Correspondence

Telaprevir for Chronic HCV Infection

N Engl J Med 2009; 361:533-535July 30, 2009

Article

To the Editor:

McHutchison et al. and Hézode et al. (April 30 issue) found an important effect of adding telaprevir to current antiviral therapy.1,2 Nevertheless, the results of the Protease Inhibition for Viral Evaluation (PROVE) trials (ClinicalTrials.gov numbers, NCT00336479 and NCT00372385) are disappointing, since they demonstrate the risk of serious side effects resulting from high dosing of a new molecule, with profound consequences for efficacy. Combined data from all telaprevir regimens in both trials show a significant difference in sustained virologic response between patients completing and those discontinuing treatment (78% and 25%, respectively; P<0.001). Although telaprevir had an acceptable initial side-effect profile, the extended administration of high doses of telaprevir was accompanied by a high rate of treatment discontinuation, mainly because of unexpected rash and more severe anemia.

The first study of telaprevir showed similar initial viral declines with different dosages; viral breakthrough occurred in the lower dosing regimen.3 The fear of selection of telaprevir-resistant variants can be negated, since mutant viruses are sensitive to peginterferon.4

We are concerned that major decisions in the development of new antiviral agents are primarily based on the reduction of hepatitis C virus (HCV) RNA levels and on the highest tolerated doses in short phase 1 trials. Subsequent trials should incorporate lower, albeit effective, dosages to reduce the risk of adverse events and to enhance treatment adherence, which might improve efficacy further.

Adriaan J.P. van der Meer, M.D.
Robert J. de Knegt, M.D.
Erasmus Medical Center, 3015 CE Rotterdam, the Netherlands
a.vandermeer@erasmusmc.nl

Dr. de Knegt reports serving on an advisory board for Schering-Plough and receiving research funding from Schering-Plough, Roche, and Vertex.

No other potential conflict of interest relevant to this letter was reported.

4 References

1. 1

   McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009;360:1827-1838
   Full Text | Web of Science | Medline

2. 2

   Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009;360:1839-1850
   Full Text | Web of Science | Medline

3. 3

   Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology 2006;131:997-1002
   CrossRef | Web of Science | Medline

4. 4

   Kieffer TL, Sarrazin C, Miller JS, et al. Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology 2007;46:631-639
   CrossRef | Web of Science | Medline

To the Editor:

Two phase 2 trials showed that in patients infected with chronic HCV genotype 1, the sustained virologic response rate with peginterferon plus ribavirin therapy for 48 weeks was 41 to 46%, whereas the response rate with the addition of 12 weeks of telaprevir to combination therapy for 24 weeks was 61 to 69%. The accompanying editorial by Hoofnagle1 thus suggested that this advance will permit future therapy to be limited to 24 weeks. Nevertheless, this suggestion might not be able to be extrapolated to Asian patients with HCV genotype 1 infection. First, the Asian population was under-represented (<5%) in both studies. Second, for patients with genotype 1 infection, Asians who have received combination therapy for 48 weeks have substantially higher rapid and sustained virologic response rates than do whites (44 to 63% vs. 11 to 13% for rapid rates and 76 to 79% vs. 41 to 46% for sustained rates),2,3 which could be explained by the kinetics of an effective early viral response.4 Moreover, 24-week combination therapy also results in a sustained virologic response rate of 56 to 59% in Asians. Further studies are awaited to see whether the addition of telaprevir could limit HCV therapy to 12 weeks in Asian patients who have not previously received treatment.

Jia-Horng Kao, M.D., Ph.D.
National Taiwan University Hospital, Taipei 10002, Taiwan
kaojh@ntu.edu.tw

4 References

1. 1

   Hoofnagle JH. A step forward in therapy for hepatitis C. N Engl J Med 2009;360:1899-1901
   Full Text | Web of Science | Medline

2. 2

   Yu ML, Dai CY, Huang JF, et al. Rapid virological response and treatment duration for chronic hepatitis C genotype 1 patients: a randomized trial. Hepatology 2008;47:1884-1893
   CrossRef | Web of Science | Medline

3. 3

   Liu CH, Liu CJ, Lin CL, et al. Pegylated interferon-alpha-2a plus ribavirin for treatment-naive Asian patients with hepatitis C virus genotype 1 infection: a multicenter, randomized controlled trial. Clin Infect Dis 2008;47:1260-1269
   CrossRef | Web of Science | Medline

4. 4

   Hsu CS, Liu CJ, Lai MY, Chen PJ, Kao JH, Chen DS. Early viral kinetics during treatment of chronic hepatitis C virus infection with pegylated interferon alpha plus ribavirin in Taiwan. Intervirology 2007;50:310-315
   CrossRef | Web of Science | Medline

Author/Editor Response

Van der Meer and de Knegt have rightly pointed out that the addition of a new agent to an existing treatment regimen would be expected to result in additional side effects, which would be the price for potential improvements in efficacy and shortened treatment durations. The telaprevir groups in the PROVE1 and PROVE2 studies did have higher rates of discontinuation due to adverse events than did the control groups. Rash was the main reason for the additional discontinuations; 7% of patients had rashes that were considered severe. Rashes resulted in hospitalization for 9 of 338 patients who were exposed to telaprevir; 2 patients also received one or two doses of intravenous corticosteroids. These were the first studies in which a severe rash was seen, and a management plan was included in subsequent studies.

The suggestion of using lower dosages of telaprevir is not supported by the scientific data. Dose selection was not based on the highest tolerated doses but on the dose that best prevented the emergence of telaprevir-resistant variants. Although telaprevir-resistant variants remain sensitive to the antiviral effect of interferon in vitro, the important factor in vivo is the extent and timing of the patient's response to interferon. In the phase 1 study cited, selection of telaprevir-resistant variants was correlated with lower trough concentrations of telaprevir.1 When telaprevir was combined with interferon and ribavirin in the PROVE studies, the viral breakthroughs observed were associated with lower telaprevir and interferon levels.2 Therefore, lower exposure to telaprevir may increase the incidence of viral breakthrough and diminish the clinical benefit of the triple combination. An analysis of the relationships between the pharmacokinetics of telaprevir and either severe rash or a decrease in the hemoglobin level (to <9.5 g per deciliter [5.9 mmol per liter]) shows no consistent reason for an improved adverse-event profile in cases of a lower dose (unpublished data).

Therefore, efforts should be directed at adverse-event awareness, monitoring, and management so that patients are able to complete treatment and maximize their chance of a successful and safe response to therapy.

We also agree with Kao. New HCV therapies that are in development should be studied in populations with favorable responses to therapy (Asians) and in populations with less favorable responses to therapy (blacks and Latinos) to fully characterize their efficacy and safety.

John McHutchison, M.D.
Duke University, Durham, NC 27715
mchut001@mc.duke.edu

Jean-Michel Pawlotsky, M.D., Ph.D.
Henri Mondor University Hospital, 94010 Créteil, France

Stefan Zeuzem, M.D.
J.W. Goethe University Hospital, 60590 Frankfurt, Germany

for the PROVE1 and PROVE2 Study Teams

2 References

1. 1

   Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology 2006;131:997-1002
   CrossRef | Web of Science | Medline

2. 2

   Jacobson IM, Everson GT, Gordon SC, et al. Interim analysis from a phase 2 study of telaprevir with peginterferon alfa-2a and ribavirin in treatment-naïve subjects with hepatitis C. Hepatology 2007;46:Suppl 1:315A-315A
   CrossRef | Web of Science