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Department of Medicine, University of Wisconsin Hospital and Clinics
Dean Health System, Madison, Wisconsin
We read with great interest the model described by Drusano and Preston [1] regarding the prediction of a sustained viral response (SVR) in patients infected with chronic hepatitis C virus (HCV) genotype 1 who were treated with pegylated interferon and ribavirin. We feel that the clearance duration (CD), although important, is overemphasized in their article. Other factors that strongly predict SVRincluding the baseline viral load before the start of treatment (<2 million IU/mL) [2] and a 2-log reduction in viral load by week 12 (early viral response ) [3, 4]are not emphasized in the study discussion. We would like to share the experience from our center regarding 5 patients with HCV genotype 1 who were treated with combination therapy (shown in table 1).
Four of 5 patients had HCV genotype 1a, had low viral loads before the start of treatment, and were treated with pegylated interferon and ribavirin for a treatment duration of 1030 weeks. All patients had undetectable HCV RNA loads at week 12. In each of the patients, the treatment was discontinued because of severe adverse effects, including psychosis, transaminitis, fatigue, depression, and neutropenia. All 4 patients successfully attained an SVR, as evidenced by an undetectable HCV RNA load as measured by polymerase chain reaction (PCR) 6 months after the discontinuation of treatment. As per the model described by Drusano and Preston, they would have needed a CD of 32 weeks to attain an 80% probability of an SVR. However, on the basis of our experience with the patients described above, there are patients with HCV genotype 1 who will respond to shorter courses of treatmentthe entire duration of therapy being shorter than the 32 weeks of CD cutoff proposed. This case series indicates that there may be a small proportion of patients with HCV genotype 1 who attain an SVR with a treatment duration shorter than the currently recommended 48 weeks. The factors that indicate a favorable response to treatment identified in previous trials are low baseline viral load, EVR, and the dose of ribavirin [5]. In Drusano and Preston' own work, a low baseline viral load was more strongly associated with SVR than was CD (their table 2) [1]. A recent study showed that the magnitude of the 24-h viral response after a single-dose interferon sensitivity test might be of value in predicting the outcome of combination therapy [6]. In patients with HCV genotype 1, there might be other factors predicting SVR in combination with CDfor example, low baseline viral load, ethnicity, degree of liver disease, and subtype 1a infectionwhich need to be studied.
Analysis of 3 large trials of hepatitis C treatment [5] showed that 79% of patients could continue treatment for >80% of the time. Most of the remainder reduced or discontinued therapy because of adverse effects. The adherence rates outside clinical-trial settings are likely to be lower. Prolonging the course of treatment past the current standard of 48 weeks will likely result in a longer duration of adverse effects and lower adherence rates.
The above-described data demonstrate that there is variability in the duration of treatment needed by patients with HCV genotype 1 for the HCV RNA load to remain undetectable and to maintain SVR. Continuing treatment for a CD of 32 weeks could substantially increase costs and likely lower adherence rates because of adverse effects. We agree with Drusano and Preston that further studies are needed that examine a longer duration of therapy before the model can be validated. The costs and benefits of frequent RNA PCR testing will need to be studied. Factors that predict SVR with a shorter CD, such as low initial viral load and subtype 1a infection, need to be studied further, primarily because of the toxicities associated with combination therapy.
References
1. Drusano GL, Preston SL. A 48-week duration of therapy with pegylated interferon 2b plus ribavirin may be too short to maximize long-term response among patients infected with genotype-1 hepatitis C virus. J Infect Dis 2004; 189:96470. First citation in article
2. Lindsay KL, Trepo C, Heintges T, et al. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology 2001; 34:395403. First citation in article
3. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358:95865. First citation in article
4. Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003; 38:64552. First citation in article
5. McHutchison JG, Manns M, Patel K, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002; 123:10619. First citation in article
6. Ferenci P, Formann E, Laferl H, et al. Randomized, double blind, placebo-controlled study of peginterferon alfa 2a (40 KD) (PEGASYS) and ribavirin (COPEGUS) and Amantidine or placebo in patients with chronic hepatitis C genotype 1 infection [abstract 534]. Poster presented at: 55th Annual Meeting of American Association for Study of Liver Disease (AASLD) conference (Boston). Alexandria, VA: AASLD, 2004: 396A. First citation in article