5
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Regional differences in hepatitis C treatment with peginterferon and ribavirin in Japan: a retrospective cohort study

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Purpose

          The aims of this study were to investigate regional differences in hepatitis C virus (HCV) infection treatment with peginterferon and ribavirin in Japan and to develop and validate statistical models for analysis of regional differences, using generalized linear mixed models.

          Methods

          Individuals with chronic HCV infection were identified from the Japanese Interferon Database (registered from December 2009 to April 2013). The total sustained virologic response rate and the rate in each prefecture were calculated. In the analysis using generalized linear mixed models, the following four models were constructed: 1) prefecture as a fixed effect, 2) prefecture and other confounding variables as fixed effects, 3) prefecture as a random effect, and 4) prefecture as a random effect and other confounding variables as fixed effects. The quality of the model fit was assessed using the Akaike information criterion and the Bayesian information criterion. All statistical analyses were performed using SAS Version 9.4 for Windows.

          Results

          From 36 prefectures, 16,349 cases were recorded in the study period. Of these, 4,677 were excluded according to certain criteria. The total sustained virologic response rate was 59.9% (range, 43.9%–71.6%). The statistical model including prefecture as a random effect and other confounding variables as fixed effects showed the best fit based on the Akaike information criterion (13,830.92) and Bayesian information criterion (13,845.17).

          Conclusion

          Regional differences may exist in HCV infection treatment in Japan. The model including prefecture as a random effect and other confounding variables as fixed effects was appropriate for analysis of such regional differences. Additional studies considering the medical situations of each patient would provide useful information that could contribute to improve and standardize HCV infection treatment.

          Related collections

          Most cited references 20

          • Record: found
          • Abstract: not found
          • Article: not found

          Diagnosis, management, and treatment of hepatitis C: an update.

            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection: 2011 Practice Guideline by the American Association for the Study of Liver Diseases

            This practice guideline has been approved by the American Association for the Study of Liver Diseases (AASLD) and endorsed by the Infectious Diseases Society of America, the American College of Gastroenterology and the National Viral Hepatitis Roundtable. Preamble These recommendations provide a data-supported approach to establishing guidelines. They are based on the following: (1) a formal review and analysis of the recently published world literature on the topic (MEDLINE search up to June 2011); (2) the American College of Physicians' Manual for Assessing Health Practices and Designing Practice Guidelines;1 (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association's Policy Statement on the Use of Medical Practice Guidelines;2 and (4) the experience of the authors in regard to hepatitis C. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a Class (reflecting benefit versus risk) and Level (assessing strength or certainty) of Evidence to be assigned and reported with each recommendation (Table 1, adapted from the American College of Cardiology and the American Heart Association Practice Guidelines).3,4 Table 1 Grading System for Recommendations Classification Description Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective Class 2 Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a diagnostic evaluation, procedure, or treatment Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy Class 2b Usefulness/efficacy is less well established by evidence/opinion Class 3 Conditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure/treatment is not useful/effective and in some cases may be harmful Level of Evidence Description Level A Data derived from multiple randomized clinical trials or meta-analyses Level B Data derived from a single randomized trial, or nonrandomized studies Level C Only consensus opinion of experts, case studies, or standard-of-care Introduction The standard of care (SOC) therapy for patients with chronic hepatitis C virus (HCV) infection has been the use of both peginterferon (PegIFN) and ribavirin (RBV). These drugs are administered for either 48 weeks (HCV genotypes 1, 4, 5, and 6) or for 24 weeks (HCV genotypes 2 and 3), inducing sustained virologic response (SVR) rates of 40%-50% in those with genotype 1 and of 80% or more in those with genotypes 2 and 3 infections.5-7 Once achieved, an SVR is associated with long-term clearance of HCV infection, which is regarded as a virologic “cure,” as well as with improved morbidity and mortality.8-10 Two major advances have occurred since the last update of treatment guidelines for chronic hepatitis C (CHC) that have changed the optimal treatment regimen of genotype 1 chronic HCV infection: the development of direct-acting antiviral (DAA) agents11-17 and the identification of several single-nucleotide polymorphisms associated with spontaneous and treatment-induced clearance of HCV infection.18,19 Although PegIFN and RBV remain vital components of therapy, the emergence of DAAs has led to a substantial improvement in SVR rates and the option of abbreviated therapy in many patients with genotype 1 chronic HCV infection. A revision of the prior treatment guidelines is therefore necessary, but is based on data that are presently limited. Accordingly, there may be need to reconsider some of the recommendations as additional data become available. These guidelines review what treatment for genotype 1 chronic HCV infection is now regarded as optimal, but they do not address the issue of prioritization of patient selection for treatment or of treatment of special patient populations. Direct-Acting Antiviral Agents There are multiple steps in the viral lifecycle that represent potential pharmacologic targets. A number of compounds encompassing at least five distinct drug classes are currently under development for the treatment of CHC. Presently, only inhibitors of the HCV nonstructural protein 3/4A (NS3/4A) serine protease have been approved by the Food and Drug Administration (FDA). Protease Inhibitors The NS3/4A serine protease is required for RNA replication and virion assembly. Two inhibitors of the NS3/4A serine protease, boceprevir (BOC) and telaprevir (TVR), have demonstrated potent inhibition of HCV genotype 1 replication and markedly improved SVR rates in treatment-naïve and treatment-experienced patients.12,13,16,17 Limited phase 2 testing has shown that TVR also has activity against HCV genotype 2 infection but not against genotype 3.20 With regard to BOC, there are limited data indicating that it too, has activity against genotype 2 but also against genotype 3 HCV infection.21 However, at this time, neither drug should be used to treat patients with genotype 2 or 3 HCV infections, and when administered as monotherapy, each PI rapidly selects for resistance variants, leading to virological failure. Combining either PI with PegIFN and RBV limits selection of resistant variants and improves antiviral response.15 Patients Who Have Never Received Therapy (Treatment-Naïve Patients) Boceprevir The SPRINT-2 trial evaluated BOC in two cohorts of treatment-naïve patients: Caucasian and black patients.12 The number of patients in the black cohort was small in comparison to that of the Caucasian cohort and may have been insufficient to provide an adequate assessment of true response in this population. All patients were first treated with PegIFN alfa-2b and weight-based RBV as lead-in therapy for a period of 4 weeks, followed by one of three regimens: (1) BOC, PegIFN, and RBV that was administered for 24 weeks if, at study week 8 (week 4 of triple therapy), the HCV RNA level became undetectable (as defined in the package insert as 80% among black patients who achieved an eRVR on a TVR-based regimen. A total of 62% of patients in the T12PR group and 53% in the T8PR group with advanced fibrosis achieved an SVR, the rate improving to >80% among those with an eRVR. In the T12PR group, the impact of high versus low viral load (>800,000 or 10-15 IU/mL at week 24. Fig. 4 Sustained virological response (SVR) rates in treatment naïve patients with genotype 1 chronic HCV infection: Telaprevir (TVR) plus peginterferon and ribavirin (PR) results overall and among those who did or did not achieve an eRVR (extended rapid virological response; undetectable HCV RNA at weeks 4 and 12). Patients who achieved an eRVR were randomized at week 20 to receive an additional 4 or an additional 28 weeks of SOC therapy; those who did not develop an eRVR were not randomized and all received an additional 24 weeks of SOC therapy.22 Recommendations: The optimal therapy for genotype 1, chronic HCV infection is the use of boceprevir or telaprevir in combination with peginterferon alfa and ribavirin (Class 1, Level A). Boceprevir and telaprevir should not be used without peginterferon alfa and weight-based ribavirin (Class 1, Level A). For Treatment-Naïve Patients: The recommended dose of boceprevir is 800 mg administered with food three times per day (every 7-9 hours) together with peginterferon alfa and weight-based ribavirin for 24-44 weeks preceded by 4 weeks of lead-in treatment with peginterferon alfa and ribavirin alone (Class 1, Level A). Patients without cirrhosis treated with boceprevir, peginterferon, and ribavirin, preceded by 4 weeks of lead-in peginterferon and ribavirin, whose HCV RNA level at weeks 8 and 24 is undetectable, may be considered for a shortened duration of treatment of 28 weeks in total (4 weeks lead-in with peginterferon and ribavirin followed by 24 weeks of triple therapy) (Class 2a, Level B). Treatment with all three drugs (boceprevir, peginterferon alfa, and ribavirin) should be stopped if the HCV RNA level is >100 IU/mL at treatment week 12 or detectable at treatment week 24 (Class 2a, Level B). The recommended dose of telaprevir is 750 mg administered with food (not low-fat) three times per day (every 7-9 hours) together with peginterferon alfa and weight-based ribavirin for 12 weeks followed by an additional 12-36 weeks of peginterferon alfa and ribavirin (Class 1, Level A). Patients without cirrhosis treated with telaprevir, peginterferon, and ribavirin, whose HCV RNA level at weeks 4 and 12 is undetectable should be considered for a shortened duration of therapy of 24 weeks (Class 2a, Level A). Patients with cirrhosis treated with either boceprevir or telaprevir in combination with peginterferon and ribavirin should receive therapy for a duration of 48 weeks (Class 2b, Level B). Treatment with all three drugs (telaprevir, peginterferon alfa, and ribavirin) should be stopped if the HCV RNA level is >1,000 IU/mL at treatment weeks 4 or 12 and/or detectable at treatment week 24 (Class 2a, Level B). Patients Who Have Previously Received Therapy Three categories have been defined for persons who had received previous therapy for CHC but who had failed the treatment. Null responders are persons whose HCV RNA level did not decline by at least 2 log IU/mL at treatment week 12; partial responders are persons whose HCV RNA level dropped by at least 2 log IU/mL at treatment week 12 but in whom HCV RNA was still detected at treatment week 24; and relapsers are persons whose HCV RNA became undetectable during treatment, but then reappeared after treatment ended. Taking these categories into account, phase 3 trials have been performed also in treatment-experienced patients with genotype 1 chronic HCV infection using BOC and TVR in combination with PegIFN and RBV. The BOC trial design included a 4-week lead-in phase of PegIFN and RBV and compared response-guided triple therapy (BOC plus PegIFN and RBV for 32 weeks; patients with a detectable HCV RNA level at week 8 received SOC for an additional 12 weeks) and a fixed duration of triple therapy given for 44 weeks (total 48 weeks of therapy), to SOC therapy.13 The TVR trial design consisted of three arms: in the first arm, patients received triple therapy for 12 weeks followed by SOC treatment for 36 weeks; in the second arm, patients received lead-in treatment with SOC for 4 weeks, followed by triple therapy for 12 weeks, ending with SOC treatment for 32 weeks; the third arm consisted of SOC treatment for 48 weeks.17 In both trials, an SVR occurred significantly more frequently in those who received the triple therapy regimens than in those who received the SOC therapy. In the BOC trial (RESPOND-2 Trial), the SVR rates were 66% and 59% in the two triple therapy arms compared to 21% in the control arm, prior relapsers achieving higher SVR rates (75% and 69%, respectively) than prior partial responders (52% and 40%, respectively) compared to the rates attained in the SOC arm (29% and 7%, respectively); null responders were excluded from this trial (Table 3 and Fig. 5).13 Similarly, the SVR rates in the TVR trial (REALIZE Study) were 64% and 66% in the TVR-containing arms (83% and 88% in relapsers, 59% and 54% in partial responders, and 29% and 33% in null responders) and 17% in the control arm (24% in relapsers, 15% in partial responders and 5% in null responders) (Fig. 6).17 Thus, the response to the triple therapy regimen in both the BOC and TVR trials was influenced by the outcome of the previous treatment with PegIFN and RBV which highlights the importance of reviewing old treatment records to document previous treatment response. In the BOC trial, the SVR rate was higher in those who were relapsers than in those who were partial responders. In the TVR trial also, the highest SVR rate occurred in prior relapsers, a lower rate in partial responders, and the lowest rate in null responders (defined as patients who had 1 log decline in HCV RNA level and treated for 48 weeks (32% and 8%, respectively).13 There are no comparable data for RGT using TVR. Nonetheless, SVR rates are at least as high in relapsers as in treatment-naïve patients, and TVR exposure is 12 weeks with both RGT and 48-week treatment options. Accordingly, although there are no direct data to support the recommendation that relapsers could be treated with TVR using an RGT approach, the FDA does endorse such a recommendation, as is the case for BOC. Utility of Lead-In There is uncertainty about the benefit of a lead-in phase. Theoretically, a PegIFN and RBV lead-in phase may serve to improve treatment efficacy by lowering HCV RNA levels which would allow for steady-state PegIFN and RBV levels at the time the PI is dosed, thereby reducing the risk of viral breakthrough or resistance. In addition, a lead-in strategy does allow for determination of interferon responsiveness and on-treatment assessment of SVR in patients receiving either BOC or TVR. Patients whose interferon response is suboptimal, defined as a reduction of the HCV RNA level of less than 1 log during the 4-week lead-in, have lower SVR rates than do patients with a good IFN response during lead-in treatment.12 Nevertheless, the addition of BOC to poor responders during lead-in still leads to significantly improved SVR rates (28% to 38% compared with 4% if a PI is not added) and thus a poor response during the lead-in phase should not be used to deny patients access to PI therapy. A direct comparison of the lead-in and non-lead-in groups in the BOC phase 2 study, however, did not show a significant difference in SVR rates for either the 28 week regimen, 56% and 54%, or the 48 week regimen, 75% and 67%, treated with and without lead-in, respectively.11 Combining data across all treatment groups in the phase 2 trial demonstrated a trend for a higher rate of virological breakthrough in the BOC-treated patients without a lead-in, 9%, than in those who received lead-in treatment, 4%, (P = 0.06). However, because all the phase 3 data were based on the lead-in strategy, until there is evidence to the contrary, BOC should be used with a 4-week lead-in. A lead-in strategy was not evaluated in the phase 3 TVR treatment-naïve trial, and therefore no recommendation can be made for this drug. Recommendations: For treatment-experienced patients: Re-treatment with boceprevir or telaprevir, together with peginterferon alfa and weight-based ribavirin, can be recommended for patients who had virological relapse or were partial responders after a prior course of treatment with standard interferon alfa or peginterferon alfa and/or ribavirin (Class 1, Level A). Re-treatment with telaprevir, together with peginterferon alfa and weight-based ribavirin, may be considered for prior null responders to a course of standard interferon alfa or peginterferon alfa and/or weight-based ribavirin (Class 2b, Level B.) Response-guided therapy of treatment-experienced patients using either a boceprevir- or telaprevir-based regimen can be considered for relapsers (Class 2a, Level B for boceprevir; Class 2b, Level C for telaprevir), may be considered for partial responders (Class 2b, Level B for boceprevir; Class 3, Level C for telaprevir), but cannot be recommended for null responders (Class 3, Level C). Patients re-treated with boceprevir plus peginterferon alfa and ribavirin who continue to have detectable HCV RNA > 100 IU at week 12 should be withdrawn from all therapy because of the high likelihood of developing antiviral resistance (Class 1, Level B). Patients re-treated with telaprevir plus peginterferon alfa and ribavirin who continue to have detectable HCV RNA > 1,000 IU at weeks 4 or 12 should be withdrawn from all therapy because of the high likelihood of developing antiviral resistance (Class 1, Level B). Adverse Events Adverse events occurred more frequently in patients treated with PIs than in those treated with PegIFN and RBV therapy alone. In the BOC trials, anemia and dysgeusia were the most common adverse events, whereas in the TVR trials, rash, anemia, pruritus, nausea, and diarrhea developed more commonly among those who received TVR than who received SOC therapy.12,16 In the phase 3 TVR trials, a rash of any severity was noted in 56% of patients who received a TVR-based regimen compared to 32% of those who received a PegIFN and RBV regimen.16 The rash was typically eczematous and maculopapular in character, consistent with a drug-induced eruption. In most patients, the rash was mild to moderate in severity but was severe (involving >50% of the body surface area) in 4% of cases. The development of rash necessitated discontinuation of TVR in 6% and of the entire regimen in 1% of the cases. The Stevens Johnson Syndrome or Drug-Related Eruption with Systemic Symptoms (DRESS) occurred in 100 IU/mL or >10-15 IU/mL at treatment week 24 and, for TVR, therapy should be stopped at either week 4 or 12 if the viral level is >1,000 IU/mL or if week 24 HCV RNA is detectable. Recommendations: Patients who develop anemia on protease inhibitor-based therapy for chronic hepatitis C should be managed by reducing the ribavirin dose (Class 2a, Level A). Patients on protease inhibitor-based therapy should undergo close monitoring of HCV RNA levels and the protease inhibitors should be discontinued if virological breakthrough (>1 log increase in serum HCV RNA above nadir) is observed (Class 1, Level A). Patients who fail to have a virological response, who experience virological breakthrough, or who relapse on one protease inhibitor should not be re-treated with the other protease inhibitor (Class 2a, Level C). Role of IL28B Testing in Decision to Treat and Selection of Therapeutic Regimen The likelihood of achieving an SVR with PegIFN and RBV and of spontaneous resolution of HCV infection differ depending on the nucleotide sequence near the gene for IL28B or lambda interferon 3 on chromosome 19.18,19 One single-nucleotide polymorphism that is highly predictive is detection of the C or T allele at position rs12979860.18 The CC genotype is found more than twice as frequently in persons who have spontaneously cleared HCV infection than in those who had progressed to CHC. Among persons with genotype 1 chronic HCV infection who are treated with PegIFN and RBV, SVR is achieved in 69%, 33%, and 27% of Caucasians who have the CC, CT, and TT genotypes, respectively; among black patients, SVR rates were 48%, 15%, and 13% for CC, CT, and TT genotypes, respectively.29 The predictive value of IL28B genotype testing for SVR is superior to that of the pretreatment HCV RNA level, fibrosis stage, age, and sex, and is higher for HCV genotype 1 virus than for genotypes 2 and 3 viruses.29,30 There are other polymorphisms near the gene for IL28B that also predict SVR, including detection of the G or T allele at position rs8099917, where T is the favorable genotype, and essentially provides the same information in Caucasians as C at rs12979860.31,32 In one study, as well as in preliminary analyses of the phase 3 registration data, IL28B genotype remained predictive of SVR even in persons taking BOC or TVR.33 In Caucasian patients randomized in the SPRINT 2 trial to take BOC for 48 weeks, SVR was achieved by 80%, 71%, and 59% of patients with CC, CT, and TT genotypes, respectively.34 In Caucasian patients randomized in the ADVANCE trial to take TVR for 12 weeks, SVR was achieved by 90%, 71%, and 73% of patients with CC, CT, and TT genotypes, respectively.35 IL28B genotype also predicts the likelihood of qualifying for RGT. In treatment-naïve Caucasian patients randomized in SPRINT 2 to BOC, the week 8 HCV RNA threshold was achieved in 89% and 52% of patients with CC and CT/TT genotypes, respectively.34 In treatment-naïve Caucasian patients randomized in the ADVANCE study to TVR, eRVR was achieved in 78%, 57%, and 45% of patients with CC, CT, and TT genotypes, respectively.35 Although the IL28B genotype provides information regarding the probability of SVR and abbreviated therapy that may be important to provider and patient, there are insufficient data to support withholding PIs from persons with the favorable CC genotype because of the potential to abbreviate therapy and the trend for higher SVR rates observed in the TVR study. In addition, the negative predictive value of the T allele with PI-inclusive therapy is not sufficiently high to restrict therapy for all patients, because SVR was achieved by more than half of Caucasians with the TT genotype.34,35 In summary, these data indicate that IL28B genotype is a significant pretreatment predictor of response to therapy. Consideration should be given to ordering the test when it is likely to influence either the physician's or patient's decision to initiate therapy. There are insufficient data to determine whether IL28B testing can be used to recommend selection of SOC over a PI-based regimen with a favorable genotype (CC) and in deciding upon the duration of therapy with either regimen. Recommendation: IL28B genotype is a robust pretreatment predictor of SVR to peginterferon alfa and ribavirin as well as to protease inhibitor triple therapy in patients with genotype 1 chronic hepatitis C virus infection. Testing may be considered when the patient or provider wish additional information on the probability of treatment response or on the probable treatment duration needed (Class 2a, Level B). Special Populations There is a paucity of information for many of the subgroups with the greatest unmet need for treatment (e.g., patients coinfected with HIV and HCV, those with decompensated cirrhosis, and those after liver transplantation). Data from phase 1 and 2 trials have provided interim information that may guide related treatment issues. BOC and TVR undergo extensive hepatic metabolism, BOC primarily by way of the aldoketoreductase (AKR) system but also by the cytochrome P450 enzyme system, whereas TVR is metabolized only by the cytochrome P450 enzyme system, and the main route of elimination is via the feces with minimal urinary excretion. Thus, no dose adjustment of BOC or TVR is required in patients with renal insufficiency. No clinically significant differences in pharmacokinetic parameters were observed with varying degrees of chronic liver impairment in patients treated with BOC and therefore, no dosage adjustment of this drug is required in patients with cirrhosis and liver impairment. Although TVR may be used to treat patients with mild hepatic impairment (Child-Turcotte-Pugh class A, score 5 or 6), it should not be used in HCV-infected patients with moderate to severe hepatic impairment, because no pharmacokinetic or safety data are available regarding its use in such patients. As noted above, BOC and TVR are both inhibitors of CYP3A4, and concomitant administration of medications known to be CYP3A4 substrates should be done with caution and under close clinical monitoring. Pharmacokinetic interactions have particular implications in HIV-coinfected and transplant populations, where drug–drug interactions will complicate treatment paradigms, so that any use of BOC or TVR in transplant or HIV-coinfected populations of patients with HCV should be done with caution and under close clinical monitoring. TVR and BOC are not recommended for use in children and adolescents younger than 18 years of age, because the safety and efficacy has not been established in this population. Thus, whereas BOC and TVR have great promise for improved SVR in special populations, many complex treatment issues remain to be evaluated in further phase 2 and 3 testing.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial.

              Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) patients with heart failure and preserved left ventricular ejection fraction assigned to spironolactone did not achieve a significant reduction in the primary composite outcome (time to cardiovascular death, aborted cardiac arrest, or hospitalization for management of heart failure) compared with patients receiving placebo. In a post hoc analysis, an ≈4-fold difference was identified in this composite event rate between the 1678 patients randomized from Russia and Georgia compared with the 1767 enrolled from the United States, Canada, Brazil, and Argentina (the Americas).
                Bookmark

                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                22 March 2016
                : 10
                : 1217-1223
                Affiliations
                [1 ]Department of Drug Evaluation and Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
                [2 ]The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
                Author notes
                Correspondence: Yohei Kawasaki, Department of Drug Evaluation and Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan, Tel/fax +81 54 264 5591, Email ykawasaki@ 123456u-shizuoka-ken.ac.jp
                Article
                dddt-10-1217
                10.2147/DDDT.S102458
                4809336
                27042013
                © 2016 Ide et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Comments

                Comment on this article