Tinkering and tailoring with HCV therapy: Can we get away with less?

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Since the introduction of interferon therapy for hepatitis C virus (HCV) infection in the early 1990s, a number of incremental advances have been made in providing improved therapeutic outcomes for patients with hepatitis C. Many of these have been directed toward enhancing response rates, while at the same time reducing exposure to therapy in those unlikely to respond. Such approaches have included defining patient groups suitable for therapy, the introduction of combination therapy, choosing effective doses and durations of current drugs, emphasizing the importance of adherence to therapy and more accurately predicting nonresponse. Results from numerous controlled trials have also conclusively demonstrated that HCV virus genotype is the most important variable influencing treatment outcomes. In this regard, patients infected with genotype 2 or 3 have the best response rates.

Abbreviations

HCV, hepatitis C virus; IFN, interferon; SVR, sustained virological response.

One of the major advances in HCV therapy occurred when the combination of ribavirin and interferon (IFN) was shown to be more effective than interferon alone as an initial treatment for HCV infected patients, or following relapse.1–3 The subsequent introduction of pegylated (peg) interferons (α2a and α2b) has incrementally enhanced response rates so that now more than half of the patients receiving pegIFN and ribavirin achieve the benefits of a sustained virological response (SVR).4, 5 In a recent large international multicentre randomized study, Hadziyannis and colleagues6 reported that while patients infected with HCV genotype 1 required 48 weeks of treatment and a higher dose of ribavirin (1000-1200 mg), patients infected with HCV genotypes 2 or 3 were effectively treated with a lower dose of ribavirin (800 mg) for 24 weeks. That is to say, genotype 2 or 3 patients required a shorter and less aggressive antiviral treatment approach. As a result, there have been a number of ongoing large-scale initiatives aimed at identifying the most effective doses, duration of therapy, safety profiles and cost effectiveness for the treatment of patients infected with genotype 2 or 3 (Table 1).

Table 1. PegIFN/Ribavirin Initiatives Evaluating Response in Genotype 2 or 3 Infected Patients
StudyType (n)*Treatment RegimenGenotype 2 or 3 Patients (n)Duration (Weeks)SVR (%)
  • *

    Total number (n) of patients enrolled in the study.

  • **

    Treatment duration was determined by early virological response at 4 weeks (Mangia et al.8) or both weeks 4 and 8 (Dalgard et al.7).

  • ***

    Comparing treatment duration in genotype 3–infected patients with high pretreatment viral levels (>800,000 IU/mL).

Manns et al.4Randomized (1530)PegIFN-α-2b 1.5 μg/kg/QW Ribavirin 800 mg/day1484882
  PegIFN-α-2b 1.5 μg/kg/QW (4 weeks), then 0.5 μg/kg/QW Ribavirin 100–1200 mg/day1544880
Fried et al.5Randomized (1121)PegIFN-α-2a 180 μg/QW, Ribavirin 1000–1200 mg/day1404876
Hadziyannis et al.6Randomized (1284)PegIFN-α-2a 180 μg/QW, Ribavirin 800 mg/day994879
PegIFN-α-2a 180 μg/QW, Ribavirin 800 mg/day962484
  PegIFN-α-2a 180 μg/QW, Ribavirin 1000–1200 mg/day1534880
  PegIFN-α-2a 180 μg/QW, Ribavirin 1000–1200 mg/day1442481
Zeuzem et al.9Nonrandomized (224)PegIFN-α-2b 1.5 μg/kg/QW, Ribavirin 800–1400 mg/day2242481
Dalgard et al.7Nonrandomized (122)PegIFN-α-2b 1.5 μg/kg/QW, Ribavirin 1000–1200 mg/day**272456
  PegIFN-α-2b 1.5 μg/kg/QW, Ribavirin 1000–1200 mg/day**951490
Mangia et al.8Randomized (283)PegIFN-α-2b 1.0 μg/kg/QW, Ribavirin 1000–1200 mg/day702476
  PegIFN-α-2b 1.0 μg/kg/QW, Ribavirin 1000–1200 mg/day**802464
  PegIFN-α-2b 1.0 μg/kg/QW, Ribavirin 1000–1200 mg/day**1331285
GermanyRandomizedPegIFN-α-2b 1.5 μg/kg/QW, Ribavirin 800–1200 mg/dayenrolling24Study in progress
  PegIFN-α-2b 1.0 μg/kg/QW, Ribavirin 800–1200 mg/day 24 
  PegIFN-α-2b 1.5 μg/kg/QW, Ribavirin 800–1200 mg/day 16 
InternationalRandomizedPegIFN-α-2a 180 μg/QW, Ribavirin 800 mg/dayenrolling24Study in progress
  PegIFN-α-2a 180 μg/QW, Ribavirin 800 mg/day 16 
Australia***RandomizedPegIFN-α-2b 1.5 μg/kg/QW, Ribavirin 800–1400 mg/dayenrolling48Study in progress
  PegIFN-α-2b 1.5 μg/kg/QW, Ribavirin 800–1400 mg/day 24 

In this issue of HEPATOLOGY, Dalgard et al.7 investigated in a nonrandomized pilot study whether a shorter treatment duration of 14 weeks for those patients who cleared the virus at both week 4 and week 8 was as effective in treating patients infected with genotypes 2 or 3. The results indicate an excellent overall SVR rate (82% by an intention to treat analysis), with a high proportion of patients in the shorter treatment schedule achieving a SVR (90%). These results are in keeping with a preliminary analysis from an Italian randomized study8 reporting a favorable SVR of 85% among genotype 2 or 3 infected patients receiving a shorter 12 weeks of combination antiviral therapy, based on early viral clearance at 4 weeks.

While the results from these studies are encouraging, they also raise appropriate and relevant questions: Which group(s) of patients would benefit the most from truncating therapy, do these observations apply equally to all patients with genotype 2 or 3 infection, what is the most effective, shorter duration therapy (14 weeks as suggested by Dalgard et al., or perhaps 12 or even fewer weeks), when would be an appropriate time to assess early virological response with short courses of therapy, are the current doses of our two drugs appropriate in these “brief” regimens or could we lower the doses and thus presumably lessen the side effects encountered and finally, how can we quantify the economic benefits of such an approach?

Selecting patient groups most likely to respond to a shorter course of therapy is very important. The patient cohort studied by Dalgard et al. was predominately young, lean, with mild liver disease and low pretreatment viral levels. Besides this “easy to treat” group, future studies should incorporate more problematic subgroups where the optimum dose and duration of therapy have not been sufficiently addressed. Among those are genotype 2 or 3 infected patients with bridging fibrosis or cirrhosis. Treatment data in this group are primarily derived from post hoc subgroup analyses from larger scale trials enrolling patients predominately infected with genotype 1 and less advanced liver disease. In such analyses, treatment duration longer than 24 weeks offered no additional efficacy for genotype 2 or 3 infected patients with cirrhosis.6 While it would seem unlikely that 12 to 14 weeks of therapy would be as effective in patients with cirrhosis, current data do not allow firm conclusions regarding duration of therapy in this group.

Dalgard et al.7 as well as others8–10 importantly highlight differences in response in patients with genotype 3 infection and high pretreatment viral concentrations (defined in most studies as HCV RNA levels > 600,000-800,000 IU/mL). In this group, SVR rates following 14 weeks of therapy were significantly lower than genotype 3–infected patients with low pretreatment viral levels (P = .019), and only 56% of these patients achieved an SVR when treated for 24 weeks. The study by Dalgard et al., however, was not sufficiently powered to evaluate the additional impact of steatosis on the suboptimal SVR observed in genotype 3 patients with high pretreatment viral levels. Published studies have variably defined and evaluated the effect of steatosis on response. Despite these differences, even the presence of fat in 5% or more of hepatocytes was associated with a reduced response in one study.9 Steatosis has also been shown to be associated with higher pretreatment viral levels and poorer response rates to therapy among genotype 3–infected patients.9, 11–13 Thus, whether patients infected with genotype 3 with high pretreatment viral levels (with or without steatosis) may benefit from alternative treatment approaches including longer, rather than shorter, treatment duration needs to be addressed. Fortunately a large multicentre study to answer this specific question is underway in Australia.

A further question is whether a high dose of pegIFN α-2b (1.5 μg/kg/wk) is necessary for all genotype 2 or 3 patients, with truncated regimens. Other larger studies have demonstrated that a lower dose of pegIFN α-2b (1.0 μg/kg/wk) is as effective in this patient group.4, 6 Presently, a multicenter study in Germany is comparing the efficacy of the two doses of pegIFN α-2b (1.5 μg/kg/wk versus 1.0 μg/kg/wk) and treatment durations (24 weeks versus 14 weeks) in genotype 2 or 3 infected patients. The results of this trial are certain to provide additional necessary answers in terms of both efficacy and safety.

Recent data evaluating HCV viral kinetics during antiviral therapy have indicated that early viral decline is predictive of SVR.14, 15 Dalgard et al.7 and others8 verify this concept and suggest that viral response at 4 weeks can reliably guide treatment duration in those with genotype 2 or 3 infection. Based on the available data, the majority of treated patients who achieve viral clearance at 4 weeks can safely receive truncated courses of therapy without compromising the SVR.

Finally, it is imperative that the economic benefits and safety profiles of shorter treatment durations be analyzed in relationship to viral efficacy, adherence to therapy, and relapse rates. The latter ideally should not increase, as re-treating those who relapsed will incur additional costs.

Overall, the results by Dalgard et al. in this nonrandomized study are encouraging. They suggest the opportunity to shorten the duration of antiviral therapy in certain subgroups of patients infected with genotypes 2 or 3. At the current time, the base of evidence and areas of doubt are too great to make this approach a solid clinical recommendation. It is likely the ongoing initiatives should be sufficient to answer many of the questions raised. We should wait for the results of these trials before we can accurately recommend shorter treatment periods in particular situations and incorporate these recommendations into current practice guidelines.

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