A SUPPLEMENT TO€¦ · SEPTEMBER 2003 • FEDERAL PRACTITIONER SUPPLEMENT • 1 T his supplement to Federal Practi- tioner contains the fifth version of the VA Treatment Recommen-

A SUPPLEMENT TO

This supplement to Federal Practitioner was supported by an unrestricted educational grant from Amgen Inc.

VA TREATMENTRECOMMENDATIONS

(VERSION 5.0)

VA TREATMENTRECOMMENDATIONS

(VERSION 5.0)

Patients withChronic

Hepatitis C

Patients withChronic

Hepatitis C

VOL. 20 SUPPL. 5

Copyright © 2003. Quadrant HealthCom Inc. All rights reserved.

SEPTEMBER 2003 • FEDERAL PRACTITIONER SUPPLEMENT • 1

This supplement to Federal Practi-tioner contains the fifth version

of the VA Treatment Recommen-dations for Patients with Chronic Hepati-tis C. The VA has more experience with

hepatitis C than any other U.S. health

system. Some 180,000 veterans with

hepatitis C virus (HCV) infection were

cared for by the VA in fiscal year 2002.

These recommendations were pre-

pared by experts from the VA’s National

Hepatitis C Program, Hepatitis C Re-

source Centers, and Hepatitis C Techni-

cal Advisory Group. The first version

was developed after the 1997 National

Institutes of Health (NIH) Consensus

Development Conference on hepatitis C.

This latest version includes the newest

FDA-approved HCV therapies and re-

flects the June 2002 NIH Consensus

Statement. The recommendations are

the result of an extensive review of pub-

lished data; CDC recommendations for

identifying, counseling, testing, and re-

ferring people at risk for HCV infection;

and input from thought leaders in-

volved in the care of veterans with HCV

infection.

Within this supplement, the recom-

mendations have been edited for

length, clarity, and journal style (in-

cluding the substitution of generic

names for trade names) by the edi-

tors of Federal Practitioner. This sup-

plement to Federal Practitioner was

prepared and produced with funding

assistance from the VA, and the VA

reviewed the final version. No fund-

ing was obtained from any pharma-

ceutical company or other private

corporation.

The opinions expressed in this sup-

plement are those of the recommenda-

tions’ authors and do not necessarily

represent the views of Federal Practi-tioner or Quadrant HealthCom Inc.

Please review complete prescribing in-

formation for specific drugs or drug

combinations—including indications,

contraindications, warnings, and ad-

verse effects—before administering

pharmacologic therapy to patients.

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2 • FEDERAL PRACTITIONER SUPPLEMENT • SEPTEMBER 2003

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CONTRIBUTORSVA National Hepatitis C Program of the Public Health Strategic Health Care Group:Michael Rigsby, MD (director), Jane Burgess, ACRN, MS, Victoria Davey, RN, MPH, Connie Raab, and Lawrence R. Deyton, MSPH, MD (chief consultant); VA Hepatitis C Resource Centers: Teresa L. Wright, MD, Helen Yee, PharmD, Samuel B. Ho, MD,Guadalupe Garcia-Tsao, MD, and Jason A. Dominitz, MD, MHS; and the VA Hepatitis CTechnical Advisory Group: Garth Austin, MD, PhD, Joseph Awad, MD, Edmund Bini,MD, FACP, FACG, Lynn Bradley, PA, Robert Dufour, MD, Judith Feldman, MD, MPH,Katherine P. Frandsen, RN, CIC, Curt Hagedorn, MD, Rhonda Jankovich, RN, BSN, KarenJones, Linda Jones, MSN-RN, Stephen Kendall, Daniel Kivlahan, PhD, Kathy Lockhart,RN, MSN, MPA, Thomas Mahl, MD, Robert McNamara, Shvawn McPherson-Baker, PhD,Timothy Morgan, MD, Linda Rabeneck, MD, David Rimland, MD, Gary Roselle, MD,Hugo Rosen, MD, Kimberly Summers, PhD, and Michael Valentino, RPh.

Dr. Wright has led development of the treatment recommendations since their incep-tion. She and Dr. Yee are the lead authors of this version.


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6 INTRODUCTION

7 SELECTING PATIENTS FOR TREATMENT

7 Patients in Whom Treatment is Clearly Indicated

7 HISTOLOGICALLY MODERATE DISEASE OR COMPENSATEDCIRRHOSIS

7 Patients in Whom Treatment Benefits are Not as Well Documented

7 HISTOLOGICALLY MILD DISEASE

8 PERSISTENTLY NORMAL SERUM ALT

8 AGE > 60 OR SIGNIFICANT NONHEPATIC DISEASE

8 HISTORY OF SOLID ORGAN TRANSPLANTATION

9 HCV-HIV COINFECTION

9 ACUTE HEPATITIS C

9 ACTIVE INJECTION DRUG USE WITH HISTOLOGICALLYMODERATE DISEASE OR COMPENSATED CIRRHOSIS

9 ONGOING ALCOHOL USE WITH HISTOLOGICALLY MODERATEDISEASE OR COMPENSATED CIRRHOSIS

10 COMPLICATIONS OF CIRRHOSIS

VA TREATMENT RECOMMENDATIONS (VERSION 5.0)

Patients with Chronic Hepatitis C

Continued on next page


10 PRETREATMENT ASSESSMENTS

10 Evidence of Liver Disease

10 Laboratory Testing

10 Psychiatric Assessment

11 Substance Use

12 Adherence

12 Autoimmune Disorders

13 Hepatitis A and B Immunizations

13 Other Causes of Liver Disease

13 Pregnancy

13 Ocular Function

13 Liver Disease Staging

13 ANTIVIRAL THERAPIES

13 Definition of Response

14 Therapy for Treatment-Naïve Patients

14 PEGYLATED IFNS

19 STANDARD IFN

19 RIBAVIRIN IN COMBINATION WITH PEGYLATED ORSTANDARD IFN

20 PEGYLATED VERSUS STANDARD IFN COMBINATIONTHERAPY

21 MONOTHERAPY WITH PEGYLATED OR STANDARD IFN

22 SUMMARY

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23 Therapy for Previously Treated Patients

23 RELAPSERS OR NONRESPONDERS TO IFN MONOTHERAPY

23 RELAPSERS TO COMBINATION THERAPY WITH STANDARDIFN AND RIBAVIRIN

23 NONRESPONDERS TO COMBINATION THERAPY WITHSTANDARD IFN AND RIBAVIRIN

23 Monitoring Treatment Safety and Efficacy

23 MONITORING THERAPY

24 DOSE MODIFICATION

24 Treatment Duration

27 SUMMARY

27 POTENTIAL SUPPORTIVE THERAPY

27 Erythropoietin

28 Growth Factors for Neutropenia and Thrombocytopenia

28 SUMMARY OF CURRENT TREATMENT

RECOMMENDATIONS

28 Concluding Comments

29 REFERENCES

32 INDEX OF TABLES


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INTRODUCTIONHepatitis C virus (HCV) is an infection thatrarely resolves spontaneously. The prevalenceof HCV is approximately 1.8% in the generalU.S. population and is believed to be higher inveterans who use VA medical services. Peopleaged 40 to 59 years, which includes the agegroup of veterans who served during the Viet-nam era, have the highest prevalence of HCVinfection—and among this age group, theprevalence is greatest in blacks (6.1%).

After initial exposure to hepatitis C, HCVRNA is detectable in blood within one to threeweeks. By three months, antibodies to hepati-tis C are present in 90% of patients (Table 1).Approximately 85% of patients with acute in-fection eventually progress to chronic infec-tion, with the majority having evidence of liverdisease, such as elevated serum alanine amino-transferase (ALT) or abnormal liver histology.

Approximately 15% to 20% of patients withchronic HCV infection go on to develop cirrho-sis. The natural history of HCV is highly vari-able, however, with some patients advancing tocirrhosis within 15 years and others never pro-gressing this far.1 Nevertheless, HCV clearly islinked to advanced liver disease and has be-come the leading indication for liver transplan-tation in the VA. This, combined with the risingincidence of hepatocellular carcinoma (one ofthe most lethal complications of long-standing

HCV infection), demonstrates the need for ef-fective therapies for veterans with HCV.

Treatment of chronic HCV is aimed at slowing disease progression, preventing com-plications of cirrhosis, and treating any compli-cations that occur. For many patients,interferon (IFN)-based antiviral regimens re-sult in a sustained virologic response (SVR),which is defined as the eradication of viralreplication.

Approximately 50% of treated patients, how-ever, do not achieve an SVR with therapy, re-gardless of dose and duration of treatment.Patients also may be unwilling to undergo IFN-based HCV treatment, which must be adminis-tered parenterally and can have significantadverse effects. In view of these problems, it’simportant to determine which patients aremost likely to benefit from antiviral therapy.These patients include those at risk for pro-gressive liver disease and those whose chronicinfection has diminished their quality of life.

A substantial number of patients with HCVhave clinical conditions—particularly psychi-atric or substance use disorders2,3—that areconsidered contraindications to IFN treat-ment. Many of these contraindications arebased on limited data. Therefore, it’s possiblethat treatment options in these patients arebeing limited arbitrarily. More research isneeded to clarify appropriate therapeutic

Table 1

General Management Guidelines for Hepatitis C Virus (HCV) Infection

For all patients who test positive for HCV antibodies by enzyme-linked immunosorbentassay, management should include:• Diagnosis of chronic infection using appropriate laboratory tests for antibody

status or detection of viremia (see the VA Under Secretary for Health’s InformationLetter on Diagnostic Testing for Hepatitis C Virus)

• Prompt notification of test results with appropriate counseling• Education regarding factors that increase the risk of progressive liver injury (such as

alcohol or medications)• Counseling on modes of HCV transmission, including parenteral and sexual trans-

mission• Medical assessment regarding need for vaccination against hepatitis A and B• Testing for HIV infection• Evaluation for potential antiviral therapy

TABLE 1.


strategies in these and other patients not cur-rently considered candidates for treatment.

These treatment recommendations havebeen updated since the FDA approval of pegin-terferon alfa-2a (40 kD) and peginterferon alfa-2b (12 kD), as monotherapy and in combi-nation with ribavirin, and since the National In-stitutes of Health (NIH) Consensus Statementin June 2002. They are the result of an exten-sive review of published data; CDC recommen-dations for identifying, counseling, testing, andreferring people at risk for HCV infection; andinput from thought leaders involved in the careof veterans with HCV infection.4,5

SELECTING PATIENTS FOR TREATMENTAll patients with chronic HCV infection are po-tential candidates for therapy. Given limita-tions of current therapies, however, treatmentis recommended more clearly in some patientsthan in others. Treatment decisions should bemade on an individual basis with the patient,following discussions of the natural history ofHCV as well as the potential risks and benefitsof therapy.

A. Patients in Whom Treatment isClearly Indicated

1. HISTOLOGICALLY MODERATEDISEASE OR COMPENSATEDCIRRHOSISThe 2002 NIH Consensus Develop-ment Conference determined thattreatment is recommended for pa-tients with chronic HCV who are atgreatest risk for progression to cir-rhosis.4 These are patients with de-tectable serum HCV RNA and liverhistology showing hepatic fibrosis.Most patients in this group have per-sistently or intermittently elevatedALT values. Good response is achiev-able in patients with significant fibro-sis, including cirrhosis6–12—thoughpatients with bridging fibrosis or cir-rhosis appear to respond less well totherapy than those with minimal orno fibrosis.10,11

Data on treating patients withcompensated cirrhosis are derived

largely from subgroup analyses ofclinical trials; few prospective studieshave focused on this populationalone. Such patients are consideredcandidates for therapy, however, andimportant goals for treating them areto delay histologic disease progres-sion and prevent clinical complica-tions, both of which are beingevaluated in the NIH-sponsored Hep-atitis Antiviral Long-Term TreatmentAgainst Cirrhosis (HALT-C) trial.

In the veteran population, certainrelative contraindications to HCVtreatment are more common thanthey are in the general U.S. popula-tion. These include substance use dis-orders (for example, injection druguse or alcohol abuse) and psychiatricdisease. Given other clinical indi-cations, patients with a history ofsubstance abuse who have been sta-bilized with appropriate addictiontreatment are candidates for HCVtherapy.4 For example, patients tak-ing methadone for opioid depen-dence have been treated successfullywith antivirals for HCV.

When therapy is provided to pa-tients with a history of substance usedisorders, proactive steps should betaken to minimize the risk of relapse.Optimal treatment is providedthrough collaboration between thetreating physician, addiction special-ists, and mental health professionals.

B. Patients in Whom TreatmentBenefits are Not as Well Documented

Note: Given the inadequacy of data regardingthe benefits of treatment in the patientgroups discussed in this section, treatmentshould be conducted in the context of a clini-cal trial whenever possible.

1. HISTOLOGICALLY MILD DISEASEPatients in whom liver biopsydemonstrates grade 1 inflammationwithout evidence of fibrosis are atlow risk for progression to cirrhosis,

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n with most never developing ad-vanced liver disease. In such situa-tions, after a thorough discussion ofHCV natural history, prognosis, andtreatment options, the physician mayadvise observation without treat-ment. During observation, serum ALTshould be measured periodically andliver biopsy repeated in three to fiveyears, particularly if serum ALT ispersistently abnormal. If liver diseasehas progressed, treatment may be re-considered.

Treatment may be provided to pa-tients with mild liver disease whoseek intervention or who have signifi-cant extrahepatic HCV symptoms. Toavoid unnecessarily exposing pa-tients to the adverse effects of ther-apy, however, the risks and benefitsshould be discussed thoroughly witheach patient.

2. PERSISTENTLY NORMAL SERUM ALTApproximately 30% of patients withchronic HCV have persistently nor-mal serum ALT levels. This does notpreclude histologic evidence of liverinjury, but injury in these patientsgenerally is milder than that observedin patients with elevated ALT levels.

Factors influencing the decision totreat include:

• patient motivation, • age, • likelihood of response to

therapy, • severity of symptoms, • severity of comorbidities, and • presence of hepatic fibrosis.A liver biopsy may be necessary to

stage liver disease. Patients with min-imal or no fibrosis on liver biopsymay be reassured about their favor-able prognosis and may choose todefer therapy.4

The limited data that exist regard-ing response to IFN plus ribavirin inthis patient population suggest thatSVR is similar in patients with normalor mildly elevated serum ALT com-pared to those with clearly elevated

serum ALT.4 Studies of pegylated IFNplus ribavirin have not been com-pleted in this population. Since pa-tients with significant hepatic fibrosis(stage 2 or higher) may be at risk forprogressive liver disease, therapyshould be considered.

3. AGE > 60 OR SIGNIFICANTNONHEPATIC DISEASETreatment is not routinely indicatedin patients who are over the age of 60years or have significant nonhepaticdisease (such as symptomatic coro-nary artery disease, uncontrolled diabetes, renal insufficiency, or symp-tomatic chronic obstructive pul-monary disease). In these individuals,the reduced life expectancy from co-morbid conditions, as well as the po-tential for increased adverse effectsfrom HCV treatment, should be takeninto account when determining thepotential benefits of treatment. Inotherwise healthy patients, however,age over 60 years alone does not pre-clude treatment.

4. HISTORY OF SOLID ORGANTRANSPLANTATIONThere are limited data regarding therisks and benefits of HCV treatmentin patients who have undergone solidorgan transplantation. Preliminary re-sults on the efficacy of HCV treat-ment with IFN plus ribavirin or withpegylated IFN in liver allograft recipi-ents suggest that SVR rates are lowerin this population than in immuno-competent individuals.13,14

Due to a higher prevalence ofrenal insufficiency, transplant reci-pients exhibit less tolerability for ribavirin, which often leads to ri-bavirin-associated anemia. IFN iscontraindicated in recipients ofrenal or cardiac allografts becauseof an increased risk of severe allo-graft rejection. Since this risk islower in recipients of liver allografts,treatment can be administered inthis population.


5. HCV-HIV COINFECTIONAll patients with HIV should be testedfor and counseled about HCV. Con-versely, those with HCV infectionshould be offered HIV testing andcounseling. Patients infected withboth HIV and HCV appear to be athigher risk for liver disease progres-sion than those with HCV infectionalone. Therefore, HCV treatmentshould be considered seriously inthese individuals.15

To date, studies have enrolled onlypatients with stable HIV infection andwell compensated liver disease.4

Outcomes with standard or pegylatedIFN plus ribavirin are not yet well de-fined—though preliminary data sug-gest better responses to pegylatedIFN plus ribavirin than to standardIFN plus ribavirin.4

These patients may be less able totolerate ribavirin because of anti-retroviral-associated anemia. In ad-dition, lactic acidosis has been reported in patients receiving anti-retroviral therapy concurrent withribavirin therapy.16,17 This may be dueto interactions between ribavirin andHIV antiretrovirals, such as didano-sine and stavudine.

6. ACUTE HEPATITIS CAcute HCV infection rarely is recog-nized and diagnosed. Studies of treat-ment for acute HCV infection havebeen heterogeneous and limited bysuch factors as small sample size;lack of randomization; and differ-ences in dose, schedule of adminis-tration, endpoints, and follow-upduration.4,18 Although high SVRs havebeen reported in patients receivingIFN monotherapy, data guiding treat-ment recommendations are limited.

Some question the necessity oftreating acute HCV infection, sincecases can resolve spontaneously. Fur-thermore, the optimal treatment regi-men and timing in these patients areunknown.4,18 In the absence of suchdata, it seems appropriate to treat pa-

tients with acute HCV4—probablywith at least three months of combi-nation therapy.

7. ACTIVE INJECTION DRUG USE WITHHISTOLOGICALLY MODERATE DIS-EASE OR COMPENSATED CIRRHOSISPatients with prior or ongoing injec-tion drug use comprise the largestgroup of individuals with HCV in theUnited States. Successful treatmentof such patients has the potential notonly to benefit the individual but alsoto prevent transmission to others.

Results of a recent, small trial havedemonstrated the feasibility and ef-fectiveness of treating HCV in peoplewho recently used illicit injectiondrugs and were enrolled in a moni-tored drug treatment program for il-licit injection drug use.19 Thesefindings should be confirmed in othersettings or with larger populations,however, before the risks and bene-fits of treatment in this populationcan be evaluated fully.

If treatment of such patients is un-dertaken, it should be administeredwith close collaboration betweenHCV providers and substance abusespecialists.

8. ONGOING ALCOHOL USE WITHHISTOLOGICALLY MODERATE DIS-EASE OR COMPENSATED CIRRHOSISAlcohol is an important cofactor inthe progression of HCV disease to cir-rhosis and hepatocellular carcinoma,4

but a history of alcohol abuse is not acontraindication to therapy. Limiteddata suggest that heavy alcohol con-sumption of more than 80 g (approxi-mately eight drinks) per daycompromises response to HCV thera-pies, though the amount of alcoholintake that leads to this compromiseis unclear. Even less is known aboutthe effects of lower levels of alcoholconsumption on treatment response.4

Ideally, patients should be treated foractive alcohol use or abuse success-fully before beginning HCV therapy.

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9. COMPLICATIONS OF CIRRHOSISOnce patients develop clinical com-plications of cirrhosis (such as gas-troesophageal bleeding, ascites,encephalopathy, impaired hepaticsynthetic function, or hepatocellularcarcinoma), liver transplantation isthe treatment of choice. While fewprospective studies have been con-ducted in this population, there arelimited data on the outcomes of an-tiviral therapy.

Typically, patients with cirrhosishave reduced responses to treatmentand may be at risk for further hepaticdecompensation. Additionally, pa-tients with decompensated liver dis-ease are at risk for life threateninginfection—a risk that may be in-creased further with the administra-tion of IFN-based therapies. Evenwith low doses of IFN-based prepara-tions, cytopenias occur frequently,often precipitating dose reduction ortherapy discontinuation.

Consultation with a transplant hepatologist is recommended prior toinitiation of antiviral therapy. If treat-ment is undertaken, patients shouldhave the option of liver transplanta-tion available, whenever possible, inthe event that their clinical conditionworsens.

PRETREATMENT ASSESSMENTS All patients with confirmed, chronic HCV in-fection should be evaluated for antiviral ther-apy. Because of limitations in efficacy and thepotential for toxicity, each patient needs care-ful assessment of the relative risks and bene-fits of beginning therapy immediately, delayingtherapy until a later time, or deferring it indefi-nitely. The assessments described in this sec-tion should be performed in all patients as partof the pretreatment evaluation (Table 2).

A. Evidence of Liver DiseaseAll patients treated for HCV must haveevidence of associated liver disease (ab-normal transaminase levels or histologicevidence of liver damage) with preservedhepatic synthetic function as indicated by

a normal or near normal serum albumin,direct serum bilirubin, and normal pro-thrombin time, unless abnormalities inthese test results can be explained byconditions other than liver disease.

B. Laboratory Testing• A platelet count of more than 75 ×

109/L and an absolute neutrophilcount of over 1.5 × 109/L are neces-sary for patients to tolerate therapy.Patients with lower counts may begintherapy but typically require dose reductions.

• Patients receiving ribavirin mustdemonstrate adequate hemoglobin(Hb) (over 13 g/dL for men and over12 g/dL for women) and normal renalfunction (creatinine less than 1.5mg/dL).

• Baseline viral load must be estab-lished using a quantitative HCV RNAassay. Information regarding the viralload may aid in counseling patientsas to their likelihood of response. Patients should be counseled thatpeople with initially low viral loads(generally defined as less than800,000 IU/L) are more likely to re-spond to treatment than are thosewith initially high viral loads (greaterthan 800,000 IU/L). There is no ab-solute predictor of response based onHCV RNA level, however. For consis-tency, the same quantitative assayshould be used to evaluate change inviral load throughout the course oftherapy. Conversion rates of commonquantitative HCV RNA assays fromcopies/mL to IU/L are not linear andshould be used only to approximate acalculated conversion (Table 3).

• Patients should be tested for infectingHCV genotype, which is an importantpredictor of SVR for all treatment regi-mens (see “Antiviral Treatment” onpage 13) and a key factor in determin-ing treatment duration.

C. Psychiatric AssessmentAll patients should be evaluated for psy-chiatric disorders, particularly depression


and suicide risk. Uncontrolled depressionis an absolute contraindication to IFN-based therapies (Table 4). Psychiatric dis-orders in remission or stabilized withtreatment are not contraindications, buttheir presence usually necessitates in-

volvement of a mental health professionalduring antiviral therapy.

D. Substance UseAll patients should be evaluated carefullyfor current substance use disorders using

Table 1.

Pretreatment Assessments

NECESSARY

• Medical history, including complications of liver disease, presence of significant extrahepatic disease, and symptoms of chronic HCV that may diminish quality of life

• Psychiatric history, including past or ongoing psychiatric and substance use disorders

• Previous antiviral therapies and response• Biochemical markers of liver injury and assessment of hepatic synthetic function,

including serum ALT, serum albumin, serum bilirubin (particularly direct bilirubin),and prothrombin time

• Hb, Hct, WBC with differential, and platelet count• TSH• Serum glucose or HbA1C in diabetics• Pregnancy test (necessary for women with childbearing potential)• Serum HBsAg • HIV serology• Quantitative HCV RNA measurement by PCR or bDNA• HCV genotype• Anti-HBc (total), anti-HBs, anti-HAV (total)• ECG in patients with preexisting cardiac disease• Screening for depression and alcohol use*• Eye exam for retinopathy in patients with diabetes or hypertension

HIGHLY RECOMMENDED

• Liver biopsy to stage the severity of liver disease (especially in patients with genotype 1 infection)

• Serum ferritin and serum ANA• Urine toxicology screen for opiates, cocaine, and amphetamines

Abbreviations: ALT = alanine aminotransferase; ANA = antinuclear antibody; anti-HAV = antibody to thehepatitis A virus; anti-HBc = antibody to the hepatitis B core antigen; anti-HBs = antibody to the hepatitis Bsurface antigen; bDNA = branched DNA amplification; ECG = electrocardiogram; Hb = hemoglobin; HbA1C =glycosylated hemoglobin; HBsAg = hepatitis B surface antigen; Hct = hematocrit; HCV = hepatitis C virus; PCR= polymerase chain reaction; TSH = thyroid-stimulating hormone; WBC = white blood cell count. *Validatedscreening instruments for depression and alcohol use are available online at: www.oqp.med.va.gov/cpg/MDD/MDD_cpg/content/appendices/mdd_app1_fr.htm and www.oqp.med.va.gov/cpg/SUD/SUD_CPG/ModuleA/frameset.htm, respectively.

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validated screening instruments.20 Thepresence of current heavy alcohol use(more than 14 drinks per week for menor more than seven drinks per week forwomen), binge alcohol use (more thanfour drinks per occasion at least once amonth),21 or active illicit injection druguse requires referral to an addiction spe-cialist prior to treatment initiation. Sincethe use of illicit noninjection drugs theo-retically may pose an obstacle to treat-ment adherence, each case should beevaluated individually. Establishing ab-stinence prior to initiating treatment isrecommended. Urine toxicology for in-jectable drugs (such as opiates, cocaine,or amphetamines) may be used to sup-plement patients’ self-reports.

Patients with substance use disorderswho have been stabilized with substanceabuse treatment are candidates for antivi-ral HCV therapy. If there is concern aboutrecidivation due to the adverse effects oftherapy, HCV treatment may be deferred.Antiviral therapy should be initiated in pa-tients with substance use disorders thatare in full remission. These patients mayrequire additional monitoring and care co-ordination by addiction specialists.

E. AdherencePatients’ ability to adhere to treatmentshould be assessed. Evidence of prior

nonadherence to medical, psychiatric, oraddiction therapies are markers of likelynonadherence to HCV therapies. The de-cision to treat also should be based onpatients’ willingness to make necessarylifestyle changes, their adherence to thepretreatment evaluation instructions, theavailability of social support systems, andthe presence of an adequate environmentfor storage and administration of IFN.

F. Autoimmune DisordersPatients with stable or controlled autoim-mune thyroid disease (with replacementtherapy if necessary), diabetes (with nor-mal or near normal serum glycosylatedHb [HbA1C]), psoriasis, rheumatoid arthri-tis, or other autoimmune diseases can betreated for HCV infection. Because IFNcan aggravate underlying autoimmunedisorders, however, these patients shouldbe monitored closely for signs of worsen-ing disease.

Patients should be evaluated for co-existing autoimmune liver disease usinga serum antinuclear antibody (ANA)test. If ANA is present in high titer, HCVtreatment should be administered withcaution. In the absence of other clinicalevidence of autoimmune disease, evenhigh titers of detectable serum antinu-clear antibody do not preclude HCVtherapy.

Table 1.

Comparison of HCV RNA Quantitative Assays

ASSAY APPROXIMATE COPIES/mL = 1 IU/L

Abbott LCX HCV-RNA* 3.8

Bayer bDNA 3.0† 5.2

NGI Superquant‡ 3.4

Roche Amplicor Monitor 2.0§ 2.4

Abbreviations: bDNA = branched DNA amplification; HCV = hepatitis C virus. *Abbott Laboratories, AbbottPark, IL. †Bayer Diagnostics, Tarrytown, NY. ‡National Genetics Institute, Los Angeles, CA. §Roche MolecularSystems Inc., Branchburg, NJ.

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G. Hepatitis A and B ImmunizationsPatients should be tested for hepatitis Bsurface antigen, antibodies to the hepati-tis B core antigen, antibodies to the hepa-titis B surface antigen, and antibodies tothe hepatitis A virus to evaluate the needfor hepatitis immunization.

H. Other Causes of Liver DiseaseSerum ferritin should be obtained to eval-uate patients for hemochromatosis, atreatable liver disease.

I. PregnancyA pregnancy test should be obtainedfrom women of childbearing age prior tothe initiation of HCV treatment.

J. Ocular FunctionA baseline ophthalmic exam should beperformed in patients with retinal diseaserisk factors (such as hypertension or dia-betes) to help identify any disease thatmight be worsened by ribavirin or IFN.

K. Liver Disease Staging Liver biopsy is the best method for deter-

mining the severity of liver injury (that is,degree of fibrosis or stage of disease).1 Italso may be helpful in excluding othercauses of liver disease.

SVR rates are high (70% to 80%) in pa-tients with genotype 2 or 3 HCV infectionwho receive antiviral treatment. For thisreason, the provider and patient maychoose to initiate therapy regardless ofthe severity of liver disease. In suchcases, the findings of liver biopsy maynot influence the treatment decision.

ANTIVIRAL TREATMENT

A. Definition of ResponseTreatment efficacy is measured bio-chemically (by normalization of serumALT), virologically (by undetectableserum HCV RNA), and histologically (byreduction in liver inflammation or fibro-sis on posttreatment liver biopsy). Thetwo main endpoints for HCV treatmentare end-of-treatment response (ETR)and SVR, which are measured by the lev-els of HCV RNA at the completion oftherapy and six months later, respec-

Table 1.

Contraindications to HCV Therapy

• Life determining extrahepatic disease (malignancy, unstable angina, severe COPD)• Clinically decompensated liver disease*• Uncontrolled autoimmune disorders• Pregnancy or unwillingness to use adequate birth control• Documented serious nonadherence to prior medical treatment or failure to

complete HCV disease evaluation appointments and procedures• Inability to self-administer or to arrange appropriate administration of parenteral

medication • Severe uncontrolled psychiatric disease, particularly depression with current suicidal

risk• Recent illicit injection drug use without substance use disorder treatment• Ongoing alcohol abuse†

Abbreviations: COPD = chronic obstructive pulmonary disease; HCV = hepatitis C virus. *Select patients withclinically decompensated liver disease may be candidates for treatment. †Definitions of alcohol abuse in HCVare evolving and await further data. The National Institutes of Health Consensus Statement concluded,“Continued alcohol use during therapy adversely affects response to treatment, and alcohol abstinence isstrongly recommended before and during antiviral therapy.”4

TABLE 4.

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tively (Table 5). Biochemical and viro-logic improvements usually are associ-ated with histologic improvement. Sincehistologic changes themselves typicallyhave no effect on treatment decisions,posttreatment liver biopsies are not rou-tinely recommended.

Recently, data have been reportedregarding the utility of “on-treatmentresponse” or “early virologic response”(EVR), which is measured at 12 weeksafter treatment initiation. EVR is de-fined as undetectable HCV RNA or a 2log10 reduction in HCV RNA from thepretreatment value, and failure toachieve this outcome is a strong predic-tor of ultimate nonresponse.4,22 In onetrial, only 3% of the patients who failedto achieve an EVR had an SVR withcontinued therapy.11 Therefore, discon-tinuation of therapy may be appropri-ate in patients who have not achieved adecline in viral load.

EVR cannot be assessed adequately ifdifferent assays are used for baseline and12-week HCV-RNA measurements or ifthe baseline value is outside the range ofreliable quantification for the assay beingused.

B. Therapy for Treatment-NaïvePatientsThe current standard of care for treatingmost patients with chronic HCV infectionis a regimen of pegylated IFN plus ri-bavirin. There are small subgroups of pa-tients in whom the optimal therapyremains undefined and for whom stan-dard IFN plus ribavirin combination ther-

apy or pegylated IFN monotherapy maybe acceptable alternatives (Table 6).4

1. PEGYLATED IFNSPegylation of IFN, which entails link-ing the IFN to a molecule of polyeth-ylene glycol (PEG), reduces IFNclearance compared with the stan-dard formulation. Peginterferon alfa-2a (40 kD) and peginterferon alfa-2b(12 kD) are both FDA approved foruse as monotherapy and in combina-tion with ribavirin.8,9 While the IFNmolecules alfa-2a and alfa-2b are sim-ilar, there are differences in the sizeof the PEG molecule (40 kD versus12 kD) and in the way the two pro-teins are linked to PEG.

These differences alter thedrugs’ pharmacologic properties.By attaching a 12-kD PEG moietyto IFN alfa-2b, drug clearance is re-duced 10-fold and the molecule iseliminated both renally and hepati-cally.8,23 The clearance of peginter-feron alfa-2a is reduced 100-foldcompared with nonpegylated IFN,and the drug is eliminated primar-ily through the liver.9,24 Both pegy-lated IFNs are administered onceweekly—instead of three timesweekly, as is necessary with stan-dard IFN.

No direct comparison has beenmade between peginterferon alfa-2aand peginterferon alfa-2b, either asmonotherapies or in combination withribavirin. Therefore, no definitive con-clusions can be drawn regarding dif-

Table 1.

Endpoints for Chronic Hepatitis C Virus (HCV) Treatment

TIME POINT FOR ENDPOINT DEFINITION MEASURING HCV RNA

EVR Early virologic response 12 weeks after therapy initiation ETR End-of-treatment response Completion of therapy SVR Sustained virologic response Six months after completion of therapy

TABLE 5.


Table 1.

Antiviral Treatments for Chronic HCV*

TREATMENT RECOMMENDED DOSE MAJOR ADVERSE EFFECTS

Peginterferon • 180 µg SC once weekly regardless • Similar to IFNalfa-2a (40 kD) of weight • Higher reported rates of neutro-(Pegasys†) with • 135 µg SC once weekly if receiving penia and thrombocytopeniaribavirin hemodialysis compared to IFN alfa-2b9

• For ribavirin dose, see below • Lower reported rates of flulike symptoms and depression compared to IFN alfa-2b11

• See ribavirin adverse effects below

Peginterferon • 1.5 µg/kg SC once weekly in combination • Similar to IFNalfa-2b (12 kD) with ribavirin • Higher reported rates of neutro-(PEG-Intron‡) • 1.0 µg/kg SC once weekly as monotherapy penia, thrombocytopenia, andwith ribavirin • FDA-approved ribavirin dose: 800 mg injection site reactions

PO daily (in two divided doses); higher compared to IFN alfa-2b8

doses may be beneficial, however, in • See ribavirin adverse effectsgenotype 1 infection (see below) below

IFN alfa-2a • IFN alfa-2a: 3 million U SC three times • Flulike symptoms(Roferon-A†), weekly • Bone marrow suppressionIFN alfa-2b • IFN alfa-2b: 3 million U SC three times • Aggravation of autoimmune(Intron A‡), weekly disordersIFN alfacon-1 • IFN alfacon-1: 9 µg SC three times • Neuropsychiatric symptoms(Infergen§) weekly • Seizures

• Acute cardiac and renal failure• Retinopathy• Interstitial pulmonary fibrosis

IFN alfa-2b • IFN alfa-2b: 3 million U SC three • Adverse effects of IFNplus ribavirin times weekly • See ribavirin adverse effects (Rebetron‡) • Ribavirin: 1,000 mg PO daily if patient below

≤ 75 kg OR 1,200 mg PO daily if patient > 75 kg (in two divided doses)

Ribavirin • Genotype 1 patients: 1,000 mg PO • Hemolytic anemia(Rebetol,‡ daily if ≤ 75 kg OR 1,200 mg PO • Significant teratogen for bothCopegus†) used daily if > 75 kg (in two divided doses) men and womenin combination • Genotype 2 and 3 patients: 800 mg • Rasheswith pegylated PO daily (in two divided doses) • HeadachesIFN • Shortness of breath

• Gastrointestinal effects

Abbreviations: HCV = hepatitis c virus; IFN = interferon. *For more information on the agents discussed here, see the following product web sites: www.rocheusa.com/products/pegasys/pi.pdf, www.schering-plough.com/documents/24564746%20Peg-ntron8.5x11.pdf, www.spfiles.com/pirebetron.pdf, www.spfiles.com/pirebetol.pdf,and www.rocheusa.com/products/copegus/pi.pdf. †Roche, Nutley, NJ. ‡Schering-Plough, Kenilworth, NJ. §InterMune, Brisbane, CA.

TABLE 6.

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ferences in efficacy between thesetwo preparations.

Efficacy and adverse effects havebeen compared, however, between pegylated IFNs and standard IFN (in combination with ribavirin). Asmonotherapy, both peginterferon alfa-2a and alfa-2b produce superior treat-ment responses compared to standardIFN monotherapy but inferior re-sponses compared to standard IFNplus ribavirin.11,25,26 As with other IFN-based preparations, pegylated IFNshave produced lower SVR rates in pa-tients with genotype 1 infection than inthose with genotype 2 or 3 infection.

Peginterferon Alfa-2a Plus RibavirinA multinational, randomized trialcompared peginterferon alfa-2a

plus either placebo or ribavirin tostandard IFN plus ribavirin intreatment-naïve patients withchronic HCV (Table 7).11 SVR rateswere higher in patients receivingpeginterferon alfa-2a plus ribavirin(dosed at 1,000 mg/day for patientsweighing 75 kg or less or 1,200mg/day for those weighing over 75kg) compared to those receivingstandard IFN alfa-2b plus ribavirin.Both combination regimens weremore effective than peginterferonalfa-2a monotherapy.

Improved efficacy of peginter-feron alfa-2a plus ribavirin overstandard IFN plus ribavirin wasobserved in patients with geno-type 1, 2, or 3 HCV infection. Thedifference in treatment responsebetween peginterferon alfa-2a plus

Table 1.

Comparison of Reported Response Rates for Peginterferon Alfa-2a Combination Therapy, Peginterferon Alfa-2a Monotherapy,and Standard IFN Combination Therapy Given Over 48 Weeks11

SVR RATE*

PEGINTERFERON PEGINTERFERONALFA-2A (40 kD) ALFA-2A (40 kD)

PATIENT GROUP PLUS RIBAVIRIN† PLUS PLACEBO‡ IFN PLUS RIBAVIRIN§

Overall 56%|| 29% 44%

HCV genotype 1 46%¶ 21% 36%High viral titer**,†† 41% 13% 33%Low viral titer††,‡‡ 56% 39% 43%

HCV genotype 2 or 3 76%§§ 45% 61%High viral titer†† 74% 40% 58%Low viral titer†† 81% 58% 65%

Abbreviations: HCV = hepatitis C virus; IFN = interferon; SVR = sustained virologic response. *Reported SVRsfrom package insert are lower than those published by Fried et al.9 †Regimen: peginterferon alfa-2a 180µg/week plus ribavirin 1,000 or 1,200 mg/day for 48 weeks. ‡Regimen: peginterferon alfa-2a 180 µg/weekplus placebo for 48 weeks. §Regimen: IFN 3 million U three times weekly plus ribavirin 1,000 or 1,200 mg/dayfor 48 weeks. ||P < .001 compared to standard IFN plus ribavirin. ¶P = .01 compared to standard IFN plus riba-virin. **Defined as > 2 million copies/mL (COBAS AMPLICOR HCV Test, v. 2.0, sensitivity 100 copies/mL). ††Statistical analysis not performed. ‡‡Defined as ≤ 2 million copies/mL (COBAS AMPLICOR HCV Test, v. 2.0,sensitivity 100 copies/mL). §§P = .005 compared to standard IFN plus ribavirin.

TABLE 7.


ribavirin and standard IFN alfa-2bplus ribavirin was 12% overall: 10%for HCV genotype 1 and 15% forHCV genotypes 2 and 3. Patientswith bridging fibrosis and cirrhosisachieved SVR rates of 43% withpeginterferon alfa-2a plus ribavirinand 33% with standard IFN alfa-2bplus ribavirin (Table 8).11 Patientswith early-stage disease receivingpeginterferon alfa-2a with or with-out ribavirin generally achievedbetter results than those with either cirrhosis or transition to cirrhosis.11,27

Three independent factorswere associated with a favorableresponse to peginterferon alfa-2aplus ribavirin: genotype non-1,younger age (40 years oryounger), and lighter body weight(75 kg or less).11 Neutropenia andthrombocytopenia appear to begreater in patients receiving pegin-terferon alfa-2a plus ribavirincompared to those receiving stan-dard IFN plus ribavirin (Table 9).9

Incidence of flulike symptoms anddepression were lower in patientsreceiving peginterferon alfa-2a

plus ribavirin compared to thosereceiving standard IFN plus ri-bavirin (P = .02 for myalgia, P < .001 for pyrexia and rigors,and P = .01 for depression).11

The optimal ribavirin dose andtreatment duration with peginter-feron alfa-2a plus ribavirin appearto differ depending on the infect-ing genotype (Table 10).28 In pa-tients with genotype 1 infection,SVR was highest (51%) in patientsreceiving 48 weeks of peginter-feron alfa-2a plus ribavirin 1,000 or1,200 mg/day. In patients withgenotype 2 or 3 infection, SVRswere similar in all treatmentgroups regardless of treatment du-ration or ribavirin dose (SVRrange, 73% to 78%). Therefore, patients with genotype 2 or 3 in-fection can be treated with pegin-terferon alfa-2a in combinationwith ribavirin 800 mg/day for 24weeks.

Peginterferon Alfa-2b Plus RibavirinA randomized, multinational trialcompared peginterferon alfa-2b

Table 1.

Comparison of Reported Response Rates for Peginterferon Alfa-2aCombination Therapy, Peginterferon Alfa-2a Monotherapy, and Stan-dard IFN Combination Therapy, According to Level of Fibrosis11,29

SVR RATE (95% CONFIDENCE INTERVAL)

PEGINTERFERON PEGINTERFERONIFN ALFA-2B PLUS ALFA-2A (40 kD) ALFA-2A (40 kD)

PATIENT GROUP RIBAVIRIN* PLUS PLACEBO† PLUS RIBAVIRIN‡

Patients with bridging fibrosis and cirrhosis 33% (22%–47%) 21% (10%–37%) 43% (30%–56%)Patients with no fibrosis or portal fibrosis only 47% (42%–52%) 31% (25%–38%) 58% (53%–63%)

Abbreviations: IFN = interferon; SVR = sustained virologic response. *Regimen: IFN alfa-2b 3 million U threetimes weekly plus ribavirin 1,000 or 1,200 mg/day. †Regimen: peginterferon alfa-2a 180 µg once weekly plusplacebo. ‡Regimen: peginterferon alfa-2a 180 µg once weekly plus ribavirin 1,000 or 1,200 mg/day.

TABLE 8.

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plus ribavirin to standard IFN alfa-2b plus ribavirin in treatment-naïvepatients with chronic HCV (Table11).10 There was no difference inSVR rates between the lower doseof peginterferon alfa-2b (1.5 µg/kgonce weekly, reduced to 0.5 µg/kgonce weekly after four weeks) plusribavirin and standard IFN alfa-2bplus ribavirin.8,10 The difference intreatment response between pegin-terferon alfa-2b at the higher dose(1.5 µg/kg once weekly maintainedthroughout the course of therapy)plus ribavirin compared to stan-dard IFN alfa-2b plus ribavirin was7% overall and 9% for genotype 1.10

These higher SVR rates were ac-counted for largely by patientswith low viral loads. Among pa-tients with both genotype 1 infec-tion and a high viral load (over 2million copies/mL, or over 800,000IU/mL), the response rates weresimilar between those who re-ceived the higher dose of peginter-

feron alfa-2b plus ribavirin andthose who received standard IFNalfa-2b plus ribavirin (30% and 29%,respectively).8

Results in patients with early-stage disease were better thanthose in patients with bridging fi-brosis and cirrhosis (Table 12).10 In-dependent variables associatedwith a favorable response to treat-ment with peginterferon alfa-2bplus ribavirin included HCV geno-type non-1, low pretreatment HCVRNA level, lighter body weight,younger age, female gender, andabsence of bridging fibrosis or cirrhosis.10 Adverse effects—suchas neutropenia, thrombocytope-nia, and injection site reactions—appear to be greater in patients receiving peginterferon alfa-2b plusribavirin than in those receivingstandard IFN alfa plus ribavirin(Table 13).8,10

There has been much discus-sion about the appropriate dose of

Table 1.

Comparison of Reported Adverse Event Rates for Peginterferon Alfa-2a and Standard IFN Combination Therapies9

PEGINTERFERON ALFA-2A (40 kD) IFN ALFA-2B PLUSADVERSE EVENT PLUS RIBAVIRIN* (N = 451) RIBAVIRIN† (N = 443)

Injection site reaction 23% 16%Pyrexia 41% 55% Rigors 25% 37% Myalgia 40% 49% Neutropenia 27% 8% Anemia 11% 11% Thrombocytopenia 5% < 1% Depression 20% 28% Irritability/anxiety 33% 38% Nausea/vomiting 25% 29% Diarrhea 11% 10%

Abbreviation: IFN = interferon. *Regimen: peginterferon alfa-2a 180 µg once weekly plus ribavirin 1,000 or1,200 mg/day. †Regimen: IFN alfa-2b 3 million U three times weekly plus ribavirin 1,000 or 1,200 mg/day.

TABLE 9.


ribavirin administered in combina-tion with peginterferon alfa-2b. TheFDA-approved dose of 800 mg/dayis lower than that approved to beused in combination with standardIFN alfa-2b. Subsequent data fromtrials of peginterferon alfa-2a havesuggested that the 800-mg dailydose is sufficient for the treatmentof genotype 2 or 3 HCV infection,but that higher doses (1,000 or1,200 mg/day, based on bodyweight) are necessary for effectivetreatment of genotype 1 HCV infection (see “Ribavirin in Combi-nation with Pegylated or StandardIFN” on this page).28

Note: Several of the recommendations inthis document are derived from data gen-erated with pegylated IFN alfa-2a plusribavirin. Comparable data currently donot exist in patients receiving pegylatedIFN alfa-2b plus ribavirin. These includerecommendations for:• treatment duration for patients with

genotype 2 or 3 HCV infection;• use of a 12-week rather than a 24-

week time point for EVR; and• ribavirin dosing of 1,000 mg/day for

patients with genotype 1 HCV infec-tion who weigh 75 kg or less, 1,200mg/day for patients with genotype 1HCV infection who weigh over 75 kg,and 800 mg/day for patients withgenotype 2 or 3 HCV infection.

2. STANDARD IFNIFN alfa-2b plus ribavirin is more ef-fective than monotherapy with eitherpegylated or standard IFN (Table14).6,7,11 For patients who cannot tol-erate pegylated IFN, standard IFNalfa-2b plus ribavirin is an acceptablealternative (see “Pegylated VersusStandard IFN Combination Therapy”on next page).

3. RIBAVIRIN IN COMBINATION WITHPEGYLATED OR STANDARD IFNRibavirin is indicated for use inchronic HCV only when administered

Table 1.

Comparison of 24 and 48 Weeks of Peginterferon Alfa-2a Combination Therapy28

SVR RATE

24 WEEKS OF TREATMENT 48 WEEKS OF TREATMENT

RIBAVIRIN RIBAVIRIN 1,000 RIBAVIRIN RIBAVIRIN 1,000PATIENT GROUP 800 mg/DAY OR 1,200 mg/DAY 800 mg/DAY OR 1,200 mg/DAY

HCV genotype 1 29% 41% 40% 51%High viral titer* 16% 26% 35% 46%Low viral titer† 41% 51% 53% 61%

HCV genotype 2 or 3 78% 78% 73% 77%High viral titer 82% 79% 70% 77%Low viral titer 72% 77% 78% 77%

Abbreviations: HCV = hepatitis C virus; SVR = sustained virologic response. *Defined as > 2 million copies/mL(COBAS AMPLICOR HCV Test, v. 2.0, sensitivity 100 copies/mL). †Defined as ≤ 2 million copies/mL (COBAS AMPLICOR HCV Test, v. 2.0, sensitivity 100 copies/mL).

TABLE 10.

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in combination with IFN-basedpreparations.

The optimal dose of ribavirinneeded to achieve maximum efficacywith tolerable adverse effects in com-bination with pegylated IFN is underinvestigation. The ribavirin dose mostextensively studied with IFN alfa-2bis 1,000 mg/day for patients weighing75 kg or less or 1,200 mg/day for pa-tients over 75 kg, administered in twodivided doses.6,7,11,28 Results of a re-cent study indicate that for patientsinfected with HCV genotype 2 or 3,ribavirin 800 mg/day in combinationwith peginterferon alfa-2a is suffi-cient.28 In contrast, for genotype 1 pa-tients, 48 weeks of ribavirin at 1,000or 1,200 mg/day in combination withpeginterferon alfa-2a yielded higherSVR rates compared with lowerdoses of ribavirin and with shortertreatment durations. The incidence ofdose modifications due to anemia

was greater in patients receiving 48weeks of the higher ribavirin dose,compared to those receiving 48weeks of the lower dose.28

The ribavirin dose studied in thepeginterferon alfa-2b combination tri-als was 800 mg/day, independent ofweight or genotype.8,10 A retrospec-tive analysis of patients receivingpeginterferon alfa-2b 1.5 µg/kg onceweekly suggests that improved SVRwas associated with ribavirin dosesgreater than 10.6 mg/kg per day (orgreater than 795 mg/day for an aver-age 75-kg person).10 Prospective stud-ies of weight-based ribavirin dosingin combination with peginterferonalfa-2b are underway.

4. PEGYLATED VERSUS STANDARD IFNCOMBINATION THERAPYCompared to standard IFN, pegylatedIFN offers the convenience of onceweekly versus three times weekly

Table 1.

Comparison of Peginterferon Alfa-2b and Standard IFN Combination Therapies10

SVR RATE*

PEGINTERFERON ALFA-2B PATIENT GROUP (12 kD) PLUS RIBAVIRIN† IFN PLUS RIBAVIRIN‡

Overall 54%§ 47%

HCV genotype 1 42%|| 33%High viral titer¶,** 30% 29%Low viral titer†† Not reported Not reported

HCV genotypes 2 and 3 82% 79%

HCV genotypes 4–6 50% 38%

Abbreviations: HCV = hepatitis C virus; IFN = interferon; SVR = sustained virologic response. *Reported SVRsfrom package insert are lower than those published by Manns et al.8 †Regimen: peginterferon alfa-2b 1.5µg/kg once weekly plus ribavirin 800 mg/day for 48 weeks. ‡Regimen: IFN 3 million U three times weekly plusribavirin 1,000 or 1,200 mg/day for 48 weeks. §P = .01 compared to standard IFN plus ribavirin. ||P < .05 com-pared to standard IFN plus ribavirin. ¶Defined as > 2 million copies/mL (NGI, sensitivity 100 copies/mL). **Sta-tistical analysis not performed; data from Peg-Intron package insert.8 ††Defined as ≤ 2 million copies/mL (NGI,sensitivity 100 copies/mL).

TABLE 11.


dosing and superior response whenused in combination with ribavirin—especially in patients with genotype 1infection. Pegylated IFNs are associ-ated with a greater incidence of cy-topenias and injection site reactions,however, when compared with stan-dard IFN alfa-2b.8–12

Peginterferon alfa-2a plus ribavirinis associated with a lower incidenceof flulike symptoms and depressioncompared to standard IFN plus ri-bavirin.11 Without direct comparativestudies, and with differences in theanalyses of adverse effects betweenthe peginterferon alfa-2a and pegin-terferon alfa-2b combination therapytrials, it’s difficult to draw definitiveconclusions about safety differencesbetween peginterferon alfa-2a andpeginterferon alfa-2b when used incombination with ribavirin.10,11

The risks and benefits of both pegylated and standard IFNs in com-bination with ribavirin should be ex-plored fully prior to initiation oftherapy. For example, in patientswith compensated cirrhosis, particu-larly those who have leukopeniaprior to therapy, IFN alfa-2b mightbe preferred because of its shorterhalf-life and reduced likelihood of

cytopenias requiring dose reduc-tions.10,11,29

5. MONOTHERAPY WITH PEGYLATEDOR STANDARD IFNFor patients with contraindicationsto ribavirin, monotherapy with stan-dard or pegylated IFN should be considered.26,30 Pegylated IFN mono-therapy has been shown to be supe-rior to standard IFN monotherapy,and thus, there are few clinical cir-cumstances in which standard IFNremains indicated as monotherapy.

Indications for Monotherapywith IFN-Based Preparations

Contraindications to Ribavirin• Renal insufficiency or failure

(serum creatinine greater than1.5 mg/dL); pegylated IFNshould be used with cautionin patients with a creatinineclearance of less than 50mL/min, and a dose reductionmay be necessary8,9

• Anemia (baseline Hb less than13 g/dL for men or less than 12g/dL for women)

• History of thalassemia orother hemoglobinopathies,

Table 1.

Comparison of Peginterferon Alfa-2b and Standard IFN Combination Therapies, According to Level of Fibrosis10,29

SVR RATE (95% CONFIDENCE INTERVAL)

IFN ALFA-2B PEGINTERFERON ALFA-2B (12 kD)PATIENT GROUP PLUS RIBAVIRIN* PLUS RIBAVIRIN†

Patients with bridging fibrosis and cirrhosis 41% (33%–50%) 44% (36%–53%) Patients with no fibrosis or portal fibrosis only 49% (44%–54%) 57%‡ (51%–62%)

Abbreviations: IFN = interferon; SVR = sustained virologic response. *Regimen: IFN alfa-2b 3 million U threetimes weekly plus ribavirin 1,000 or 1,200 mg/day. †Regimen: peginterferon alfa-2b 1.5 µg/kg once weeklyplus ribavirin 800 mg/day. ‡P < .05 compared to standard IFN plus ribavirin.

TABLE 12.

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even in the absence of ane-mia, because of theoreticalrisk of precipitating profoundhemolysis

• Significant cardiac disease(arrhythmias, angina, coro-nary artery bypass surgery,myocardial infarction) in thepast 12 months

• Men and women who fail topractice adequate contracep-tion during the course of treat-ment and for six monthsfollowing treatment

Ribavirin IntolerabilityThe primary adverse effect of ri-bavirin is hemolytic anemia. Whilemost patients who develop thiscomplication respond to ribavirindose reductions, some are unableto maintain stable Hb levels withany exposure to the drug. Othersignificant adverse effects includenausea, vomiting, diarrhea, short-ness of breath, and rashes. If these

toxicities are intolerable, ribavirinmust be discontinued.

SUMMARYIn patients previously untreated for HCVinfection, the following regimens are rec-ommended:• Genotype 1: pegylated IFN plus ri-

bavirin 1,000 mg/day (in patientsweighing 75 kg or less) or 1,200mg/day (in patients weighing over 75kg) in two divided doses

• Genotype 2 or 3: pegylated IFN plusribavirin 800 mg/day in two divideddoses OR standard IFN plus ribavirin1,000 mg/day (in patients weighing 75kg or less) or 1,200 mg/day (in pa-tients weighing over 75 kg) in two di-vided doses

Treatment decisions should be individu-alized based on patient specifics and ad-verse effect profiles of the IFN-basedpreparations in combination with ri-bavirin. Treatment duration should be tai-lored according to the infecting genotype

Table 1.

Comparison of Reported Adverse Event Rates for PeginterferonAlfa-2b and Standard IFN Alfa-2b Combination Therapies8

PEGINTERFERON ALFA-2B (12 kD) IFN ALFA-2B PLUSADVERSE EVENT PLUS RIBAVIRIN* (N = 511) RIBAVIRIN† (N = 505)

Injection site reaction 75% 49% Pyrexia 46% 33% Rigors 48% 41% Myalgia 56% 50% Neutropenia 26% 14% Anemia 12% 17% Thrombocytopenia 5% 2% Depression 31% 34% Irritability/anxiety 47% 47% Nausea/vomiting 57% 45% Diarrhea 22% 17%

Abbreviation: IFN = interferon. *Regimen: peginterferon alfa-2b 1.5 µg/kg once weekly plus ribavirin 800mg/day. †Regimen: IFN alfa-2b 3 million U three times weekly plus ribavirin 1,000 or 1,200 mg/day.

TABLE 13.


and response to therapy (see “TreatmentDuration” on next page).

C. Therapy for Previously TreatedPatientsLimited data are available regardingtreatment of patients who had an initialresponse to previous HCV treatment fol-lowed by a loss of virologic response (re-lapsers) and those who were treatedpreviously but never attained a virologicresponse (nonresponders).

1. RELAPSERS OR NONRESPONDERS TOIFN MONOTHERAPYBoth IFN alfa-2b plus ribavirin ther-apy and IFN monotherapy are FDAapproved for treating relapsers toIFN monotherapy.31,32 Preliminarydata suggest that retreatment withpegylated IFN plus ribavirin results ina response of 20% to 25%, which mayjustify therapy.33 Since combinationtherapy has been the standard of careover the past five years, however, fewpatients currently being evaluated fortreatment have received standardIFN monotherapy.

2. RELAPSERS TO COMBINATIONTHERAPY WITH STANDARD IFN AND RIBAVIRINThere is insufficient data from clini-

cal trials to recommend retreatmentwith pegylated IFN plus ribavirin.Clinicians have observed a favorabletreatment response, however, insome of these patients.

3. NONRESPONDERS TO COMBINATIONTHERAPY WITH STANDARD IFNAND RIBAVIRINFurther treatment with pegylated IFNplus ribavirin resulted in an SVR ofonly about 15% to 20%. Risks andbenefits of retreatment should beevaluated on a case-by-case basis.4

The severity of underlying liver dis-ease, infecting genotype, and tolera-bility of prior treatment regimensshould be included in the decision toretreat.4 Maintenance therapy withpegylated IFN regimens aimed at in-ducing viral suppression and prevent-ing complications of liver disease isunder evaluation for this population.

D. Monitoring Treatment Safetyand Efficacy

1. MONITORING THERAPYPeriodic monitoring of such values asHb, hematocrit, white blood cellcount with differential, plateletcount, and serum AST/ALT is neces-sary in all patients receiving HCV an-

Table 1.

Comparison of 24 and 48 Weeks of IFN Monotherapy or Combi-nation Therapy7

IFN* PLUS PLACEBO IFN* PLUS RIBAVIRIN†

OUTCOME 24 WEEKS 48 WEEKS 24 WEEKS 48 WEEKS

Overall ETR 29% 24% 53% 50%Overall SVR 6% 13% 31% 38% Genotype 1 SVR 2% 7% 16% 28%Genotype non-1 SVR 16% 29% 69% 66%

Abbreviations: ETR = end-of-treatment response; IFN = interferon; SVR = sustained virologic response. *IFN dose: 3 million U three times weekly. †Ribavirin dose: 1,000 or 1,200 mg/day.

TABLE 14.

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ttiviral therapy (Table 15). Increasingthe frequency of these tests is ad-vised in patients with significant re-ductions in hematocrit, white bloodcell count, or platelet count or whohave experienced significant adverseevents, including psychiatric disease.Particular attention must be given tothe development of anemia in pa-tients receiving combination therapywith IFN-based preparations and ri-bavirin.

Additional recommendations formonitoring patients during HCV ther-apy include the following:• Evaluate patients for treatment-

related adverse effects at one- totwo-month intervals. Provideguidance in managing these ad-verse effects.

• Check serum ALT at month 1 andthen at two- to three-month inter-vals to monitor biochemical re-sponse.

• Measure HCV RNA by quantita-tive assay at 12 weeks to assessfor EVR. Consider discontinuingtreatment in patients who, at thispoint, have failed to achieve atleast a 2 log10 reduction in HCVRNA.4,28

• Measure HCV RNA by sensitiveassay (lower detection limit of nomore than 50 IU/mL) at the end oftherapy and six months later todetermine the presence and dura-bility of response.

• Evaluate patients for depressionat each clinic visit using a stan-dardized questionnaire, such asthe Beck Depression Inventory(BDI) or the Brief Symptom In-ventory (see Appendix 1 of theVA/DoD Clinical Practice Guide-line on the Management of MajorDepressive Disorder in Adults,available online at: www.oqp.med.va.gov/cpg/MDD/MDD_cpg/content/appendices/mdd_app1_fr.htm).34,35 Patients with BDIscores greater than 10 should beevaluated further for depression

by a mental health professionaland may be considered for antide-pressant treatment. Patients withpretreatment scores below clini-cal cutoffs also should receive aclinical evaluation by a mentalhealth professional if their depres-sion scores increase during treat-ment.

• Consider urine toxicology screen-ing in patients with a history of asubstance use disorder. Assess al-cohol intake and illicit drug usemonthly. Indications of relapsewarrant consultation with treat-ment specialists.

• Assess adherence to therapy atevery visit through patient inter-views and prescription reviews.

• To prevent HCV transmission, in-struct patients to refrain from do-nating blood, organs, tissue, orsemen. Strongly encourage pa-tients with multiple sexual part-ners to use safe sexual practices.Advise patients to avoid sharingrazors or toothbrushes.

• Measure thyroid function usingserum thyroid-stimulating hor-mone testing every six months.

• Instruct all patients to practice ad-equate contraception (barriercontraceptives plus at least oneother reliable form of contracep-tion) during therapy and for sixmonths afterward. The only ex-ception is patients who under-went surgical sterilization at leastone year prior.

• Consider monthly pregnancy teststo aid in timely decision making inthe event that a patient becomespregnant during or six monthsafter therapy.

2. DOSE MODIFICATIONSee Tables 16 and 17 on page 26.

E. Treatment DurationRecent data with peginterferon alfa-2a incombination with ribavirin at a dose of800 mg/day suggest that 24 weeks of


Monitoring Parameters for IFN-Based Preparations With or Without Ribavirin

PARAMETER INTERVAL COMMENTS

Hb, Hct, WBC with Week 1 or 2, week 4, then monthly See Tables 16 and 17 on next page fordifferential, platelet or bimonthly during therapy; dose modificationscount monthly intervals are recommended in

patients with values below the lower limit of normal

Serum ALT Month 1, then every two to three Monitor when performing other testsmonths

Pregnancy test Monthly during therapy and Patients receiving IFN plus ribavirin for six months after completing therapy and their partners should usetherapy effective contraception throughout

therapy and for six months afterward; if pregnancy occurs, therapy shouldbe discontinued and the pregnancymonitored closely

TSH Before treatment and at six and 12 If TSH becomes elevated, confirm resultmonths after therapy initiation and consider thyroid replacement therapy

HCV RNA by At 12 weeks after therapy initiation Consider discontinuing treatment inquantitative assay patients who remain viremic at 12 weeks

and who have not achieved at least a2 log10 reduction in viral load fromthe pretreatment level

HCV RNA by qualitative End of therapy and six months Essential for defining end-of-treatmentassay (minimum lower following the completion of therapy and posttreatment responselimit of detection of < 50 IU/mL)

Assessment for adverse At each routine visit Nonadherence impairs responseeffects and adherence

Depression screen At each routine visit For patients screening positive, consider antidepressant therapy or referral tomental health specialist

Substance abuse Monthly If positive, refer to addiction specialistassessment (history of alcohol, cocaine, opiate, or amphet-amine use)

Liver biopsy Baseline Repeat after baseline rarely needed (see “Definition of Response” on page 13)

Abbreviations: ALT = alanine aminotransferase; Hb = hemoglobin; Hct = hematocrit; HCV = hepatitis C virus;IFN = interferon; TSH = thyroid-stimulating hormone; WBC = white blood cell count.

TABLE 15.

Tre

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t


treatment is sufficient for patients withgenotype 2 or 3 HCV infection.28 For pa-tients with genotype 1 HCV infection,however, evidence supports continuing

treatment for 48 weeks with a higherdose of ribavirin (1,000 to 1,200 mg/day,based on body weight). It’s recom-mended that these ribavirin doses and

Table 1.

General Guidelines for Dose Reduction or Discontinuation of Pegylated or Standard IFN8,9

PARAMETER RECOMMENDATION

WBC< 1.5 x 109/L Reduce dose by 50% and reevaluate

< 1.0 x 109/L Discontinue until resolution and reevaluation

Neutrophils< 0.75 x 109/L Peginterferon alfa-2a: reduce dose by 25% and reevaluate;

peginterferon alfa-2b: reduce dose by 50% and reevaluate;standard IFN alfa: reduce dose by 50% and reevaluate

< 0.5 x 109/L Discontinue until resolution and reevaluation

Platelets< 80 x 109/L Peginterferon alfa-2b: reduce dose by 50% and reevaluate

< 50 x 109/L Peginterferon alfa-2a: reduce dose by 50% until resolutionand reevaluation; peginterferon alfa-2b: discontinue until resolution and reevaluation; standard IFN alfa: reduce by50% and reevaluate

< 25 x 109/L Peginterferon alfa-2a: discontinue until resolution and reevaluation; standard IFN alfa: discontinue until resolution and reevaluation

Abbreviations: IFN = interferon; WBC = white blood cell count.

TABLE 16.

Table 1.

General Guidelines for Dose Reduction or Discontinuation ofRibavirin8,9,*

PARAMETER RECOMMENDATION

Hb< 10.0 g/dL Decrease to 600 mg/day in two divided doses< 8.5 g/dL Discontinue until resolution and reevaluation

Abbreviation: Hb = hemoglobin. *In patients with stable underlying cardiac disease, it’s recommended thatribavirin be reduced to 600 mg/day for any 2-g/dL or greater drop in Hb over a four-week period. If the Hblevel is less than 12 g/dL after four weeks of dose reduction, discontinue ribavirin until resolution and reeval-uation.

TABLE 17.

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t


Su

pp

ortiv

eT

he

rap

ytherapy durations also be applied to pa-tients receiving peginterferon alfa-2bcombination therapy.

Patients receiving combination ther-apy with either standard or pegylatedIFN who have less than a 2 log10 dropfrom baseline HCV RNA levels after 12weeks of treatment rarely attain viraleradication with additional treatment.22

Therefore, treatment should be discon-tinued in these patients.

An exception to this is the patient witheither moderate fibrosis or cirrhosis whoappears to be benefiting in part fromtreatment (for example, serum ALT hasnormalized). Such patients clearly are inneed of therapy and may derive benefitfrom its continuation. The risks and ben-efits of treatment beyond one year for pa-tients who have not achieved viralclearance are under investigation.

SUMMARY• Treatment duration should be 48

weeks in patients with genotype 1 in-fection who have an EVR to standardor pegylated IFN in combination withribavirin.

• Treatment duration should be 24weeks in patients with genotype 2 or 3infection who have an EVR to stan-dard or pegylated IFN in combinationwith ribavirin.

• Treatment generally should be discon-tinued in patients who have failed toachieve an EVR by 12 weeks.

• In patients who have significant he-patic fibrosis (stage 3 or 4 disease),treatment beyond 12 weeks can beconsidered, even in the absence of anEVR, particularly if a reduction in viralload has been observed.

POTENTIAL SUPPORTIVE THERAPY

A. ErythropoietinThe kidneys produce the hormone ery-thropoietin to stimulate erythrocyte pro-duction. Recombinant erythropoietin isFDA approved for treating anemia in pa-tients taking zidovudine for HIV,36 patientswith nonmyeloid malignancies receiving

chemotherapy,37 patients with chronicrenal failure,38 and patients who are ane-mic prior to surgery and do not wish to betransfused.39 Although erythropoietin isnot approved for anemia associated withHCV therapy, some clinicians advocateusing it to treat the hemolytic anemia ob-served in patients receiving ribavirin forchronic HCV infection.

The mean Hb decrease in patients tak-ing ribavirin is 2 to 3 g/dL, a fall thatshould lead to a ribavirin dose reduction(see Table 17 on previous page). In con-trast to drug discontinuation, this reduc-tion appears to have only minor effectson therapeutic efficacy.22 If erythropoi-etin can improve treatment responsethrough its effects on ribavirin dosing, itseems that it would be most useful inpreventing discontinuation of ribavirin inpatients with profound hemolysis.

In one study, 17 patients taking IFNand ribavirin for chronic HCV infectionbecame anemic (median Hb decrease, 3.6g/dL) and were treated with recombinanterythropoietin 10,000 to 40,000 units SConce weekly.40 Of these patients, 14achieved a median Hb increase of 2.7g/dL and were able to continue IFN plusribavirin therapy. Fatigue and dyspnea ei-ther improved or resolved with erythro-poietin treatment.

In an open-label, multicenter study, 44patients taking IFN and ribavirin forchronic HCV infection became anemic(Hb less than 12 g/dL) during the first sixmonths of treatment. The patients wererandomized to receive either epoetin alfa(erythropoietin) 40,000 units SC onceweekly for up to 36 weeks or “standard ofcare” treatment (ribavirin dose reductionfor significant anemia). Epoetin alfa sig-nificantly increased Hb compared to stan-dard of care treatment (mean change, 2.5g/dL versus 0.3 g/dL). Alleviation of ri-bavirin-associated anemia also allowedfor higher doses of ribavirin in the epoetinalfa group than in the standard of caregroup (982 mg/day and 678 mg/day, re-spectively, at week 16; P = .003). Adverseevents were similar in both groups. Theauthors concluded that treatment with


Su

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ary

epoetin alfa was well tolerated and per-mitted the maintenance of “optimal” ri-bavirin dosing in most patients.41

The cost-effectiveness of erythropoi-etin therapy and the impact on responserates and quality of life remain to be de-termined. Until such data are available,the routine use of erythropoietin for pa-tients with chronic HCV who becomeanemic during treatment with IFN andribavirin cannot be recommended. Dosereduction of ribavirin remains the first in-tervention in such patients. Administra-tion of erythropoietin 40,000 units SConce weekly may benefit the subgroup ofpatients with severe symptomatic anemia(Hb below 10 g/dL) and those with per-sistent symptomatic anemia despite ri-bavirin dose reduction.

B. Growth Factors for Neutropeniaand ThrombocytopeniaIFN causes neutropenia and thrombocy-topenia by suppressing the bone marrowproduction of white blood cells andmegakaryocytes, respectively. Both ofthese cytopenias are more common inpatients receiving pegylated IFN than inthose receiving standard IFN. (For guid-ance in modifying standard or pegylatedIFN doses in patients who develop neu-tropenia or thrombocytopenia, see Ta-bles 16 and 17 on page 26.)

Granulocyte colony stimulating factor(G-CSF) and granulocyte macrophagecolony stimulating factor stimulate neu-trophil production and reduce infectiouscomplications. Both growth factors havebeen used to treat neutropenia in pa-tients infected with HIV and in those un-dergoing cancer chemotherapy.36,42

The limited data available on the useof recombinant G-CSF for managing IFN-induced neutropenia in chronic HCV dis-ease and in patients undergoing livertransplantation for HCV suggest that G-CSF increases white blood cell count andmay permit administration of full-doseIFN.43–48 Typical dosing of G-CSF is 300µg SC on Mondays and Thursdays.48 Thestudies of G-CSF have been small and un-controlled, however, and the treatment’s

efficacy, cost-effectiveness, and ability toimprove HCV treatment responses areunproven. Until such data are available,routine use of G-CSF cannot be recom-mended for patients with HCV who be-come neutropenic during IFN therapy.

Thrombopoietin stimulates the pro-duction of platelets in the blood. As liverdisease worsens, the liver producesthrombopoietin and serum levelsdecline.49 Recombinant thrombopoietinis commercially available for the treat-ment of thrombocytopenia in patients un-dergoing cancer chemotherapy.50 One invitro study has suggested that throm-bopoietin may be beneficial for treatingIFN-induced thrombocytopenia.51 Untilsafety and efficacy data are available,however, thrombopoietin cannot be rec-ommended for patients with HCV whobecome thrombocytopenic during IFNtherapy.

SUMMARY OF CURRENT TREATMENT RECOMMENDATIONSSee Table 18 on next page.

Concluding CommentsThrough continued HCV research, response totreatments should improve, adverse effectsshould be reduced, and populations for whomtreatment is appropriate should expand. Asthese advances occur, new recommendationswill be made.

Therapy should be provided to those indi-viduals who are most at risk for progressiveliver disease and to those whose quality of lifeis impaired by HCV infection—as long as theylack contraindications to therapy.

Prospective data are needed on the risksand benefits of treatment in veterans. Much ofthe data reviewed for these recommendationshave been derived from highly selected popu-lations in clinical trials. Extrapolation of out-comes to the general veteran population isproblematic.

Additionally, it’s essential that safe and ef-fective therapies be developed for those pa-tients who have been served inadequately;those with contraindications to treatmentwith IFN or ribavirin; and those in whomtreatment response is suboptimal. These in-


clude minority populations and patients whohave uncontrolled psychiatric disease, use il-licit injection drugs, have advanced and de-compensated HCV disease, are receivingdialysis for renal failure, experience difficultyadhering to injection regimens, or are coin-fected with HIV. These populations often areexcluded from currently available treatment.It’s likely that, for many, effective therapy willcome from drugs in development. Meanwhile,optimization of HCV treatment in veterans re-quires knowledge of current therapeutic op-tions, enhanced care delivery system, andongoing clinical and basic research to evaluate

the safety and efficacy of current and futuretreatments. �

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fibrosis progression in patients with chronic hepatitis C.The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRCgroups. Lancet. 1997;349:825–832.

2. Edlin BR, Seal KH, Lorvick J, et al. Is it justifiable to with-hold treatment for hepatitis C from illicit-drug users? N Engl J Med. 2001;345:211–215.

3. Ho SB, Nguyen H, Tetrick LL, Opitz GA, Basara ML,Dieperink E. Influence of psychiatric diagnoses on Inter-feron-alpha treatment for chronic hepatitis C in a veteranpopulation. Am J Gastroenterol. 2001;96:157–164.

4. National Institutes of Health Consensus Development

Table 1.

Summary of Current Treatment Recommendations

A. TREATMENT-NAÏVE PATIENTS

• Patients with genotype 1 HCV and no contraindications to ribavirin: Pegy-lated IFN weekly plus ribavirin 1,000 or 1,200 mg/day (in two divided doses) basedon body weight, with a decision to continue or withdraw therapy based on viro-logic response at 12 weeks. In patients with an EVR, treatment should be continuedfor a total of 48 weeks.

• Patients with genotype 2 or 3 HCV and no contraindications to ribavirin:Pegylated IFN weekly plus ribavirin 800 mg/day (in two divided doses) or standardIFN plus ribavirin 1,000 or 1,200 mg/day (in two divided doses) based on bodyweight, with a decision to continue or withdraw therapy based on virologic re-sponse at 12 weeks. In patients with an EVR, treatment should be continued for atotal of 24 weeks.

• Patients with contraindications to ribavirin: Pegylated IFN once weekly for 48weeks, with a decision to continue or withdraw therapy based on the virologic response at 12 weeks, regardless of the infecting genotype.

B. RELAPSERS OR NONRESPONDERS TO COMBINATION THERAPY WITH STANDARD ORPEGYLATED IFN PLUS RIBAVIRIN

• Relapsers to IFN alfa-2b plus ribavirin: There are no approved therapies for thispopulation. Retreatment with peginterferon plus ribavirin may be considered.

• Nonresponders to IFN alfa-2b plus ribavirin: There are no approved treat-ments for this population. Preliminary results suggest that retreatment with pegin-terferon plus ribavirin results in low SVR rates.4

• Relapsers or nonresponders to pegylated IFN plus ribavirin: There are no ap-proved therapies for this population. Treatment with experimental therapies in aclinical trial should be considered.

Abbreviations: EVR = early virologic response; HCV = hepatitis C virus; IFN = interferon; SVR = sustained viro-logic response.

TABLE 18.

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Conference Panel Statement: Management of hepatitis C:2002—June 10, 2002. Hepatology. 2002;36(5 Suppl1):S3–S20. Available at: www.consensus.nih.gov/cons/116/116cdc_intro.htm. Accessed July 14, 2003.

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interferon alfa2b plus ribavirin for 48 weeks or for 24weeks versus interferon alfa2b plus placebo for 48 weeksfor treatment of chronic infection with hepatitis C virus.International Hepatitis Interventional Therapy Group(IHIT). Lancet. 1998;352:1426–1432.

7. McHutchison JG, Gordon SC, Schiff ER, et al. Interferonalfa-2b alone or in combination with ribavirin as initialtreatment for chronic hepatitis C. International HepatitisInterventional Therapy Group. N Engl J Med. 1998;339:1485–1492.

8. Peg-Intron [package insert]. Kenilworth, NJ: ScheringCorporation; July 2002.

9. Pegasys [package insert]. Nutley, NJ: Hoffman-La RocheInc; December 2002.

10. Manns MP, McHutchison JG, Gordon SC, et al. Peginter-feron alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitisC: A randomized trial. Lancet. 2001;358:958–965.

11. Fried MW, Shiffman ML, Reddy RK, et al. Peginterferonalfa-2a plus ribavirin for chronic hepatitis C virus infec-tion. N Engl J Med. 2002;347:975–982.

12. Sylvestre DL. Treating hepatitis C in methadone mainte-nance patients: An interim analysis. Drug Alcohol

Depend. 2002;67:117–123.13. Everson GT, Trouillot T, Trotter J, et al. Treatment of de-

compensated currhotics with a slow-accelerating doseregimen (LADR) of interferon-alfa-2b plus ribavirin:Safety and efficacy [abstract]. Hepatology. 2000;32:308A.

14. Crippin JS, McCashland T, Terrault N, Sheiner P, CharltonMR. A pilot study of the tolerability and efficacy of antivi-ral therapy in hepatitis C virus-infected patients awaitingliver transplantation. Liver Transpl. 2002;8:350–355.

15. Benhamou Y, Bochet M, Di Martino V, et al. Liver fibrosisprogression in human immunodeficiency virus and hepa-titis C virus coinfected patients. The Multivirc Group. Hepatology. 1999;30:1054–1058.

16. Lafeuillade A, Hittinger G, Chadapaud S. Increased mito-chondrial toxicity with ribavirin in HIV/HCV coinfection.Lancet. 2001;357:280–281.

17. Salmon-Ceron D, Chauvelot-Moachon L, Abad S, Silber-mann B, Sogni P. Mitochondrial toxicity effects and ri-bavirin. Lancet 2001;357:1803–1804.

18. Jaeckel E, Cornberg M, Wedemeyer H, et al, and the Ger-man Acute Hepatitis C Therapy Group. Treatment ofacute hepatitis C with interferon alfa-2b. N Engl J Med.2001;345:1452–1457.

19. Backmund M, Meyer K, Von Zielonka M, Eichenlaub D.Treatment of hepatitis C infection in injection drug users.Hepatology. 2001;34:188–193.

20. Babor TF, Higgins-Biddle JC, Saunders JB, Monteiro M.AUDIT—The Alcohol Use Disorders Identification Test:

Guidelines for Use in Primary Care. 2nd ed. Geneva,Switzerland: World Health Organization, Department of

Mental Health and Substance Dependence; 2001. Avail-able at: www.who.int/substance_abuse/PDFfiles/auditbro.pdf. Accessed July 14, 2003.

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Physician’s Guide to Helping Patients with Alcohol

Problems. Bethesda, MD: National Institutes of Health;1995. NIH publication no. 95-3769.

22. Ferenci P, Shiffman ML, Fried MF, et al. Early predictionof response to 40 kDA Peginterferon alfa-2A (Pegasys®)plus ribavirin (RBV) in patients with chronic hepatitis C(CHC). Hepatology. 2001;34:351A.

23. Glue P, Fang J, Rouzier-Panis R, et al. Pegylated inter-feron-alpha2b: Pharmacokinetics, pharmacodynamics,safety, and preliminary efficacy data. Hepatitis C Interven-tion Therapy Group. Clin Pharmacol Ther. 2000;68:189A.

24. Algranati NE, Sy S, Modi M. A branched methoxy 40 kDapolyethylene glycol (PEG) moiety optimizes the pharma-cokinetics (PK) of peginterferon α-2a (PEG-IFN) and mayexplain its enhanced efficacy in chronic hepatitis C (CHC)[abstract]. Hepatology. 1999;30:190A. Abstract 120.

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2000;343:1666–1672.26. Lindsay K, Trepo C, Heintges T, et al, and the Hepatitis In-

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feron alfa-2a in patients with chronic hepatitis C and cir-rhosis. N Engl J Med. 2000;343:1673–1680.

28. Hadziyannis SJ, Cheinquer H, Morgan T, et al. Peginter-feron alfa-2a (40 kD) (Pegasys) in combination with ri-bavirin (RBV): Efficacy and safety results from a phaseIII, randomized, double-blind, multicentre study examin-ing effect of duration of treatment and RBV dose [ab-stract]. Presented at: 37th Annual Meeting of theEuropean Association for the Study of the Liver; April18–21, 2002; Madrid, Spain. Abstract 536.

29. Wright TL. Treatment of patients with hepatitis C and cir-rhosis. Hepatology. 2002;36(5):S185–S194.

30. Poynard T, Bedossa P, Chevallier M, et al. A comparisonof three interferon alfa-2b regimens for the long-termtreatment of chronic non-A, non-B hepatitis. MulticenterStudy Group [erratum in N Engl J Med. 1996;334:1143]. NEngl J Med. 1995;332:1457–1462.

31. Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon alfa-2b alone or in combination with ribavirin for the treat-ment of relapse of chronic hepatitis C. InternationalHepatitis Interventional Therapy Group. N Engl J Med.

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36. Scadden DT. Cytokine use in the management of HIV dis-ease. J Acquir Immune Defic Syndr Hum Retrovirol.

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treatment of anemic patients with hematological malig-nancies. Ann Hematol. 2001;80:319–329.

38. Richardson D, Bartlett C, Will EJ. Optimizing erythropoi-etin therapy in hemodialysis patients. Am J Kidney Dis.

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with iron supplementation to prevent allogeneic bloodtransfusion in total hip joint arthroplasty: A randomized,controlled trial. Ann Intern Med. 2000;133:845–854.

40. Sulkowski M, Wasserman R, Brooks L, et al. Changes inhemoglobin during therapy with interferon alfa-2b plusribavirin in IFNα-naïve and IFNα-experienced patients[abstract]. Presented at: 51st Annual Meeting of theAmerican Association for the Study of Liver Diseases;October 27–31, 2000; Dallas, TX. Abstract 834.

41. Weisz K, Kreiswirth S, McMeeking M, et al, and the Hepatitis Resource Network. Erythropoietin use for ri-bavirin/interferon induced anemia in patients with hepa-titis C [abstract]. Hepatology. 1998;28:288A.

42. Wasserman R, Brau N, Hassanein T et al. Once-weeklyepoetin alfa increases hemoglobin and decreases ri-bavirin dose reductions among HCV-infected patientswho develop anemia on ribavirin/interferon alfa-2b ther-apy [abstract]. Presented at: 51st Annual Meeting of theAmerican Association for the Study of Liver Diseases;October 27–31, 2000; Dallas, TX. Abstract 829.

43. Lorber C, Willfort A, Ohler L, et al. Granulocyte colony-stimulating factor (rh G-CSF) as an adjunct to interferon

alpha therapy of neutropenic patients with hairy cellleukemia. Ann Hematol. 1993;67:13–16.

44. Ishizone S, Makuuchi M, Kawasaki S, et al. Effect of gran-ulocyte colony-stimulating factor on neutropenia in livertransplant recipients with hypersplenism. J Pediatr

Surg. 1994;29:510–513.45. Rolando N, Clapperton M, Wade J, Wendon J. Adminis-

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tion treatment of advanced HCV associated liver diseasewith interferon and G-CSF. Hepatogastroenterology.

1995;42:907–912.47. Pardo M, Castillo I, Navas S, Carreno V. Treatment of

chronic hepatitis C with cirrhosis with recombinanthuman granulocyte colony-stimulating factor plus re-combinant interferon-alpha. J Med Virol. 1995;45:439–444.

48. Gopal DV, Rabkin JM, Berk BS, et al. Treatment of pro-gressive hepatitis C recurrence after liver transplantationwith combination interferon plus ribavirin. Liver

Transpl. 2001;7:181–190.49. Kawasaki T, Takeshita A, Souda K, et al. Serum throm-

bopoietin levels in patients with chronic hepatitis andliver cirrhosis. Am J Gastroenterol. 1999;94:1918–1922.

50. Vadhan-Raj S, Murray LJ, Bueso-Ramos C, et al. Stimula-tion of megakaryocyte and platelet production by a sin-gle dose of recombinant human thrombopoietin inpatients with cancer. Ann Intern Med. 1997;126:673–681.

51. Peck-Radosavljevic M, Wichlas M, Pidlich J, et al.Blunted thrombopoietin response to interferon alfa-induced thrombocytopenia during treatment for hepatitisC. Hepatology. 1998;28:1424–1429.

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Ind

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Ta

ble

sINDEX OF TABLESTable 1. General Management Guidelines for

Hepatitis C Virus (HCV) Infection. Page 6.

Table 2. Pretreatment Assessments. Page 11.

Table 3. Comparison of HCV RNA QuantitativeAssays. Page 12.

Table 4. Contraindications to HCV Therapy. Page 13.

Table 5. Endpoints for Chronic Hepatitis C Virus (HCV) Treatment. Page 14.

Table 6. Antiviral Treatments for Chronic HCV.Page 15.

Table 7. Comparison of Reported Response Rates for Peginterferon Alfa-2a Combina-tion Therapy, Peginterferon Alfa-2a Monotherapy, and Standard IFN Combination Therapy Given Over 48Weeks. Page 16.

Table 8. Comparison of Reported Response Rates for Peginterferon Alfa-2a Combination Therapy, Peginterferon Alfa-2a Monotherapy, and Standard IFN Combination Therapy, According to Level of Fibrosis. Page 17.

Table 9. Comparison of Reported Adverse Event Rates for Peginterferon Alfa-2a andStandard IFN Combination Therapies.Page 18.

Table 10. Comparison of 24 and 48 Weeks of Peginterferon Alfa-2a Combination Ther-apy. Page 19.

Table 11. Comparison of Peginterferon Alfa-2band Standard IFN Combination Therapies.Page 20.

Table 12. Comparison of Peginterferon Alfa-2b and Standard IFN Combination Therapies, According to Level of Fibrosis.Page 21.

Table 13. Comparison of Reported Adverse Event Rates for Peginterferon Alfa-2b andStandard IFN Alfa-2b Combination Thera-pies. Page 22.

Table 14. Comparison of 24 and 48 Weeks of IFN Monotherapy or Combination Ther-apy. Page 23.

Table 15. Monitoring Parameters for IFN-Based Preparations With or Without Ribavirin. Page 25.

Table 16. General Guidelines for Dose Reduc-tion or Discontinuation of Pegylated orStandard IFN. Page 26.

Table 17. General Guidelines for Dose Reduc-tion or Discontinuation of Ribavirin. Page26.

Table 18. Summary of Current Treatment Recommendations. Page 29.


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APRIL 2001 • FEDERAL PRACTITIONER SUPPLEMENT • VA1

This supplement to Federal Practitioner was supported by funding from the Public Health Strategic Health Care Group, Office of Public Health and Environmental Hazards, Veterans Health Administration, Department of Veterans Affairs.

Department of Veterans AffairsIB 10-169P95950September 2003

Documents

A SUPPLEMENT TO€¦ · SEPTEMBER 2003 • FEDERAL PRACTITIONER SUPPLEMENT • 1 T his supplement to Federal Practi- tioner contains the fifth version of the VA Treatment Recommen-