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Sofosbuvir and ribavirin exert their anti-hepatitis C virus (anti-HCV) activity following metabolic activation in the liver. However, intrahepatic concentrations of the pharmacologically active nucleotide metabolites in humans are poorly characterized due to the inaccessibility of tissue and technical challenges with measuring nucleotide levels. A clinical study assessing the efficacy of sofosbuvir and ribavirin administered prior to liver transplantation to prevent HCV recurrence provided a unique opportunity to quantify nucleotide concentrations in human liver. We analyzed nucleotides using high-performance liquid chromatography coupled to tandem mass spectrometry in liver tissue from 30 HCV-infected patients with hepatocellular carcinoma who were administered sofosbuvir (400 mg/day) and ribavirin (1,000 to 1,200 mg/day) for 3 to 52 weeks prior to liver transplantation. Median total hepatic metabolite concentrations (the sum of nucleoside and mono-, di-, and triphosphates) were 77.1 μM for sofosbuvir and 361 μM for ribavirin in patients on therapy at the time of transplantation. Ribavirin and sofosbuvir efficiently loaded the liver, with total hepatic metabolite concentrations exceeding maximal levels in plasma by approximately 30-fold. Ribavirin metabolite levels suggest that its monophosphate is in great excess of its inhibition constant for IMP dehydrogenase and that its triphosphate is approaching the binding constant for incorporation by the HCV NS5B RNA-dependent RNA polymerase. In accordance with the potent antiviral activity of sofosbuvir, these results demonstrate that the liver triphosphate levels achieved following sofosbuvir administration greatly exceed the inhibition constant for HCV NS5B. In conclusion, this study expands the quantitative understanding of the pharmacology of sofosbuvir and ribavirin by establishing efficient hepatic delivery in the clinic. (This study has been registered at ClinicalTrials.gov under identifier NCT01559844.)., (Copyright © 2018 American Society for Microbiology.)

Background & Aims: There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease., Methods: In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12)., Results: We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%-89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%-98% of patients without cirrhosis or with compensated cirrhosis, by 85%-88% of patients with moderate hepatic impairment, by 60%-75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation., Conclusion: The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Patients with hepatitis C virus (HCV) infection and cirrhosis are underrepresented in clinical trials of interferon-free regimens of direct-acting antiviral agents, making it difficult to optimize therapy. We performed a post-hoc analysis of data from seven clinical trials to evaluate the efficacy and safety of the fixed-dose combination of ledipasvir (LDV) and sofosbuvir (SOF), with and without ribavirin (RBV), in 513 treatment-naïve and previously treated patients with genotype 1 HCV and compensated cirrhosis. All patients received LDV-SOF for 12 or 24 weeks with or without RBV. We determined the rates of sustained virological response (SVR) 12 weeks after treatment (SVR12) overall and for subgroups. Of the 513 patients analyzed, 69% were previously treated and 47% had failed previous treatment with a protease-inhibitor regimen. Overall, 493 patients (96%; 95% confidence interval [CI]: 94%-98%) achieved SVR12, 98% of treatment-naïve and 95% of previously treated patients. SVR12 rates did not vary greatly by treatment duration (95% of patients receiving 12 weeks and 98% of patients receiving 24 weeks of treatment), nor by addition of RBV (95% of patients receiving LDV-SOF alone and 97% of those who received LDV-SOF plus RBV), although previously treated patients receiving 12 weeks of LDV-SOF without RBV had an SVR12 rate of 90%. One patient discontinued LDV-SOF because of an adverse event (AE). The most common AEs were headache (23%), fatigue (16%-19%), and asthenia (14%-16%). One patient (<1%) of those receiving LDV-SOF alone, and 4 (2%) of those receiving LDV-SOF plus RBV had treatment-related serious AEs., Conclusions: This analysis suggests that 12 weeks of LDV-SOF is safe and effective for treatment-naïve patients with HCV genotype 1 and compensated cirrhosis. The relatively lower SVR in treatment-experienced patients treated with 12 weeks of LDV-SOF raises the question of whether these patients would benefit from adding RBV or extending treatment duration to 24 weeks., (© 2015 by the American Association for the Study of Liver Diseases.)

Unlabelled: In phase III studies, treatment with the once-daily fixed-dose combination tablet of ledipasvir/sofosbuvir (LDV/SOF) with and without ribavirin (RBV) resulted in high rates of sustained virological response (SVR) in patients chronically infected with genotype 1 hepatitis C virus, including those with compensated cirrhosis. We conducted an analysis of data from these trials to compare the safety and tolerability profile of LDV-SOF with and without RBV. We analyzed treatment-emergent adverse events (AEs) and laboratory abnormalities in patients who were randomized to 8, 12, and 24 weeks of LDV/SOF with or without RBV. In total, data from 1,952 patients (of whom 872 received LDV/SOF with RBV and 1,080 received LDV/SOF alone) were analyzed. Overall, 308 patients (16%) were African American, 224 (11%) had compensated cirrhosis, 501 (26%) had a body mass index ≥30 kg/m(2) , and 440 (23%) were treatment experienced. Treatment-related AEs occurred in 71% and 45% of patients treated with and without RBV, respectively, including fatigue, insomnia, irritability, and rash/pruritus. Patients receiving RBV with LDV/SOF were more likely to require dose modification, interruptions of treatment resulting from AEs, or require the use of concomitant medications than those receiving LDV/SOF alone. Rates of treatment-related serious AEs and discontinuations resulting from AEs were similarly low (<1%) in both groups. The rate of SVR in those receiving RBV and those not receiving RBV was the same (97%)., Conclusion: LDV/SOF plus RBV was associated with a greater incidence of AEs as well as concomitant medication use than LDV/SOF alone. Use of RBV did not impact the efficacy of LDV/SOF regimens in the ION phase III studies., (© 2015 by the American Association for the Study of Liver Diseases.)

Unlabelled: Treatment with interferon (IFN) and ribavirin (RBV) significantly impairs quality of life and other patient-reported outcomes (PROs). Patient experience with IFN- and RBV-free anti-HCV (hepatitis C virus) regimens has not been reported. We assessed PROs in patients treated with ledipasvir and sofosbuvir (LDV/SOF) with and without RBV. Four different PRO questionnaires were administered at baseline, during, and post-treatment in HCV genotype 1 patients treated with LDV/SOF±RBV (ION-1, -2, and -3). A total of 1,952 patients were enrolled to be treated for 8 (N = 431), 12 (N = 867), or 24 weeks (N = 654) with LDV/SOF (N = 1,080) or LDV/SOF+RBV (N = 872). Baseline demographics and psychiatric disorders were similar between treatment groups (all P > 0.05). Patients receiving LDV/SOF regimens showed significant improvement of PRO scores during treatment (up to +7.4%, +7.0%, and +6.7% on a normalized 0%-100% scale in the 8-, 12-, and 24-week-long treatment groups, respectively (all P < 0.0001). These PRO improvements coincided with early viral suppression after 2 weeks of treatment and maximized by the end of treatment. On the other hand, during treatment with LDV/SOF+RBV, PRO scores declined (up to -5.5% regardless of treatment duration; P < 0.0001). Receiving RBV was an independent predictor of PRO impairment in multivariate analysis (beta up to -5.9%; P < 0.0001). Patients who achieved sustained virological response at 12 weeks showed significant improvement of their PROs post-treatment (up to +8.3%; P < 0.0001)., Conclusion: IFN- and RBV-free regimens with LDV/SOF result in early HCV suppression with simultaneous improvement in PROs that continued throughout the duration of treatment and post-treatment., (© 2015 by the American Association for the Study of Liver Diseases.)

Background & Aims: Patients with detectable hepatitis C virus (HCV) RNA at the time of liver transplantation universally experience recurrent HCV infection. Antiviral treatment before transplantation can prevent HCV recurrence, but existing interferon-based regimens are poorly tolerated and are either ineffective or contraindicated in most patients. We performed a trial to determine whether sofosbuvir and ribavirin treatment before liver transplantation could prevent HCV recurrence afterward., Methods: In a phase 2, open-label study, 61 patients with HCV of any genotype and cirrhosis (Child-Turcotte-Pugh score, ≤7) who were on waitlists for liver transplantation for hepatocellular carcinoma, received up to 48 weeks of sofosbuvir (400 mg) and ribavirin before liver transplantation. The primary end point was the proportion of patients with HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients with this HCV-RNA level at their last measurement before transplantation., Results: Sixty-one patients received sofosbuvir and ribavirin, and 46 received transplanted livers. The per-protocol efficacy population consisted of 43 patients who had HCV-RNA level less than 25 IU/mL at the time of transplantation. Of these 43 patients, 30 (70%) had a post-transplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died (2 from nonfunction of the primary graft and 1 from complications of hepatic artery thrombosis). Of all 61 patients given sofosbuvir and ribavirin, 49% had a post-transplantation virologic response. Recurrence was related inversely to the number of consecutive days of undetectable HCV RNA before transplantation. The most frequently reported adverse events were fatigue (in 38% of patients), headache (23%), and anemia (21%)., Conclusions: Administration of sofosbuvir and ribavirin before liver transplantation can prevent post-transplant HCV recurrence. ClinicalTrials.gov: NCT01559844., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV., Methods: For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800,000 IU/mL vs ≥800,000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01329978., Results: We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5). In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77-96) in cohort A, 97 patients (89%, 82-94) in cohort B, and by 135 (87%, 81-92) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0·94), or in cohort C (p=0·78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug--anaemia and neutropenia--were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event., Interpretation: Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis., Funding: Gilead Sciences., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background & Aims: Chronic hepatitis C is associated with an increased prevalence of insulin resistance, which might result from liver disease, metabolic factors, or the hepatitis C virus (HCV) itself. The effect of antiviral treatment on insulin sensitivity is not well-known. We evaluated changes in insulin resistance and weight in patients with hepatitis C during and after peginterferon and ribavirin therapy., Methods: Virahep-C was a prospective, multicenter study of a 48-week course of combination antiviral therapy in patients infected with HCV genotype 1. Insulin resistance (IR) was estimated by the homeostasis model assessment index (HOMA2-IR) based on fasting glucose and insulin levels., Results: Among 341 patients, 40% had insulin resistance (HOMA2-IR > 2.0). The presence of insulin resistance was associated with increasing age, body mass index (BMI), and fibrosis stage. Among patients with insulin resistance at the start of the trial, median decreases in HOMA2-IR values during treatment were 0.74 at 24 weeks and 0.89 at 48 weeks, whereas BMI decreased by 1.2 and 2.2 at the same time points (P < .001 for all). At follow-up, HOMA2-IR and BMI levels returned toward baseline values in patients who did not respond or relapsed, but HOMA2-IR values remained significantly lower in patients with sustained virologic response (SVR) (P < .001), despite increases in BMI., Conclusions: In patients with HCV genotype 1 infections, therapy with peginterferon and ribavirin is associated with decreases in body weight and insulin resistance. Among patients with insulin resistance before treatment, resolution of HCV infection results in sustained improvements in the HOMA-IR index, suggesting that HCV could have a direct role in the pathogenesis of insulin resistance., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Merimepodib (MMPD) is an orally administered, inosine monophosphate dehydrogenase inhibitor that has shown antiviral activity in nonresponders with chronic hepatitis C (CHC) when combined with pegylated interferon alfa 2a (Peg-IFN-alfa-2a) and ribavirin (RBV). We conducted a randomized, double-blind, multicenter, phase 2b study to evaluate the antiviral activity, safety, and tolerability of MMPD in combination with Peg-IFN-alfa-2a and RBV in patients with genotype 1 CHC who were nonresponders to prior therapy with Peg-IFN and RBV. Patients received 50 mg MMPD, 100 mg MMPD, or placebo every 12 hours, in addition to Peg-IFN-alfa-2a and RBV, for 24 weeks. Patients with a 2-log or more decrease from baseline or undetectable hepatitis C virus (HCV) RNA levels at week 24 were then eligible to continue Peg-IFN-alfa-2a and RBV for a further 24 weeks, followed by 24 weeks of follow-up. The primary efficacy endpoint was sustained virological response (SVR) rate at week 72 in all randomized patients who received at least one dose of study drug and had a history of nonresponse to standard therapy. A total of 354 patients were randomized to treatment (117 to placebo; 119 to 50 mg MMPD; 118 to 100 mg MMPD), and 286 completed the core study. The proportion of patients who achieved SVR was similar among the treatment groups: 6% (6/107) for 50 mg MMPD, 4% (5/112) for 100 mg MMPD, and 5% (5/104) for placebo (P = 0.8431). Adverse-event profiles for the MMPD combination groups were similar to that for Peg-IFN-alfa and RBV alone. Nausea, arthralgia, cough, dyspnea, neutropenia, and anemia were more common in patients taking MMPD., Conclusion: The addition of MMPD to Peg-IFN-alfa-2a and RBV combination therapy did not increase the proportion of nonresponder patients with genotype 1 CHC achieving an SVR.

Unlabelled: This prospective, multicenter, community-based and academic-based, open-label, investigator-initiated, U.S. study evaluated efficacy and safety of pegylated interferon (PEG-IFN) alfa-2b plus a flat or weight-based dose of ribavirin (RBV) in adults with chronic hepatitis C. Patients (n = 5027) were randomly assigned to receive PEG-IFN alfa-2b 1.5 microg/kg/week plus flat-dose (800 mg/day) or weight-based (800-1400 mg/day) RBV for 48 weeks (patients with genotype 1, 4, 5, or 6) and for 24 or 48 weeks (genotype 2/3 patients). Primary end point was sustained virologic response (undetectable [<125 IU/mL] serum hepatitis C virus RNA at 24-week follow-up). Sustained virologic response, but not end-of-treatment, rates were significantly higher with weight-based than with flat-dose RBV (44.2% versus 40.5%; P = 0.008). Sustained virologic response rates by intention-to-treat analysis were 34.0% and 28.9%, respectively, in genotype 1 patients (P = 0.005) and 31.2% and 26.7%, respectively, in genotype 1 patients with high baseline viral load (P = 0.056). In genotype 2/3 patients, rates were not significantly different (61.8% and 59.5%, respectively) regardless of treatment duration. Besides greater hemoglobin reductions with weight-based RBV, safety profiles were similar across RBV dosing groups, including the 1400-mg/day group., Conclusion: PEG-IFN alfa-2b plus weight-based RBV is more effective than flat-dose RBV, particularly in genotype 1 patients, providing equivalent efficacy across all weight groups. RBV 1400 mg/day is appropriate for patients 105 to 125 kg. For genotype 2/3 patients, 24 weeks of treatment with flat-dose RBV is adequate; no evidence of additional benefit of extending treatment to 48 weeks was demonstrated.

Background & Aims: Compared with Caucasian Americans (CA), African Americans (AA) with chronic hepatitis C are less likely to respond to interferon-based antiviral therapy., Methods: In a multicenter treatment trial, 196 AA and 205 CA treatment-naive patients with hepatitis C virus (HCV) genotype 1 infection were treated with peginterferon alfa-2a (180 microg/wk) and ribavirin (1000-1200 mg/day) for up to 48 weeks. The primary end point was sustained virologic response (SVR)., Results: Baseline features were similar among AA and CA, including HCV-RNA levels and histologic severity, but AA had higher body weights, a higher prevalence of diabetes and hypertension, and lower alanine transaminase levels (P < .001 for all). The SVR rate was 28% in AA and 52% in CA (P < .0001). Racial differences in viral responses were evident as early as treatment week 4. Breakthrough viremia was more frequent among AA than CA (13% vs 6%, P = .05); relapse rates were comparable (32% vs 25%, P = .30). Proportions of patients with serious adverse events and dose modifications and discontinuations were similar among AA and CA. In multiple regression analyses, CA had a higher SVR rate than AA (relative risk, 1.96; 95% confidence interval, 1.48-2.60; P < .0001). Other factors independently associated with higher SVR included female sex, lower baseline HCV-RNA level, less hepatic fibrosis, and more peginterferon taken., Conclusions: AA with chronic hepatitis C genotype 1 have lower rates of virologic response to peginterferon and ribavirin than CA. These differences are not explained by disease characteristics, baseline viral levels, or amount of medication taken.

Summary: Background: Elbasvir‐grazoprevir is indicated for chronic hepatitis C virus (HCV) genotypes 1 and 4. Aim: To evaluate the utilization and outcomes of chronic HCV patients treated with elbasvir‐grazoprevir in the United States. Methods: We conducted a retrospective cohort study of adults treated with elbasvir‐grazoprevir with or without ribavirin for chronic HCV genotypes 1 or 4 infection. Data were collected from healthcare providers and specialty pharmacies through Innervation Platform, a proprietary, cloud‐based disease management program from Trio Health. The primary endpoint was per protocol sustained virological response 12 weeks post‐treatment (SVR12). Results: Among 470 patients treated in 2016, 95% had HCV genotype 1 infection, 80% (373/468) were HCV treatment naïve and 70% (327/468) had non‐cirrhotic disease. Almost 3 quarters (73%) of patients received care in community practices. The majority (89%) of patients received elbasvir‐grazoprevir for 12 weeks. Per protocol SVR12 rates were 99% (396/402) for HCV genotype 1 and 95% (21/22) for HCV genotype 4. Among patients with Stage 4 or 5 chronic kidney diseases, 99% (113/114) achieved SVR12. In univariate analyses, variables significantly associated with per protocol SVR12 for the entire sample were therapy duration (P = 0.001), treatment experience (P = 0.016), and cirrhosis status (P = 0.001). However, among HCV genotype 1 patients, no variables were significant. Intent‐to‐treat SVR12 rates were 89% (396/447) for HCV genotype 1 and 91% (21/23) for HCV genotype 4. Conclusion: Elbasvir‐grazoprevir is highly effective, and in this 2016 cohort, its use was predominantly in patients with HCV genotype 1 and as a 12‐week therapy without ribavirin. [ABSTRACT FROM AUTHOR]

Portal hypertension is a predictor of liver-related clinical events and mortality in patients with hepatitis C and cirrhosis. The effect of interferon-free hepatitis C treatment on portal pressure is unknown. Fifty patients with Child-Pugh-Turcotte ( CPT) A and B cirrhosis and portal hypertension (hepatic venous pressure gradient [ HVPG] >6 mm Hg) were randomized to receive 48 weeks of open-label sofosbuvir plus ribavirin at Day 1 or after a 24-week observation period. The primary endpoint was sustained virologic response 12 weeks after therapy ( SVR12) in patients who received ≥1 dose of treatment. Secondary endpoints included changes in HVPG, laboratory parameters, and MELD and CPT scores. A subset of patients was followed 48 weeks posttreatment to determine late changes in HVPG. SVR12 occurred in 72% of patients (33/46). In the 37 patients with paired HVPG measurements at baseline and the end of treatment, mean HVPG decreased by -1.0 ( SD 3.97) mm Hg. Nine patients (24%) had ≥20% decreases in HVPG during treatment. Among 39 patients with pretreatment HVPG ≥12 mm Hg, 27 (69%) achieved SVR12. Four of the 33 (12%) patients with baseline HVPG ≥12 mm Hg had HVPG <12 mm Hg at the end of treatment. Of nine patients with pretreatment HVPG ≥12 mm Hg who achieved SVR12 and completed 48 weeks of follow-up, eight (89%) had a ≥20% reduction in HVPG, and three reduced their pressure to <12 mm Hg. Patients with chronic HCV and compensated or decompensated cirrhosis who achieve SVR can have clinically meaningful reductions in HVPG at long-term follow-up. (Eudra CT 2012-002457-29). [ABSTRACT FROM AUTHOR]

Background Treatment of genotype 1 hepatitis C virus ( HCV) infection with combination direct acting anti-virals is associated with very high rates of sustained virological response ( SVR). Daily combination of ledipasvir and sofosbuvir for 12 weeks is approved for the treatment of genotype 1 HCV patients, though noncirrhotic patients who are naïve to treatment with a baseline HCV RNA <6 million IU/mL can be treated for 8 weeks. This guidance stemmed from a post hoc analysis of the ION 3 clinical trial, which demonstrated similar SVR for patients treated with ledipasvir and sofosbuvir with or without ribavirin for 8 or 12 weeks. Aim To compare the SVR for 8 weeks vs 12 weeks of ledipasvir and sofosbuvir in HCV infected patients in a real-world setting. Methods We performed an observational real-world cohort study of treatment success following 8 or 12 weeks of ledipasvir and sofosbuvir for treatment-naïve genotype 1 HCV patients. Results A total of 826 patients were treated for either 8 (n=252) or 12 weeks (n=574) with ledipasvir and sofosbuvir and achieved SVR rate of 95.3% and there was no statistical difference in SVR rates in the two groups irrespective of any clinical or virological variables. Conclusions In treatment-naïve HCV genotype 1 patients, SVR was 95% in those treated for either 8 weeks or 12 weeks with ledipasvir and sofosbuvir. 8 week ledipasvir and sofosbuvir can reduce costs without compromising outcomes for those patients who qualify for such regimen. [ABSTRACT FROM AUTHOR]

Early data regarding the 'real-world' experience with novel therapies for hepatitis C ( HCV) are encouraging. Data are still limited, however, regarding real-world rates of sustained virologic response ( SVR) for ledipasvir-sofosbuvir ( LDV- SOF), particularly for patients with prior treatment failure. We performed a retrospective cohort study of 1597 patients with chronic genotype 1 HCV who were treated using 12 weeks of the following regimens LDV- SOF±ribavirin ( RBV) (n=1521 without RBV, n=76 with RBV). The primary outcome was SVR-determined at 12 weeks in an intention-to-treat design. Prescription according to Food and Drug Administration ( FDA) approved labelling (adding RBV for patients with cirrhosis and treatment failure) was assessed in multivariate models. The study population was aged 60 years on average (range 19-89), 60% male, 50% Caucasian, 43% cared for at an academic centre and 30% cirrhotic. Overall, LDV- SOF resulted in a 94% SVR rate. Only 44 (2.9%) patients relapsed. LDV- SOF+ RBV yielded SVR in 97% with 0 viral relapses. While cirrhosis and thrombocytopenia were associated with lower odds of SVR, in a multivariable regression model, only treatment at an academic centre and prescriptions contrary to FDA labelling were significantly associated with lower SVR-odds ratios, 0.56 95% CI (0.35-0.87) and 0.29 95% CI(0.12-0.68), respectively. The real-world experience with LDV- SOF mirrors the SVR rates observed in clinical trials. Efforts to promote prescription within FDA recommendations are warranted. [ABSTRACT FROM AUTHOR]

Affecting 2-3% of the world's population, hepatitis C is a common viral infection which is a significant cause of morbidity and mortality. Hepatitis C genotype 1 is the dominant viral genotype among Western patients. For the last 20 years, in the era of interferon-based therapy, it was far more difficult to treat relative to genotypes 2 and 3. Accordingly, a significant focus of research was on new antiviral agents for the dominant genotype 1 patient. Now, as promising specific treatments are being introduced for genotype 1, the attention of clinicians and researchers has turned back to the 50-70 million patients infected with a nongenotype 1 hepatitis C. Furthermore, after recent, larger randomized trials, we have realized that genotype 2 is truly interferon sensitive while genotype 3 patients are far less successful with therapy. In this fundamentally altered landscape, genotype 3 is now potentially the most difficult to treat genotype and an area of intense research for new drug development. Herein we review the virology, natural history and the treatment of genotype 3 hepatitis C. [ABSTRACT FROM AUTHOR]

Summary. The aim of this study is to review clinical trial data on the newly approved protease inhibitors boceprevir and telaprevir to develop consensus recommendations on the optimal use of these agents for the treatment of patients with chronic hepatitis C virus (HCV) infection. An expert panel of seven leading authorities in viral hepatitis was convened to establish and disseminate a practical guide on best practices for incorporating boceprevir and telaprevir into therapy for HCV infection in both treatment-naive and treatment-experienced patients. The topics covered include selecting candidates for boceprevir- or telaprevir-based treatments, predictors of response and early viral kinetics, response-guided therapy approaches, on-treatment management strategies to optimize the likelihood of response and minimize the risk of drug resistance, management of adverse effects during therapy and key considerations for special populations. The expert panel incorporated the best available clinical evidence into recommendations on how boceprevir and telaprevir should be used in the clinical setting. They indicated how treatment regimens may differ according to the baseline factors, such as presence of cirrhosis and when therapy may need to be modified or stopped altogether because of adverse events or poor virologic response. This practical guide will serve as a valuable resource for clinicians embarking on the new treatment paradigm of boceprevir or telaprevir in combination with peginterferon/ribavirin for chronic genotype 1 HCV infection. [ABSTRACT FROM AUTHOR]

. Low-density lipoprotein cholesterol (LDL-C) levels and interleukin 28B ( IL28B) polymorphism are associated with sustained viral response (SVR) to peginterferon/ribavirin (pegIFN/RBV) for chronic hepatitis C (CHC) infection. IL28B has been linked with LDL-C levels using a candidate gene approach, but it is not known whether other genetic variants are associated with LDL-C, nor how these factors definitively affect SVR. We assessed genetic predictors of serum lipid and triglyceride levels in 1604 patients with genotype 1 (G1) chronic hepatitis C virus (HCV) infection by genome-wide association study and developed multivariable predictive models of SVR. IL28B polymorphisms were the only common genetic variants associated with pretreatment LDL-C level in Caucasians (rs12980275, P = 4.7 × 10−17, poor response IL28B variants associated with lower LDL-C). The association was dependent on HCV infection, IL28B genotype was no longer associated with LDL-C in SVR patients after treatment, while the association remained significant in non-SVR patients ( P < 0.001). LDL-C was significantly associated with SVR for heterozygous IL28B genotype patients ( P < 0.001) but not for homozygous genotypes. SVR modelling suggested that IL28B heterozygotes with LDL-C > 130 mg/dL and HCV RNA ≤600 000 IU/mL may anticipate cure rates >80%, while the absence of these two criteria was associated with an SVR rate of <35%. IL28B polymorphisms are the only common genetic variants associated with pretreatment LDL-C in G1-HCV. LDL-C remains significantly associated with SVR for heterozygous IL28B genotype patients, where LDL-C and HCV RNA burden may identify those patients with high or low likelihood of cure with pegIFN/RBV therapy. [ABSTRACT FROM AUTHOR]

To compare young adult (18-25) and elderly (80+) populations with HCV by patient, treatment, and disease characteristics and effectiveness of DAA treatment. Methods Data were collected using Trio Health disease management program and are specific to patients initiating anti-HCV therapy between October 2015 to February 2019 with >=9 months follow up and serviced by Trio Specialty Pharmacy Partners. [Extracted from the article]