Asian patients with chronic hepatitis C (CHC) are known to have better virological responses to pegylated (Peg) IFN-based therapy than Western patients. Although IL28B gene polymorphisms may contribute to this difference, whether favorable hepatitis C virus (HCV) kinetics during treatment plays a role remains unclear. We enrolled 145 consecutive Taiwanese patients with CHC receiving Peg-IFN α-2a plus ribavirin for the study. Blood samples were taken more frequently at defined intervals in the first 3 d. Peg-IFN was administered at week 1. It was then administered weekly in combination with daily ribavirin for 24 or 48 wk. A mathematical model fitted to the observed HCV kinetics was constructed, which could interpret the transient HCV titer elevation after Peg-IFN treatment. The results demonstrated a comparable viral clearance rate (c = 3.45 ± 3.73) (day −1 , mean ± SD) but lower daily viral production rate (P = 10 6 -10 12 ) in our patients than those reported previously in Western patients. Of 110 patients with a sustained virological response (SVR), 47 (43%) had a transient elevation of viral titer within 12 h (proportion of 12 h/3 d: 44% in non-SVR vs. 70% in SVR; P = 0.029). Among 91 patients with available rs8099917 data, patients with the TT genotype had an early surge of viral titer after therapy and a higher SVR and viral clearance rate than those with the GT genotype. In conclusion, Taiwanese patients with CHC receiving Peg-IFN plus ribavirin therapy have a lower daily viral production rate than Western patients, and the rs8099917 TT genotype may contribute to the increased viral clearance rate and better virological responses in these patients. H epatitis C virus (HCV) infection is the major etiology of chronic liver disease, liver cirrhosis, and hepatocellular carcinoma (1, 2). According to the estimate from the World Health Organization, there are more than 180 million chronic HCV-infected persons worldwide (1-3); hence, effective treatment of chronic hepatitis C (CHC) is important. Nevertheless, the current standard of care for CHC using pegylated (Peg) IFN plus ribavirin is expensive, is effective in only a certain proportion of patients who have CHC, and has many unpleasant adverse effects (4, 5). Therefore, identifying predictive factors of therapeutical response in patients with CHC is important.Several factors have been linked to the therapeutical response of patients who have CHC, including viral factors (6-11), host factors (12-15), metabolic factors (16-18), histological factors (19), types of regimen (4), and duration of infection (20). Among these factors, viral kinetics following antiviral therapy has become widely accepted in both clinical trials and daily practice (21) and increasingly recognized as the most outweighing predictor of sustained virological response (SVR) to IFN-based therapy (22). Using mathematical models of hepatitis C viral kinetics may further clarify the mechanisms of antiviral therapy, the evolution of resistant viral strains, and the length of time necessary to er...
We appreciate the comments of Guedj et al.(1) on our paper addressing the association of IL28B gene variations with mathematical modeling of viral kinetics in patients with chronic hepatitis C treated with pegylated IFN plus ribavirin therapy (2). Regarding the distribution of the blips among hepatitis C virus (HCV) genotypes, we not only found a lower virion production rate but earlier blips among patients with HCV genotype 2 infection than those with genotype 1 infection. The time for the observed maximal viral load and the estimated time for maximal viral load were significantly different between these two genotypes (genotype 1 vs. 2: 0.33 ± 0.35 vs. 0.19 ± 0.12; P = 0.0048 and P = 0.0106 for the t test and Wilcoxon test), and the time for the maximal value also showed that patients with HCV genotype 1 infection had a poorer virological response than those with genotype 2 infection (Table 1). However, as reported in our paper, although HCV genotype has long been known as a predictor of achieving sustained virological response (SVR) in patients treated with combination therapy, it also serves as a latent factor of viral kinetics, especially for virion production rate. Thus, the impact of HCV genotype on SVR was not significant in our regression models, and viral kinetic parameters were still better than HCV genotype in the prediction of SVR.As to the modeling of HCV kinetics during combination therapy, we assumed that target cells remained constant in the first 2 wk and estimated K 1 ′ and K 2 ′ by fitting the viral load data of the first 3 d for each patient. Because all patients had persistent HCV infection, their viral loads would be in the steady state (a state of equilibrium), almost remain constant before therapy, and not increase before therapy, as raised by Guedj et al. (1). However, this does not indicate that the viral loads will surely decline after treatment because there could be a transition state in the very early stage of therapy. Thus, we chose the solution (three-parameter solution) that could model the observed earlier blips of the earlier transition state. The earlier transition state corresponds to the condition δ = c, which is necessary for the three-parameter solution to hold. In other words, we have a state of equilibrium, δ = c, in the earlier transition state. On the other hand, the four-parameter solution, the choice of the standard mathematical model for HCV infection and treatment (3), represents the other state of "equilibrium." According to this standard model, "c is approximately 50 times larger than δ" (4), and we believe that the patients with this kind of condition are not analyzed under the consideration of earlier transition state but are only focused on in the state of viral load progression before SVR and that this later equilibrium is achieved under the complex interactions of therapy, the host immune system, and HCV from the earlier transition state.Therefore, our three-parameter model and the standard model indeed present different equilibrium states of HCV kinetics. F...
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