Reply to: “Pre-treatment prediction of response to pegylated-interferon plus ribavarin for chronic hepatitis C using RVR”
Authors: Masayuki Kurosaki, Namiki Izumi
Journal: Journal of Hepatology (2011)

Pre-treatment prediction of response to pegylated-interferon plus ribavirin for chronic hepatitis C using genetic polymorphism in IL28B and viral factorsJournal of HepatologyVol. 54Issue 3PreviewPegylated interferon and ribavirin (PEG-IFN/RBV) therapy for chronic hepatitis C virus (HCV) genotype 1 infection is effective in 50% of patients. Recent studies revealed an association between the IL28B genotype and treatment response. We aimed to develop a model for the pre-treatment prediction of response using host and viral factors. Full-Text PDF Pre-treatment prediction of response to pegylated-interferon plus ribavarin for chronic hepatitis C using RVRJournal of HepatologyVol. 55Issue 5PreviewWe read with interest the paper of Kurosaki and colleagues [1] and applaud their use of data mining to develop a decision tree to predict HCV treatment outcomes. We agree with them that prediction of treatment outcome is very important in the process of physician and patient making a decision to commence treatment for HCV infection, especially genotype 1. This prevents futile therapy in patients with little chance of cure, and the decision tree presentation also offers the opportunity for patients to be actively involved in setting the level of futility. Full-Text PDF Open Access We appreciate the interest of Dr. Wahed in our article recently published in the Journal of Hepatology [[1]Kurosaki M. Tanaka Y. Nishida N. Sakamoto N. Enomoto N. Honda M. et al.Pre-treatment prediction of response to pegylated-interferon plus ribavirin for chronic hepatitis C using genetic polymorphism in IL28B and viral factors.J Hepatol. 2011; 54: 439-448Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar]. We were impressed of their validation of our prediction model by substituting rapid virological response (RVR) for IL28B genotype (modified model) [[2]Jafferbhoy H. et al.Pre-treatment prediction of response to pegylated-interferon plus ribavirin for chronic hepatitis C using RVR.J Hepatol. 2011; 55: 1162-1163Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. Wahed et al. showed that among patients with RVR, those with high platelet counts (⩾140 × 109/L), and low HCV RNA (<600,000 IU/ml)) had 90% chance of sustained virological response (SVR). Their results confirmed our finding that platelet count and pretreatment HCV RNA level are predictors of SVR, independently of early virological dynamics and showed that combination of these factors improved the prediction accuracy. However, according to their data, a modified model could not identify patients who have high chance of SVR among those who failed to achieve RVR. In a study by Thompson et al. [[3]Thompson A.J. Muir A.J. Sulkowski M.S. Ge D. Fellay J. Shianna K.V. et al.Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus.Gastroenterology. 2010; 139: 120-129Abstract Full Text Full Text PDF PubMed Scopus (658) Google Scholar], RVR was correlated with the IL28B genotype and was a strong predictor of SVR regardless of IL28B genotype. On the other hand, the major IL28B genotype (CC at rs12979860) was associated with a higher rate of SVR (among Caucasians, 66% (IL28B major genotype) vs. 31% (IL28B minor hetero-genotype) and 24% (IL28B minor genotype)) among patients who failed to achieve RVR. There were similar findings in our cohort, where patients with RVR had a high rate of SVR independent of IL28B genotype (97% for IL28B major type vs. 100% for IL28B minor type) but among non-RVR patients, the IL28B major genotype was associated with significantly higher rate of SVR (45% for IL28B major genotype vs. 12% for IL28B minor genotype). Collectively, IL28B genotype has a significant predictive power even after virological response at week 4 of therapy was determined. This means that RVR is associated with IL28B genotype but RVR could not entirely replace IL28B genotype for the accurate prediction of SVR. In order to assess if our model still has the power to predict SVR after virological response at week 4 of therapy was determined, we modified our predictive model by adding RVR as a first splitting variable and applied the data of our cohort. As a result, among patients who failed to achieve RVR in our cohort, patients with IL28B major genotype who had (1) high platelet counts (⩾140 × 109/L), and low HCV RNA (<600,000 IU/ml) had 87% chance of SVR, (2) high platelet counts (⩾140 × 109/L), and high HCV RNA (⩾600,000 IU/ml) had 60% chance of SVR, and (3) low platelet counts (<140 × 109/L), and more than 2 mutations in interferon sensitivity determining region (ISDR) [[4]Enomoto N. Sakamoto I. Asahina Y. Kurosaki M. Murakami T. Yamamoto C. et al.Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection.N Engl J Med. 1996; 333: 77-81Crossref Scopus (991) Google Scholar] had 69% chance of SVR (Fig. 1). Patients who fall into these three groups constitute 39% of non-RVR patients. Thus, our predictive model could determine patients with high probability of SVR even after virological response at week 4 of therapy was determined. We fully agree with Dr. Wahed that it is important to identify the patients who would be cured with current standard of care to reduce the implementation costs of new drugs such as protease inhibitors and that RVR is the most reliable predictor of SVR. In addition, we believe that determination of IL28B and ISDR could further improve the prediction accuracy and that predictive model incorporating RVR, IL28B genotype and ISDR could be used not only for negative prediction but also for positive prediction. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.