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Management and Treatment of Hepatitis C Viral Infection: Tables

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Management and Treatment of Hepatitis C Viral Infection

Hepatitis C Resource Center Program
National Hepatitis C Program Office

October 2006

Table 1. Grading System Adapted from the AASLD Practice Guidelines on the Diagnosis, Management, and Treatment of Hepatitis C (7)
GradeDefinition
IRandomized, controlled trials
II-1Controlled trials without randomization
II-2Cohort or case-control analytic studies
II-3Multiple time-series, dramatic uncontrolled experiments
IIIOpinions of respected authorities, descriptive epidemiology

Table 2. Pretreatment Assessments in Patients with Chronic HCV Infection

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
  • Screening for depression and alcohol use
  • Biochemical markers of liver injury and assessment of hepatic function, including ALT, albumin, bilirubin (particularly direct bilirubin), and prothrombin time
  • White blood cell counts with differential, hemoglobin, hematocrit, and platelets
  • Thyroid function tests
  • Serum creatinine
  • Serum glucose or glycosylated hemoglobin (HbA1c) in diabetics
  • Pregnancy test (in women of childbearing age)
  • HIV serology
  • Serum HBsAg, anti-HBc, anti-HBs, anti-HAV (total)
  • Quantitative HCV RNA measurement
  • HCV genotype
  • Previous antiviral therapies and response
  • Electrocardiogram in preexisting cardiac disease

HIGHLY RECOMMENDED

  • Liver biopsy to stage severity of liver disease (especially in HCV genotype 1 infection)
  • Eye exam for retinopathy in patients with diabetes or hypertension
  • Serum ferritin, iron saturation and serum ANA
  • Urine toxicology screen for opiates, cocaine, and amphetamines
ALT = alanine aminotransferase; HBsAg = hepatitis B surface antigen; anti-HBc = antibodies to hepatitis B core antigens; anti-HBs = antibodies to hepatitis B surface antigens; anti-HAV = antibodies to hepatitis A virus; ANA = antinuclear antibodies.

Table 3. Contraindications to HCV Therapy

  • Life-determining extrahepatic disease (malignancy, unstable angina, severe chronic obstructive pulmonary disease)
  • Clinically decompensated liver disease*
  • Uncontrolled autoimmune disorders
  • Pregnancy or planned pregnancy in a patient or the patient's sexual partner or unwillingness to use adequate birth control
  • Documented 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
  • Ongoing injection drug use
  • Ongoing alcohol abuse†
*Select patients with clinically decompensated liver disease may be candidates for treatment.
†NIH Consensus 2000 Statement concluded, "Continued alcohol use during therapy adversely affects response to treatment, and alcohol abstinence is strongly recommended before and during antiviral therapy."
Table 4. Monitoring Parameters for Interferon-Based Therapies With or Without Ribavirin
PARAMETERINTERVALCOMMENTS
ALT = alanine aminotransferase; ANC = absolute neutrophil counts; EVR = early virologic response; Hb = hemoglobin; Hct = hematocrit; WBC = white blood cell count.
WBC with differential, Hb, Hct, platelets, serum creatinineBefore treatment, week 1 or 2, week 4, then monthly or bimonthly during therapy or more frequently as indicated.Prior to therapy, acceptable hematological and biochemical indices: Hb ≥12 g/dL for men and ≥11 g/dL for women; ANC >1.5 k/mm3; platelets >70 k/mm3; serum creatinine <1.5 mg/dL; creatinine clearance >50 mL/min. See Table 8 and Table 9 for dose modifications.
Serum ALTBefore treatment, month 1, then every 1-2 monthsMonitor when performing other tests.
Pregnancy testBefore treatment, monthly during therapy and for 6 months after completing therapyPatients and their partners should use two forms of contraception throughout therapy and for 6 months afterwards; if pregnancy occurs, therapy should be discontinued and the pregnancy monitored closely.
Thyroid-stimulating hormone (TSH)Before treatment and at least every 12 wk during therapyIf TSH becomes elevated, confirm result and check a free thyroxine (T4) level; consider thyroid replacement therapy if indicated.
Blood glucoseBefore treatment and at least every 12 wk during therapyIf blood glucose is elevated, confirm result by checking glycosylated Hb. If elevated, consider starting insulin sensitizer.
HCV RNA by quantitative and/or qualitative assayBefore treatment, 4, 12, and 24 wk during therapy, at end-of-therapy, and 6 months following the completion of therapyConsider discontinuing treatment at 12 wk if <2 log10 reduction in pretreatment HCV RNA. If EVR is not achieved and treatment is continued, discontinue treatment if HCV RNA is detectable at 24 wk if the goal is viral eradication.

An assay with a minimum lower detection limit of HCV RNA <50 IU/mL should be used at 24 wk, end-of-therapy, and 6 months following completion of therapy.
Assess for adverse effects and adherenceAt each routine visitNonadherence impairs response.
Depression screenAt baseline and each routine visitFor patients screening positive, consider antidepressant therapy and/ or referral to mental health specialist.
Substance use assessment (history of alcohol, cocaine, opiate, heroin, or amphetamine use)At baseline and each routine visitIf positive, refer to addiction specialist.

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Table 5. Antiviral Treatments for Chronic HCV (11, 12, 60, 61)
TREATMENTRECOMMENDED DOSE
Clcr = creatinine clearance; IFN = interferon; PO = orally; SC = subcutaneous; U = units.
Combination Peginterferon Alfa Regimens with Ribavirin
Peginterferon alfa-2a (Pegasys®)180 mcg SC once weekly regardless of weight
Peginterferon alfa-2b (PEG-Intron®)1.5 mcg/kg SC once weekly up to 150 mcg/week
Ribavirin (Rebetol®, Copegus®)Genotype 1: 1,000 mg ≤75 kg OR 1,200 mg if >75 kg PO daily (in two divided doses)

Genotype 2 and 3: 800 mg PO daily (in two divided doses)
Regimens in Certain Clinical Circumstances
Peginterferon alfa-2a (Pegasys®) in hemodialysis135 mcg SC once weekly
Peginterferon alfa-2b (Peg-Intron®) in renal dysfunctionReduce dose by 25% if Clcr 30-50 mL/min

Reduce dose by 50% if Clcr 10-29 mL/min
Peginterferon alfa-2a (Pegasys®) monotherapy180 mcg SC once weekly regardless of weight
Peginterferon alfa-2b (PEG-Intron®) monotherapy1.0 mcg/kg SC once weekly up to 150 mcg/week
IFN alfa-2a (Roferon-A®)3 million U SC three times weekly
IFN alfa-2b (Intron A®)3 million U SC three times weekly
IFN alfacon-1 (Infergen®) also known as consensus IFN9 mcg SC three times weekly

15 mcg SC three times weekly in IFN nonresponders
Ribavirin dose with IFN1,000 mg PO daily if patient ≤75 kg (in two divided doses) OR

1,200 mg PO daily if patient >75 kg (in two divided doses)
Table 6. Comparison of Sustained Virologic Response (SVR) Rates for Peginterferon Alfa-2a Combination Therapy, Peginterferon Alfa-2a Monotherapy, and Interferon Alfa Combination Therapy Given Over 48 wk (14)
*peginterferon alfa-2a 180 mcg/week plus ribavirin 1,000 or 1,200 mg/day

†peginterferon alfa-2a 180 mcg/week plus placebo

‡IFN 3 million U three times/week plus ribavirin 1,000 or 1,200 mg/day

§Compared to interferon alfa plus ribavirin

**Defined as >2 million copies/mL (COBAS AMPLICOR HCV Test, v. 2.0, sensitivity 100 copies/mL); equivalent to >800,000 IU/mL

Defined as ≤2 million copies/mL (COBAS AMPLICOR HCV Test, v. 2.0, sensitivity 100 copies/mL); equivalent to ≤800,000 IU/mL

PATIENT GROUPSVR
Peginterferon alfa-2A (40 kDa) plus ribavirin*Peginterferon alfa-2A (40 kDa) plus placebo†Interferon alfa plus ribavirin‡
Overall56% (p<0.001)§29%44%
HCV genotype 146% (p<0.01)§21%36%
High viral
titer**		41%13%33%
Low viral
titer		56%39%43%
HCV genotype 2, 3 76% (p<0.01)45%61%
High viral
titer**		74%40%58%
Low viral
titer		81%58%65%

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Table 7. Comparison of Sustained Virologic Response (SVR) Rates for Peginterferon Alfa-2b and Interferon Alfa Combination Therapies Given Over 48 Wk (13)

* Peginterferon alfa-2b 1.5 mcg/kg/wk and ribavirin 800 mg/day.

†IFN 3 million U three times weekly plus ribavirin 1,000 or 1,200 mg/day.

‡Compared to interferon alfa plus ribavirin.

§Defined as >2 million copies/mL (NGI, sensitivity 100 copies/mL); equivalent to >800,000 IU/mL.

Statistical analysis not performed; data from Peg-Intron package insert.

||Defined as ≤2 million copies/mL (NGI, sensitivity 100 copies/mL); equivalent to ≤800,000 IU/mL.

PATIENT GROUPSVR
Peginterferon alfa-2b plus ribavirin*Interferon alfa plus ribavirin†
Overall54% (p=0.01)‡47%
HCV genotype 142% (p<0.05)‡33%
High viral
titer§		30%29%
Low viral
titer||		Not reportedNot reported
HCV genotype 2 or 382%79%
HCV genotypes 4-650%38%

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Table 8. General Guidelines for Peginterferon Dose Reduction or Discontinuation
LABORATORY VALUESMANUFACTURER PACKAGE INSERT RECOMMENDATIONS

ANC = absolute neutrophil count; WBC = white blood cell counts

*If dose is maintained outside of manufacturer recommendations, monitor ANC more frequently and counsel patient on neutropenic precautions. In cirrhotic, post-liver transplantation or HIV/HCV coinfected patients who remain neutropenic despite dose reduction, consider starting GCSF until resolution.

†If dose is maintained outside of manufacturer recommendations, monitor platelet counts more frequently and for signs and symptoms of unusual bleeding or bruising.

WBC
<1.5 x 109/LReduce peginterferon alfa-2b dose by 50% and reevaluate
<1.0 x 109/LDiscontinue peginterferon alfa-2b until resolution
ANC*
<0.75 x 109/LPeginterferon alfa-2a: reduce dose to 135 mcg/wk and reevaluate
Peginterferon alfa-2b: reduce dose by 50% and reevaluate
<0.50 x 109/LDiscontinue peginterferon alfa until resolution
Platelets†
<80 k/mm3Peginterferon alfa-2b: reduce dose by 50% and reevaluate
<50 k/mm3Peginterferon alfa-2a: reduce dose to 90 mcg/wk and reevaluate
Peginterferon alfa-2b: discontinue until resolution
<25 k/mm3Peginterferon alfa-2a: discontinue until resolution
Table 9. General Guidelines for Ribavirin Dose Reduction or Discontinuation
PARAMETERRECOMMENDATION
In stable underlying cardiac disease, reduce ribavirin by 200 mg/day for ≥2 g/dL drop in Hb over a four-wk period. If the Hb level is <12 g/dL after four wk of dose reduction, discontinue ribavirin until resolution and reevaluation.
Hemoglobin (Hb)
<11.0 but >10 g/dLNo change in ribavirin dose if patient has minimal symptoms
In a symptomatic patient, consider ribavirin dose reduction by 200 mg/day and/or starting an erythropoietic growth factor
<10.0 but >8.5 g/dLDecrease ribavirin by 200 mg/day and/or consider starting an erythropoietic growth factor
Recheck Hb levels at least every 2 wk or more frequently if indicated
<8.5 g/dLDiscontinue until resolution
Table 10. Endpoints for Chronic Hepatitis C Virus (HCV) Treatment
ENDPOINTDEFINITIONTIME POINT FOR MEASURING HCV RNA
Rapid virologic response (RVR)HCV RNA <50 IU/mL4 weeks after treatment initiation
Early virologic response (EVR)≥2 log10 reduction in pre-treatment HCV RNA12 weeks after treatment initiation
End-of-treatment response (ETR)HCV RNA <50 IU/mLCompletion of therapy
Sustained virologic response (SVR)HCV RNA <50 IU/mL Six months after completion of therapy

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