Search

Summary: Background: Hepatitis B surface antigen (HBsAg) seroclearance marks regression of hepatitis B virus (HBV) infection. However, more than one‐fifth of patients with functional cure following pegylated interferon‐based therapy may experience HBsAg seroreversion. The mechanisms causing the HBV relapse remain unclear. Aim: To investigate the level and origin of HBV transcripts in patients with functional cure and their role in predicting relapse. Methods: Liver tissue obtained from patients with functional cure, as well as uncured and treatment‐naïve HBeAg‐negative patients with chronic hepatitis B (CHB) were analysed for intrahepatic HBV markers. HBV capture and RNA sequencing were used to detect HBV integration and chimeric transcripts. Results: Covalently closed circular DNA (cccDNA) levels and the proportion of HBsAg‐positive hepatocytes in functionally cured patients were significantly lower than those in uncured and treatment‐naïve HBeAg‐negative patients. Integrated HBV DNA and chimeric transcripts declined in functionally cured patients compared to uncured patients. HBsAg‐positive hepatocytes present in 25.5% of functionally cured patients, while intrahepatic HBV RNA remained in 72.2%. The levels of intrahepatic HBV RNA, integrated HBV DNA, and chimeric transcripts were higher in functionally cured patients with intrahepatic HBsAg than in those without. The residual intrahepatic HBsAg in functionally cured patients was mainly derived from transcriptionally active integrated HBV DNA; meanwhile, trace transcriptional activity of cccDNA could also remain. Two out of four functionally cured patients with intrahepatic HBsAg and trace active cccDNA experienced HBV relapse. Conclusion: Integrated HBV DNA and cccDNA maintain transcriptional activity and maybe involved in HBsAg seroreversion in intrahepatic HBsAg‐positive patients with functional cure and linked to virological relapse. [ABSTRACT FROM AUTHOR]

BackgroundRisks and benefits of protease inhibitor (PI) (telaprevir or boceprevir) triple therapy in hepatitis C virus (HCV)-infected patients with mildly decompensated cirrhosis, including those wait-listed for liver transplantation (LT), are incompletely known.AimTo assess virological responses and safety of PI triple therapy in patients with mildly decompensated Child-Pugh (CP) CP ≥6 vs. compensated (CP = 5) cirrhosis.MethodsMulticentre cohort of 160 adults with cirrhosis treated with peginterferon/ribavirin (peg-IFN/RBV) plus telaprevir (69%) or boceprevir (31%), comparing outcomes between those with CP = 5 and CP ≥6.ResultsPatients, 47% with CP ≥6 cirrhosis (CP range 6-10), received PI triple therapy for a targeted duration of 48 weeks. The cohort was median age 59 years, 32% female, 59% genotype 1a, 35% previous null/partial responders. Sustained virological response at 12 weeks (SVR12) was achieved by 35% of patients with CP ≥6 vs. 54% of those with CP = 5 (P = 0.02). CP = 5, achievement of rapid virological response and genotype 1b/other, independently predicted SVR12. Compared to those with CP = 5, patients with CP ≥6 had more peg-IFN dose reductions, eltrombopag use, transfusions and hospitalisations to manage adverse events (all P < 0.05). Overall, 67 (42%) discontinued treatment early. Nine wait-listed patients were treated for a median of 97 days (IQR 60-160) prior to liver transplantation and five achieved post-LT SVR.ConclusionsIn the presence of mild decompensation (Child-Pugh ≥6), SVR12 rates with protease inhibitor triple therapy are significantly reduced and adverse events increased. Thus, treatment with protease inhibitor triple therapy, if judged as necessary, should be undertaken with close monitoring and awareness of the significant risks.

Summary: Background: We conducted a prospective study using gadolinium‐ethoxybenzyl‐diethylenetriamine pentaacetic acid–enhanced magnetic resonance imaging (Gd‐EOB‐MRI) to determine whether sustained virological response (SVR) by direct‐acting anti‐viral (DAA) drugs suppresses hepatocarcinogenesis in patients with hepatitis C virus (HCV) infection. Aim: To use serial Gd‐EOB‐MRI to assess the impact of DAAs on hepatocarcinogenesis. Methods: Between February 2008 and December 2018, 1083 consecutive patients with HCV infection underwent Gd‐EOB‐MRI. Of these, 719 patients were enrolled, including 210 patients in the 'Non‐DAA group', who did not receive DAAs before the introduction of DAAs, and 509 patients in the 'DAA group', who achieved SVR after the introduction of DDAs. Factors associated with hepatocarcinogenesis were analysed by a Cox proportional hazard model. In addition, hepatocarcinogenesis was classified into two types, 'multistep' and 'de novo', on the basis of Gd‐EOB‐MRI findings. Factors associated with each type were analysed by Fine and Gray proportional hazards models. Results: Hepatocarcinogenesis was observed in 67 of 719 (9.3%) patients. Factors associated with hepatocarcinogenesis were male gender, albumin‐bilirubin (ALBI) grade 2 or 3, Lens culinaris agglutinin–reactive fraction of alpha‐fetoprotein (AFP‐L3) ≥5%, the presence of nonhypervascular hypointense nodules (NHHNs) and Non‐DAA group. Of 67 patients, multistep hepatocarcinogenesis occurred in 58 patients (86.6%) and de novo hepatocarcinogenesis occurred in nine patients (13.4%). Factors associated with multistep hepatocarcinogenesis were male gender and Non‐DAA group. Conclusion: The eradication of HCV by DAA therapy reduces multistep hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

Summary: Background: Chronic kidney disease (CKD) was a relative contraindication to hepatitis C virus (HCV) treatment in the interferon/ribavirin era. Aim: To determine the efficacy, tolerability and safety of sofosbuvir/ledipasvir (SOF/LDV) and paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) regimens in persons with CKD. Methods: We identified persons initiated on a SOF/LDV or PrOD regimen from October 30, 2014 to April 30, 2016. We excluded those with missing HCV genotype or eGFR values. We determined treatment completion and sustained virologic response (SVR) rates, and proportion developing worsening renal function or grade 3/4 haematologic toxicity. Results: Among 13 663 persons on SOF/LDV±ribavirin, 14% and 1% persons had CKD Stage 3 and 4‐5 respectively, 67.8% completed treatment, 98.2% achieved SVR. Treatment completion or SVR rates did not decline with advanced CKD or ribavirin administration. Among 3961 persons on PrOD±ribavirin, 9% and 3% persons had CKD Stage 3 and 4‐5, respectively, 74.0% completed treatment and 98.2% achieved SVR. A decrease in treatment completion rates was seen in CKD stage 4‐5 and those on ribavirin, but this did not impact SVR rates. A >10 mL/min/1.73 m2 drop in eGFR from baseline was observed in 30%‐38% of persons with baseline eGFR ≥60 mL/min/1.73 m2, but in only 0%‐6% with CKD4‐5. Grade 3/4 anaemia was more frequent in persons with CKD4‐5, but ribavirin co‐administration did not appear to affect this. Conclusions: SOF/LDV and PrOD achieved high SVR rates in CKD population. Treatment completion rates were lower than expected. A decline in eGFR and development of anaemia were observed in a substantial proportion of persons, but the clinical implications remain unclear. [ABSTRACT FROM AUTHOR]

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]

Summary: Background: Combination therapy of simeprevir (SIM)/sofosbuvir (SOF) is an approved treatment for hepatitis C genotype (gen) 1 with overall SVR12 rate of 85%‐95%. The single tablet fixed‐dose combination of ledipasvir (LDV)/SOF is also approved for gen 1 with sustained virologic response at 12 weeks (SVR12) rates ≥95%. No data are available on the efficacy of retreatment with LDV/SOF in patients who failed initial treatment with SIM/SOF. Aim: To evaluate the efficacy of retreatment with LDV/SOF ± ribavirin (RBV) in gen 1 patients who had previously failed treatment with SIM/SOF. Methods: Data from a combined treatment cohort of 2 hepatology centres, which included patients previously treated with SIM/SOF ± RBV for 12 weeks but failed to achieve SVR and then underwent retreatment with LDV/SOF ± RBV, were analysed (n = 30). LDV/SOF ± RBV was administered for 12‐24 weeks based on the discretion of the treating hepatologist. Results: Of the 30 patients, 23 (77%) were male, 77% were Caucasian and 26 (87%) were gen 1a. 26 (86%) had cirrhosis, of which 16 (62%) had decompensated, Child's class B or C cirrhosis. Three patients were liver transplant recipients with recurrent hepatitis C. Overall, 27/30 (90%) achieved SVR. Treatment was well tolerated with 37% reporting no adverse events. The most common adverse events were fatigue, headache, insomnia and nausea. Two patients with Child's B cirrhosis required hospitalization during treatment for variceal haemorrhage and abdominal pain respectively. However, no treatment discontinuations or deaths occurred. Conclusion: Single tablet fixed‐dose combination LDV/SOF ± RBV is efficacious and well tolerated in patients who previously failed treatment with SIM/SOF, including those with decompensated cirrhosis and recurrent hepatitis C following liver transplantation. [ABSTRACT FROM AUTHOR]

Summary: Background: Interferon‐free regimens are associated with high sustained virological response; however, associated adverse effects have yet to be fully reported. Aim: To evaluate the adverse effects associated with the different direct‐acting antiviral drug (DAA) regimens in Egyptian patients. Methods: This multicenter retrospective study included all adverse effects during and after treatment with DAA regimens of 149 816 chronic hepatitis C treated Egyptian patients. Patients received sofosbuvir (SOF)/ribavirin (RBV) (n = 21 835), SOF/simeprevir (n = 24 215) SOF/daclatasvir (DCV) (n = 58 477), SOF/DCV/RBV (n = 45 188) and paritaprevir/ombitasvir/ritonavir/RBV (n = 101). The duration of treatment varied between 12 and 24 weeks. All changes in the treatment regimens, discontinuation, mortality, and serious side effects were reported. Results: Adverse effects developed in 2475 (1.7%) (mean age [54 ± 9], male gender [53%]) patients. Serious side effects developed in 68% of these patients, and SOF/RBV was the most common causing regimen (73%, P < 0.001). Anaemia and hyperbilirubinemia were the most common side effects (731/149816, 0.5% and 463/149816, 0.3%, respectively) and SOF/RBV (588/21835, 3% and 353/21835, 1.6%, respectively) showed the highest incidence in the treated patients. Hepatocellular carcinoma and mortality were reported in 0.02% and 0.06% of all treated patients, respectively. Patients with liver cirrhosis showed higher incidence of serious side effects (Log rank P = 0.045) and mortality (Log rank P = 0.025) than patients without liver cirrhosis. Male gender (P = 0.012), lower haemoglobin (P < 0.001), platelets (P < 0.001) and albumin (P = 0.001), higher bilirubin (P = 0.002) and cirrhosis (P < 0.001) were factors associated with serious side effects development. Conclusion: Adverse effects associated with DAAs are few, anaemia being the most common. SOF/RBV regimen showed the highest rate of side effects while SOF/DCV showed the least. [ABSTRACT FROM AUTHOR]

Summary: Background: The Daclatasvir and Sofosbuvir combination therapy (SOF/DCV) has shown efficacy in patients with chronic hepatitis C in clinical trials. Aim: To investigate the efficacy and safety of SOF/DCV for treatment of patients with hepatitis C‐related liver cirrhosis genotype 4. Methods: Multicentre study involving 551 patients with liver cirrhosis genotype 4; 432 naïve patients and 119 treatment‐experienced patients. All patients received SOF (400 mg) and DCV (60 mg) daily in addition to weight‐based ribavirin (RBV) for 12 weeks and when RBV is contraindicated the treatment duration was extended to 24 weeks. Results: Sustained virological response at 12 weeks after end of treatment (SVR12) rate was 92% in naïve cirrhotic patients and 87% in previous treated patients (by ITT analysis). Virological failure was infrequent, occurring in 42 patients (8%) overall. Thirty‐two (6%) were non responders; and 10 (2%) cases were relapsers, 31 patients (7%) were CTP‐A and 11 (13.3%) patients were CTP‐B (by ITT analysis). The most common adverse events were anaemia, fatigue, headache, pruritus. Serious side effects were recorded mainly in CTP‐B cirrhotic patients including HCC and hepatic encephalopathy. Conclusions: The SOF/DCV combination therapy has proven efficacy and safety in treating patients with hepatitis C‐related liver cirrhosis genotype 4 in a large cohort of patients in the real world. [ABSTRACT FROM AUTHOR]

Summary: Background: Treatment of chronic hepatitis C using combination of sofosbuvir (SOF) and daclatasvir (DCV) was used in several clinical trials and multicentre studies, which were somewhat limited to genotypes 1‐3. The national program in Egypt is using SOF‐DCV combination for large scale treatment. Aim: To assess the efficacy and safety of combined SOF‐DCV in treating patients with HCV‐G4 in a real‐world setting. Methods: Data and outcome of chronic HCV patients who were treated for 12 weeks with generic medications: DCV 60 mg plus SOF 400 mg ± ribavirin (RBV) within the national hepatitis C treatment program in Egypt are presented. Treatment‐naïve patients without cirrhosis were treated without RBV, and those who had cirrhosis or were treatment‐experienced (interferon experienced or SOF experienced) received RBV. Efficacy and safety were assessed, and baseline factors associated with sustained virological response at post‐treatment week 12 (SVR12) were explored. Results: During the first 2 months of the programme, 18 378 patients with HCV‐G4 started treatment with SOF‐DCV with or without RBV. Overall, 95.1% achieved SVR12 (95.4% among patients treated without RBV and 94.7% for patients treated with RBV, P = .32). Treatment was prematurely discontinued in only 1.5% of patients. The most common events leading to discontinuation were patient withdrawal (n = 76) and pregnancy (n = 5). Five deaths occurred within this group. Conclusions: Real‐world experience of generic SOF‐DCV in patients with chronic HCV‐G4 proved to be safe and associated with a high SVR12 rate, in patients with different stages of fibrosis. [ABSTRACT FROM AUTHOR]

Summary: Background: Higher risk of hepatitis B reactivation (HBV‐r) has been reported in patients with hepatitis C treated with newer directly acting antiviral agents (DAAs). Aim: To determine the proportion of persons who develop HBV‐r and its clinical consequences among DAA treated vs pegylated interferon/ribavirin (PEG/RBV) treated persons. Methods: We calculated the proportion of persons who developed HBV viral reactivation (HBV‐r; new detectable HBV DNA or increase of >1 log10); serum alanine aminotransferase flare (>5 times baseline); all‐cause mortality and hepatic decompensation in persons treated with a newer DAA regimen or PEG/RBV. Kaplan‐Meier curves were used to demonstrate survival and hepatic decompensation by treatment group and HBV‐r. Results: In 34 632 persons treated with DAA and 23 475 treated with PEG/RBV, HBV‐r rate per 1000 person‐years was 30.04 (10.41, 49.67) and 25.42 (95% CI 17.23, 33.62) respectively (P = .8). When stratified by SVR or by baseline HBsAg status, HBV‐r was not different between groups. Kaplan‐Meier survival curves comparing each regimen stratified by presence or absence of HBV‐r did not demonstrate a significant difference in incidence of hepatic decompensation over time. For overall survival, there was no difference between PEG/RBV treated persons with or without HBV‐r. For DAA treated persons, those with HBV‐r had a shortened survival, though the numbers at risk were small. Conclusions: HBV‐r is relatively uncommon after DAA therapy and not higher than among those treated with a PEG/RBV regimen. The small numbers of persons treated with a DAA regimen who do develop HBV‐r have a shortened survival compared to those without HBV‐r. [ABSTRACT FROM AUTHOR]

Summary: Background: Antiviral therapy for hepatitis C has the potential to improve liver function in patients with decompensated cirrhosis. Aims: To examine the virological response and effect of viral clearance in patients with decompensated hepatitis C cirrhosis all with MELD scores ≥15 following sofosbuvir/daclatasvir ± ribavirin. Methods: We prospectively collected data on patients who commenced sofosbuvir/daclatasvir for 24‐weeks under the Australian patient supply program (TOSCAR) and analysed outcomes including sustained viral response at 12 weeks (SVR12), death and transplant. Results: 108 patients (M/F, 79/29; median age 56years; Child‐Pugh 10; MELD 16; genotype 1/3, 55/47) received sofosbuvir/daclatasvir and two also received ribavirin. On intention‐to‐treat, the SVR12 rate was 70% (76/108). Seventy‐eight patients completed 24‐weeks therapy. SVR12 was achieved in 56 of these patients on per‐protocol‐analysis (76%). SVR12 was 80% in genotype 1 compared to 69% in genotype 3. Thirty patients failed to complete therapy. In patients achieving SVR12, median MELD and Child‐Pugh fell from 16(IQR15‐17) to 14(12‐17) and 10(9‐11) to 8(7‐9), respectively (P<.001). In those who died, MELD increased from 16 to 23 at death (P=.036). Patients who required transplantation had a significantly higher baseline MELD (20) compared to those patients completing treatment (16) (P=.0010). The odds ratio for transplant in patients with baseline MELD ≥20 was 13.8(95%CI 2.78‐69.04). Conclusions: SVR12 rates with sofosbuvir/daclatasvir in advanced liver disease are lower than in compensated disease. Although treatment improves MELD and Child‐Pugh in most patients, a significant proportion will die or require transplantation. In those with MELD ≥20, it may be better to delay treatment until post‐transplant. [ABSTRACT FROM AUTHOR]

Background In the era of highly effective direct-acting antivirals (DAAs) for treatment of patients with chronic hepatitis C virus (HCV) infection, ribavirin (RBV) is still considered beneficial in certain patients. Aim To assess the association between RBV steady-state plasma levels and sustained virological response (SVR). Methods Consecutive HCV-infected patients treated with DAAs plus RBV from four Dutch academic medical centres were enrolled. RBV steady-state plasma levels were prospectively measured at treatment week 8 using validated assays. Logistic regression analyses were performed to assess the influence of RBV steady-state plasma level on SVR, and RBV therapeutic range was explored using area under the ROC curve analyses. Results A total of 183 patients were included, of whom 85% had one or more difficult-to-cure characteristics (ie treatment experienced, HCV genotype 3, cirrhosis). The majority was treated with a sofosbuvir-based regimen and 163 (89%) patients achieved SVR. Median RBV dose was 12.9 (interquartile range 11.2-14.7) mg/kg/d, and median RBV steady-state plasma level was 2.66 (1.95-3.60) mg/L. In multivariable analyses, higher RBV steady-state plasma level (adjusted odds ratio 1.79 [95% CI 1.09-2.93]) was an independent predictor of SVR. With regard to the optimal RBV therapeutic range, 2.28 mg/L was the optimal lower cut-off for achieving SVR and 3.61 mg/L was the upper cut-off for preventing significant anaemia (Haemoglobin < 10 g/dL). Conclusion In this cohort of mainly difficult-to-cure patients treated with DAAs plus RBV, higher RBV steady-state plasma level was an independent predictor of SVR. [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]

Background Ledipasvir and sofosbuvir is a well-tolerated regimen with high sustained virological response ( SVR) rates in pre-liver transplant patients infected with chronic hepatitis C virus ( HCV), but data in liver transplant recipients outside of clinical trials is limited. Aim To address this knowledge gap and assess SVR rates without the use of ribavirin in liver transplant recipients Methods This is a retrospective study examining the treatment of 75 post-liver transplant recipients with ledipasvir and sofosbuvir without ribavirin. Differences between SVR cohorts and predictors of SVR were analysed in an intention-to-treat ( ITT) fashion. Results A total of 408 genotype 1, HCV patients were treated with ledipasvir/sofosbuvir from October 2014 to August 2015 at our centre. Seventy-three patients were post-liver transplant and were treated with a median of 2.9 years from transplant. Ledipasvir/sofosbuvir achieved an SVR12 of 95.9%. African Americans made up 28.8% of the cohort. Sixty-three per cent of patients were treated previously, including 13.7% of patients previously treated with direct-acting antivirals. Only 2.7% had recurrent allograft cirrhosis, and the majority (90.4%) was on calcineurin inhibitor based immunosuppressive therapy. Approximately 82% of patients had chronic kidney disease ( CKD) stage 2 or 3. In univariate logistic regression, only detectable week 8 viral load was predictive of failure to achieve SVR. Conclusion Our data confirm excellent SVR outcomes and favourable safety and tolerability profiles with ledipasvir/sofosbuvir without ribavirin in post-liver transplant recipients infected with HCV, despite treatment guidelines to use ribavirin. [ABSTRACT FROM AUTHOR]

Background Antiviral therapy improves hepatic outcomes in hepatitis C virus ( HCV)-infected cancer patients. However, such patients are not treated simultaneously with antivirals and chemotherapy, owing to overlapping toxicities with previous standard of care treatment of pegylated interferon and ribavirin. Aim To examine the safety and clinically-significant drug-drug interactions observed in patients who received simultaneous treatment with direct-acting antivirals ( DAAs) and chemotherapy. Methods Safety was determined by the presence of adverse events which were graded according to the division of AIDS Table (version 2.0). Adverse events were monitored throughout antiviral treatment and up to 3 months after its completion. Drug-drug interactions were assessed using current online databases. Sustained virological response ( SVR) was defined as absence of serum HCV RNA 12 weeks after end of DAA treatment. Cirrhosis was diagnosed via imaging, biopsy or with the use of non-invasive fibrosis markers. Results Twenty-one patients received concomitant treatment with DAAs and chemotherapy between January 2013 and September 2016. Concomitant treatment was started either for virological (14; 67%) or oncologic (7; 33%) reasons. DAAs used were sofosbuvir, ledipasvir, simeprevir, daclatasvir ± ribavirin. The adverse events observed were mainly constitutional (12; 57%), hematological and gastrointestinal (7; 33% each). Physicians changed the DAA regimens in two patients (10%) in anticipation of drug-drug interactions with daclatasvir and dexamethasone. The overall SVR rate was 95% (20/21). Conclusions Hepatitis C virus-targeted antiviral therapy can be used concomitantly with selected anti-neoplastic agents under close monitoring for drug-drug interactions. This therapeutic intervention may prevent delay in the administration of chemotherapy in HCV-infected cancer patients. [ABSTRACT FROM AUTHOR]

LINKED CONTENT This article is linked to Mecci et al paper. To view this article, visit https://doi.org/10.1111/apt.15296. [ABSTRACT FROM AUTHOR]

Background Virologic and safety outcomes of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) therapy have shown high sustained virologic response (SVR) rates and good tolerability in most patient populations in pre-registration studies. Aim To confirm these clinical trial findings in the treatment of genotype 1 and 4 hepatitis C under real-world conditions. Methods Patients enrolled for treatment with OBV/PTV/r ± DSV ± RBV based on therapeutic guidelines were included, and the regimen was administered according to product characteristics. Clinical and laboratory data, including virologic response, were collected at baseline, end of treatment (EOT) and 12 weeks after EOT. Results A total of 209 patients with chronic hepatitis C were enrolled, most were genotype 1b-infected (84.2%) and 119 (56.9%) had liver cirrhosis. Among these, 150 (71.7%) had failed previous anti-viral therapies and 84 (40.2%) were null-responders. At 12 weeks after EOT, SVR was achieved by 207 (99.0%) patients, ranging from 96.4% to 100.0% across subgroups. All Child-Pugh B and post-orthotopic liver transplantation patients achieved SVR. Adverse events occurred in 151 (72.2%) patients and were mostly mild and associated with the use of RBV. Serious adverse events, including hepatic decompensation, renal insufficiency, anaemia, hepatotoxicity and diarrhoea, were reported in eight (3.8%) patients. In five (2.4%) patients, adverse events led to treatment discontinuation. On-treatment decompensation was experienced by seven (3.3%) patients. Conclusions The results of our study confirm previous findings. They demonstrate excellent effectiveness and a good safety profile of OBV/PTV/r± DSV±RBV in HCV genotype 1-infected patients treated in the real-world setting. [ABSTRACT FROM AUTHOR]

Background Ribavirin is a key component of several hepatitis C virus ( HCV) treatment regimens. However, its utility in combination with newer directly acting anti-viral agents regimens is unclear. Aim To determine the SVR rates with paritaprevir/ritonavir/ombitasvir/dasabuvir (Pr OD) regimen ± ribavirin and compare this with sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens. Methods We used Electronically Retrieved Cohort of HCV Infected Veterans ( ERCHIVES), a well-established national cohort of HCV-infected Veterans to identify HCV genotype 1 infected persons initiated on the above regimens. We excluded those with HIV coinfection, positive HBsAg and missing HCV RNA. Results We identified 1235 persons on Pr OD (75.5% ribavirin), 1254 on sofosbuvir/simeprevir (16.9% ribavirin) and 4247 on sofosbuvir/ledipasvir (23.3% ribavirin). Among HCV genotype 1a infected persons, ribavirin was prescribed to 99.2% on Pr OD, 18.2% on sofosbuvir/simeprevir and 23.3% on sofosbuvir/ledipasvir. The SVR rates ranged from 92.6% to 100% regardless of the treatment regimen, presence of cirrhosis or HCV subtype, except in Pr OD group without ribavirin, HCV genotype 1a without cirrhosis ( SVR 80%, N = 5). There were minor, clinically insignificant differences in SVR rates in those treated with or without ribavirin in each of the treatment groups, regardless of presence of cirrhosis at baseline. In multivariable logistic regression analysis, ribavirin use was not associated with achieving SVR in any group. Conclusions In HCV genotype 1 infected persons, Pr OD, sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens, are associated with high rates of SVR in actual clinical settings, which are comparable to clinical trials results (except Pr OD genotype 1a with cirrhosis where the number was too small). The benefit of adding ribavirin to these regimens in the ERCHIVES treated cohort is not established. [ABSTRACT FROM AUTHOR]

Background Eradication of hepatitis C virus (HCV) is increasing but its residual impact on the pro-inflammatory milieu in cirrhosis, which is associated with gut dysbiosis, is unclear. Aim To define the impact of sustained virological response (SVR) on gut dysbiosis and systemic inflammation in HCV cirrhosis patients. Methods Cirrhotic out-patients with HCV with/without SVR (achieved >1 year prior) and age-matched healthy controls underwent serum and stool collection. Serum was analysed for IL-6, TNF-α and endotoxin while stool microbiota analysis was performed using multitagged pyrosequencing. Microbial comparisons were made using UNIFRAC and cirrhosis dysbiosis ratio (lower score indicates dysbiosis). Comparisons were performed between cirrhotics with/without SVR and controls vs. cirrhotic patients. Results A total of 105 HCV cirrhotics and 45 age-matched healthy controls were enrolled. Twenty-one patients had achieved SVR using pegylated interferon + ribavrin a median of 15 months prior. No significant differences on demographics, cirrhosis severity, concomitant medications or diabetes were seen between cirrhotics with/without SVR. There was no significant difference in overall microbiota composition (UNIFRAC P = 0.3) overall or within specific microbial families (cirrhosis dysbiosis ratio median 1.3 vs. 1.0, P = 0.45) between groups with/without SVR. This also extended towards IL-6, TNF-α and endotoxin levels. Both cirrhosis groups, however, had significant dysbiosis compared to healthy controls [UNIFRAC P = 0.01, cirrhosis dysbiosis ratio (1.1 vs. 2.9, P < 0.001)] along with higher levels of endotoxin, IL-6 and TNF-α. Conclusions Gut dysbiosis and a pro-inflammatory systemic milieu, are found in HCV cirrhosis regardless of SVR. This persistent dysbiosis could contribute towards varying rates of improvement after HCV eradication in cirrhosis. [ABSTRACT FROM AUTHOR]

Background Real-world data are needed to inform hepatitis C virus ( HCV) treatment decisions. Aim To assess the comparative effectiveness of ledipasvir/sofosbuvir ± ribavirin ( LDV/ SOF ± RBV) vs. ombitasvir/paritaprevir/ritonavir + dasabuvir ( OPrD) ± RBV in genotype 1 HCV patients treated in routine medical practice. Methods Observational intent-to-treat cohort of genotype 1 patients initiating 8 or 12 weeks of LDV/ SOF ± RBV or 12 weeks of OPrD ± RBV. Sustained virological response ( SVR) required RNA below the limit of quantification at least 10 weeks after end of treatment. Results 6961 patients initiated LDV/ SOF ( N = 4478), LDV/ SOF + RBV ( N = 1269), OPrD ( N = 297), and OPrD + RBV ( N = 917) at 126 facilities. Intention-to-treat SVR rates were 91.4% (3813/4170) for LDV/ SOF, 90.0% (1098/1220) for LDV/ SOF + RBV, 95.1% (269/283) for OPrD and 85.8% (746/869) for OPrD + RBV. SVR rates in those completing 8 weeks of LDV/ SOF were 91.7% (1223/1333) and 12 weeks of LDV/ SOF 94.6% (2475/2615), LDV/ SOF + RBV 92.2% (1033/1120), OPrD 98.0% (248/253) and OPrD + RBV 95.5% (705/738). Significant predictors of SVR were African American race ( OR 0.71, 95% CI 0.59-0.86, P < 0.001), body mass index ( BMI) > 30 kg/m2 ( OR 0.73, 95% CI 0.60-0.89, P = 0.002), FIB4 > 3.25 ( OR 0.60, 95% CI 0.49-0.72, P < 0.001), OPrD + RBV compared to LDV/ SOF ( OR 0.60, 95% CI 0.48-0.76, P < 0.001) and subtype 1b ( OR 1.38, 95% CI 1.11-1.71, P = 0.003). For those completing 12 weeks, FIB-4 > 3.25 and high BMI remained significant predictors. Conclusions In this robust real-world cohort, SVR rates were similar to clinical trials. FIB-4 > 3.25 and high BMI were significant negative predictors of SVR. Reduced odds of SVR in African Americans and with OPrD + RBV likely arose from excess early discontinuation as these factors were no longer significant, when limited to patients completing a 12-week course. [ABSTRACT FROM AUTHOR]

Background In Hong Kong, most patients with hepatitis C virus ( HCV) have either genotype 6a or 1b infection. Aim To evaluate the efficacy and safety of sofosbuvir with ribavirin in treatment-naïve patients in Hong Kong with HCV genotype 1 or 6. Methods In an open-label study, patients were randomised to sofosbuvir 400 mg once daily plus ribavirin 1000-1200 divided twice daily for 12 ( n = 10), 16 ( n = 11) or 24 ( n = 10) weeks. The primary endpoint was the percentage of patients with HCV RNA < LLOQ (lower limit of quantification, 25 IU/ mL) 12 weeks after cessation of therapy ( SVR12). Results All 31 patients (20 HCV genotype 1 and 11 genotype 6) had HCV RNA < LLOQ by Week 4 of treatment and at their last on-treatment visit. SVR12 rates were high in all treatment groups: 100% (10/10) for 12 weeks, 100% (11/11) for 16 weeks and 90% (9/10) for 24 weeks of therapy. The only patient who did not reach SVR12 had genotype 1 HCV and relapsed at post-treatment Week 4. Sofosbuvir with ribavirin was generally well tolerated. The most common adverse events were malaise (13%) and upper respiratory tract infection (13%), followed by anaemia (10%). No patients experienced serious adverse events. One patient discontinued treatment at Week 16 because of an adverse event. The event, upper respiratory tract infection, was not considered treatment related by the investigator. This subject achieved SVR12. Conclusions The all-oral regimen sofosbuvir plus ribavirin is effective in treatment-naïve patients in Hong Kong with genotype 1 or 6 HCV. Trial registration number: NCT02021643. [ABSTRACT FROM AUTHOR]

Background Alisporivir ( ALV) is an oral, host-targeting agent with pangenotypic anti-hepatitis C virus ( HCV) activity and a high barrier to resistance. Aim To evaluate efficacy and safety of ALV plus peginterferon-α2a and ribavirin ( PR) in treatment-naïve patients with chronic HCV genotype 1 infection. Methods Double-blind, randomised, placebo-controlled, Phase 3 study evaluating ALV 600 mg once daily [response-guided therapy ( RGT) for 24 or 48 weeks or 48 weeks fixed duration] or ALV 400 mg twice daily RGT with PR, compared to PR alone. Following a Food and Drug Administration partial clinical hold, ALV/placebo was discontinued and patients completed treatment with PR only. At that time, 87% of patients had received ≥12 weeks and 20% had received ≥24 weeks of ALV/ PR triple therapy. Results A total of 1081 patients were randomised (12% cirrhosis, 55% CT/ TT IL28B). Addition of ALV to PR improved virological response in a dose-dependent fashion. Overall, sustained virological response ( SVR12; primary endpoint) was 69% in all ALV groups vs. 53% in PR control. Highest SVR12 (90%) was achieved in patients treated with ALV 400 mg twice daily and PR for >24 weeks. Seven cases of pancreatitis were reported, with similar frequency between ALV/ PR and PR control groups (0.6% vs. 0.8% respectively). Adverse events seen more frequently with ALV/ PR than with PR alone were anaemia, thrombocytopenia, hyperbilirubinaemia and hypertension. Conclusions Alisporivir, especially the 400 mg twice daily regimen, increased efficacy of PR therapy in treatment-naïve patients with HCV genotype 1 infection. The mechanism of action and pangenotypic activity suggest that alisporivir could be useful in interferon-free combination regimens. [ABSTRACT FROM AUTHOR]

Background Interferon and ribavirin negatively impact health-related quality of life (HRQL) during treatment. Aim To compare the impact of interferon and/or ribavirin-containing regimens on HRQL to interferon- and ribavirin-free regimens. Methods HRQL data from nine multinational phase 3 clinical trials of sofosbuvir (SOF)- based regimens with and without ledipasvir (LDV), pegylated interferon (IFN) or ribavirin (RBV) were used. The Short Form-36 (SF-36) HRQL questionnaire was administered to subjects prospectively at baseline, during treatment, and 12 and 24 weeks after treatment cessation. Results A total of 3460 CH-C with SF-36 data were included (52.2 ± 10.3 years, 62.6% male, 73.6% treatment-naïve, 15.0% cirrhotic, 68.2% HCV genotype 1 and 20.1% genotype 3). Compared to baseline HRQL, at the end of treatment, severe HRQL decrements were noted in IFN + RBV ± SOF regimens (on average, -3.8 to -24.3 on a 0-100 scale for different HRQL domains), while moderate decrements were noted in SOF + RBV ± LDV (-2.8 to -8.6). In contrast, in SOF/LDV without RBV, HRQL improvements were noted during treatment (+2.3 to +5.2). By 12 weeks post-treatment, HRQL returned to baseline in IFN + RBV ± SOF (P > 0.05) and improved in all IFN-free arms (+2.6 to +7.8). In multivariate analysis, a lower end of treatment HRQL was associated with IFN + RBV + SOF and a higher end of treatment HRQL was associated with SOF/LDV. By post-treatment-12, SOF/LDV was additionally associated with higher mental health scores. These improvements in HRQL scores were maintained 24 weeks post-treatment. Conclusions Removing interferon and ribavirin has led to substantial improvement of health-related quality of life during treatment. This may result in better patient experience and higher adherence to treatment regimen. [ABSTRACT FROM AUTHOR]

Background Sofosbuvir, an oral NS5B nucleotide polymerase inhibitor, is indicated for the treatment of patients infected with hepatitis C virus ( HCV). Aim To evaluate the long-term health economic outcomes of sofosbuvir + pegylated interferon alfa/ribavirin (peg IFN/ RBV) compared with current treatments in patients infected with HCV genotype 1 in the US. Methods A decision-analytic Markov model was developed to estimate health outcomes, number needed to treat and short-term and long-term economic outcomes, including incremental cost-effectiveness ratios and cost per sustained virological response ( SVR), for several sofosbuvir-comparator regimen pairings for a cohort of 10 000 patients. It considered three patient cohorts: treatment-naïve, treatment-experienced and treatment-naïve human immunodeficiency virus ( HIV) co-infected. Subgroup analyses were conducted for treatment-naïve patients with and without cirrhosis. Results Reductions in the incidence of new cases of liver-disease complications with sofosbuvir + peg IFN/ RBV compared with peg IFN/ RBV, boceprevir + peg IFN/ RBV, telaprevir + peg IFN/ RBV and simeprevir + peg IFN/ RBV were 64-82%, 50-68%, 43-58% and 33-56%, respectively. Sofosbuvir + peg IFN/ RBV was typically associated with the lowest 1-year cost per SVR. When considering the lifetime incremental cost per quality-adjusted life-year gained, sofosbuvir + peg IFN/ RBV was the most cost-effective treatment option assessed. Sofosbuvir + peg IFN/ RBV generally dominated (less costly and more effective than) boceprevir + peg IFN/ RBV, telaprevir + peg IFN/ RBV and simeprevir + peg IFN/ RBV. Conclusion Sofosbuvir + peg IFN/ RBV yields more favourable future health and economic outcomes than current treatment regimens for patients across all levels of treatment experience and cirrhosis stage, as well as for individuals with or without HIV co-infection. [ABSTRACT FROM AUTHOR]

Background Health utilities measure patients' preferences for a health state. Aim To assess health utilities for sofosbuvir-containing therapy for chronic hepatitis C. Methods The SF-6D utility scores were derived from the SF-36 instrument administered at baseline, during and post-treatment to participants of the previously reported clinical trials of sofosbuvir. EQ-5D utility scores were also approximated from the SF-36 using a regression model. Results Nine hundred and ninety-four patients were enrolled. Baseline SF-6D and EQ-5D scores were 0.66 ± 0.13 and 0.71 ± 0.22, respectively (the POSITRON trial), 0.71 ± 0.16 and 0.76 ± 0.23 ( FISSION), 0.70 ± 0.14 and 0.75 ± 0.22 ( FUSION), 0.72 ± 0.15 and 0.79 ± 0.22 ( NEUTRINO). In all studies, SF-6D and EQ-5D scores were highly correlated with each other. ( r = 0.83-0.87, P < 0.0001). After 12 weeks, patients receiving sofosbuvir + ribavirin ( POSITRON) had similar utility scores to placebo ( P > 0.05). Patients receiving 12 and 16 weeks of sofosbuvir + ribavirin ( FUSION) had similar utility scores ( P > 0.05). In FISSION, patients receiving sofosbuvir + ribavirin had significantly better utilities compared to patients receiving interferon + ribavirin ( P < 0.001). Patients receiving sofosbuvir + ribavirin + interferon ( NEUTRINO) had a decrease in utilities during treatment ( SF-6D: from 0.72 to 0.62, EQ-5D: 0.79 to 0.65; P < 0.0001) similar to that observed in patients receiving pegylated interferon + ribavirin for 24 weeks in FISSION (0.72 to 0.62 and 0.77 to 0.65, respectively, P < 0.0001). After 12 weeks post-treatment, patients with SVR ( FUSION) had improvement in SF-6D (+0.026 from baseline, P = 0.013) and EQ-5D (+0.043, P = 0.013). In multivariate analyses, baseline depression, anxiety, fatigue, insomnia and treatment-related anaemia were the most consistent predictors of utilities. Conclusions Patients' health utilities are minimally impacted by sofosbuvir + ribavirin treatment, as compared to interferon-based, therapy regardless of treatment duration. Clinical trials' numbers: NCT01542788 ( POSITRON), NCT01497366 ( FISSION), NCT01604850 ( FUSION), NCT01641640 ( NEUTRINO). [ABSTRACT FROM AUTHOR]

Background The treatment of chronic hepatitis C is changing rapidly. Aim To review clinical studies of the efficacy and safety of sofosbuvir-containing regimens in the treatment of chronic hepatitis C. Methods Using PubMed and search terms 'sofosbuvir,' 'emerging HCV treatment,' and ' HCV polymerase inhibitor,' literature on the clinical development of sofosbuvir, as well as abstracts presented at the November 2013 annual meeting of the American Association for the Study of Liver Diseases ( AASLD), was reviewed. The last search was undertaken on 15 November 2014. Results In a dose of 400 mg once daily, the drug has been safe and generally well tolerated with most adverse reactions attributable to the concurrent use of ribavirin or peginterferon plus ribavirin. A high barrier to resistance has been demonstrated. In genotype 1 (G1) patients, the addition of sofosbuvir to peginterferon plus ribavirin yielded sustained virological response rates at week 12 after discontinuation of treatment ( SVR12) of about 90% with slightly lower levels in G1b and in patients with cirrhosis, but with no major impact of IL28B genotype, high viral load, body mass index ( BMI), alanine aminotransferase ( ALT) or race/ethnicity. In genotype 2 (G2), sofosbuvir and ribavirin for 12 weeks also resulted in SVR12 of 90% or better with little effect from cirrhosis. In contrast, genotype 3 (G3) was less responsive to 12 weeks of sofosbuvir plus ribavirin, especially in the presence of cirrhosis. Conclusion The efficacy and safety of sofosbuvir-containing regimens with ribavirin alone or with peginterferon plus ribavirin signal a new era in treatment. [ABSTRACT FROM AUTHOR]

Background A novel dinucleotide variant TT/∆G ( ss469415590) has been associated with hepatitis C virus clearance. Aim To assess the role of the ss469415590 variant, compared with the known IL28B polymorphisms ( rs8099917, rs12979860 and rs12980275) for predicting virological response to therapy in chronic hepatitis C, and its association with the CXCL10 chemokine serum levels - a surrogate marker of interferon-stimulated genes activation. Methods Multivariate analysis of factors predicting rapid and sustained virological response in 280 consecutive, treatment-naïve, nondiabetic, Caucasian patients with chronic hepatitis C treated with peginterferon alpha and ribavirin. Results In hepatitis C virus genotype 1, the OR (95% CI) for rapid and sustained virological response for the wild-type ss469415590 TT was 9.88 (1.99-48.99) and 7.25 (1.91-27.51), respectively, similar to those found for rs12979860 CC [9.55 (1.93-47.37) and 6.30 (1.71-23.13)] and for rs12980275 AA [9.62 (1.94-47.77] and 7.83 (2.02-30.34)], but higher than for rs8099917 TT [4.8 (1.73-13.33) and 4.75 (2.05-10.98)]. In hepatitis C virus genotype 1, mean ( SD) CXCL10 levels in patients with the TT/ TT, TT/∆G and ∆G/∆G variants were, respectively, 355.1 (240.6), 434.4 (247.4) and 569.9 (333.3) ( P = 0.04). In patients with genotypes 2 and 3 no significant association was found for TT/∆G with viral response. The predictive value of ss469415590 was stronger in patients with advanced fibrosis. Conclusions The novel IL28B variants at marker ss469415590 predict response to IFN alpha in chronic hepatitis C patients, especially in those with advanced fibrosis. Their determination may be superior to that of known IL28B variants for patient management using IFN-based regimens. [ABSTRACT FROM AUTHOR]

Background Data about adverse events are needed to optimise telaprevir-based therapy in a broad spectrum of patients. Aim To investigate adverse events of telaprevir-based therapy in patients with and without advanced fibrosis or cirrhosis in a real-world setting. Methods Data on 174 hepatitis C-infected patients initiating telaprevir-based therapy at Mount Sinai and Montefiore medical centres were collected. Biopsy data and FIB-4 scores identified patients with advanced fibrosis. Multivariable fully adjusted models were built to assess the effect of advanced fibrosis on specific adverse events and discontinuation of treatment due to an adverse event. Results Patients with ( n = 71) and without ( n = 103) advanced fibrosis were similar in BMI, ribavirin exposure, gender, prior treatment history, haemoglobin and creatinine, but differed in race. Overall, 47% of patients completed treatment and 40% of patients achieved SVR. Treated patients with and without advanced fibrosis or cirrhosis had similar rates of adverse events; advanced fibrosis, however, was independently associated with ano-rectal discomfort ( P = 0.03). Three patients decompensated and had advanced fibrosis. The discontinuation of all treatment medications due to an adverse event was significantly associated with older age ( P = 0.01), female gender ( P = 0.01) and lower platelets ( P = 0.03). Conclusions Adverse events were common, but were not significantly related to the presence of advanced fibrosis or cirrhosis. More critical monitoring in older and female patients with low platelets throughout treatment may reduce adverse event-related discontinuations. [ABSTRACT FROM AUTHOR]

Background The IL28B genotype in rs12979860 predicts success of peginterferon/ribavirin ( PEG/ RBV) therapy in patients with chronic hepatitis C ( CHC). Recently, a dinucleotide frame shift variant in ss469415590 ( TT or ΔG) was described, which generates the novel interferon lambda 4 protein ( IFNL4). IFNL4 ss469415590 (ΔG) allele carriers have an impaired clearance of HCV infection and response to IFN-α therapy. In this study, we compared the role of IFNL4 polymorphism with the two commonly used IL28B SNPs rs12979860 and rs8099917 on response to PEG/ RBV in patients with CHC. Aim To compare the role of IFNL4 polymorphism with the two commonly used IL28B SNPs rs12979860 and rs8099917 on response to PEG/ RBV in patients with CHC. Methods A total of 754 PEG/ RBV patients treated (male/female = 484/270; Caucasians: 98.8%; mean age: 42.8 [CI 95%: 42.0-43.6] y; genotype (GT)1: n = 435, GT2: n = 23, GT3: n = 185, GT4: n = 114) were investigated. Liver fibrosis was assessed by liver biopsy in 456 patients. Single nucleotide polymorphisms ( SNPs) in ss469415590, rs12979860 and rs8099917 were analysed by RT- PCR system. Results Of the patients, 12.9% ( n = 97) had the ss469415590 ΔG/ΔG genotype (IFNL4), 51.3% ( n = 387) were heterozygous (TT/ΔG) and 35.8% ( n = 270) had TT/TT. IFNL4 polymorphism was independently associated with SVR in GT1 ( OR: 2.539, CI 95%: 1.629-3.021, P < 0.001) and GT4 (OR: 12.573, CI 95%: 3.427-46.133, P < 0.001), but not in GT3 (OR: 1.514, CI 95%: 0.933-2.458, P = 0.093). IFNL4 correlated strongly with rs12979860 (ρ = 0.988, P < 0.001), but only moderately with rs8099917 (ρ = 0.598, P < 0.001). Conclusions These findings underscore the role of IFNL4 for treatment response in patients with CHC genotypes 1 and 4. However, due to its strong correlation with rs12979860 in IL28B, there is no benefit in additional testing for IFNL4 for treatment prediction in Caucasian patients. By contrast, IFNL4 improves prediction of response to interferon-based therapies, if SNP rs8099917 is used. [ABSTRACT FROM AUTHOR]

Background Antiviral treatment is recommended for chronic hepatitis C patients with advanced fibrosis to reduce and prevent cirrhosis-related complications. Aim To evaluate the efficacy and safety of telaprevir (TVR)-based triple therapy for patients with advanced fibrosis in a clinical practice setting. Methods This prospective, multicentre study consisted of 102 patients with advanced fibrosis (METAVIR score F3-4) who were infected with HCV genotype 1b. All received 12 weeks of TVR in combination with 24 weeks of pegylated interferon (PEGIFN) a2b and ribavirin (RBV). Results The sustained virological response (SVR) rate was 69.6% (71 of 102). Notably, for treatment-naïve and prior relapse patients the SVR rate was over 80%. Previous treatment response, interleukin 28B polymorphism (rs8099917) and rapid virological response (undetectable HCV RNA at week 4) were independently associated with SVR. To achieve SVR, an adequate dosage of PEG-IFNa2b (≥ 1.2 lg/kg/week) and RBV (=7.5 mg/kg/day) is preferable; however, the mean weight-adjusted TVR dosage had little impact on treatment outcome. Although severe blood cytopaenia and a dermatological disorder were frequently found, the rate of discontinuation due to adverse effects was 12.7%. The inosine triphosphatase CC allele (rs1127354) was independently associated with the development of severe anaemia, and lower serum albumin level (<35 g/L) was associated with the occurrence of infection. Conclusions The great gain in the SVR rate by telaprevir-based triple therapy offsets the problems with adverse effects; thus, it should be considered as a potent treatment protocol for patients with advanced fibrosis, especially for those with treatment naïve and prior relapse. [ABSTRACT FROM AUTHOR]

Background The introduction of direct-acting anti-virals has increased sustained virological response ( SVR) rates in chronic hepatitis C genotype 1 infection. At present, data on long-term durability of viral eradication after successful triple therapy are lacking. Aim To evaluate the long-term durability of viral eradication in patients treated with triple therapy, including direct-acting anti-virals. Methods Patients who participated in randomised, controlled trials or an extended access programme of treatment with peginterferon-α2a/ribavirin in combination with a direct-acting anti-viral (telaprevir, danoprevir, faldaprevir, simeprevir, mericitabine, balapiravir) were followed after achieving SVR. The median follow-up after the patients was 21 (range: 7-64) months. Results One hundred and three patients with chronic hepatitis C genotype 1 infection [f/m: 34/69; GT-1b: 67 GT-1a: 34, GT-4: 2; mean age: 47.6 years (45.5-49.7; 95% CI)] achieving a SVR triple therapy were followed. Two cases of late relapses (2/103, 1.9%; 95% CI: 0.24-6.8) were observed. One patient was cirrhotic, both carried the genotype 1b and completed the prescribed treatment. The relapses occurred 8 and 12 months after cessation of anti-viral treatment. Cloning sequencing revealed identical sequence in both patients. Resistance analysis revealed no presence of viral resistance. Conclusion Like the SVR after peginterferon-α2/ribavirin combination treatment, HCV eradication after triple therapy remains durable after long-term follow-up. [ABSTRACT FROM AUTHOR]

Background Chronic hepatitis C virus ( HCV) infection and its treatment impact patients' health-related quality of life ( HRQL). Aim To report on treatment impact and predictors of HRQL among treatment-naïve patients with genotype 1 chronic HCV infection who received 12-week telaprevir (T) with 24 (T12PR24) or 48 weeks (T12PR48) peginterferon alpha-2a/ribavirin ( PR), or 48 weeks of PR in the ADVANCE study. Methods The EQ-5D-3L (EQ-5D) questionnaire (index range: 0-1) was completed at baseline and weeks 4, 12, 24, 36, 48 and 72. Patients indicated their health state on five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Descriptive statistics for the EQ-5D index and descriptive system and area under the curve from baseline to week 12 were calculated. Predictors of EQ-5D index were identified using multivariate analyses. Results Data from 722 patients were included. The mean EQ-5D index decreased during the first 12 weeks and returned to baseline by week 72 (T12PR24 by week 36) across treatments. In multivariate analysis, sustained virological response ( SVR) at week 72 was associated ( P < 0.0001) with improved EQ-5D index [mean; SVR+ (0.90), SVR− (0.86)], a 4% difference, within the published range of minimal clinically important difference. Conclusions Post hoc analyses of data from ADVANCE suggested that HRQL worsened during the first 12 weeks of therapy and returned to baseline by week 72 across treatments. Improvements were observed early following completion of a 24-week treatment (T12PR24). Telaprevir combination therapy was associated with slightly higher reductions in HRQL during the first 12 weeks (vs. PR). SVR was a statistically significant and meaningful predictor of HRQL at week 72. [ABSTRACT FROM AUTHOR]

Background Adherence to therapeutic regimens affects the efficacy of peginterferon alfa (P) and ribavirin (R) therapy in patients with chronic hepatitis C virus genotype 1. Aim To determine if medication adherence impacts efficacy [sustained virological response ( SVR)] with triple therapy that includes boceprevir (BOC) plus P/R. Methods Adherence was determined in two Phase 3 clinical studies with BOC: SPRINT-2 (previously untreated patients) and RESPOND-2 (patients who failed previous therapy with P/R). Adherence to the assigned duration of the dosing regimen and adherence to the three times a day (t.d.s.) dosing interval of 7-9 h for BOC were assessed by the recording of data from patients' dosing diaries and by the amount of study drug dispensed and returned. Results Most patients (63-71%) adhered to ≥80% of their assigned treatment duration and achieved SVR rates of 86-90%. In contrast, patients who adhered to <80% of their assigned treatment duration achieved SVR rates of 8-32% ( P < 0.0001), particularly low in patients who failed previous therapy ( SVR = 8-15%). Different rates of adherence (<60% to >80%) to the t.d.s. dosing interval (7-9 h) with BOC did not influence the SVR rates ( SVR = 60-83%) with the exception of patients who failed previous treatment and adhered to <60% of the t.d.s. dosing interval with BOC ( SVR = 48-50%; P = 0.005). Conclusions The achievement of an SVR is more dependent on adherence to the assigned duration of treatment than adherence to the t.d.s. dosing interval with boceprevir. Adherence to >60% of t.d.s. dosing with boceprevir is important in patients who failed previous therapy. [ABSTRACT FROM AUTHOR]

Background A Cochrane meta-analysis established that pegylated interferon α-2a is more effective than peginterferon α-2b in terms of sustained virological response ( SVR) in the treatment of chronic hepatitis C. Rapid virological response ( RVR) and early virological response ( EVR) are crucial to reach SVR and to make clinical decisions. Aim To compare RVR and EVR rates of peginterferon α-2a vs. peginterferon α-2b through a meta-analysis of previously published randomised control trials ( RCT). Methods MEDLINE, EMBASE and LILACS databases were systematically searched up to September 2011. Seven RCT that reported complete early virological response ( cEVR) were selected. A meta-analysis focusing on RVR and cEVR outcomes was conducted and Relative Efficacy (RE) was calculated. Results Meta-analysis of cEVR included seven trials ( n = 4359), and yielded an estimated effect in favour of peginterferon α-2a: Crude Efficacy (CEf) was 53.3% vs. 43.8%, RE = 1.118 (CI 95% = 1.039-1.203; P = 0.0028), heterogeneity Q = 8.959; I2 = 33.0% ( P = 0.1759). A sub-analysis of three studies with 3409 genotype-1 patients yielded CEf: 49.4% vs. 40.2%, RE = 1.151 (CI 95% = 0.968-1.369; P = 0.1124), Q = 9.802; I2 = 79.6% ( P = 0.0074). Meta-analysis of RVR included five trials ( n = 3833) with an estimated effect in favour of peginterferon α-2a: CEf = 25.0% vs. 16.8%, RE = 1.151 (CI 95%:1.042-1.272; P = 0.0056), Q = 1.461; I2 = 0.0% ( P = 0.8335). Analysis of four studies reporting RVR including 3499 patients with genotypes 1 and 4 resulted in CEf: 18.3% vs. 12.7% RE = 1.206 (CI 95% = 1.059-1.374; P = 0.0048), Q = 1.116; I2 = 0.0% ( P = 0.7733). Conclusions Peginterferon α-2a may be associated with a higher cEVR and RVR than peginterferon α-2b. These findings could help to achieve higher SVR rates and support clinical decision-making in the present scenario of triple combination therapy. [ABSTRACT FROM AUTHOR]

Background Recently, the therapeutic landscape with regard to anti- HCV therapy has changed dramatically. The new directly acting anti-virals ( DAAs) have demonstrated improved sustained virological response ( SVR) compared with pegylated-interferon and ribavirin. Aim To examine and present the latest data with regard to anti-viral therapy in genotype 1 HCV-positive transplant candidates and recipients. Methods An electronic search using Medline was performed. Search terms included ' HCV, DAA and protease inhibitor' in combination with 'treatment pre-transplantation' and 'treatment post-transplantation'. Results Patients with advanced fibrosis and cirrhosis have inferior SVR rates compared with patients with minimal fibrosis. A low accelerating dose regimen ( LADR) of pegylated interferon and ribavirin ( PR) appears to be a safe therapeutic option. Side effects also appear to be more pronounced in patients with advanced disease. Data from the large registration studies with triple therapy (boceprevir or telaprevir plus PR) demonstrated improved SVR rates even in patients with advanced disease, although virological relapse rates were highest amongst these patients. In transplant recipients, initial data are being reported on the use of triple therapy, and although no SVR data are available, promising results are accruing. The drug-drug interactions appear to be manageable. Side effects in particular anaemia appear to be markedly increased in the posttransplant setting. Conclusions The use of the new DAAs in patients with advanced fibrosis/cirrhosis pretransplant and posttransplant appears possible, with manageable side effects and drug-drug interactions, and improved early virological response rates. We recommend that these patients are managed in centres with the appropriate expertise. [ABSTRACT FROM AUTHOR]

Background Chronic hepatitis C ( HCV) treatment with pegylated-interferon ( PEG- IFN)/ribavirin ( RBV) is often limited by preexisting medical, psychiatric and psychosocial contraindications. However, limited data exist in general patient populations. Aim To evaluate the percentage of HCV-infected patients in the general US population who may have contraindications to PEG- IFN/ RBV. Methods The General Electric ( GE) Centricity dataset was used to screen the US population between 2004 and 2009 for HCV infection and contraindications to PEG- IFN/ RBV. HCV diagnosis and contraindications were identified using ICD-9- CM codes or laboratory values. Only patients with an encounter 180 days prior to HCV diagnosis were included. Demographic differences were calculated using Pearson's chi-squared test. Frequencies and percentages for absolute and relative contraindications to PEG- IFN and/or RBV were determined and proportions and rates/1000 person-months were calculated. Results A total of 15 561 021 patients were screened, and 45 690 (0.3%) were HCV-positive and were evaluated. Those with contraindications were significantly younger, female, White, not currently married and receiving Medicare or Medicaid coverage (all P < 0.0001). 17.3% had at least one contraindication to PEG-IFN/RBV (5.5 events/1000 person-months); bipolar disorder (6.5%), anaemia (Hgb < 10 g/dL; 5.9%), pregnancy (1.9%) and neutropenia (neutrophils <750 cells/mm3; 1.2%) were most frequently cited. Conclusions Approximately, 17% of HCV-infected patients in the general US population had at least one contraindication to PEG- IFN/ RBV. Most contraindications were relative and potentially modifiable. Clinical assessment of contraindications as relative and/or modifiable should be considered and used to determine if patients could benefit from current PEG- IFN-containing triple therapy or future PEG- IFN- or RBV-free regimens. [ABSTRACT FROM AUTHOR]

Background Insulin resistance has been strongly associated with the attainment of sustained viral response ( SVR) in hepatitis C patients. Aim To determine, in a cohort of Spanish patients with chronic hepatitis C treated with peginterferon plus ribavirin (P+R), whether insulin resistance predicts SVR independently of interleukin-28B rs12979860 polymorphism. Methods Insulin resistance was measured as [ HOMA- IR = Insulin (IU/mL)*glucose (mmol/L)/22.5]. Genotype, viral load and histological fibrosis using Scheuer score were also measured. Binary logistic regression analysis was used for statistical purposes. Results In a cohort of 240 patients [78% genotype 1, 24% showing advanced fibrosis, 71% high viral load (≥800 000 IU/mL), 31% IL28b genotype CC and 50% with HOMA >2] treated with P+R, 126 (53%) reached SVR. HOMA- IR index ( HOMA <2: 63% vs. HOMA >2: 42%; P = 0.001 and IL28b (genotype CC: 68% vs. genotype CT/ TT: 45%; P = 0.002) were significantly associated with SVR. In multivariable logistic regression analysis in the overall cohort, variables independently associated were: viral genotype OR: 0.29 (95% CI: 0.11-0.78), P = 0.01; fibrosis OR: 1.62 (95% CI: 1.22-2.16), P = 0.001; HOMA- IR OR: 1.22 (95% CI: 1.02-1.47), P = 0.03; and IL28B genotype OR: 2.43 (95% CI: 1.45-4.07), P = 0.001. The analyses also showed that degree of steatosis, HOMA- IR >2, mild fibrosis and IL28B CC genotype were significantly related to SVR in patients infected with HCV genotypes 1&4, but not in those with genotypes 2&3. No differences were seen in glucose, insulin level or HOMA- IR index segregated according to IL28B genotypes. Conclusion Our results suggest that insulin resistance, fibrosis stage and IL28B polymorphisms were independent variables associated with sustained viral response. [ABSTRACT FROM AUTHOR]

Background Limited data are available on the efficacy and safety of antiviral therapy in geriatric patients with chronic hepatitis C virus ( HCV) infection. Aim To evaluate the efficacy and safety of pegylated interferon (peg IFN) plus ribavirin ( RBV) therapy in geriatric HCV-infected patients. Methods Ninety-one geriatric patients (age ≥65 years; the elderly group) with HCV infection and 91 gender- and HCV genotype-matched middle-aged patients (age 50-64 years; the younger group) were assigned to receive weekly peg IFN injection plus weight-based oral RBV for 24 weeks. The on- and off-treatment virological responses were evaluated for treatment efficacy. Results In intention-to-treat analysis, the sustained virological response ( SVR) rate was substantially decreased in the elderly patients (elderly group vs. younger group, 40.7% vs. 61.5%, respectively; P = 0.005). The SVR rate was significantly lower in geriatric patients than in middle-aged patients with HCV genotype non-1 (54.3% vs. 82.9%; P = 0.01), but the difference was not significant with HCV genotype 1 (32.1% vs. 48.2%; P = 0.083). Furthermore, the older patients infected with HCV genotype non-1 who achieved a rapid virological response had a similar SVR rate to that of the younger patients. The withdrawal rate was 13.2% in the elderly group and 7.7% in the younger group. Conclusions Compared with middle-aged patients, the therapeutic efficacy of pegylated interferon plus ribavirin therapy is lower in hepatitis C virus-infected geriatric patients with an acceptable withdrawal rate. Considering prolonged lifespan in geriatric patients, we recommend treating geriatric hepatitis C virus-infected patients who have significant hepatic fibrosis and no other health problems. [ABSTRACT FROM AUTHOR]

Background Protease inhibitors have improved sustained virological response ( SVR) rates for subjects with genotype 1 hepatitis C virus infection ( HCV). There is however uncertainty regarding how, and in whom, these agents should be used. In previously treated subjects, prior response to interferon has a major effect on SVR rates with protease inhibitor therapy. Aim To assess the benefits of treatment and to understand the utility of a stopping rule for subjects with a poor interferon response following a 4-week lead-in with pegylated interferon and ribavirin. Methods Treatment responses and long-term outcomes were modelled using hypothetical 1000 subject cohorts with 5 years of follow-up. Treatment strategies were compared with number needed to treat ( NNT) and comparative effectiveness approaches. Results Over 5 years of follow-up the NNT to prevent liver-related mortality for subjects with advanced fibrosis was substantially lower than that for subjects with all fibrosis stages (18 vs. 60) indicating particular benefit in this high-risk population. The use of a stopping rule for subjects with advanced fibrosis and a poor interferon response after a 4-week lead-in reduces the number of subjects exposed to a protease inhibitor by 55%. However, 33% fewer liver-related deaths are prevented using this strategy, indicating that there is unacceptable harm associated with this approach over a 5-year follow-up period. Conclusions Subjects with advanced fibrosis should be prioritised for triple therapy on the basis of need. Treatment should be continued regardless of initial interferon response to maximise the early prevention of hepatitis C virus-related mortality. [ABSTRACT FROM AUTHOR]

Background Combination therapy with the ribavirin ( RBV) prodrug taribavirin ( TBV) and pegylated interferon ( PIFN) has produced lower rates of anaemia than with RBV and PIFN. Studies have demonstrated that the sharpest decline in viral load during TBV therapy occurs at Weeks 4 through 6, when TBV reaches steady-state blood levels. Aim The current proof-of-concept study was conducted to examine whether first-order viral kinetics could be influenced by pre-dosing TBV to steady state before introducing PIFN. Methods Therapy-naïve patients with chronic hepatitis C virus ( HCV) genotype 1 ( G1) were randomised to receive (i) TBV 600 mg BID monotherapy for 4 weeks followed by combination therapy with PIFN [pre-dosing arm ( n = 23)] or (ii) TBV administered concurrently with PIFN [standard dosing arm ( n = 19)]. Results More patients achieved undetectable virus or a ≥2-log10 reduction of HCV RNA at Week 4 in the pre-dosing vs. the standard dosing arm [33% vs. 22% ( P = 0.497)]. There was also a trend towards greater reduction in mean log10 change in HCV RNA in the pre-dosing vs. the standard dosing arm, which was statistically significant at Day 1 [−0.34 ± 0.46 vs. 0.09 ± 0.32 ( P < 0.003)] but not at other time points up to Week 24. No significant difference was observed in the rates of anaemia (haemoglobin <10 g/dL) between study arms (4.5% vs. 5.3%). Conclusions Pre-dosing TBV prior to starting PIFN produces a trend towards improved efficacy although statistical significance was not reached in this small patient population. These results warrant larger clinical trials of TBV pre-dosing. [ABSTRACT FROM AUTHOR]

Background Interleukin ( IL) 28 B single nucleotide polymorphisms can predict sustained virological response ( SVR) in hepatitis C virus ( HCV) patients following pegylated interferon-alpha ( PEG IFN-α) and ribavirin treatment. Aim To design a meta-analysis to determine IL28 B genotypes', rs12979860 CC and rs8099917 TT, correlation with SVR in PEG IFN-α/ribavirin-treated HCV patients. Methods Meta-analysis was performed in 17 studies of rs12979860 CC vs. CT/ TT and 17 of rs8099917 TT vs. TG/ GG. Odds ratios ( OR) and confidence intervals (95% CI) were calculated by fixed- or random-effects models. Heterogeneity, sensitivity analysis and publication bias were also assessed. Results Of 4252 Asian, Caucasian and African HCV patients analysed for rs12979860, SVR was more frequent in CC (vs. CT/ TT; OR = 4.76, 95% CI: 3.15-7.20). Moreover, CC was associated with SVR for HCV genotype-1 or -4 infections ( ORgenotype 1 = 5.52, 95% CI: 3.74-8.15; ORgenotype 4 = 8.11, 95% CI: 4.13-15.93), regardless of ethnicity. Of 4549 Caucasian and Asian HCV patients analysed for rs8099917, SVR was more frequent in TT (vs. TG/ GG; OR = 3.31, 95% CI: 2.39-4.59). Moreover, TT was associated with SVR for HCV-1 ( ORgenotype 1 = 4.28, 95% CI: 2.87-6.38). Rs8099917 TT predictive value was stronger in Asians ( ORAsians = 8.09, 95% CI: 5.63-11.61; ORCaucasians = 3.00, 95% CI: 2.03-4.45). Ethnicity stratification revealed that rs8099917 TT had slight predictive value in Asian HCV-2/3 patients ( OR = 1.99, 95% CI: 1.09-3.62). Conclusions IL28B rs12979860 CC and rs8099917 TT are strong SVR predictors for PEG IFN-α/ribavirin-treated HCV-1 patients, regardless of ethnicity. In HCV-2/3, rs12979860 CC has no SVR predictive value, but rs8099917 TT was slightly associated with SVR in Asians. [ABSTRACT FROM AUTHOR]

Background Polymorphisms in the IL-28 B region are a strong predictor of sustained virologic response ( SVR) in individual studies of HCV genotype 1 patients receiving peginterferon (peg IFN) and ribavirin. Aim To obtain a pooled odds ratio ( OR) of SVR in patients of varying race with the favourable IL-28 B genotype compared to those with the unfavourable genotype. Methods A literature search was conducted using online databases and a review of conference abstracts. A random effects meta-analysis was performed and study heterogeneity and publication bias were assessed. Results There were 21 individual studies of HCV genotype 1 patients of varying ethnicity treated with peg IFN and ribavirin. The pooled prevalence of the favourable IL-28 B genotype varied by race (73% vs. 41% vs. 13% in 2612 Asians, 3110 Caucasians and 452 African-Americans, respectively, P < 0.001). However, the strength of association of the IL-28 B genotype with SVR was similar in all three racial groups (Caucasians: odds ratio ( OR) 3.88, 2.75-5.49, African-Americans: OR 4.63, 2.52-8.50 and Asians OR 5.66, 3.99-8.02, all P < 0.001). The IL-28 B genotype was also associated with SVR in 263 HIV/ HCV co-infected Caucasians ( OR 5.49, 3.02-9.96, P < 0.001). Study quality score and anti-viral treatment regimen did not impact the strength of the association in patient subgroups nor in the pooled population. Conclusions IL-28 B genotype is significantly associated with SVR in HCV genotype 1 patients of varying race, as well as in HIV co-infected patients, receiving peg IFN and ribavirin. IL-28 B testing in conjunction with other pre-treatment parameters may prove useful in counselling HCV patients. [ABSTRACT FROM AUTHOR]

Background Homozygosity for the PNPLA3 p. I148 M polymorphism influences steatosis and fibrogenesis in chronic hepatitis C ( CHC). Aim To evaluate the effect of p.148 M/ M on sustained virological response ( SVR) and viral kinetics in patients who underwent antiviral therapy with peg-interferon and ribavirin, stratified according to viral genotype and fibrosis severity, and secondarily, the interaction with interleukin- 28 B ( IL28B) genotype on liver damage. Methods In this observational study, we considered 602 treatment-naïve consecutive patients from tertiary referral centres in Milan and Vienna [61% genotype 1 ( G1), 30% advanced fibrosis, 33% IL28B rs12979860 CC]. Results The p.148 M/ M genotype, detected in 8% of patients, did not influence SVR in the overall series ( P = 0.29), but it was associated with SVR (3/17, 17% vs. 56/121, 46%; P = 0.034) and complete early viral response (4/17, 23% vs. 68/121, 56%; P = 0.018) in G1/4 patients with advanced fibrosis. After adjustment for age, viral load, IL28B CC genotype, treatment dose, and steatosis, p.148 M/ M remained a predictor of SVR in G1/4 patients with advanced fibrosis ( OR 0.23, 95% CI 0.04-0.87). The p.148 M/ M genotype was associated with more advanced fibrosis in the overall series ( P = 0.049), whereas the rs12979860 IL28B CC genotype only in patients negative for p.148 M/ M ( P = 0.017), independently of age, BMI and alanine transaminase levels ( OR 1.51, 95% CI 1.01-2.27). Conclusions PNPLA3 p.148 M/ M genotype was negatively associated with SVR and early viral kinetics independently of steatosis, albeit only in difficult-to-cure G1/4 patients with advanced fibrosis, whereas stratification for the p.148 M/ M PNPLA3 genotype unmasked an association between IL28B CC genotype and more severe liver fibrosis. [ABSTRACT FROM AUTHOR]

Background Amongst Caucasian, Hispanic and African Americans with genotype 1 hepatitis C virus ( HCV), there is a wide variation in response to treatment with peginterferon alfa-2a ( PEG- IFN alfa-2a) and ribavirin. Aim To evaluate the pharmacokinetics ( PK) of PEG- IFN alfa-2a and ribavirin among these three groups. Methods Forty-seven patients with genotype 1 CHC (17 African Americans, 14 Hispanics and 16 Caucasians) received 8 weeks of PEG- IFN alfa-2a (180 &g/week) and ribavirin (1000 or 1200 mg/day). PEG- IFN alfa-2a serum concentrations and ribavirin plasma concentrations were measured following the first dose and at week 8. Pharmacokinetic parameters ( Cmax, Tmax, AUC, CL/ F) were estimated using noncompartmental methods. Results There was no difference in the pharmacokinetic parameters for PEG- IFN alfa-2a following single-dose or steady-state administration between African American or Hispanic patients compared with Caucasian patients. Ribavirin pharmacokinetic parameters were similar between Hispanic and Caucasian patients for single-dose and steady-state administration. The single-dose Cmax was 33% lower ( P < 0.05) in African American compared with Caucasian patients. Other ribavirin single-dose and steady-state pharmacokinetic parameters were slightly decreased (approximately 20% lower) in African American patients, but were not considered clinically meaningful. Conclusions No differences were observed in PEG- IFN alfa-2a pharmacokinetic parameters between African American or Hispanic patients compared with Caucasian patients. For ribavirin, no differences were observed in pharmacokinetic parameters between Hispanic and Caucasian patients. While a trend towards increased ribavirin clearance and decreased exposure was observed in African American patients vs. Caucasian patients, the differences were small and not considered clinically meaningful (Clinical Trial Number: NP17354). [ABSTRACT FROM AUTHOR]

Summary Background The nonstructural 3 serine protease inhibitors ( PIs), boceprevir and telaprevir, represent the first in a new generation of directly acting antivirals against genotype 1 hepatitis C ( HCV) infection. When used in combination with pegylated interferon and ribavirin, these drugs greatly improve sustained virological response rates in both treatment-naïve patients and patients who have had previous virological failure on treatment. However, the addition of these new agents will increase the complexity of therapeutic regimens, the rates of side-effects and costs. Aims To review concisely the current evidence and to suggest current best practice, for the use of telaprevir and boceprevir in the management of chronic genotype 1 HCV infection. Methods These guidelines for the use of boceprevir and telaprevir have been formulated following extensive review of the current literature, are based on the consensus opinion of a panel of national experts, and have been openly discussed and debated at a national meeting of HCV care providers. Results We have made recommendations on a number of the key practical issues facing HCV care providers: (i) Which patients to treat?; (ii) Standards for the provision of care; (iii) Pre-treatment considerations; (iv) Which treatment regimens to use?; (v) Stopping rules; and (vi) Management of adverse effects. Finally, we have produced suggested algorithms for the assessment and treatment of these patients. Conclusions These UK Consensus guidelines indicate the current best practice for the use of boceprevir and telaprevir in the management of genotype 1 chronic HCV infection. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 2011; 34: 1306-1317 Summary Background Treatment of hepatitis C with peginterferon and ribavirin is associated with psychiatric side-effects, frequently necessitating dose reduction or therapy cessation. Aim To assess the efficacy of prophylactic escitalopram to prevent psychiatric side-effects during peginterferon and ribavirin treatment in a randomised, double-blind, placebo-controlled trial. Methods Seventy-nine hepatitis C patients were treated with peginterferon and ribavirin. Patients received escitalopram ( n = 40, 10 mg) or placebo ( n = 39), which was initiated together with peginterferon and ribavirin. Primary outcomes were an increase of two points or more on the items reported sadness, inner tension and impaired concentration of the Montgomery-Asberg Depression Rating Scale, and hostile feelings of the Brief Anxiety Scale. Secondary outcome was the development of depression diagnosed by the Mini-International Neuropsychiatric Interview. Measurements were performed at baseline, week 4, 12 and 24 during anti-viral treatment, and 24 weeks thereafter. Results The incidence of psychiatric side-effects was significantly lower in patients treated with escitalopram compared with placebo for all primary and secondary outcomes, except for impaired concentration: reported sadness 27.5 vs. 48.7% ( P = 0.052), inner tension 17.5 vs. 38.5% ( P = 0.038), impaired concentration 55.0 vs. 66.7% ( P = 0.288) and hostile feelings 22.5 vs. 43.6% ( P = 0.046) (escitalopram vs. placebo, Chi-squared test). The sum scores of all four endpoints showed an overall beneficial effect of escitalopram ( P = 0.009, Mann-Whitney U-test). Depression occurred in 12.5% of the patients in the escitalopram-group vs. 35.9% in the placebo-group ( P = 0.015, Chi-squared test). Conclusions Prophylactic treatment with escitalopram is effective in the prevention of psychiatric side-effects during interferon-based treatment of hepatitis C. [ABSTRACT FROM AUTHOR]