Chronic hepatitis C virus (HCV) infection is a major public health problem and is one of the main causes of serious liver disease worldwide [1-4]. Effective treatment for HCV infection is required to reduce the impact of this global health problem. The primary goal of administering antiviral agents, which eliminate detectable circulating HCV, is to cure the chronic HCV infection. The sustained virological response (SVR) has become an indication of curative therapy for chronic HCV infection, and is associated with both a histological improvement and a more favorable clinical outcome. Achieving an SVR is therefore an essential strategy in treating chronic HCV infection. However, the combination therapy of pegylated interferon (PEG-IFN) and ribavirin results in a SVR in only 40% to 50% of patients with HCV genotype 1 and in 70% to 80% of those with genotypes 2 or 3 [5,6]. In recent years, the directing antiviral agents (DAA) has improved cure rates of 80% to 100%, but many patients are still not available DAA therapy because of high cost [7].

Factors that may influence the rate of response to therapy are being investigated extensively, and the results are awaited with great interest. Although the HCV genotype and HCV RNA level are known to be the strongest predictors of SVR, several other factors have also been found to affect treatment responses [8]. Various studies have shown that histological factors (including the amount of fibrosis) are traditional predictors of response, regardless of the genotype [9,10]. In addition, the platelet count has been suggested as a reliable standard for assessing fibrosis [11].

The aim of this study was to evaluate the SVR and to identify the predictive baseline (pretreatment) factors and treatment-related factors associated with SVR in treatment-naïve patients with chronic HCV infection treated with the combination of PEG-IFN α-2a/-2b and ribavirin, especially in Asian country.

This study investigated the factors that may contribute to an SVR in treatment-naive patients with chronic HCV infection who are treated with the combination of PEG-IFN α-2a/-2b and ribavirin. Since baseline predictors of response are useful for advising patients about their likelihood of an SVR, and treatment-related predictors are useful for determining the treatment course and duration, factors that may influence the rate of an SVR to therapy have been investigated extensively [8]. The present study therefore focused on the SVR predictive ability of both baseline factors and treatment-related factors. Several predictors have been identified in previous clinical trials, of which the HCV genotype and HCV RNA levels have been considered the most important [5,8,13-15].

In the current study, the baseline (i.e., pretreatment) predictive factors of SVR were young age, genotype 2, HCV RNA level of < 800,000 IU/mL, and a baseline platelet count of > 150 × 10³/μL. Similar to previous studies [15,16], the SVR rate for antiviral therapy was higher in younger patients than in older patients in the present study. As mentioned above, HCV genotype is one of the most important SVR predictors. Consistent with previous studies, we found that the SVR rate was higher in genotype 2 patients than in genotype 1 patients, by intention-to-treat analysis (63% vs. 79.5%, p = 0.001).

Interestingly, the SVR rates of both genotypes 1 and 2 in this study were higher than those reported previously [5,15,17]. However, the high SVR rate reported herein is compatible with the findings of previous Korean studies [18-20]. Although the reasons for this difference are largely unknown, the good outcomes of Eastern (including Korean) patients regarding treatment efficacy could be due to the favorable interleukin 28B (IL-28) gene polymorphism [21,22], the lower proportion of obese patients, and greater treatment adherence [12,19,20]. Another possible reason for the present outcome could be the low number of cirrhotic patients and the > 60% high rate of a treatment adherence of ≥ 80/80/80. In particular, the treatment was maintained for a sufficient period of time in 83% of patients. In the current study, adherence to treatment was an independent predictive factor for achievement of SVR, and the SVR rates of genotypes 1 and 2 patients were as high as 74.7% and 84.4%, respectively, when a per-protocol analysis was applied. It is well known that improved adherence to treatment can enhance SVR rates [12,18,23]. Therefore, the present findings suggest that efforts to improve adherence to treatment could increase the SVR rate among patients who obtain better outcomes on antiviral therapy.

A low baseline HCV RNA level is associated with a significantly higher probability of achieving SVR. Our results did confirm the importance of baseline HCV RNA levels (< 800,000 IU/mL) for achieving SVR by multivariate analysis [8,15].

While baseline predictive factors of SVR are useful for predicting the efficacy of antiviral therapy, they are not sufficient for clinical decision making. Therefore, knowledge of predictive factors during treatment would be extremely valuable. This study found that achievement of RVR and a treatment adherence of ≥ 80/80/80 were related to treatment-related predictive factors of SVR. This is consistent with it previously being shown that RVR at 4 weeks is an excellent predictor of SVR, especially in genotype 1 [24,25]. EVR, which is known to be one of the most important predictors of SVR, could not perform in regression analysis [26]. It would be impossible to analyses it as a predictive factor of SVR, because treatment was stopped in patients without EVR in accordance with the guidelines.

Another interesting finding of the present study is the association between platelet count and SVR in treatment for chronic HCV infection. It is well known that thrombocytopenia is associated with chronic HCV infection and could be significantly correlated with liver fibrosis stage [11,27]. In patients with chronic HCV infection, advanced fibrosis tends to be associated with a lower platelet count, and a decreased platelet count is in turn known to be associated with a diminished treatment response [28,29]. Mild thrombocytopenia is generally defined as a platelet count of ≤ 150 × 10³/μL, and a platelet count of < 100 × 10³/μL has been used to identify liver cirrhosis in patients with chronic viral hepatitis [11,30]. In the present study, the rate of liver cirrhosis did not differ significantly between SVR and non-SVR patients. Nevertheless, a baseline platelet count of > 150 × 10³/μL was identified as a predictive factor for SVR in entire patients with chronic HCV infection. This suggests that even in the absence of definitive evidence of liver cirrhosis based on clinical measurements, a platelet count of ≤ 150 × 10³/μL is associated with advanced fibrosis in patients with chronic HCV infection. In agreement with this result, it has been reported that patients with a baseline platelet count of > 120 × 10³/μL had a higher probability of an SVR [31-33]. Thus, the findings of the present study suggest that thrombocytopenia is an important factor for SVR prediction; it is considered beneficial in predicting the response of patients treated with PEG-IFN plus ribavirin.

Treatment in patients with chronic HCV infection is changing from interferon based therapy to DAA. However, although DAA has high cure rate, many patients are not treated with DAA for cost and insurance problems [7]. Therefore, patients who have good baseline predictors such as a baseline platelet count of > 150 × 10³/μL, young age, genotype 2 and low HCV RNA level can be treated with interferon based therapy instead of DAA.

This study was subject to several potential limitations. Selection bias was present due to the retrospective study design, and the unavailability of some data in the current study may have affected the results of the multivariate analysis. Despite these concerns, this study makes an important contribution to the understanding of predictive factors of SVR. Deviations from intention-to-treat analysis could introduce potential investigator bias with respect to interpretation of the results. This study did not investigate the IL-28 gene polymorphism. About 95% of Korean patients with chronic HCV infection have favorable IL-28 gene polymorphism to virologic response. Therefore, guidelines of the Korean Association for the Study of the Liver did not recommend the evaluation of IL-28 gene polymorphism for prediction of SVR. Finally, it was possible to underestimate the degree of fibrosis and cirrhosis, because a liver biopsy or indirect fibrosis diagnosis method such as fibroscan were not performed in all of the patients. To overcome this limitation, liver cirrhosis was diagnosed in accordance with criteria based on clinical guidelines. The possibility of cirrhosis may be suggested by the history, clinical manifestation, histology, or compatible laboratory and imaging criteria.

In conclusion, young age, genotype 2, low HCV RNA level, RVR, and treatment adherence were significantly associated with SVR. Another finding of this study demonstrates that platelet count appears to be a significant factor predicting a greater likelihood of SVR, and could thus be a useful predictor for SVR. Platelet count might therefore be useful for developing individualized treatments and optimizing treatment outcomes in patients with chronic HCV infection. Further studies are needed to confirm this.