Professional Documents
Culture Documents
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.
410
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-
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
All
90
G1
G2/3
82
Patients, % SVR
80
76
70
60
50
56
54
46
42
40
30
20
10
0
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,
413
Partial response
Null response
7
Breakthrough
Relapse
5
4
2-log10 decline
3
2
Limit of detection
1
0
0
12
Week 4 Week 12
(RVR)
(EVR)
*
18
24
30
36
Weeks
42
48
54
60
Week 48
(EOT)
66
72
Week 72
(SVR)
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.
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
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.
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.
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
References
Afdhal, N. H., Dieterich, D. T., Pockros, P. J., Schiff, E. R., Shiffman, M. L.,
Sulkowski, M. S., . . . Bowers, P. (2004). Epoetin alfa maintains ribavirin
dose in HCV-infected patients: A prospective, double-blind, randomized
controlled study. Gastroenterology, 126, 13021311.
R
(darbepoetin alfa) for injection. Thousand
Amgen, Inc. (2008a). Aranesp
Oaks, CA: Amgen, Inc.
R
(epoetin alfa) for injection. Thousand Oaks,
Amgen, Inc. (2008b). EPOGEN
CA: Amgen, Inc.
Asnis, G. M., & De La Garza R II (2006). Interferon-induced depression in
chronic hepatitis C: A review of its prevalence, risk factors, biology, and
treatment approaches. Journal of Clinical Gastroenterology, 40, 322335.
Bacon, B. R., Shiffman, M. L., Mendes, F., Ghalib, R., Hassanein, T., Morelli,
G., . . . Gitlin, N. (2009). Retreating chronic hepatitis C with daily interferon
alfacon-1/ribavirin after nonresponse to pegylated interferon/ribavirin:
DIRECT results. Hepatology, 49, 18381846.
Berg, T., von Wagner, M., Nasser, S., Sarrazin, C., Heintges, T., Gerlach, T., . . .
Zeuzem, S. (2006). Extended treatment duration for hepatitis C virus type
1: Comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin.
Gastroenterology, 130, 10861097.
Bordens, R., Xie, L., Wylie, D., Grace, M., & Schreiber, G. (2006). Site and size
of interferon pegylation alters affinity to the IFNAR2-extracellular domain.
Presented at the 6th International Cytokine Conference, Vienna, Austria.
Carrat, F., Bani-Sadr, F., Pol, S., Rosenthal, E., Lunel-Fabiani, F., Benzekri, A.,
. . . Perronne, C. (2004). Pegylated interferon alfa-2b vs standard interferon
alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: A
randomized controlled trial. Journal of the American Medical Association, 292,
28392848.
Centers for Disease Control and Prevention. (2008). Hepatitis C fact sheet.
Centers for Disease Control and Prevention. Retrieved March 28, 2008,
from http://www.cdc.gov/hepatitis
Chevaliez, S., & Pawlotsky, J.-M. (2006). Hepatitis C virus serologic and
virologic tests and clinical diagnosis of HCV-related liver disease.
International Journal of Medical Sciences, 3, 3540.
Chung, R. T., Andersen, J., Volberding, P., Robbins, G. K., Liu, T., Sherman, K.
E., . . . van der Horst, C. (2004). Peginterferon alfa-2a plus ribavirin versus
interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected
persons. New England Journal of Medicine, 351, 451459.
Collantes, R. S., & Younossi, Z. M. (2005). The use of growth factors to manage
the hematologic side effects of PEG-interferon alfa and ribavirin. Journal of
Clinical Gastroenterology, 39, S9S13.
Del Rio, R. A., Post, A. B., & Singer, M. E. (2006). Cost-effectiveness of
hematologic growth factors for anemia occurring during hepatitis C
combination therapy. Hepatology, 44, 15981606.
Dienstag, J. L., & McHutchison, J. G. (2006). American gastroenterological
association technical review on the management of hepatitis C.
Gastroenterology, 130, 231264.
Dieterich, D. T., Wasserman, R., Brau, N., Hassanein, T. I., Bini, E. J., Bowers,
P. J., and Sulkowski, M.S. (2003). Once-weekly epoetin alfa improves
anemia and facilitates maintenance of ribavirin dosing in hepatitis C
virus-infected patients receiving ribavirin plus interferon alfa. American
Journal of Gastroenterology, 98, 24912499.
Everson, G. T., Hoefs, J. C., Seeff, L. B., Bonkovsky, H. L., Naishadham, D.,
Shiffman, M. L., . . . Morishima, C. (2006). Impact of disease severity on
outcome of antiviral therapy for chronic hepatitis C: Lessons from the
HALT-C trial. Hepatology, 44, 16751684.
Ferenci, P., Laferl, H., Scherzer, T. M., Gschwantler, M., Maieron, A., Brunner,
H., . . . Steindl-Munda, P. (2008). Peginterferon alfa-2a and ribavirin for 24
weeks in hepatitis C type 1 and 4 patients with rapid virological response.
Gastroenterology, 135, 451458.
Ferrero, S., Lungaro, P., Bruzzone, B. M., Gotta, C., Bentivoglio, G., &
Ragni,N. (2003). Prospective study of mother-to-infant transmission of
hepatitis C virus: A 10-year survey (19902000). Obstetrical and
Gynecological Survey, 58, 636637.
Fried, M. W. (2002). Side effects of therapy of hepatitis C and their
management. Hepatology, 36, S237S244.
Fried, M. W., Shiffman, M. L., Reddy, K. R., Smith, C., Marinos, G., Goncales
F. L. Jr., . . . Yu, J. (2002). Peginterferon alfa-2a plus ribavirin for chronic
hepatitis C virus infection. New England Journal of Medicine, 347, 975982.
Ghany, M. G., Strader, D. B., Thomas, D. L., & Seeff, L. B. (2009). Diagnosis,
management, and treatment of hepatitis C: An update. Hepatology, 49,
13351374.
Grace, M. J., Lee, S., Bradshaw, S., Chapman, J., Spond, J., Cox, S., . . .
Bordens, R. (2005). Site of pegylation and polyethylene glycol molecule
size attenuate interferon-alpha antiviral and antiproliferative activities
through the JAK/STAT signaling pathway. Journal of Biological Chemistry,
280, 63276336.
Hadziyannis, S. J., Sette, H. Jr., Morgan, T. R., Balan, V., Diago, M., Marcellin,
P., . . . Ackrill, A.M. (2004). Peginterferon-2a and ribavirin combination
therapy in chronic hepatitis C: A randomized study of treatment duration
and ribavirin dose. Annals of Internal Medicine, 140, 346355.
Hauser, P., Khosla, J., Aurora, H., Laurin, J., Kling, M. A., Hill, J., . . . Howell,
C.D. (2002). A prospective study of the incidence and open-label treatment
of interferon-induced major depressive disorder in patients with hepatitis
C. Molecular Psychiatry, 7, 942947.
Hezode, C., Forestier, N., Dusheiko, G., Ferenci, P., Pol, S., Goeser, T., . . .
Zeuzem, S. (2009). Telaprevir and peginterferon with or without ribavirin
for chronic HCV infection. New England Journal of Medicine, 360, 18391850.
Hoffman La Roche, Inc. (2008). Pegasys (peginterferon alfa-2a). Nutley, NJ:
Hoffman-La Roche, Inc.
Kim, W. R. (2002). The burden of hepatitis C in the United States. Hepatology,
36, S30S34.
Kraus, M. R., Schafer, A., Al-Taie, O., & Scheurlen, M. (2005). Prophylactic
SSRI during interferon alpha re-therapy in patients with chronic hepatitis
C and a history of interferon-induced depression. Journal of Viral Hepatitis,
12, 96100.
Kraus, M. R., Schafer, A., Faller, H., Csef, H., & Scheurlen, M. (2002).
Paroxetine for the treatment of interferon--induced depression in chronic
hepatitis C. Alimentary Pharmacology and Therapeutics, 16, 10911099.
Kwo, P., Lawitz, E., McCone, J., Schiff, E., Vierling, J., Pound, D., . . . Albrecht,
J.K. (2008). Interim results from HCV SPRINT-1: RVR/EVR from phase 2
study of boceprevir plus PegintronTM (peginterferon alfa-2b)/Ribavirin in
treatment-nave subject with genotype-1 CHC [abstract]. Presented at the
43rd Annual Meeting of the European Association for the Study of the
Liver, Milan, Italy.
Lavanchy, D. (2009). The global burden of hepatitis C. Liver International, 29,
7481.
Lawitz, E. J., Zaman, A., Muir, A. J., Shiffman, M. L., Yoffe, B., Zhang, T., . . .
Hausman, D.F. (2008). Interim results from a phase 1b dose-escalation
study of 4 weeks of PEG-interferon lambda (PEG-RIL-29) treatment in
subjects with hepatitis C virus (HCV) genotype 1 with prior virologic
response and relapse to peginterferon alfa and ribavirin. Hepatology 48,
385A.
Leevy, C. B. (2008). Consensus interferon and ribavirin in patients with
chronic hepatitis C who were nonresponders to pegylated interferon
alfa-2b and ribavirin. Digestive Diseases and Sciences, 53, 19611966.
Maddock, C., Baita, A., Orru, M. G., Sitzia, R., Costa, A., Muntoni, E., . . .
Pariante, C.M. (2004). Psychopharmacological treatment of depression,
anxiety, irritability and insomnia in patients receiving interferon-: A
prospective case series and a discussion of biological mechanisms. Journal of
Psychopharmacology, 18, 4146.
Maddock, C., Landau, S., Barry, K., Maulayah, P., Hotopf, M., Cleare, A. J., . . .
Pariante, C.M. (2005). Psychopathological symptoms during interferon-
and ribavirin treatment: Effects on virologic response. Molecular Psychiatry,
10, 332333.
419
Mangia, A., Minerva, N., Bacca, D., Cozzolongo, R., Ricci, G. L., Carretta, V.,
. . . Andriulli, A. (2008). Individualized treatment duration for hepatitis C
genotype 1 patients: A randomized controlled trial. Hepatology, 47,
4350.
Mangia, A., Santoro, R., Minerva, N., Ricci, G. L., Carretta, V., Persico, M., . . .
Andriulli, A . (2005). Peginterferon alfa-2b and ribavirin for 12 vs. 24
weeks in HCV genotype 2 or 3. New England Journal of Medicine, 352,
26092617.
Manns, M. P., McHutchison, J. G., Gordon, S. C., Rustgi, V. K., Shiffman, M.,
Reindollar, R., . . . Albrecht, J.K. (2001). Peginterferon alfa-2b plus ribavirin
compared with interferon alfa-2b plus ribavirin for initial treatment of
chronic hepatitis C: A randomised trial. Lancet, 358, 958965.
Maylin, S., Martinot-Peignoux, M., Moucari, R., Boyer, N., Ripault, M. P.,
Cazals-Hatem, D., . . . Marcellin, P. (2008). Eradication of hepatitis C virus
in patients successfully treated for chronic hepatitis C. Gastroenterology, 135,
821829.
McHutchison, J. G., Bartenschlager, R., Patel, K., & Pawlotsky, J.-M. (2006).
The face of future hepatitis C antiviral drug development: Recent biological
and virologic advances and their translation to drug development and
clinical practice. Journal of Hepatology, 44, 411421.
McHutchison, J. G., Everson, G. T., Gordon, S. C., Jacobson, I. M., Sulkowski,
M., Kauffman, R., . . . Muir, A.J. (2009a). Telaprevir with peginterferon and
ribavirin for chronic HCV genotype 1 infection. New England Journal of
Medicine, 360, 18271838.
McHutchison, J. G., Lawitz, E. J., Shiffman, M. L., Muir, A. J., Galler, G. W.,
McCone, J., . . . Sulkowski, M.S. (2009b). Peginterferon alfa-2b or alfa-2a
with ribavarin for treatment of hepatitis C infection. New England Journal of
Medicine, 361, 580593.
McHutchison, J. G., Manns, M., Patel, K., Poynard, T., Lindsay, K. L., Trepo,
C., . . . Albrecht, J.K. (2002). Adherence to combination therapy enhances
sustained response in genotype-1-infected patients with chronic hepatitis
C. Gastroenterology, 123, 10611069.
Muir, A. J., Bornstein, J. D., Killenberg, P. G., & the Atlantic Coast Hepatitis
Treatment Group. (2004). Peginterferon alfa-2b and ribavirin for the
treatment of chronic hepatitis C in blacks and non-Hispanic whites. New
England Journal of Medicine, 350, 22652271.
Muir, A. J., & McHutchison, J. G. (2006). Growth factors during HCV therapy
may be cost-effective, but are they effective? Hepatology, 44,
14001403.
Nader, F., Bai, C., Terra, K., Gurung, C., Srishord, M., Fang, Y., . . . Younossi, Z.
M. (2007). The use of growth factors (GF) in the re-treatment of patients
with chronic hepatitis C (CHC) who are previous non responders (NR) to
combination therapy. Presented at the 42nd Annual Meeting of the
European Association for the Study of the Liver, Barcelona, Spain.
National Institute of Diabetes and Digestive and Kidney Diseases. (2006).
Chronic hepatitis C: current disease management. National Digestive Diseases
Information Clearinghouse. Retrieved March 16, 2009, from
http://digestive.niddk.nih.gov/ddiseases/pubs/chronichepc/index.htm
Ong, J. P., & Younossi, Z. M. (2004). Managing the hematologic side effects of
antiviral therapy for chronic hepatitis C: Anemia, neutropenia, and
thrombocytopenia. Cleveland Clinic Journal of Medicine, 71, S17S21.
Pearlman, B. L., Ehleben, C., & Saifee, S. (2007). Treatment extension to 72
weeks of peginterferon and ribavirin in hepatitis C genotype 1-infected
slow responders. Hepatology, 46, 16881694.
Poynard, T., Yuen, M.-F., Ratziu, V., & Lai, C. L. (2003). Viral hepatitis C.
Lancet, 362, 20952100.
Raison, C. L., Borisov, A. S., Broadwell, S. D., Capuron, L., Woolwine, B. J.,
Jacobson, I. M., . . . Miller, A.H. (2005a). Depression during pegylated
interferon-alpha plus ribavirin therapy: Prevalence and prediction. Journal
of Clinical Psychiatry, 66, 4148.
Raison, C. L., Broadwell, S. D., Borisov, A. S., Manatunga, A. K., Capuron, L.,
420