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REVIEW

Role of the nurse practitioner in the management of patientswith chronic hepatitis C

Mary Olson,NP (Clinical Trials Program Director)& Ira M. Jacobson,MD (Vincent Astor Professor of ClinicalMedicine)

Weill Medical College of Cornell University, New York, New York

Correspondence

MaryOlson, 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: [email protected]

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 conflict of

interest. I.M.J. has been paid by Schering-

Plough 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 hep-

atitis 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 mea-

sures are available for the management of these events that permit the contin-

uation 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 se-

lected patients with neutropenia or anemia and may help to improve treatment

adherence.

Implications for practice: Hepatitis C is a widespread problem; approxi-

mately 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-riskpatients, 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 in-

fected each year (Lavanchy, 2009). According to the Cen-

ters for Disease Control and Prevention (CDC, 2008),

an estimated 1.6% of the U.S. adult population is in-

fected with the hepatitis C virus (HCV). Of those 4.1

million persons (National Institute of Diabetes and Di-

gestive and Kidney Diseases [NIDDK], 2006), 3.2 million

have chronic infection (CDC, 2008). HCV infection ac-

counts 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). Morbid-

ity and mortality levels associated with chronic hepatitis

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 car-

cinoma (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 man-

agement 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

410 Journal of the American Academy of Nurse Practitioners23 (2011) 410420 C2011 The Author(s)Journal compilation C2011 American Academy of Nurse Practitioners


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M. Olson & I. M. Jacobson Chronic hepatitis C management of side

Table 1 Risk factors for hepatitis C

Illicit intravenous drug use Intranasal drug use Comorbid condition (e.g., HIV/HBV infection) Hemodialysis

Birth to HCV-infected mother Organ transplantation Needlestick injury Military service 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

referralRisk factors

Transmission of HCV occurs primarily through con-

tact with infected blood or blood products. The cur-

rent primary risk factor for infection is IV drug use

(from sharing of needles); however, anyone who re-

ceived a blood transfusion before June 1992 (when sensi-

tive blood screening tests were introduced in most coun-

tries) 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 previ-

ous 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 im-

munoassays are available that can detect antibodies with

high specificity (> 99%; Chevaliez & Pawlotsky, 2006).

If the HCV antibody test result is positive, an HCV poly-

merase 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 hepati-

tis 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 inter-

national normalized ratio [INR]). The status of immunity

to hepatitis A and B should be assessed, and seronega-

tive persons should be vaccinated. Baseline abdominalultrasound 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, pa-

tients whose hepatitis C is diagnosed by a primary carephysician should be referred for care to a specialist in

gastroenterology, hepatology, or, in some areas, infec-

tious 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 consid-

ered potential candidates for treatment; however, antivi-

ral therapy is not recommended for patients with hep-

atic decompensation (those with ascites, varices, hepatic

encephalopathy, spontaneous bacterial peritonitis, jaun-

dice, 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 molec-

ular 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 ba-sis for determining the planned duration of antiviral ther-

apy 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

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Chronic hepatitis C management of side M. Olson & I. M. Jacobson

standard of care for patients with CHC is a combina-

tion 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-IFNalfa-2a (Pegasys R), which is administered as a fixed 180

g/week dose (Hoffman La Roche, Inc., 2008), and PEG-

IFN alfa-2b (PegIntron R), which is administered accord-

ing to the patients body weight (1.5 g/kg/week; Scher-

ing 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 recom-

mended 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). Du-

ration of treatment depends on genotype. Current treat-

ment recommendations specify that G1 patients receive

treatment for 48 weeks and that G2 or G3 patients re-

ceive 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 treat-

ment, 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 im-

proved treatment outcomes include younger age, non-

African 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 standardof 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 fibro-

sis or cirrhosis; SVR was 48%49% in patients with no

steatosis compared with 35%36% in those with steato-

sis (McHutchison et al., 2009b). Other recent studies in-

dicated 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 Amer-

ican compared with non-Hispanic white patients (19%

vs. 52%,p .001; Muir, Bornstein, Killenberg, & the At-

lantic Coast Hepatitis Treatment Group, 2004). Finally,

several studies have reported that SVR rates among pa-

tients with HIV and HCV coinfection are 27%40% (Car-

rat et al., 2004; Chung et al., 2004; Torriani et al., 2004),which is markedly lower than SVR rates of 54%56% re-

ported 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 in-

clude genotype and baseline viral load. There is gener-

ally less hesitation to treat patients with G2 or G3 infec-

tion 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 anindication 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).

Efficacy of CHC treatment

The clinical efficacy of PEG-IFN and ribavirin combina-

tion 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, PEG-

IFN alfa-2a (180 g/week) plus ribavirin (10001200

mg/day) or PEG-IFN alfa-2b (1.5 g/kg/week) plus rib-

avirin (800 mg/day) was significantly more effective

than standard IFN (3 MIU three times daily) plus rib-

avirin (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 associ-

ated with pegylation of the interferon molecule in terms

of a once-weekly administration schedule (vs. three times

weekly with standard interferon), coupled with signif-icantly 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 molecu-

lar 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

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5654

46

42

76

82

0

10

20

30

40

50

60

70

80

90

Fried, et al., 2002 Manns, et al., 2001

PEG-IFN alfa-2a PEG-IFN alfa-2b

Patients,

%S

VR

All G1 G2/3

Figure 1 Summary of efficacy 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 parame-

ters such as plasma half-life (which is longer with the 40-

kDa 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-to-

head 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 simi-

lar 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 alfa-

2a (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% [PEG-

IFN alfa-2b 1.5 g/kg/week] and 20.0% [PEG-IFN alfa-2b 1.0 g/kg/week] vs. 31.5% [PEG-IFN alfa-2a 180 g/

week]; McHutchison et al., 2009b). Tolerability was sim-

ilar 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 unde-

tectable 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 log10decrease 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

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Partial response Sustained virologic response

BreakthroughRelapse

Limit of detection

8

7

6

54

3

2

1

00

Week 4(RVR)

Week 12(EVR)

Week 48(EOT)

WeeksWeek 72

(SVR)

HCVRNAlog10,IU/mL

6 12 18 24 30 36 42 48 54 60 66 72

2-log10

decline

Undetectable HCV RNA; gol-2* 10decrease in HCV RNA from baseline.

Null responseRapid virologic response Early v irologic response* 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

frombaseline(partialEVR) or undetectable HCV

RNA (complete EVR) at week 12; end of treat-

ment (EOT), undetectable HCV RNA at EOT

(the graph depicts a 48-week treatment pe-

riod);breakthrough,undetectable HCVRNA dur-

ing treatment that become detectable before

EOT; sustained virologic response (SVR), unde-

tectableHCV RNA24 weeksaftertreatment ces-

sation; relapse, undetectable HCV RNA at EOT

that becomes detectable during follow-up. Fig-

ure adapted with permission from Zeuzem &

Herrmann, 2002. Dynamics of hepatitis C virus

infection.Annals of Hepatology, 1, 5663.

motivate patients to continue therapy, especially early inthe course of treatment, when they frequently experi-

ence side effects. A few studies have suggested that G1 pa-

tients 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 short-

ened treatment duration in G2/3 patients still showed su-

periority 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 indi-

cate 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 gener-

ally stopped at week 12. G1 patients who attain > 2 log10

reduction in HCV RNA by week 12 with subsequent vi-

ral clearance (slow responders) have a high likelihood (>

50%) of experiencing relapse when treated for 48 weeks.

Recent studies suggest that these patients may derive ad-

ditional 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.

Clinical vignetteIntroduction

A 31-year-old white woman went to her primary care

provider for an annual physical examination. Her blood

work revealed elevated liver enzymes. In reviewing hermedical and behavioral history for risk factors for HCV in-

fection, 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 attempt-

ing conception and to prevent vertical transmission in

the event of pregnancy. The vertical transmission rate

for HCV is < 5% (Ferrero et al., 2003). Treatment ini-

tiation was supported by her moderate level of liver

fibrosis, which indicated that the fibrosis was progress-

ing. She was advised to use two methods of contra-

ception while on treatment and for 6 months after

treatment cessation. The potential side effects of PEG-

IFN alfa-based therapy, including fatigue and depression,

were discussed thoroughly with the patient before treat-ment. Finally, the close relationship between poor adher-

ence and a reduced likelihood of SVR was discussed, and

the patient was counseled to adhere closely to her pre-

scribed regimen.

Safety profile of PEG-IFN alfa

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

are commonly associated with IFN-based therapy oc-

curring in approximately 35%56% of treated patients

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(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). Inaddition, patients may take acetaminophen (maximum,

2 g/24 h) or nonsteroidal antiinflammatory drugs (al-

lowed in patients with good synthetic liver function [in-

cluding normal albumin levels and reduced clotting fac-

tors]) to alleviate symptoms.

Headaches are another common side effect of IFN-

based 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; main-

taining adequate hydration; avoiding loud noises, bright

lights, and strong odors; and establishing regular eatingand 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 IFN-

based 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 sta-

bilize during the following 4 weeks as steady state PEG-

IFN concentrations are established. Clinical trials indi-

cate 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 ther-

apy should be suspended until ANC recovers to 1000

cells/mm3 (Hoffman La Roche, Inc., 2008). Among pa-

tients receiving PEG-IFN alfa-2b, doses should be re-

duced by 50% in patients whose ANC is < 750 cells/mm3

and should be permanently discontinued in patients

whose ANC reaches 500 cells/mm3 (Schering Corpo-

ration, 2009). Serious infections in patients with IFN-

induced neutropenia, however, are uncommon (Fried

et al., 2002; Manns et al., 2001), and many clinicians,

including the authors, do not always reduce the PEG-

IFN 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; filgras-

tim), significantly increase white blood cell counts by in-

teracting with receptors on the myeloid progenitor cells

in the bone marrow to induce cell proliferation, differ-

entiation, 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 con-

sidered the use of recombinant G-CSF and other stud-ies are ongoing, at this time recombinant G-CSF is not

approved by the FDA for use in patients with hepati-

tis C. Furthermore, although recombinant G-CSF ana-

logues have been shown to improve neutrophil counts

in patients with hepatitis C receiving IFN-based antivi-

ral 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 ma-

jor depressive disorders. A formal approach to estimat-

ing the incidence of depression using a validated rating

scale has suggested that 39% of patients with CHC re-

ceiving PEG-IFN alfa-2b plus ribavirin experience mod-

erate to severe symptoms of depression (Raison et al.,

2005a).

Patients with a history of depression are generally con-

sidered more likely to develop depression during IFN-

based therapy. Some studies suggest that baseline de-

pression score is a significant predictor of depression

(Raison et al., 2005a); other studies have indicated thatthe 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 in-

crease in Zung self-rating depression scale [SDS] Index

score) had undetectable HCV RNA at 24 weeks com-

pared with 59% (24/41) of patients with 10- to 19-point

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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 conven-tional antidepressant drugs such as citalopram or parox-

etine, 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 pro-

phylactic use of antidepressant medication in patients

who are considered at significant risk for developing IFN-

related 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.

Citalopram (Celexa R; Forest Pharmaceuticals, St. Louis,

MO) 20 mg/day by mouth was started for depression,and zolpidem (Ambien CR R; Sanofi-Aventis, Bridgewa-

ter, NJ) 12.5 mg as needed (PRN) was prescribed at bed-

time for sleep. Treatment week 4 laboratory test results

showed a hemoglobin (Hb) value of 9.5 g/dL. The pa-

tient 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 be-

tween 10.0 and 10.5 g/dL. The full ribavirin dose was re-

instated, 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.

Safety profile of ribavirin

Anemia, defined as an Hb level 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 be-

cause of anemia (Fried et al., 2002; Manns et al., 2001).

Pooled data from 569 patients enrolled in two phase 3 tri-

als of 48 weeks duration with PEG-IFN alfa-2a and rib-

avirin showed that the development of anemia and sub-

sequent 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 signifi-

cant 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 baselineHb, non-African American or Asian race, and low crea-

tinine clearance (Reau, Jensen, Hadziyannis, Messinger,

& Fried, 2006). Current prescribing information recom-

mends reducing the ribavirin dose by 200 mg/day in pa-

tients with Hb levels < 10.0 g/dL and discontinuing rib-

avirin 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 treat-

ment of patients with CHC, erythropoietic growth fac-

tors 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(Epogen R and Aranesp R both from Amgen, Inc., Thou-

sand Oaks, CA) can be effectively used to manage ane-

mia 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, discontinu-

ations, blood transfusions; Afdhal et al., 2004; Dieterich

et al., 2003).

Thus, erythropoietic growth factors appear to be auseful option for the management of anemia in se-

lected patients with hepatitis C receiving antiviral ther-

apy. The use of these agents can help maintain higher

doses of ribavirin and higher Hb levels and also im-

prove health-related quality of life (Afdhal et al., 2004;

Dieterich et al., 2003). However, it should also be cau-

tioned that use of these agents is known to substan-

tially increase treatment costs (Del Rio, Post, & Singer,

2006) and has not been shown to increase SVR. In ad-

dition, based on recent observations from other patient

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Figure 3 Recent recommendations for use of erythropoiesis-stimulating

agent (ESA) therapy in patients with hepatitis C receiving antiviral ther-

apy. 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 sufficient

to avoid red blood cell transfusion. a The dose of ESA should be reduced

as theHb level approaches 12 g/dL or increases by>1 g/dL inany 2-week

period (Aranesp R prescribing information [revised], Amgen Inc., 2008a;

Epogen R 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 lev-

els 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 re-

vised 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 ex-

treme caution must be taken to avoid pregnancy both

during therapy and for a period of 6 months after com-

pletion of treatment (Schering Corporation, 2008). It

is advisable that at least two effective forms of con-

traception be used during ribavirin treatment and dur-ing 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 pru-

ritic papular rash on the trunk and extremities that can

be managed with topical steroid creams or oral antihis-

tamines. Occasionally, the rash is severe enough to re-

quire 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 receiv-

ing 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 main-

tain full doses of PEG-IFN alfa-2b and ribavirin withoutgrowth factor supplementation. Her mood and sleep dis-

turbances improved with citalopram and zolpidem treat-

ment, 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


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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, af-

ter 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 inlong-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 theprimary care NP

NPs can help reduce morbidity and improve outcomes

in patients with CHC receiving PEG-IFN alfa plus rib-

avirin therapy. They are well placed to provide educa-

tion and information to patients and caregivers about

potential side effects of treatment and, importantly, pro-vide reassurance that these events are manageable. This

encourages caregivers and patients to introduce precau-

tionary measures that will also help limit the impact of

side effects. In addition to discussing the potential prob-

lems associated with therapy, NPs should educate pa-

tients regarding the benefits of therapy and especially to

persevere with therapy. The importance of adherence to

therapy cannot be overemphasized and is essential for op-

timizing treatment outcomes (McHutchison et al., 2002).

Adherence may be improved when patients understand

the consequences of not adhering to the optimal treat-

ment regimen. Finally, it is important that NPs schedulepatients for appropriate follow-up visits and laboratory

tests to ensure that side effects are identified and man-

aged as early as possible.

Future of hepatitis C treatment

Given the limitations of current standard of care, es-

pecially for patients with HCV G1 infection, intense

efforts to develop novel treatment approaches are ongo-

ing. Recent research has focused on new IFN formula-

tions, specifically targeted antiviral drugs, and immune

modulators.An alternative IFN formulation in early clinical de-

velopment is PEG-IFN lambda. PEG-IFN lambda is of

interest because it binds predominantly to hepato-

cytes, unlike the broader binding activity of PEG-IFN

alfa; therefore, it may be associated with less toxi-

city (Lawitz et al., 2008). Studies have also exam-

ined the efficacy and tolerability of a consensus INF

(CIFN) CIFN molecule in retreating patients who pre-

viously did not respond to PEG-IFN alfa plus ribavirin

(Bacon et al., 2009; Leevy, 2008).

Viral enzyme inhibition disrupts the viral replication

machinery by inhibiting key enzymes such as HCV

NS3/4A serine proteases, which are involved in the pro-

duction of functional proteins necessary for viral replica-

tion. Viral enzyme inhibitors, such as the HCV NS3/4A

serine protease inhibitors telaprevir and boceprevir andthe NS5B polymerase inhibitor R7128, have shown great

promise and are in advanced stages of development. Re-

cent 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 at-

tained with a shorter duration of therapy. For example,

PROVE was a phase 2 study of patients with poor re-

sponse (null or partial responders and relapsers) to pre-

vious therapy with PEG-IFN alfa-2a and ribavirin whowere treated with telaprevir plus PEG-IFN alfa-2a and rib-

avirin (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 PEG-

IFN 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). Bocepre-

vir 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 treat-

ment (Schiff et al., 2008). Ultimately, it is hoped that

combinations of specifically targeted antiviral drugs of dif-

ferent classes, such as protease and polymerase inhibitors,

will be effective and well tolerated and replace IFN alfa-

based 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 con-

tinually evolving. Individualized therapy maximizes the

chance of attaining SVR while minimizing tolerabilityconcerns. 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 mea-

sures are in place in a preemptive manner. NPs in-

volved in the management of patients with CHC are also

well positioned to provide supportive care and contribute

to the development of effective treatment strategies

418


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that maximize the opportunity for successful treatment

outcomes.

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Lesson 9 Article 2(1)

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