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• W2894902832 abstract "With the rapid evolution of treatment for chronic hepatitis C (CHC), the novel direct-acting antivirals (DAAs) have become the standard of care (SOC) in western countries with very high sustained virological response (SVR) rate [1,2]. Nevertheless, the peginterferon alfa (PEG-IFN)/ribavirin combination therapy, the SOC treatment regimen since 2004, remained the important therapy in some countries or areas where DAAs are not available or not universally used due to their high cost [3]. Hence the providers of health care are want to determine whether there is a place remaining for the less expensive interferon-containing regimes in the future treatment paradigms. With the efforts on optimizing the treatment strategies, hepatologists have learnt much in the decades of experience gained by exploring the predictors for response and developing the efficient individualized therapy. Researchers have identified the important factors ether pretreatment or on-treatment which help greatly the optimization of therapy. When considering the pretreatment predictors, both the viral and host factors have been identified. It has been well demonstrated that HCV genotypes, viral load, the degree of viral quasi-species complexity and the number of mutations within specific regions of the HCV genome (i.e. the NS5A region). In consideration of the host factors associated with response, factors such as age, gender, ethnicity, body mass index (BMI), insulin resistance, etc. have been found. With regard to concurrent diseases, the liver steatosis severity and fibrosis stage are also considered as important predictors. In host factors, serologic markers have been reported to be associated with a response. For example, serum protein levels [4,5] or several microRNAs levels such as miR-21, miR-122, miR-34a, miR-195, miR-192 or let-7g [6–8] are predictors for response to PEG-IFN/ribavirin. Polymorphisms of host genes have been shown to be important determinants for SVR. In previous Taiwanese studies, tumor necrosis factor-α promoter polymorphism and human leukocyte antigen alleles have been reported as independent predictors for response to interferon-based therapy [9,10]. In 2009, host genetic variability of the genome-wide association studies (GWAS) reported that the interleukin (IL) 28B locus, located on the long arm of chromosome 19 were associated significantly with high and maybe the most important baseline predictor for the SVR rate for PEG-IFN/ribavirin therapy [11]. The different role of IL28B genotypes are elucidated with the highly association of SVR in genotype 1- but not genotype 2/3-infected patients [11,12]. The pretreatment predictors indeed provide the possibility to be able to select and design the therapeutic strategies for patients before initiation of PEG-IFN/ribavirin therapy. Another major breakthrough in the treatment of CHC with PEG-IFN/ribavirin is the identification of the on-treatment predictors for SVR which is based on the different pattern of changes of the viral load. With the recommended treatment of 48 and 24 weeks of PEG-IFN/ribavirin for HCV-1/4 and HCV 2/3 patients, an abbreviated 24 weeks of PEG-IFN/ribavirin therapy can achieve a fair SVR rate in CHC patients based majorly on the rapid virological response (RVR) which is defined as the polymerase chain reaction (PCR)-seronegative (< 50 IU/mL) HCV RNA after 4 weeks of therapy. For patients without an early virological response (EVR), defined by HCV RNA being seronegative or at least a two logs decrease of HCV RNA rom baseline after 12 weeks of therapy, the very low SVR rate will be achieved which implicates the suggestion of stopping further treatment. According to the concept of response-guided therapy (RGT), the roadmap for individualized therapy for CHC has been recommended broadly. In Taiwan, an abbreviated 24-week regimen for HCV-1/4 patients with baseline viral loads < 400,000 IU/mL and an RVR, and an abbreviated 12 to 16-week regimen with standard dose of ribavirin, 1000-1200 mg/day for HCV-2/3 patients with an RVR was recommended in guidelines of the European Association for the Study of the Liver Disease and Asia-Pacific Association of the Study of the Liver. In addition, the treatment regimen is applied in the reimbursement criteria for treatment of CHC in Taiwanese National Health Insurance [13]. In this issue of the Journal, Wen et al. conducted a retrospective study to assess the pretreatment clinical factors and on-treatment virological response to predict SVR in 158 Taiwanese patients with CHC treated with PEG-IFN/ ribavirin [14]. According to the Taiwanese National Health Insurance guideline for treatment of CHC, authors reported the RVR, complete EVR, partial EVR, null response and relapse and SVR rates were 102 (64.6%), 28 (17.7%), 13 (8.2%), 14 (8.9%), 16 (10.1%) and 113 (71.5%), respectively. In evaluating the independent predictors for SVR, non-genotype 1 and non-cirrhosis were pretreatment factors and an RVR was the only on-treatment factor, respectively. Indeed the study reveals the real-world experience which has been described in previous Taiwanese reports, even though the patient number is relatively limited. Actually for discussion of the predictors of SVR, the lack of IL28B genotypes is the major concern to get the final conclusions. In addition, with the important role of cirrhosis, advanced fibrosis in other words, elucidated in the present study, the acute diagnosis of the cirrhosis is critical. Without liver biopsies which have been considered the “gold standard” of assessment of hepatic fibrosis, the use of sonography definitions for cirrhosis and evaluate the AST/ALT ratio seem not sufficient. Methods of the non-invasive assessment of hepatic fibrosis including biomarkers by blood tests (such as the Fibrotest, the AST/platelet ratio index, enhanced liver fibrosis or FIB-4) and novel technologies such as transient elastography, acoustic radiation force impulse imaging and magnetic resonance elastography have been established which enable assessment of fibrosis rapidly and safely [15]. The more important role of the viral-kinetics than the other factors has been elucidated in previous studies in Taiwan. For genotype 1-infected patients, the IL-28B polymorphisms are predictor for RVR in cohorts treated for 24-week and 48-week. However, further analyses have shown that impact of IL28B genotype on treatment efficacy was only observed among patients without an RVR, but not among those with an RVR. Furthermore, achieving an EVR, but not IL28B genotype, was the most important predictor of achieving an SVR among patients who did not achieve an RVR. For genotype 2-infected patients, achieving an RVR was the only important factors predicting SVR even though IL28B genotype may predict an RVR. It is interesting that recently we studied the dynamic cytokine levels showing that the serum levels of interferon- gamma (IFN-gamma) were significantly elevated in the non-SVR patients compared with the SVR patients at week 4 and week 12 which indicated the earlier detection of the increased IFN-gamma might predict poor response [16]. On the other hand, the development of the predictors earlier than the traditional “stopping rule” (without EVR) at week 12 for non-response to PEG-IFN/ribavirin is also an important aspect in clinical studies. For genotype 1-infected naïve patients, Taiwanese studies have shown that at week 4 if the HCV RNA level decreased less than 1 log than the baseline level or if patients with unfavorable IL28B genotypes have the HCV RNA level higher than 10,000 IU/mL or decreased less than 3 logs than the baseline level, the SVR rate was less than 11%. To get an earlier predictive tool, we have recently developed a model established by using the dynamic expression profile of 8 target genes (RSAD2, LOC26010, HERC5, HERC6, IFI44, SERPING1, IFITM3, and DDX60) in peripheral blood mononuclear cells at week 1 showed a good performance in predicting SVR, which is superior to traditional predictors including the RVR, viral load and IL28B genotype. [17]. The poor response rate might indicate an earlier stopping rule for PEG-IFN/ribavirin therapy to either discontinue the therapy in areas where DAAs are not available. Two regimens of all-oral DAAs therapy (daclatasvir/asunaprevir and paritaprevir/ritonavir/ombitasvir/dasabuvir) have been reimbursed in the Taiwanese NHI for genotype 1- infected patients who fail to respond to PEG-IFN/ribavirin since January, 2017. For patients who are predicted to have a poor response at week 4, stop the PEG-IFN/ribavirin or switch to more potent all-oral DAAs treatment in areas where all-oral DAAs remain the second line therapy for naïve patients such as Taiwan. Before all the barriers for DAAs therapy overcome, the better individualized therapy for PEG-IFN/ribavirin remains an unmet need and further effort to refine the regimen seems mandatory rapid virological response. The author declares no conflicts of interest." @default.
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• W2894902832 date "2017-03-01" @default.
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• W2894902832 title "Further refining individualized therapy with peginterferon alfa/ribavirin for chronic hepatitis C" @default.
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• W2894902832 doi "https://doi.org/10.1002/aid2.12001" @default.
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