Treatment of patients infected with chronic hepatitis C genotype 2 and 3: More data, more questions?

Authors

  • Ivo W. Graziadei,

    1. Department of Internal Medicine II, (Gastroenterology and Hepatology), Medical University of Innsbruck, Innsbruck, Austria
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  • Wolfgang Vogel

    Corresponding author
    1. Department of Internal Medicine II, (Gastroenterology and Hepatology), Medical University of Innsbruck, Innsbruck, Austria
    • Dept. of Internal Medicine II (Gastroenterology and Hepatology), Medical University of Innsbruck, Anichstraé 35, A-6020 Innsbruck, Austria
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    • fax: +43-512 504 24052


  • See Article on Page 358

  • Potential conflict of interest: Dr. Graziadei is on the speakers' bureau of and received grants from Roche and Schering-Plough.

The efficacy of antiviral therapy for hepatitis C virus (HCV) infection has improved substantially over recent decades. The current standard therapy with pegylated interferon (peg-IFN) α and ribavirin (RBV) for 48 weeks has an overall success rate of about 55%.1, 2 Important predictive factors associated with treatment response, irrespective of genotype, include age, gender, weight (body mass index [BMI]), biochemical and histologic characteristics of the patients, and RBV dose. Viral genotype, viral kinetics, and to a lesser extent baseline viral load are the strongest (pre)treatment variables predicting the sustained virologic response (SVR) rate, defined as a negative HCV RNA 6 months after therapy is stopped.

Abbreviations

BMI, body mass index; ETR, end-of-treatment response; HCV, hepatitis C virus; peg-IFN, pegylated interferon; RBV, ribavirin; RVR, rapid virologic response.

It has been shown that in patients infected with genotype 2 and 3, a 24-week course of combined peg-IFN and RBV therapy is sufficient to obtain SVR rates from 70%-90%.3 Therefore, current guidelines recommend a 24-week treatment for patients infected with genotype 2 and 3 in contrast to 48 weeks for patients infected with genotype 1 and 4.4, 5

Because of substantial side effects and costs associated with this therapy, several studies have attempted to determine the possibility to further reduce the treatment duration in patients with HCV genotype 2 and 3. However, differences in study design (fixed versus variable duration treatment strategy), in baseline patient characteristics (e.g., age, BMI), histology (fibrosis) and treatment modalities (RBV dose) have made their collective interpretation difficult (Table 1).

Table 1. Comparison of Randomized Trials Dealing with a Shortened Peginterferon α and Ribavirin Treatment in Patients Infected with HCV Genotypes 2 and 3
AuthorCountryTx Duration (Weeks)Sample SizeAge (Years)BMIF3/F4RBV DoseRVRTx StrategyETRSVRRelapse
  • *

    P < 0.001.

  • **

    Non-inferiority between both groups could not be achieved.

  • Abbreviations: n.a., not available; RBV, ribavirin; Tx, treatment; U.S., United States.

  • Treatment strategy: variable duration treatment = only patients with RVR were randomized to an abbreviated or standard therapy; fixed duration treatment = randomization of patients regardless of RVR.

Mangia et al6Italy12 vs. 24283482615weight-based63%variable85% vs. 79%77% vs. 76%9% vs. 4%
von Wagner et al.7Germany16 vs. 2415340n.a.n.a.weight-based93%variable94% vs. 85%82% vs. 80%12% vs. 5%
Shiffman et al.8Mainly U.S.16 vs. 241469462824fixed66%fixed89% vs. 82%62% vs. 70%*31% vs. 18%*
Yu et al.12Taiwan16 vs. 24150502521weight-based87%fixed100% vs. 98%94% vs. 95%6% vs. 3%
Dalgard et al9Scandinavia14 vs. 244284025n.a.weight-based71%variable92% vs. 96%81% vs. 91%**11% vs. 5%**
Lagging et al.10Scandinavia12 vs. 24382422553fixed62%fixed92% vs. 90%59 vs. 78%*33% vs. 12%*
             
Current Study            
Mangia et al.11Italy124965226n.a.weight-based69%variable96%82.5%14%

Two randomized European studies demonstrated that peg-IFN and RBV therapy for 12-16 weeks had equivalent response rates compared to a 24-week treatment. In both studies, only patients with genotype 2 and 3, who achieved a rapid virologic response (RVR) defined as an undetectable HCV RNA level by polymerase chain reaction analysis at week 4, were included.6, 7 In the Italian trial, patients with RVR were randomized to a 12-week or 24-week therapy, and both SVR rates did not differ significantly.6 The same results were obtained in the German study, which randomized patients with an RVR to a standard 24-week or a shortened 16-week arm.7 This abbreviation of the treatment duration did not lead to a loss of treatment efficacy. Only in patients with genotype 3 and a high viral load >800,000 IU/mL was a significantly lower SVR rate found.7

In contrast, a large, mainly U.S. multicenter trial (ACCELERATE), with a fixed duration treatment strategy could not confirm these findings. In this study, patients with genotype 2 and 3 were randomized either to a 16-week or a 24-week combined antiviral therapy, regardless of RVR status.8 The data clearly indicated that 16 weeks of treatment were markedly inferior to 24 weeks of therapy, in particular in patients with genotype 2. Although the end-of-treatment response (ETR) was better in the shorter duration group (mainly due to higher dropout rates in the 24-week groups), a significantly higher relapse rate led to the lower SVR rates in the 16-week regimen (62% versus 70%). Furthermore, a subgroup analysis showed that the 24-week therapy was also superior in patients who had an RVR.

Similar findings were reported in two current Nordic trials.9, 10 In the study by Dalgard et al., patients with an RVR were randomized to 14 or 24 weeks of therapy. Patients treated for 24 weeks showed a 9.6% higher SVR rate compared to the 14-week group (90.7% versus 81.1%). Because the 95% confidence interval overlapped the predefined noninferiority margin of 10%, the authors could not prove that the 14-week treatment regimen is noninferior to 24 weeks of treatment.9 In the second Nordic trial, Lagging and co-workers showed that peg-IFN/RBV therapy for 12 weeks was inferior to 24 weeks of treatment in the intention-to-treat population (56% versus 82%) as well as in the subgroups of patients infected with genotype 2 or 3 and in the subgroup of patients who achieved an RVR.10 Again in both trials, the lower SVR rates in the shorter duration treatment regimen were due to higher relapse rates. Therefore, the major concern about the implementation of an abbreviated treatment regimen is primarily based on the higher relapse rate.

In this issue of HEPATOLOGY, Mangia et al. report on predictive factors of relapse after an overall 12-week course of antiviral therapy in patients with chronic HCV infected with genotype 2 and 3.11 In addition, the authors evaluated the efficacy of retreatment of patients who relapsed after an initial 12-week regimen for the standard 24 weeks.

In this prospective, open-labeled, multicenter study, only patients who achieved an RVR (69% of the overall study cohort of 718 patients) were assigned to a 12-week treatment arm. After an ETR of 96%, 14% of patients had a viral relapse leading to an SVR rate of 82%. Logistic regression analysis was used to determine predictive factors for relapse. Upon univariate analysis, age > 40 years, a BMI > 30 kg/m2, and a platelet count < 140,000/mm3 were significantly associated with a viral relapse after ETR. Upon multivariate analysis, only BMI and platelet count remained statistically significant. BMI and advanced fibrosis/cirrhosis are established predictive factors for treatment response. Although it has been shown that a low platelet count is an indirect parameter for advanced fibrosis, it would be interesting to know if there is a direct correlation between liver fibrosis and relapse rate. However, this was not possible in this study, because liver biopsies were not available in the majority of patients.

Patients infected with genotype 2 and 3 responded similarly with respect to SVR and relapse rates; for both genotypes, the platelet count and BMI were independently associated with antiviral response. On post-hoc evaluation, patients with a BMI < 30 and a platelet count > 140,000 had an SVR rate of 92% and a relapse rate of 8% compared to 72.5% and 27.5%, respectively, in patients with a BMI > 30 and/or platelet count < 140,000.

Does this study by Mangia and co-workers finally tell us what the best treatment duration for patients infected with HCV genotype 2 and 3 is and who might be the ideal candidate for a shortened treatment duration or if we need more trials? Due to the study design, this trial is not capable of demonstrating that the efficacy of an abbreviated treatment regimen for patients with RVR is equivalent to the standard therapy for 24 weeks. This study confirms that reducing the treatment duration to 12 (and up to 16) weeks is effective in patients achieving an RVR. In addition, two other prognostic favorable parameters are described in this article—low BMI and normal platelet count—suggesting that a patient with a BMI < 30 and a normal platelet count is the ideal candidate for a shorter duration of antiviral therapy. The reported SVR rate of 92% is extremely high and almost impossible for further improvements. However, the predictive power of these two parameters needs to be confirmed in prospective, randomized trials.

All together, there are six studies addressing shortened duration of therapy in patients infected with genotype 2 and 3 that tip the balance in favor of the equality of reduced treatment regimens. Considering the fact that the two Nordic and the ACCELERATE study used different margins of noninferiority in their study design, these trials still provide evidence that reduced treatment duration is safe in selected patients.

For those patients relapsing after an abbreviated therapy, the study by Mangia et al. gives the first evidence that a repeated course of therapy for an extended duration of 24 weeks is effective in providing standard 24-week treatment SVR rates.11

The open question of the adequate RBV dose has been addressed indirectly in this study. With the lack of a prospective randomized trial comparing weight-based and fixed RBV dosing in abbreviated treatment regimens for patients with genotype 2 and 3, it is apparent that studies using weight-based RBV dosing (800-1400 mg) had lower relapse rates (<12%)6, 7, 9, 12 than did studies using a fixed dose of 800 mg (relapse rates >25%)8, 10 (Table 1), suggesting that similar to genotype 1 studies,1, 3, 13 weight-based RBV seems to be more effective in preventing viral relapse in shortened treatment regimens in patients infected with genotypes 2 and 3 than fixed RBV dosing. A meta-analysis, presented at the last American Association for the Study of Liver Diseases meeting, confirmed the importance of weight-based RBV dosing.14 A suggested treatment algorithm for patients infected with chronic HCV genotypes 2 or 3 is depicted in Fig. 1.

Figure 1.

Suggested treatment algorithm for patients infected with chronic hepatitis C genotype 2 or 3.

In summary, this study by Mangia and co-workers confirms RVR as an important predictive factor and adds BMI and platelet count as further possibly predictive variables for SVR. However, due to the study design it does not finally prove that shortened therapy is as effective as standard treatment.

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