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Viral Hepatitis

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Management and Treatment of Hepatitis C Viral Infection: Therapy for Previously Untreated Patients

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Therapy for Previously Untreated Patients

With pegylation, the interferon molecule is linked to a polyethylene glycol (PEG) molecule, resulting in reduced interferon clearance. Peginterferon alfa-2a (40 kDa) and peginterferon alfa-2b (12 kDa) are both FDA-approved for use as monotherapy and in combination with ribavirin. Both peginterferon alfa products are administered subcutaneously once weekly. Peginterferon alfa plus ribavirin produces superior responses compared with prior therapies and is the current standard of care for treatment-naïve patients with chronic HCV (Table 5).

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)

(Print table 5)

Peginterferon Alfa Plus Ribavirin

In two randomized, controlled trials (RCTs), peginterferon alfa combined with ribavirin was more effective than interferon alfa plus ribavirin in HCV genotype 1 infection and at least as effective in genotype non-1 infection (Table 6 and Table 7) (13, 14) . SVR with peginterferon alfa plus ribavirin was observed in 42-46% with HCV genotype 1 infection and in 76-82% with HCV genotype 2 or 3 infection (Table 6 and Table 7) (13, 14) . Patients with early-stage disease generally had better results than those with bridging fibrosis or cirrhosis (57-58% vs 43-44%, respectively) (13, 14, 15) .

The optimal ribavirin dose to achieve maximum efficacy with tolerable adverse effects in combination with peginterferon alfa is under investigation. In practice, ribavirin doses of 1,000-1,200 mg/day (or alternatively 10.6 mg/kg/day) for genotype 1 infection are given with either peginterferon alfa product (Table 5) (13, 16) . Lower ribavirin doses (800 mg/day) appear sufficient for genotype 2 and 3 infections (16) .

The spectrum of adverse effects for peginterferon alfa-2a plus ribavirin is similar to those of peginterferon alfa-2b plus ribavirin in clinical trials. In general, neutropenia and thrombocytopenia appear greater in those receiving peginterferon alfa plus ribavirin than for interferon plus ribavirin (11, 13, 14) .

RECOMMENDATIONS FOR TREATMENT IN PREVIOUSLY UNTREATED PATIENTS

1. Peginterferon alfa plus ribavirin is the standard of care for treatment of chronic HCV (I).

2. The peginterferon alfa-2a standard dose is 180 mcg/wk and the peginterferon alfa-2b standard dose is 1.5 mcg/kg/wk administered subcutaneously in combination with ribavirin (I).

3. For patients with genotype 1 infection, the ribavirin dose is 1,000 mg/day if ≤75 kg or 1,200 mg/day if >75 kg in combination with peginterferon alfa (I).

4. For patients with genotype 2 or 3 infection, the ribavirin dose is 800 mg/day in combination with peginterferon alfa (I).

Monotherapy with Peginterferon Alfa

For patients with absolute or relative contraindications to ribavirin (Table 3), peginterferon alfa alone or with reduced ribavirin doses, respectively, should be considered. SVR is lower with peginterferon monotherapy compared with peginterferon alfa plus ribavirin (Table 6), and this should be taken into account when counseling patients about the benefits of treatment.

RECOMMENDATION FOR MONOTHERAPY WITH PEGINTERFERON ALFA

1. Peginterferon alfa monotherapy (Table 5) may be used to treat patients with contraindications to ribavirin (Table 3)(III).

Interferon Alfa Plus Ribavirin

Interferon alfa-2b plus ribavirin is more effective than peginterferon alfa monotherapy but less effective than peginterferon alfa plus ribavirin (Table 6) (14) . For patients who cannot tolerate peginterferon alfa because of severe cytopenias, interferon alfa-2b plus ribavirin may be an acceptable alternative.

Predictors of Treatment Response to Peginterferon Alfa Plus Ribavirin

BASELINE PREDICTORS. Genotype 1 infection is the strongest negative predictor of response to peginterferon alfa and ribavirin (Table 6 and Table 7) (13, 14) . Additional independent negative predictors of response with peginterferon alfa-2a or alfa-2b plus ribavirin include high pretreatment HCV RNA level, age ≥40 yr, heavier body weight, and cirrhosis (13, 14, 16) . Gender has not been shown to be an independent predictor of response. African Americans consistently have lower responses to peginterferon alfa plus ribavirin than Caucasians (section "African Americans") (17) .

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 placeboInterferon 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%

(Print table 6)

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%

(Print table 7)

ON-TREATMENT PREDICTORS. SVR is more likely to occur in patients who have early viral suppression than a delayed or incomplete viral response on treatment. RVR and EVR can be useful predictors of SVR (section "Duration of Treatment") (14, 18) .

Treatment-naïve patients who achieve an EVR with peginterferon alfa plus ribavirin have a 65-76% likelihood of attaining SVR (14, 18) . Conversely, those without an EVR have ≤3% chance of achieving SVR and treatment discontinuation should be considered (14, 18) . Lack of an EVR was also useful in predicting treatment nonresponse in African Americans and those with HIV coinfection (17, 19) . In patients who fail to achieve an EVR, the decision to stop treatment should be made after full consideration of any viral response, treatment tolerability, and underlying liver disease (section "Patients with Compensated Cirrhosis").

RECOMMENDATIONS FOR VIROLOGIC END POINTS ON TREATMENT

1. RVR and EVR should be measured (II-2).

2. Treatment may be discontinued in those failing to achieve an EVR (II-2).

3. In patients with advanced liver disease, treatment may be continued even without an EVR, depending on tolerance of therapy (III).

Duration of Treatment

Genotype 1

In genotype 1-infected patients, SVR with peginterferon alfa plus ribavirin is greater with 48 wk than with 24 wk of treatment (51% vs 41%, respectively) (16) . Emerging data suggest that treatment duration may be shortened or lengthened depending on viral response at 4 wk and/or 12 wk.

Extending Treatment Duration Beyond 48 Weeks

Two RCTs suggest that for treatment-naïve genotype 1-infected patients who have a slow decline in virus (detectable HCV RNA at 4 and/or at 12 wk), extending therapy to 72 wk may be beneficial. One study in which >90% had genotype 1 infection, higher SVR occurred with 72 versus 48 wk of peginterferon alfa-2a 180 mcg/wk plus ribavirin 800 mg/day in patients who had detectable HCV RNA (≥50 IU/mL) at week 4 (SVR 45% and 32%, respectively, p = 0.014) (20) . A second study showed a trend toward higher SVR with 72 versus 48 wk of the same treatment regimen in patients who were still HCV RNA positive (≥50 IU/mL) at 12 wk and who subsequently had undetectable HCV RNA by 24 wk (SVR 30% and 18%, respectively, p = 0.08) (21) .

Shortening Treatment Duration to 24 Weeks

Some studies suggest that 24 wk of treatment may be sufficient in treatment-naïve genotype 1 patients who demonstrate RVR (22, 23) . In a retrospective analysis, high SVR was achieved in patients developing an RVR with peginterferon alfa-2a plus ribavirin for 24 versus 48 wk (SVR 88% and 91%, respectively) (22) . In an ongoing interim analysis of a prospective RCT, high SVR (67%) was achieved with 24 wk of treatment in patients achieving an RVR on peginterferon alfa-2a and ribavirin (23) .

In summary, viral response at 4 wk and/or 12 wk may be useful in tailoring treatment duration. For patients developing RVR but who are poorly tolerant of therapy, discontinuing treatment at 24 wk may not compromise response. However, for those who have slow viral response but demonstrate undetectable virus by 24 wk into treatment and who are tolerating therapy well, extending treatment to 72 wk may be beneficial.

RECOMMENDATIONS FOR TREATMENT DURATION IN GENOTYPE 1 INFECTION

1. For patients who achieve RVR, 24 wk of treatment may be sufficient (III).

2. For patients who fail to achieve RVR but achieve EVR, 48 wk is usually sufficient (I).

3. For patients without an RVR and/or EVR, extending duration to 72 wk may be beneficial if virus is undetectable by 24 wk of therapy (III).

4. For patients who continue to have detectable virus at 24 wk, treatment should be discontinued if the goal of therapy is viral eradication (I).

Genotype 2 or 3

Patients with genotype 2 or 3 infection are more responsive to antiviral therapy than those with genotype 1 infection. SVR for genotype 2 or 3 infection is similar among patients treated for 24 versus 48 wk (SVR range 73-78%); thus, treatment for 24 wk is usually sufficient (16) .

Extending Treatment Duration Beyond 24 Weeks

Data suggest that SVR is lower in patients with genotype 3 infection than those with genotype 2 infection (SVR 66-79% vs 80-93%, respectively) (24, 25) . In genotype 3-infected patients with a baseline HCV RNA >600,000 IU/mL and steatosis, a high relapse rate has been demonstrated following 24 wk of therapy with peginterferon alfa-2b and ribavirin. Although data are limited, some have suggested that extending treatment beyond 24 wk may be beneficial in this group (26) .

Shortening Treatment Duration

In general, shortening treatment duration appears to compromise SVR. Several studies have evaluated shorter treatment durations of 12-16 wk (24, 25, 27) . In a large RCT, overall SVR was lower with peginterferon alfa-2a plus ribavirin for 16 versus 24 wk in genotype 2- or 3-infected patients (SVR 65% vs 72%, p < 0.0001). SVR was lower with 16 versus 24 wk of treatment even when HCV RNA <600 IU/mL was achieved by week 4 of therapy (SVR 82% vs 90%, respectively). In a subgroup who had a low pretreatment HCV RNA (≤600,000 IU/mL), SVR was similar when treated for 16 versus 24 wk (SVR 83% vs 87% for genotype 2 and 78% vs 81% for genotype 3, respectively) (25) . Another smaller RCT demonstrated lower SVR with peginterferon alfa-2b and ribavirin for 12 versus 24 wk in genotype 2- and 3-infected patients achieving an RVR, although this difference was not statistically significant (SVR 85% and 91%, respectively). Of potential clinical significance, a higher relapse rate occurred with 12 versus 24 wk of treatment (8.9% and 3.6%, respectively, p = 0.16), but there were fewer early treatment discontinuations (24) .

RECOMMENDATIONS FOR TREATMENT DURATION IN GENOTYPE 2 or 3 INFECTION

1. Standard treatment duration is 24 wk (I).

2. In patients with a low pretreatment RNA (≤600,000 IU/mL) who are not tolerating therapy, 16 wk of treatment may be sufficient (I).

3. For patients with genotype 3 infection and a baseline HCV RNA >600,000 IU/mL or steatosis, treatment beyond 24 wk may improve response (III).