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Copyright of Casos & Revisiones de Salud is the property of Victor Manuel Mendoza Nunez, Universidad Nacional Autonoma de Mexico and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Yi-Chun Lin,1 Shih-Wei Li,2 Shin-Yen Ku,3 Hui-Ting Hsieh,3 Mei-Hui Lin,3 Shu-Yin Chang,3 Wei-Wei Wu,3 Na-Lee Sun,3 Shu-Hsing Cheng,1,4 Chien-Yu Cheng1,51Department of Internal Medicine, Division of Infectious Diseases, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan City, Taiwan; 2Division of Gastroenterology, Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan City, Taiwan; 3Comprehensive HIV Care Center, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan City, Taiwan; 4School of Public Health, Taipei Medical University, Taipei, Taiwan; 5School of Public Health, National Yang-Ming University, Taipei, TaiwanBackground and aims: We aimed to evaluate the efficacy and tolerability of grazoprevir/elbasvir in patients with chronic genotype 1 hepatitis C virus (HCV) and HIV co-infection who experienced peginterferon alfa plus ribavirin (PegIFN/RBV) (clinicaltrials.gov NCT03098121).Methods: This non-randomized, open-label trial study was conducted in Taoyuan General Hospital. HIV-infected patients were screened for HCV antibody since June 1, 2012, and HCV and HIV co-infected patients were tested for HCV RNA. The subjects who experienced PegIFN/RBV were enrolled in the study, and of whom with chronic genotype 1a or 1b received grazoprevir 100 mg and elbasvir 50 mg in a fixed-dose combination tablet once daily with or without ribavirin for 12 to 16 weeks.Results: Of 2,419 HIV-infected patients, 40 patients with chronic genotype 1 HCV and HIV co-infection who failed PegIFN/RBV treatment were enrolled. Sixteen patients had genotype 1a and 24 patients had genotype 1b, with or without cirrhosis. The median age was 42 (41–47) years, and 5 patients (12.5%) were diagnosed with liver cirrhosis (child Pugh score A). The median CD4 count was 504 cells/μL (321–689). All patients (100%) had HIV viral load 10 IU/mL (3.98–7.12). At the end of treatment, all patients (100%, 40/40) had undetectable HCV viral load, and 95.0% (38/40) of patients achieved sustained virologic response at 12 weeks.Conclusion: Grazoprevir/elbasvir was effective in genotype 1 patients co-infected with HIV with or without cirrhosis. This finding is consistent with that of previous trials of this regimen in monoinfected population.Keywords: hepatitis C, grazoprevir and elbasvir, PEGylated interferon plus ribavirin, direct-acting antiviral, HCV genotype 1, HCV/HIV co-infection

Background: Elbasvir/grazoprevir (EBR/GZR) is a new generation, fixed‐dose, combination antiviral drug used in chronic hepatitis C virus (HCV) genotype (GT) 1 or 4 infection. Our study evaluates the clinical efficacy and safety of EBR/GZR after its launch in Taiwan. Methods: This is a retrospective observational study. Patients who had received EBR/GZR for chronic HCV GT 1 between June 2017 and April 2018 were recruited. Patients' age, sex, HCV GT, changes in HCV RNA level before and after treatment, sustained virologic response 12 weeks (SVR12) after the cessation of drug administration, side effects, and interaction effects were used to evaluate the clinical efficacy and safety. Results: A total of 149 patients were recruited. Of them, 145 (97.3%) had HCV GT 1b, and the rest had HCV GT 1a; most of the EBR/GZR‐related side effects in this study were mild. Three participants were discontinued because their alanine transaminase levels were elevated to over 10 times the upper limit of normal. The therapeutic effect analyses revealed a rapid virologic response rate of 95.3% and an SVR12 rate of 98%. Subgroup analyses performed using SVR12 as the outcome variable revealed three demographic factors HCV GT 1, hepatocellular carcinoma medical history, and noncirrhosis plus HCV RNA level. Conclusions: This study confirmed that EBR/GZR is safe and effective for treating patients with HCV GT 1 and exhibited excellent overall clinical efficacy in Taiwan. The therapeutic effects are unrelated to factors such as sex, HCV RNA level before treatment, and history of liver cirrhosis. Highlight: EBR/GZR is safe and effective for HCV GT 1 in Taiwan.SVR rate is high and compare with western country.Medication related side effect is mild and tolerable.There are no significant statistic difference in renal function in each group during the period of treatment and follow‐up. [ABSTRACT FROM AUTHOR]

Objectives: To compare the efficacy of sofosbuvir/ledipasvir (SOF/LDV) for 8 weeks (SL8) versus a 12-week course of SOF/LDV (SL12) among HIV/HCV-coinfected patients in clinical practice. In addition we compared sustained virological response (SVR) rates achieved with SL8 in HCV-monoinfected and HIV/HCV-coinfected patients in a real life setting.Methods: HCV-infected patients were retrospectively selected from the HEPAVIR-DAA and GEHEP-MONO real-life prospective cohorts if they fulfilled the following criteria: 1) Infected with genotype 1; 2) Treatment with SL8 or SL12; 3) Treatment naïve prior to receiving SL8 or SL12; 4) Absence of cirrhosis; 5) Baseline HCV RNA<6 × 106 IU/mL; 6) Reached the scheduled time-point for SVR (SVR12) assessment. SVR12 and relapse rates of HCV-monoinfected and HIV/HCV-coinfected patients were compared on an intention to treat basis. The responses with SL8 and SL12 were also compared.Results: In the SL8 group, 107 (51%) HCV-monoinfected and 102 (49%) HIV/HCV-coinfected patients were included. One hundred and sixty-four (43%) HCV-monoinfected subjects and 220 (57%) HIV/HCV-coinfected patients received SL12. SVR12 rates for HIV/HCV-coinfected patients treated with SL8 vs SL12 were SVR12 92.2% vs. 97.3% (p = 0.044) and the respective relapse rates were 4.9% vs. 0.5% (p = 0.013). SVR12 rates for SL8 among HCV-monoinfected and HIV/HCV-coinfected patients were: 96.3% vs. 92.2% (p = 0.243), respectively. The corresponding relapse rates were 0.9% vs. 4.9% (p = 0.112).Conclusion: HIV/HCV-coinfected patients reach high rates of SVR12 with SL8, although lower than with SL12, mainly due to a higher probability of relapse. SVR12 rates with SL8 are numerically lower and the proportion of relapses higher in HIV/HCVcoinfected patients than in HCV-monoinfected subjects. [ABSTRACT FROM AUTHOR]

Introduction: Boceprevir (BOC) was one of the first oral inhibitors of hepatitis C virus (HCV) NS3 protease to be developed. This study assessed the safety and efficacy of BOC + pegylated interferon-α2a/ribavirin (PEG-IFN/RBV) in the retreatment of HIV–HCV co-infected patients with HCV genotype 1. Methods: This was a phase III prospective trial. HIV–HCV (genotype 1) co-infected patients from 16 hospitals in Spain were included. These patients received 4 weeks of PEG-IFN/RBV (lead-in), followed by response-guided therapy with PEG-IFN/RBV plus BOC (a fixed 44 weeks was indicated in the case of cirrhosis). The primary endpoint was the sustained virological response (SVR) rate at 24 weeks post-treatment. Efficacy and safety were evaluated in all patients who received at least one dose of the study drug. Results: From June 2013 to April 2014, 102 patients were enrolled, 98 of whom received at least one treatment dose. Seventy-three percent were male, 34% were cirrhotic, 23% had IL28b CC, 65% had genotype 1a, and 41% were previous null responders. The overall SVR rate was 67%. Previous null-responders and cirrhotic patients had lower SVR rates (57% and 51%, respectively). Seventy-six patients (78%) completed the therapy scheme; the most common reasons for discontinuation were lack of response at week 12 (12 patients) and adverse events (six patients). Conclusions: Response-guided therapy with BOC in combination with PEG-IFN/RBV led to an overall SVR rate of 67%, but an SVR rate of only 51% in patients with cirrhosis. The therapy was generally well tolerated. Although the current standards of care do not include BOC + PEG-IFN/RBV, the authors believe that this combination can be beneficial in situations where new HCV direct antiviral agent interferon-free therapies are not available yet.

Objective: To assess the true efficacy of direct acting antiviral (DAA) therapy in real-world clinical practice, taking into account those patients that do not complete therapy or the necessary follow-up to establish sustained viral response (SVR).Methods: Retrospective data collection of 261 genotype 1 HCV-infected patients, treatment naïve or treatment experienced, treated with ledipasvir/sofosbuvir combination therapy at an academic medical center. All patients received individualized teaching and counseling prior to starting therapy stressing importance of compliance with laboratory monitoring and treatment completion. Intention to treat SVR rates (ITT-SVR) and per-protocol SVR rates (PP-SVR) were calculated. Chi-squared test was used to compare the number of subjects lost to follow-up in the treatment-naïve vs. treatment-experienced groups. Characteristics of noncompliant patients were compared to compliant patients.Results: ITT-SVR rates for the entire cohort were 74%, significantly lower than the 95% PP-SVR rate for the compliant patients (p < 0.001). ITT-SVR was lower in treatment-naïve patients compared to treatment-experienced patients (68% vs. 86%). Among the entire cohort, 22% of patients either discontinued therapy prematurely (7%) or did not return for SVR assessment (15%). Failure to complete therapy or return for SVR assessment was statistically more common among treatment-naïve patients compared to treatment-experienced patients (28% vs. 11%, p = 0.0016).Conclusions: There is a significant rate of noncompliance among patients treated with DAA in real-world clinical practice despite pre-treatment education efforts. The ITT-SVR rates observed in clinical practice were significantly lower than those reported by clinical trials, and this difference was most pronounced among treatment-naïve patients. [ABSTRACT FROM AUTHOR]

Depression is a major reason for interferon (IFN) therapy cessation. IFN-free direct-acting antiviral (DAA) therapy for depression is not well-documented. Thus, four different IFN-free regimens were assessed in genotype-1 hepatitis C virus (HCV) patients with depression. Overall, 287 HCV genotype-1 patients who received combination therapies with IFN-free DAAs of daclatasvir/asunaprevir (DCV/ASV) (n=84), sofosbuvir/ledipasvir (SOF/LDV) (n=95), ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) (n=74), and elbasvir/grazoprevir (EBR/GZR) (n=34) were included. Treatment-induced depression as a complication of HCV therapy in IFN-free DAA regimens was assessed. The severity of depression was evaluated using the Beck Depression Inventory-II (BDI-II) questionnaire. It was demonstrated that all four DAA regimens achieved similar high efficacy in Japanese patients with HCV genotype-1 infection. Moreover, in seven patients with depression who received the 24-week DCV/ASV treatment regimen, the BDI-II scores significantly increased at week 4 as compared with pretreatment values; furthermore, they decreased below baseline at week 12 despite the rapid decline of serum HCV levels after the initiation of DCV/ASV therapy. The BDI-II scores gradually decreased during therapy in the remaining 77 DCV/ASV-treated patients without depression. The BDI-II scores showed a significant decrease from baseline to the end of treatment with 12-week regimens, including SOF/LDV and EBR/GZR. The 12-week DAA regimen of SOF/LDV and EBR/GZR can be safely used with high efficacy in patients with genotype-1 HCV infection, including those with depression. [ABSTRACT FROM AUTHOR]

Background & Aims Ledipasvir/sofosbuvir (LDV/SOF) for 8 to 24 weeks is approved for the treatment of chronic hepatitis C virus infection (HCV). In the ION-3 study, 8 weeks of LDV/SOF was non-inferior to 12 weeks in previously untreated genotype 1 (GT1) patients without cirrhosis. According to the Summary of Product Characteristics (SmPC), 8-week treatment may be considered in naïve non-cirrhotic GT1-patients. However, there are only limited data on the effectiveness of an 8-week regimen of LDV/SOF under real-world conditions. The aim of the present study was to characterise patients receiving 8 weeks of LDV/SOF compared to those receiving 12 weeks of LDV/SOF, and to describe therapeutic outcomes in routine clinical practice. Methods The German Hepatitis C-Registry is a large national real-world cohort that analyses effectiveness and safety of antiviral therapies in chronic HCV. This data set is based on 2,404 patients. Treatment with SOF/LDV (without RBV) for 8 or 12 weeks was initiated on or before September 30, 2015. Results Overall, 84.6% (2,034/2,404) of the safety population (intention-to-treat-1 [ITT1]) and 98.2% (2,029/2,066) of the per protocol (PP) population achieved sustained virological response at week 12 (SVR12). In the 8-week group, 85.1% (824/968) of ITT1 and 98.3% (821/835) of PP patients achieved SVR12, while in the 12-week group, 85.5% (1,210/1,415) of ITT1, and 98.1% (1,208/1,231) of PP patients achieved SVR12. When treated according to the SmPC, 98.7% (739/749) of the patients achieved SVR12 (PP). Relapse was observed in 9.5% (2/21) of cirrhotic patients treated for 8 weeks (PP). Conclusions Under real-world conditions a high proportion of eligible patients receiving 8-week LDV/SOF treatment achieved SVR12. Relapse occurred more frequently in patients who did not meet the selection criteria according to the SmPC. Lay summary In a large real-world cohort of patients mainly treated by physicians in private practice in Germany, shorter HCV treatment (8-week) resulted in equivalent cure rates to 12-week treatment in genotype 1 HCV-infected patients. Thus, shorter treatment can be recommended in these patients which would substantially reduce costs of therapy. Clinical Trial number: DRKS00009717 (German Clinical Trials Register, DRKS) [ABSTRACT FROM AUTHOR]

Background & Aims The efficacy of NS5A inhibitors for the treatment of patients chronically infected with hepatitis C virus (HCV) can be affected by the presence of NS5A resistance-associated substitutions (RASs). We analyzed data from 35 phase I, II, and III studies in 22 countries to determine the pretreatment prevalence of various NS5A RASs, and their effect on outcomes of treatment with ledipasvir-sofosbuvir in patients with genotype 1 HCV. Methods NS5A gene deep sequencing analysis was performed on samples from 5397 patients in Gilead clinical trials. The effect of baseline RASs on sustained virologic response (SVR) rates was assessed in the 1765 patients treated with regimens containing ledipasvir-sofosbuvir. Results Using a 15% cut-off, pretreatment NS5A and ledipasvir-specific RASs were detected in 13% and 8% of genotype 1a patients, respectively, and in 18% and 16% of patients with genotype 1b. Among genotype 1a treatment-naïve patients, SVR rates were 91% (42/46) vs. 99% (539/546) for those with and without ledipasvir-specific RASs, respectively. Among treatment-experienced genotype 1a patients, SVR rates were 76% (22/29) vs. 97% (409/420) for those with and without ledipasvir-specific RASs, respectively. Among treatment-naïve genotype 1b patients, SVR rates were 99% for both those with and without ledipasvir-specific RASs (71/72 vs. 331/334), and among treatment-experienced genotype 1b patients, SVR rates were 89% (41/46) vs. 98% (267/272) for those with and without ledipasvir-specific RASs, respectively. Conclusions Pretreatment ledipasvir-specific RASs that were present in 8--16% of patients have an impact on treatment outcome in some patient groups, particularly treatment-experienced patients with genotype 1a HCV. Lay summary The efficacy of treatments using NS5A inhibitors for patients with chronic hepatitis C virus (HCV) infection can be affected by the presence of NS5A resistance-associated substitutions (RASs). We reviewed results from 35 clinical trials where patients with genotype 1 HCV infection received treatments that included ledipasvir-sofosbuvir to determine how prevalent NS5A RASs are in patients at baseline, and found that ledipasvir-specific RASs were present in 8--16% of patients prior to treatment and had a negative impact on treatment outcome in subset of patient groups, particularly treatment-experienced patients with genotype 1a HCV. [ABSTRACT FROM AUTHOR]

Aim The aim of the current study was to characterize the population pharmacokinetics of a triple direct-acting antiviral (DAA) regimen (3D) (ombitasvir, paritaprevir-ritonavir and dasabuvir) and adjunctive ribavirin, and estimate covariate effects in a broad spectrum of subjects with hepatitis C virus (HCV) genotype 1 infection. Methods Pharmacokinetic data from six phase III studies and one phase II study in subjects receiving the currently approved doses of the 3D ± ribavirin regimen for treating HCV genotype 1 infection for 12 weeks or 24 weeks were characterized using separate population pharmacokinetic models, built using each component of the regimen from nonlinear mixed-effects methodology in NONMEM 7.3. In the models, demographic and clinical covariates were tested. Models were assessed via goodness-of-fit plots, visual predictive checks and bootstrap evaluations. Results The population pharmacokinetic models for each component of the 3D ± ribavirin regimen (DAAs and ritonavir, n = 2348) and ribavirin ( n = 1841) adequately described their respective plasma concentration-time data. Model parameter estimates were precise and robust, and all models showed good predictive ability. Significant covariate effects associated with apparent clearance and volume of distribution included age, body weight, gender, cirrhosis, HCV subtype, opioid or antidiabetic agent use, and creatinine clearance. Conclusion The population pharmacokinetics of the 3D ± ribavirin regimen components in HCV-infected patients were characterized using phase II and III HCV clinical trial data. Although several statistically significant covariates were identified, their effects were modest and not clinically meaningful to necessitate dose adjustments for any component of the 3D regimen. [ABSTRACT FROM AUTHOR]

High rates of sustained virologic response ( SVR) has been achieved in Japanese patients with chronic hepatitis C virus ( HCV) genotype ( GT)1 and GT2 infection treated with ledipasvir/sofosbuvir ( LDV/ SOF) ±ribavirin ( RBV) and SOF+ RBV, respectively. We evaluated the effect of baseline HCV NS5A and NS5B resistance-associated variants ( RAVs) on treatment outcome and characterized variants at virologic failure. Baseline deep sequencing for NS5A and NS5B genes was performed for all GT1 patients. Deep sequencing of NS5A ( GT1 only) and NS5B ( GT1 and GT2) was performed for patients who failed treatment or discontinued early with detectable HCV RNA (i.e., >25 IU/ mL). In patients with HCV GT1 infection, 22.3% ( GT1a: 2/11; GT1b: 74/330) had ≥1 baseline NS5A RAV. The most frequent NS5A RAVs in GT1b were Y93H (17.9%, 59/330) and L31M (2.4%, 8/330). Despite the presence of NS5A RAVs at baseline, 100% and 97% of patients achieved SVR12, compared with 100% and 99% for those with no NS5A RAVs with LDV/ SOF and LDV/ SOF+ RBV, respectively. All patients with NS5B RAVs at baseline achieved SVR12. Of the 153 patients with GT2 infection ( GT2a 60.1%, GT2b 39.9%), 3.3% (5/153) experienced viral relapse. No S282T or other NS5B RAVs were detected at baseline or relapse; no change in susceptibility to SOF or RBV was observed at relapse. In conclusion, LDV/ SOF and SOF+ RBV demonstrate a high barrier to resistance in Japanese patients with HCV GT1 and GT2 infection. The presence of baseline NS5A RAVs did not impact treatment outcome in GT1 Japanese patients treated with LDV/ SOF for 12 weeks. [ABSTRACT FROM AUTHOR]

Aims Paritaprevir is a direct acting antiviral agent for use as part of a multidrug hepatitis C virus infection treatment regimen. To characterize the pharmacokinetics, safety, and tolerability of paritaprevir and determine an optimal dosing regimen for subsequent evaluations, clinical studies were conducted with paritaprevir alone or with ritonavir, a cytochrome P450 3A4 inhibitor anticipated to increase paritaprevir exposure. Methods Two phase 1, double-blind, placebo-controlled, parallel group studies were conducted in healthy volunteers (NCT00850044 and NCT00931281). Single dose study participants ( n = 87) were randomized to one time administration of either paritaprevir or placebo, or paritaprevir with ritonavir or placebo. Participants ( n = 38) enrolled in the multiple dose study received paritaprevir with ritonavir or placebo once or twice daily for 14 days. Pharmacokinetics, safety and tolerability were assessed throughout the study treatment periods. Results After single or multiple dose administration, paritaprevir displayed non-linear pharmacokinetics, with maximum plasma concentration and area under the plasma concentration-time curve increasing in a greater than dose proportional manner. Concomitant administration of 100 mg ritonavir increased paritaprevir exposure from a 300 mg dose approximately 30- to 50-fold and extended paritaprevir half-life. The tolerability of paritaprevir was similar with or without ritonavir. Asymptomatic, transient increases in bilirubin were observed but were not associated with abnormalities in other liver function tests. Conclusions Paritaprevir exhibits non-linear pharmacokinetics with greater than dose proportional increases in exposure after single or multiple dosing. Co-administration with ritonavir increases paritaprevir exposure and half-life without adversely influencing tolerability. [ABSTRACT FROM AUTHOR]

Objective: The combined PEG-IFN alpha and RBV therapy achieved SVR in 40 - 50% of patients infected with HCV genotype 1. Identification of virological and host paramemeters predicting SVR will be useful to tailor therapy. Methods: 71 patients with chronic HCV genotype 1 infection were treated with PEG-IFN alpha2a and RBV for 12 months. Predictors of SVR were analyzed by using nonparametric correlation test. Results: SVR was found in 57 / 71 of subjects (80,3%). The significant differences in baseline level of HCV RNA, sex, age, baseline ALT and present of liver cirrhosis between the patients with or without SVR were not found. Correlation was not proved between SVR and all these factors when they were analyzed separately. High correlation was found between serum levels of HCV RNA at the end of 3-th month therapy (Early Virological Response) and SVR (r=0,759; p=0,011).Conclusion: The viral response during the first 3 months of PEG-IFN alpha and RBV therapy is the strongest independent predictor among the all baseline viral and host predictive factors for achieving of SVR.

Background Direct-acting antiviral agents (DAAs) combined with pegylated-interferon (PegIFN) and ribavirin (RBV) are still a standard treatment in patients with genotype 1HCV infection. However, virologic response could be impaired by baseline or early selection of resistant HCV strains. Objectives The aim of this study was to determine the onset and persistence of resistance-associated mutations (RAMs) in the NS3 and NS5B genes of DAA-naïve patients failing treatment. Study design Direct sequencing of HCV NS3 was performed in 49 DAA-naïve patients with HCV genotype 1 infection. Results Eight out of 23 patients (34.7%) failed PegIFN/RBV/telaprevir during the 12-weeks of therapy. Treatment failure was associated with the development of RAMs at amino-acids 36,54,80 and 155 of the HCV protease in 6/8 patients (75%). Among patients treated with PegIFN/RBV/boceprevir treatment, 4/18 (22.2%) failed therapy. Of these, 2 (50%) carried virus strains which developed a RAM at amino-acids 54 and 155. Among HCV strains with RAMs, 7 belonged to genotype 1a and 1 to 1b. Finally, in 6/10 (60%) patients, drug-resistant variants could still be detected for up to 3–7 months after stopping therapy. Conclusions A higher rate ( p = 0.49) of treatment failure was observed in patients receiving telaprevir- compared to the boceprevir-based combination. In addition, compared with genotype 1b, genotype 1a was associated with higher rates ( p = 0.01) of treatment failure due to virus resistant strains. Resistance testing at baseline and during DAA treatment should be taken into consideration when treating patients with new HCV combination therapies. [ABSTRACT FROM AUTHOR]

New and more promising therapies for chronic hepatitis C ( CHC) genotype 1 (G1) naive patients have recently been approved in the United States and Europe, and several more regimens are expected to become available within the next several years. While this scenario unfolds, it is necessary to develop a rational method to allocate current treatment in CHC G1 patients. We performed a cost-effectiveness analysis of boceprevir ( BOC)- and telaprevir ( TVR)-based triple therapy according to different patients' selection strategies. A semi-Markov model of CHC natural history and progression towards end-stage liver disease was built. We considered 3 selection strategies based on METAVIR fibrosis stage: (i) treat all patients with F1-F4 fibrosis, (ii) only F2-F4 and (iii) only F3-F4. For each strategy, TVR interleukin-28B-guided ( IL28B-guided) and BOC rapid virologic response-guided (RVR-guided) therapies were applied. The model assessed the costs and outcomes, using a lifetime and 5-year time horizon, and adopting the Italian National Health System perspective. The incremental cost-effectiveness ratio ( ICER) for F1-F4 strategy relative to F3-F4 was €5132 per quality-adjusted life years gained, across TVR IL-28B-guided therapy, and €7042 in the BOC RVR-guided therapy. Conversely, in the 5-year scenario, the ICER for F1-F4 strategy relative to F3-F4 was €1 818 679 ( TVR IL28B-guided) and €1 866 437 ( BOC RVR-guided) per end-stage liver disease or death ( ESLD-D) avoided. In view of anticipated improvement in the efficacy of future regimens, selective treatment of only patients with advanced fibrosis and cirrhosis with TVR or BOC could represent the most cost-effective strategy to optimize resource utilization. [ABSTRACT FROM AUTHOR]

Background In HCV genotype 1-infected patients with HIV co-infection, tritherapy [ HCV protease inhibitors ( PIs) plus peg-interferon and ribavirin] has been shown to have an increased rate of sustained virological response. However, complex drug-to-drug interactions and tolerability issues remain a concern. Methods Under the auspices of four French scientific societies of medicine, a committee was charged of establishing guidelines on the use of first-generation HCV PIs in these patients. This scientific committee based its work on preliminary results from tritherapy clinical trials in co-infected patients and, since data on these patients are still scarce, on the statements already made by the French Association for the Study of the Liver ( AFEF) on the use of tritherapy in HCV mono-infected patients, written in May 2011 and updated in 2012. Each AFEF guideline concerning HCV monoinfection was examined to determine whether it could be used in the context of HIV/ HCV coinfection. Results These guidelines are addressed for the treatment of coinfected patients with various profiles, including treatment-naïve or patients with failure to previous bitherapy and mention those patients for whom tritherapy should start or those for whom it should be delayed. Preliminary results of triple therapy as well as factors associated to virological response are also discussed. Other issues include virological monitoring, clinical and virological criteria to stop therapy, practical treatment management, treatment adherence and the management of side effects and interactions with antiretroviral drugs. These guidelines were submitted for critical review to independent experts. [ABSTRACT FROM AUTHOR]

Background and Aims The aim of this study was to examine the distribution of interferon lambda-3 ( IFN-λ3) gene polymorphisms in previously untreated Australian patients with genotype 1 ( Gt1) chronic hepatitis C ( CHC) and to compare the IFN-λ3 genotype frequency among the different ethnic populations. Methods This was a prospective, multicenter, observational study undertaken by the Australian Liver Association Clinical Research Network. Eligible subjects had Gt1 CHC and were being considered for and/or undergoing treatment. IFN-λ3 single nucleotide polymorphisms were genotyped by the Applied Biosystems's Taqman single nucleotide polymorphism genotyping assay. Results Between May 2012 and June 2012, 1132 patients were recruited from 38 treatment clinics across Australia. Also, 561 subjects from the CHARIOT (collaborative group hepatitis C study using high dose Pegasys RBV Induction dose in genotype one) study of high-dose interferon who had baseline serum available were retrospectively tested. The overall frequency of IFN-λ3 rs12979860 CC/CT/TT genotypes was 36%, 52%, and 12%, and that of rs8099917 TT/TG/GG genotypes was 54%, 41%, and 5%, respectively. The prevalence of the favorable IFN-λ3 rs12979860 CC and rs8099917 TT genotypes in Causcasians, Asians, Aboriginals, Maori/ Pacific Islanders, and Mediterraneans was 32% and 52%, 80% and 86%, 33% and 63%, 77% and 88%, and 19% and 29%, respectively. Compared with Caucasians, the frequency of IFN-λ3 CC was significantly higher among Asians ( P < 0.0001) and Maori/ Pacific Islander subjects ( P < 0.0001). Conclusions The distribution of IFN-λ3 polymorphisms among untreated patients with Gt1 CHC in Australia appears similar to that reported from North America. The frequency of the favorable response alleles varies considerably according to ethnicity, being more common in self-reported Asians and Maori/ Pacific Islanders than Caucasians, Aboriginals, and Mediterraneans. [ABSTRACT FROM AUTHOR]

We describe a patient infected with hepatitis C virus (HCV) genotype 1 who failed to respond to interferon with or without ribavirin seven times but who then achieved sustained virological response by the combination of interferon-beta plus ribavirin treatment for 48 weeks. He did not respond to stronger treatment such as prolonged peginterferon plus ribavirin treatment for 87 weeks. It might be rare to treat a patient with interferon 8 times considering the cost and time, since patients failing interferon treatment several times are regarded to be refractory to interferon. It is possible that the difference in biological effects between interferon-alfa and interferon-beta might have resulted in a different outcome in our patient. Interferon-beta plus ribavirin therapy might be one of the treatment options for certain patients chronically infected with HCV who do not respond to standard care treatment. [ABSTRACT FROM AUTHOR]

Abstract: Recently, genome-wide associated studies (GWAS) have identified that host genetics IL28B SNPs rs12979860 and rs8099917 were significantly associated with SVR in patients infected with chronic HCV genotype 1 to PEG-INF/RBV therapy. Results from these studies remain conflicting. We conducted this meta-analysis to estimate the overall association of SVR with rs12979860 and rs8099917. We searched the PubMed, Embase, Scholar Google, ISI Web of Knowledge, and Chinese National Knowledge Infrastructure (CNKI) databases for all articles before July 30, 2012. The odds ratio (OR) corresponding to the 95% confidence interval (CI) was used to assess the association. The statistical heterogeneity among studies was assessed with the I2 statistics. Begg''s test and Egger''s test were performed to evaluate the publication bias. Eventually, twenty studies were selected for the meta-analysis. The IL-28B SNPs rs12979860 genotype CC and rs8099917 genotype TT significantly positive associated with SVR in patients infected chronic HCV genotype 1 to PEG-INF/RBV therapy (OR=4.473, 95% CI=3.814–5.246, OR=5.171, 95% CI=4.372–6.117 respectively). The results suggested that rs12979860 genotype CC and rs8099917 genotype TT could be used as independent predictors of the HCV-1 infected patients. [Copyright &y& Elsevier]

. It is unclear whether the current threshold for 'high' hepatitis C virus (HCV) RNA level (800 000 IU/mL) is optimal for predicting sustained virological response (SVR). We retrospectively analysed pretreatment HCV RNA levels and SVR rates in 1529 mono-infected and 176 HIV-HCV co-infected patients treated with peginterferon alfa-2a (40 kD) plus ribavirin. We improved the threshold for differentiating low and high viral load by fitting semiparametric generalized additive logistic regression models to the data and constructing receiver operating characteristics curves. Among HCV genotype 1 mono-infected patients, the difference in SVR rates between those with low and high baseline HCV RNA levels was 27% (70% vs 43%) when 400 000 IU/mL was used and 16% (59% vs 43%) when 800 000 IU/mL was used. In HIV-HCV genotype 1 co-infected patients, the difference was 51% (71% vs 20%) when 400 000 IU/mL was used and 43% (61% vs 18%) when 800 000 IU/mL was used. A lower threshold (200 000 IU/mL) was identified for genotype 1 mono-infected patients with 'normal' alanine aminotransferase (ALT) levels. No threshold could be identified in HCV genotype 2 or 3 patients. A threshold HCV RNA level of 400 000 IU/mL is optimal for differentiating high and low probability of SVR in genotype 1-infected individuals with elevated ALT. [ABSTRACT FROM AUTHOR]

Abstract: Background: Inappropriate persistence of chemokines expression in hepatitis C virus (HCV) infection can drive tissue damage, intrahepatic inflammation, and liver cell injury. The aim of study was to study the association of plasma fractalkine (CX3CL1) levels with fibrosis stage and necroinflammatory activity grade of liver biopsies in human immunodeficiency virus (HIV)/HCV co-infected patients with HCV genotype 1. Methods: We carried out a cross-sectional study on 125 patients. Grading and staging of liver biopsies were carried out by METAVIR score. Plasma CX3CL1 was measured using an immunoassay kit. Results: Patients with advanced fibrosis had higher CX3CL1 levels than those with mild or no fibrosis (p =0.010); and patients with severe activity grade had higher CX3CL1 levels than those with low activity grade (p =0.040). Plasma CX3CL1 levels were significantly associated with increased odds of significant fibrosis (odds ratio (OR): 3.47 (95% of confidence interval (95%CI): 1.04; 11.58)), advanced fibrosis (OR: 6.78 (95%CI: 1.70; 26.93)), and moderate necroinflammatory activity grade (OR: 4.09 (95%CI: 1.21; 13.87)). When we analyzed fibrosis stages and activity grades of METAVIR score together, we found a positive significant association of CX3CL1 levels with moderate activity grade/significant fibrosis (OR: 5.49 (95%CI: 1.46; 20.58)) and moderate activity grade/advanced fibrosis (OR: 8.99 (95%CI: 2.06; 39.23)). Conclusion: Plasma CX3CL1 levels were independently associated with several characteristics of severe liver disease in HIV/HCV coinfected patients with HCV-genotype 1, suggesting a role of CX3CL1 in the pathogenesis of HCV infection. [Copyright &y& Elsevier]

Abstract: In our program to discover non-nucleoside, small molecule inhibitors of genotype 1 HCV polymerase, we investigated a series of promising analogs based on a benzothiadiazine screening hit that contains an ABCD ring system. After demonstrating that a methylsulfonylamino D-ring substituent increased the enzyme potency into the low nanomolar range, we explored a minimum core required for activity by truncating to a three-ring system. Described herein are the syntheses and structure–activity relationship of a set of inhibitors lacking the A-ring of an ABCD ring system. We observed that small aromatic rings and alkenyl groups appended to the 5-position of the B-ring were optimal, resulting in inhibitors with low nanomolar potencies. [Copyright &y& Elsevier]

HCV infections are two-times more prevalent in black Americans than in whites. We previously reported that treatment with peginterferon alfa-2a plus ribavirin produced a sustained virologic response (SVR) rate of 26% in blacks, a lower efficacy compared with the SVR in whites. Here we detail the safety profile of peginterferon alfa-2a plus ribavirin and the relationship between treatment adherence, defined by cumulative drug exposure, and SVR in 78 black patients infected with HCV genotype 1. Sixty-two (79%) patients completed 48 weeks of combination treatment. Peginterferon alfa-2a dose was modified for neutropenia in 36 patients (46%), whereas ribavirin dose was modified due to anemia in 31 patients (40%). The SVR rate was related to medication exposure, based on the percentage of the planned doses of peginterferon and ribavirin that the patients received. The SVR rates were 33, 25 and 0% in patients who received >80, 61–80 and ≤60% of the planned peginterferon, respectively. The SVR rates were 28, 33 and 18% in patients who received >80, 61–80 and ≤60% of the planned ribavirin. The SVR rate was 29% (11 of 38) in patients who received >80% of the total planned doses of both peginterferon and ribavirin and 7% (1 of 14) in patients who received ≤80% of both medicines. The SVR was 30% in patients who received >60% exposure to both, and 0% in patients with ≤60% exposure. In conclusion, peginterferon alfa-2a plus ribavirin demonstrated good safety and tolerability profiles in blacks infected with HCV genotype 1. Adherence to at least >60% of the planned peginterferon alfa-2a and ribavirin doses for 48 weeks was associated with a greater SVR in black patients with HCV genotype 1 infections. [ABSTRACT FROM AUTHOR]

Background/Aims: The aim of the present, open-labeled, randomized study was to determine the efficacy and safety of different doses of consensus interferon plus ribavirin in the initial treatment of chronic hepatitis C.Methods: One hundred and one genotype 2/3 patients were randomized to receive 9 mcg (group A, n=48) or 18 mcg (group B, n=53) of consensus interferon thrice weekly plus ribavirin (1000/1200 mg/daily) for 24 weeks and 92 genotype 1 patients to receive 9 mcg (group C, n=47) or 18 mcg (group D, n=45) of consensus interferon plus ribavirin for 48 weeks.Results: In an intention-to-treat analysis, the sustained virologic response at 24-week follow-up was 69% and 66% for group A and B (P=0.77) and 40% and 36% for group C and D (P=0.63). The overall sustained response was 67% and 38% in patients with genotype 2/3 and 1, respectively. Among genotype 1 patients the sustained virologic response was 39% and 41% for high or low baseline viremia levels.Conclusions: Higher consensus interferon dose does not increase sustained virologic response. Naive genotype 1 patients may achieve significant response rate of approximately 40% if treated with 9 mcg of consensus interferon plus ribavirin for 48 weeks. [Copyright &y& Elsevier]