary for viral replication. Viral enzyme inhibitors, such as the HCV NS3/4A
serine protease inhibitors telaprevir and boceprevir and
the NS5B polymerase inhibitor R7128, have shown great
promise and are in advanced stages of development. Recent results from phase 2 clinical trials have shown that
telaprevir and boceprevir each increase SVR rates when
combined with PEG-IFN alfa plus ribavirin in HCV G1
treatment-naive patients (Hezode et al., 2009; Kwo et al.,
2008; McHutchison et al., 2009a). These trials provide
strong evidence that augmented SVR rates can be attained with a shorter duration of therapy. For example,
PROVE was a phase 2 study of patients with poor response (null or partial responders and relapsers) to previous therapy with PEG-IFN alfa-2a and ribavirin who
were treated with telaprevir plus PEG-IFN alfa-2a and ribavirin (Hezode et al., 2009; McHutchison et al., 2009a).
In PROVE1 and PROVE2, SVR rates were significantly
lower in patients receiving PEG-IFN alfa plus ribavirin
for 48 weeks than in those receiving PEG-IFN alfa plus
ribavirin plus telaprevir for 12 weeks followed by PEGIFN alfa plus ribavirin for a further 12 weeks (PROVE1,
41% vs. 61%, p = .02; PROVE2, 46% vs. 69%, p = .004;
McHutchison et al., 2009a; Hezode et al., 2009). Boceprevir also has antiviral activity when used in combination
with PEG-IFN alfa plus ribavirin in patients who did not
respond to previous PEG-IFN alfa-2b plus ribavirin treatment (Schiff et al., 2008). Ultimately, it is hoped that
combinations of specifically targeted antiviral drugs of different classes, such as protease and polymerase inhibitors,
will be effective and well tolerated and replace IFN alfabased regimens. However, it is anticipated that IFN-based
regimens will remain a cornerstone of therapy for years
to come.

Conclusions
Treatment options for patients with CHC are continually evolving. Individualized therapy maximizes the
chance of attaining SVR while minimizing tolerability
concerns. Although PEG-IFN alfa plus ribavirin therapy
is associated with a well-described series of side effects,
effective measures are available for the management of
these events that permit continuation of treatment and
ultimately enhance the likelihood of attaining SVR. The
NP can play a pivotal role in ensuring that these measures are in place in a preemptive manner. NPs involved in the management of patients with CHC are also
well positioned to provide supportive care and contribute
to the development of effective treatment strategies

M. Olson & I. M. Jacobson

that maximize the opportunity for successful treatment

outcomes.

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