Discussion

In the United States, hepatitis C virus (HCV) genotypes 2 and 3 comprise approximately 25 to 30% of all HCV infections[1,2]. Genotypes 2 and 3 are distinct from the other genotypes, genotype 1 in particular, for their more favorable response to treatment with peginterferon and ribavirin. Multiple studies have shown that sustained virologic response (SVR) occurs in approximately 40 to 50% of patients with HCV genotype 1 who receive 48 weeks of dual therapy with peginterferon and ribavirin, whereas SVR rates of approximately 80% are achieved in patients with genotypes 2 or 3 with only 24 weeks of peginterferon and ribavirin therapy[3,4,5]. This discussion will review the current treatment of genotypes 2 and 3, as well as provide some background on clinical factors that may influence the management of patients with these genotypes.

Recommended Regimens for Treatment of Genotype 2 or 3

The 2009 American Association for the Study of Liver Disease (AASLD) guidelines recommend treatment of genotype 2 and 3 HCV infection with peginterferon plus ribavirin for a total of 24 weeks. The peginterferon is administered as a once-weekly subcutaneous injection, using either peginterferon-2a (Pegasys) 180 ug or peginterferon alfa-2b (Pegintron) 1.5 ug/kg, and the ribavirin is given as a fixed dose of 800 mg total daily (Figure 1)[4].  A previous trial demonstrated benefit of adding ribavirin to peginterferon for the treatment regimen of patients with genotype 2 or 3 infection, including an improved end-of-treatment response, and a significantly decreased relapse rate when compared with peginterferon monotherapy[3].  The FDA-approved HCV protease inhibitors—telaprevir (Incivek) and boceprevir (Victrelis)—are not recommended for use in the treatment of patients with genotype 2 and 3 HCV infection, given the lack of supportive data[6].  Limited data in small numbers of patients with genotype 2 and 3 suggest telaprevir exerts moderate antiviral activity against genotype 2 and minimal activity against genotype 3[7]. Early data suggest some polymerase inhibitors have greater activity across all genotypes and may have a role in the treatment of genotype 2 or 3 infection[8].  Two recently published trials reported excellent results with only 12 weeks of therapy for patients with genotype 2 or 3 hepatitis C using an all-oral regimen of the novel polymerase inhibitor sofosbuvir combined with ribavirin[8,27]. It is anticipated that in the near future treatment options for HCV genotype 2 or 3 will include a short-course all-oral therapy regimen consisting of a direct acting polymerase inhibitor plus ribavirin.  As of July 2013, however, there are no direct-acting antiviral agents with FDA approval for use in genotype 2 or 3 infection.

Recommended Duration of Therapy

Several trials with peginterferon and ribavirin combination therapy demonstrated, as had prior studies with standard interferon and ribavirin, that patients with genotypes 2 and 3 had consistently higher SVR rates with 48 weeks of treatment than patients with genotype 1: 76% versus 46% when using peginterferon alfa-2a and ribavirin[3] and 82% versus 42% with peginterferon alfa-2b and ribavirin[9]. These findings raised the question of whether patients with genotypes 2 or 3 could still achieve high SVR rates with a shorter treatment duration.  Investigators addressed this issue in a study that randomized patients to receive either 24 or 48 weeks of peginterferon alfa-2a with either fixed-dose (800 mg/day) or weight-based dosing (1000 mg/day for weight less than 75 kg or 1200 mg/day for weight 75 kg or greater) of ribavirin with use of a 2 x 2 factorial design (Figure 2)[10]. Of the 1232 patients enrolled, 492 (40%) had genotype 2 or 3 infection.  Among the patients with genotype 2 or 3 infection, no statistically significant differences in sustained virologic response rates were detected between patients treated for 24 versus 48 weeks, or between those treated with low fixed (800 mg/day) dose (LD) versus standard-dose (SD), weight-based ribavirin (SVR rates: 84% for 24-week/LD, 81% for 24-week/SD, 79% for 48-week/LD and 80% for 48-week/SD)  (Figure 3). Further subset analysis revealed that patients with genotype 2 or 3 infection who had higher viral loads or advanced liver fibrosis did not benefit from a more intensive regimen. The 2009 AASLD guidelines therefore recommend that treatment of all patients with genotypes 2 or 3 should consist of peginterferon plus ribavirin at a low, fixed daily dose of 800 mg for 24 weeks[4].

Short-Course (12 to 16 Weeks) of Therapy

The substantial costs and toxicity of HCV treatment, along with the high response rates for genotypes 2 or 3 with 24 weeks of therapy, have propelled the debate about reducing treatment duration even further for those with genotypes 2 or 3. Multiple trials have assessed whether 12 to 16 weeks of therapy could be as effective as 24 weeks. Initial, small studies suggested that treatment for 12 or 16 weeks with peginterferon and standard dose, weight-based ribavirin produced similar SVR rates (approximately 80%) to that of 24 weeks of comparable therapy[11,12,13,14].  In the largest randomized, multicenter trial (ACCELERATE) to address this question, 1,469 patients with HCV genotype 2 or 3, were randomized to receive either a 16- or 24-week course of treatment with peginterferon and fixed-dose ribavirin (800 mg/day)[15]. Those who received therapy for 16 weeks had significantly lower overall SVR rates than those that received 24 weeks of therapy (62 versus 70%, P<0.001) (Figure 4). This difference was driven largely by a higher relapse rate in the 16-week therapy group compared with the 24-week group (31 versus 18%, respectively)[15]. Findings from further studies and meta-analyses comparing 24 weeks of therapy with shorter-course therapy (ranging from 12 to 16 weeks) confirmed 24 weeks as the optimal duration of therapy for genotypes 2 and 3[16,17,18].  These studies, however, also noted similar SVR rates with shorter duration of therapy in those patients who attain a rapid virologic response (undetectable HCV RNA after 4 weeks of treatment). Although current guidelines recommend 24 weeks as optimal therapy for genotypes 2 and 3, these same guidelines acknowledge that shorter duration of therapy may be considered in those who attain a rapid virologic response[4].

Ribavirin Dosing Readdressed: Weight Based versus Fixed Dose

The ACCELERATE trial used a lower, fixed-dose of ribavirin (800 mg/day), whereas previous studies had utilized weight-based ribavirin dosing (1000 to 1200 mg/day), yielding conflicting results and raising the question whether the lower, fixed-dose of ribavirin could be associated with lower SVR rates and/or higher rates of relapse. One study demonstrated that in patients with genotype 2 and 3 treated with the standard, fixed-dose ribavirin (800 mg/day), SVR rates were greater in the patients who were exposed to the higher mean dose of ribavirin, based on body weight [19]. Similarly, other studies have found an association between higher average doses of ribavirin per kilogram of body weight and higher SVR rates[9,10].  In contrast, in a large multicenter trial that involved 1,831 patients with genotype 2 or 3 infection, investigators found similar overall SVR rates with weight-based versus fixed ribavirin dosing (67.7% and 65.0% respectively) as part of a 24-week treatment course[20]. Of note, within the weight-based ribavirin group, SVR rates were consistent across all weight categories, whereas SVR significantly decreased with increasing weight in the fixed-dose group (Figure 5).  Weight-based ribavirin dosing could be considered for those patients that may be more difficult to treat due to underlying host characteristics such as obesity or advanced fibrosis.

Extended Treatment for Patients who do not Achieve RVR

Patients with genotype 2 or 3 who do not achieve a rapid virological response have low SVR rates, ranging from 26 to 41% (Figure 6)[15,21].  Although current guidelines recommend treating all patients with genotype 2 or 3 infection for 24 weeks, the benefit of longer therapy for these non-RVR patients continues to be debated. Weight-based ribavirin may also benefit this subset of patients with genotypes 2 or 3 infection who do not achieve a RVR. One retrospective analysis of genotype 2 or 3 patients who did not achieve an RVR found a trend toward higher SVR rates among those who received 48 weeks of weight-based ribavirin compared with those in other treatment categories (24 weeks of weight-based ribavirin, 24 weeks of fixed-dose ribavirin, or 48 weeks of fixed-dose ribavirin)[22].  Another study found that treatment up to 36 weeks resulted in a small but statistically insignificant increase in SVR compared with the standard 24 weeks among genotype 3 patients who did not achieve an RVR (62% versus 52%, P=0.25)[23]. There are currently insufficient data to make clear recommendations supporting the strategy of intensifying treatment for this patient group. 

Differential Treatment Responses with Genotype 2 and 3

Genotypes 2 and 3 have historically been grouped together as easy-to-treat and comparable in response, but studies suggest that patients with genotype 3 may have lower SVR rates and higher relapse rates than those with genotype 2[24]. In a meta-analysis of 12 clinical trials comparing outcomes between genotype 2 and 3 patients after 24 weeks of therapy, the SVR rates were 74% in genotype 2 patients and 68% in genotype 3 patients (pooled odds ratio 1.49, 95% CI 1.23-1.80)[16]. This difference, however, was more striking in the subset of patients with high baseline HCV viral levels (greater than 400,000 to 600,000 IU/mL); for those patients with a high baseline HCV RNA level, the SVR rates were 75% in genotype 2 and 58% in genotype 3 patients, which compared with SVR rates of 79% and 75% respectively among those with low baseline viral levels. Among those that attained a rapid virologic response, SVR rates were similar (83 to 86%) between genotype 2 and 3 patients, regardless of duration of therapy (12 to 16 weeks or 24 weeks) or baseline HCV RNA levels.  For those patients who did not achieve RVR and received treatment for 24 weeks, the SVR rates were much higher for genotype 2 than 3 (62% versus 46%, respectively). These data suggest that patient with genotype 3 may benefit from a longer duration of therapy, particularly if other poor prognostic factors, such as high baseline viral level and lack of RVR, exist. Nevertheless, further studies are needed before this approach can be routinely recommended.

IL-28 Polymorphisms

Investigators have discovered that a single nucleotide polymorphism (SNP) upstream from the IL28B gene is associated with both spontaneous clearance of HCV infection as well as sustained virologic response to combination treatment of chronic HCV genotype 1 infection. This has led to the identification of a subset of patients with genotype 1 HCV infection (those with the IL28B CC genotype) who have higher SVR rates with interferon-based therapy (compared to those with the IL28B CT or TT alleles)[25]. In contrast, the association between the IL28B polymorphism and SVR does not appear to be a consistent finding for patients with genotype 2 or 3 infection; the influence of this genetic variation on SVR appears to be more attenuated in this population. A more recent study noted that the IL28B CC genotype was an independent predictor of SVR primarily in patients with genotype 2 or 3 infection who did not achieve an RVR[26]. Further data may help clarify how these predictors of SVR can be used to individualize HCV therapy in patients with genotype 2 or 3. At present, we do not recommend obtaining IL28b testing for patients with genotype 2 or 3 infection until further research elucidates its role in individualized therapy. 

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  • The following link will open in a new window.
    Figure 1. Dosing of Peginterferon-alfa and Ribavirin for Treatment of Hepatitis C Genotypes 2 or 3

    Source: Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009; 49:1335-74.

    Figure 1
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    Figure 2. Randomized Study of Treatment Duration and Ribavirin Dose in Chronic Hepatitis C Patients: Study Design

    This phase III, randomized, double-blind trial used a 2 x 2 factorial design to assess differences in sustained viral response in 1,311 patients treated for 24 or 48 weeks of peginterferon-alfa-2a combined with either a low dose or standard weight-based dose of ribavirin.
    Source: Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha 2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346-55.

    Figure 2
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    Figure 3. Randomized Study of Treatment Duration and Ribavirin Dose in Chronic Hepatitis C Patients: Study Results.

    Rates of sustained virologic response among patients with genotype 2 or 3 hepatitis C infection, shown for each study arm and stratified by low or high baseline HCV viral level.
    Source: Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha 2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346-55.


    Figure 3
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    Figure 4. Peginterferon alfa-2a and Ribavirin for 16 or 24 Weeks in Patients with Hepatitis C Genotypes 2 or 3 (ACCELERATE trial)

    Sustained virologic response rates were significantly lower in patients treated for 16 weeks compared with 24 weeks (odds ratio 0.67; 95% confidence interval 0.54 to 0.84, P<0.001). Results are shown above, stratified by HCV genotype.
    Source: Shiffman ML, Suter F, Bacon BR et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med. 2007;357:124-34.


    Figure 4
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    Figure 5. Peginterferon plus Ribavirin for 16 or 24 Weeks in Patients with Hepatitis C Genotypes 2 or 3

    Sustained virologic response rates were notably very different between patients who achieved a rapid virologic response (RVR, or undetectable HCV RNA by week 4) and those who did not achieved an RVR.
    Source: Shiffman ML, Suter F, Bacon BR et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med. 2007;357:124-34.


    Figure 5
  • The following link will open in a new window.
    Figure 6. Randomized Study of Peginterferon-alfa-2b and Weight-based versus Flat-dose Ribavirin

    In the subset of HCV genotype 2 or 3 patients in this study, sustained virologic response rates were not significantly different amongst weight categories of patients who received weight-based ribavirin. However, patients in the heavier categories (weight greater than 85-100 kg or weight greater than 105 kg) did show lower SVR rates compared to patients who weighed 65-85 kg among those who received the flat (or fixed) dosed ribavirin.
    Source: Shiffman ML, Suter F, Bacon BR et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med. 2007;357:124-34.


    Figure 6