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Predicting hepatitis C treatment outcomes is of great benefit to patient and clinician. Baseline predictors of response or failure can set the appropriate expectations for the patient and may aid in decision making about starting therapy. An accurate assessment of the potential for treatment success involves using rapid and early viral kinetics at weeks 4 and 12. These time points are useful to set up stopping rules and to provide motivation for the patient and health care provider to continue when appropriate. Relapse is an unfortunate consequence of therapy in a significant number of patients. Baseline and on-treatment viral assessments are useful in helping predict and perhaps reduce this phenomenon.

Pegylated interferon and ribavirin are currently the standard of care therapy for chronic hepatitis C. In the near future, protease inhibitors are likely to be part of a three-drug regimen with interferon and ribavirin. It is not yet clear if therapy duration will be shorter, but it appears that anemia will be more severe. Ribavirin has to date been proven indispensible as a member of the treatment regimen, despite the potentially dangerous side effect of anemia. Taribavirin (viramidine), a purine nucleoside analog, is a prodrug of ribavirin. In a Phase III registration trial, it failed to show adequate efficacy but did have significantly less anemia when compared with weight-adjusted ribavirin. The dosing of taribaivirin may have been the flaw of that study, and indeed interim results of a Phase IIb study currently underway appear to have better antiviral effects with weight-based dosing. Sustained viral response rates comparable to ribavirin in a larger prospective study will be needed to supplant the current regimen. However, even if taribavirin efficacy is slightly lower than ribavirin, but anemia rates are considerably lower, there may still be a role for taribaivirin in a triple regimen where a protease molecule will be the predominant antiviral agent.

The treatment of chronic hepatitis C is a rapidly changing arena with new medications, new guidelines, and an evolving understanding of the virus, host factors and natural history. With the explosion of new information, the educational infrastructure to update clinicians has been outpaced; many feel uncertain if the tools they are using to care for patients are meeting the standard of practice. This review focuses on the most common genotype of the hepatitis C virus and the rules of engagement when treating with pegylated interferon and ribavirin. Viral assessment guideposts are evaluated and put into context for a clinical audience. The expected arrival of newer antiviral therapies is still years away, and maximizing the current treatment regimens is of utmost importance to eradicate virus when feasible, while minimizing toxicity.

Robert Gish1, Ting-Tsung Chang2, Ching-Lung Lai3, Robert de Man4, Fred Poordad5, Dong Xu6, Helena Brett-Smith6, Melissa Harris6, Uchenna Iloeje6, Hong Tang6 1Division of Hepatology and Complex GI, Physicians Foundation California Pacific Medical Center, San Francisco, California, USA; 2National Cheng Kung University Medical College, Tainan, Taiwan; 3Department of Medicine, University of Hong Kong, Hong Kong SAR, China; 4Erasmus Medical Center, University Hospital Rotterdam, The Netherlands; 5Department of Hepatology and Liver Transplantation, Cedars-Sinai Medical Center, Los Angeles, California, USA; 6Bristol-Myers Squibb Company, Research & Development, USA

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Approximately one-third of all patients infected with hepatitis C virus (HCV) genotype 1 who complete pegylated interferon α-based therapy and have undetectable serum HCV RNA at the end of treatment will experience relapse. Although relapse is a common outcome of therapy, its pathology and strategies for optimal management are poorly understood; however, optimized ribavirin dosing is recognized as pivotal in mitigating relapse. Recent data also suggest that early viral kinetics might help identify particular patient groups, such as slow responders, who are predisposed to relapse. This review provides a comprehensive overview of the importance of relapse in patients with chronic hepatitis C, including its underlying pathobiology, potential predictors and strategies to optimize the retreatment of previous relapsers.

Objectives: Although effective, direct acting antiviral (DAA) therapies for genotype 1 (GT 1) hepatitis C virus (HCV) have been associated with compliance challenges. Additionally, treatment at predominantly community-based centers has been associated with low retention of patients on treatment and higher dropout rates. The OPTIMAL Phase IV interventional trial ( ClinicalTrials.gov Identifier: NCT01405027) was designed to evaluate the impact of an education program for community investigator (CI) sites participating in a Chronic Liver Disease Foundation study treating chronic GT 1 HCV patients. Methods: This physician educational program was administered by 22 Hepatology Centers of Educational Expertise (HCEE) academic sites to 33 CI sites asked to participate from December 2011 to July 2012. The HCEE mentors from DAA-experienced academic sites educated those at CI sites on therapeutic management, practice, and patient outcomes through a series of four standardized educational sequence visits regarding the use of first generation HCV protease inhibitors and the overall treatment of HCV. Results: Treatment duration compliance rates for patients treated at CI sites versus those treated at HCEE academic sites were evaluable in 77 of 84 HCEE academic site patients, 102 of 113 patients treated at CI sites, and 179 of 197 overall patients. The treatment duration compliance rates for patients treated at HCEE academic sites, CI sites and overall were 85.4 ± 25.39%, 83.8 ± 27.37%, and 84.5 ± 26.48%, respectively, and did not differ statistically between the groups ( p = 0.49). Almost half (47%) of the patients in the study achieved a sustained virological response for 24 weeks (SVR24) regardless of the type of site ( p = 0.64). Safety profiles were similar at both HCEE and CI sites. Conclusions: These results demonstrated that education of CI sites unfamiliar with DAAs resulted in patient outcomes consistent with those observed at DAA-experienced academic sites.

Background & Aims Patients with chronic hepatitis C virus (HCV) infection and cirrhosis have a higher risk for liver-related complications and have historically been more difficult to cure than patients without cirrhosis. We evaluated the safety and efficacy of ombitasvir/paritaprevir/ritonavir and dasabuvir, without ribavirin, for 12 weeks in patients with HCV genotype 1b infection and compensated cirrhosis. Methods Treatment-naïve and peginterferon/ribavirin treatment-experienced patients received 12 weeks of ombitasvir/paritaprevir/ritonavir (25/150/100 mg once daily) and dasabuvir (250 mg twice daily). Key inclusion criteria were hemoglobin ≥10 g/dl, albumin ≥2.8 g/dl, platelet count ≥25 × 109/L, creatinine clearance ≥30 ml/min, and Child-Pugh score ≤6. Efficacy was assessed by the percentage of patients achieving SVR (HCV RNA, SCOPUS: ar.j, info:eu-repo/semantics/published

The antiviral activity of all-oral, ribavirin-free, direct-acting antiviral regimens requires evaluation in patients with chronic hepatitis C virus (HCV) infection.To determine the rates of sustained virologic response (SVR) in patients receiving the 3-drug combination of daclatasvir (a pan-genotypic NS5A inhibitor), asunaprevir (an NS3 protease inhibitor), and beclabuvir (a nonnucleoside NS5B inhibitor).This was an open-label, single-group, uncontrolled international study (UNITY-1) conducted at 66 sites in the United States, Canada, France, and Australia between December 2013 and August 2014. Patients without cirrhosis who were either treatment-naive (n = 312) or treatment-experienced (n = 103) and had chronic HCV genotype 1 infection were included.Patients received a twice-daily fixed-dose combination of daclatasvir, 30 mg; asunaprevir, 200 mg; and beclabuvir, 75 mg.The primary study outcome was SVR12 (HCV-RNA25 IU/mL at posttreatment week 12) in patients naive to treatment. A key secondary outcome was SVR12 in the treatment-experienced cohort.Baseline characteristics were comparable between the treatment-naive and treatment-experienced cohorts. Patients were 58% male, 26% had IL28B (rs12979860) CC genotype, 73% were infected with genotype 1a, and 27% were infected with genotype 1b. Overall, SVR12 was observed in 379 of 415 patients (91.3%; 95% CI, 88.6%-94.0%): 287 of 312 treatment-naive patients (92.0%; 95% CI, 89.0%-95.0%) and 92 of 103 treatment-experienced patients (89.3%; 95% CI, 83.4%-95.3%). Virologic failure occurred in 34 patients (8%) overall. One patient died at posttreatment week 3; this was not considered related to study medication. There were 7 serious adverse events, all considered unrelated to study treatment, and 3 adverse events (1%) leading to treatment discontinuation, including 2 grade 4 alanine aminotransferase elevations. The most common adverse events (in ≥10% of patients) were headache, fatigue, diarrhea, and nausea.In this open-label, nonrandomized, uncontrolled study, a high rate of SVR12 was achieved in treatment-naive and treatment-experienced noncirrhotic patients with chronic HCV genotype 1 infection who received 12 weeks of treatment with the oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir.clinicaltrials.gov Identifier: NCT01979939.

To provide an understanding of the detrimental impact of cirrhosis and its complications, strengths and weaknesses of current treatment options for the management of these complications, and new developments in this rapidly changing field.Relevant publications were identified via PubMed and Cochrane databases, with additional references obtained by reviewing bibliographies from selected articles.Cirrhosis, a progressive liver disease, is characterized by fibrosis caused by chronic liver injury. Liver fibrosis impairs hepatic function and causes structural changes that result in portal hypertension. Most patients with cirrhosis remain asymptomatic until they develop decompensated cirrhosis. At this stage, patients experience complications associated with portal hypertension (i.e., the abnormal increase in portal vein pressure), including ascites, spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE), hepatorenal syndrome, portopulmonary hypertension, or variceal bleeding. In addition, intestinal microbial translocation in patients with cirrhosis might also cause SBP and HE. Because the survival rate for patients with cirrhosis substantially decreases once complications develop, the key goals in treating patients with cirrhosis include both managing the underlying liver disease and preventing and treating related complications. In patients with compensated cirrhosis, the management strategy is to prevent variceal bleeding and other complications that can lead to decompensated cirrhosis. Patients with decompensated cirrhosis are typically referred for liver transplantation, and the main focus of pre-transplant management is to eliminate the cause of cirrhosis (e.g., excess alcohol consumption, hepatitis virus) and prevent the recurrence of each decompensating complication.Although substantial progress has been made to prevent the complications and mortality associated with cirrhosis, liver transplantation in combination with resolution of the etiology of cirrhosis remains the only curative option for most patients. Emerging therapies such as anti-fibrotic agents hold promise in potentially halting or reversing the progression of cirrhosis, even in patients with decompensated cirrhosis.

In 247 subjects with hepatitis C virus genotype 1 infection treated with the interferon-free regimen of ABT-450/ritonavir, ombitasvir, and dasabuvir plus ribavirin, concordance of a sustained virologic response at 12 and 24 weeks supports the use of the earlier time point as a primary efficacy endpoint for trials of this interferon-free regimen.

Nonalcoholic fatty liver disease is an umbrella term that includes steatosis, nonalcoholic steatohepatitis and advanced fibrosis or cirrhosis. The terminology, although cumbersome, was intended to differentiate these disorders from alcohol-related liver disorders, as they are histologically similar. The term was first used by Ludwig in 1980, but has received a tremendous amount of attention in the past several years as a result of a better understanding of the scope of the problem [1]. Although the pathogenesis has not been fully elucidated, there is a tremendous amount of research ongoing in this arena, both clinical and basic, to determine how the course of the disease can be altered. This text reviews the epidemiology of the disease, leading theories of pathogenesis, and treatment options.

Many forms of liver disease may ultimately lead to fibrosis of the liver, the most advanced state being cirrhosis. Cirrhosis is a morphologic disease that eventually results in a functional change of the liver. It is generally not accompanied by signs or symptoms early in its course, and is often diagnosed late when signs of liver failure become overt. Imaging studies may suggest cirrhosis, but only if there have been gross changes in the appearance of the liver, and this is often not the case. The only way to diagnose cirrhosis reliably has been through direct histologic examination of liver tissue. The drawback to histologic diagnosis has been the risks and discomfort associated with liver biopsy. Hesitation to perform the procedure also exists due to lack of experience of many practitioners and the low reimbursement rates for a procedure that is viewed as time consuming and potentially dangerous. The search for noninvasive modalities to assess fibrosis through biochemical and other means has begun. Several markers are currently under investigation, many of which are combined with clinical assessment and other biochemical parameters, to establish the presence of liver fibrosis. FIBROSpect II is an example of a commercially available assay that employs a combination of three markers to distinguish between no, minimal and advanced fibrosis.

Screening of blood products and attention to stricter infection control measures in hemodialysis units have reduced the incidence of hepatitis C virus (HCV) infection among dialysis patients. HCV can be transmitted via transplanted organs. Renal transplantation may accelerate the course of liver disease, which has an impact on patient and graft survival. Interferon (IFN) alfa monotherapy has produced promising results during treatment but disappointing long-term results in patients with HCV-associated glomerulonephritis. Dialysis patients with HCV infection respond well to IFN-based therapy, and there appears to be clinical benefit in clearing HCV in renal transplantation candidates. Larger prospective trials are required to fully determine the role of IFN in these patient groups, including the potential use of IFN plus ribavirin and pegylated IFNs. IFN therapy in renal transplantation patients is not recommended because of potential graft rejection.

Current prophylactic measures have greatly reduced recurrence rates of hepatitis B after liver transplantation. HBIG remains a critically important compound and although there is variability in dosing regimens and target anti-HBs levels, it is the backbone of recurrence prevention. Adjuvant therapies with nucleoside/nucleotide analogs alone have been limited by drug-resistant strains of HBV, but the armamentarium of these molecules continues to grow and hence the management of the post-LT HBV patient will evolve further. Currently lamivudine with HBIG remains an excellent option provided the patient has not developed resistance, especially in the pre-LT period. Adefovir is the drug of choice in that setting and perhaps the preferred drug in the pre-LT setting to allow the use of lamivudine post-LT. Further testing with tenofovir and newer compounds in development will expand these options. The use of multiple nucleoside analogs is an intriguing option, based on the HIV experience of reducing drug resistance and optimizing viral suppression, and will likely be further studied.

Summary Background : Sirolimus is a potent immunosuppressive medication that acts by inhibiting T-cell proliferation. It has been used in kidney transplantation because of its lack of nephrotoxicity. It is now being investigated in liver transplantation, but there are concerns about safety and long-term side effects such as dyslipidaemia. Hypertriglyceridaemia is a common adverse event seen with sirolimus use, and often does not respond to dose reduction or anti-lipemic drugs. Method : We report six patients who have developed significant hyperlipidaemia while receiving sirolimus, in spite of therapeutic trough levels. Conclusion : All six patients showed either resolution or improvement in lipid levels with discontinuation of sirolimus.

Management of obesity and decompensated cirrhosis in those requiring liver transplantation (LT) is a challenging dilemma. Because of concerns for perioperative complications, many centers avoid transplant in those with a body mass index (BMI) greater than 40 kg/m(2) . Bariatric surgery is associated with increased risk attributable to complications of portal hypertension, including variceal rupture. Therefore, weight loss and LT options are limited. Several new classes of weight loss drugs are commercially available, including the anoretic, lorcaserin. This case illustrates the successful use of lorcaserin in a morbidly obese individual with decompensated cirrhosis evaluated for LT listing. (Hepatology 2016;64:301-302).

Hepatitis C virus infection accounts for 40% of chronic liver disease in the United States and is the most common indication for liver transplantation. Estimates suggest that 4 million people, or 1.8% of the American population, have or have had hepatitis C virus infection. Pegylated interferon and ribavirin are the current standard of care for treatment. Recent studies have suggested that ribavirin dose and duration of therapy may be adjusted based on genotype. The goals of therapy are to slow disease progression, improve hepatic histology, reduce infectivity, and decrease the risk of hepatocellular carcinoma. Sustained virologic response, which generally implies the absence of viremia 6 or more months following completion of therapy, is increasingly being regarded as a cure, with evidence of slowing or even regression of fibrosis on follow-up liver biopsy. Assessment by liver biopsy of disease severity and evaluation of comorbidities and possible contraindications to therapy should be weighed in the decision to begin treatment. Counseling patients regarding transmission, natural history, and drug and alcohol abstinence should also be included in management. Close monitoring should be done during treatment for interferon and ribavirin side effects, including depression, bone marrow suppression, and hemolytic anemia.

Hepatitis C virus (HCV) remains common in patients with end-stage renal disease (ESRD) and is an important cause of liver disease in this population. Acquisition of HCV infection continues to occur in dialysis patients because of nosocomial spread. The natural history of HCV in dialysis patients remains controversial because the course of HCV typically extends over decades, whereas dialysis patients have higher morbidity and mortality rates than those of the general population limiting long-term follow-up. However, recent reports suggest that HCV infection affects the survival of chronic dialysis patients as well as renal transplant (RT) recipients. The severity of preexisting liver disease on pretransplantation liver biopsy may provide useful prognostic information about clinical outcome after RT; liver biopsy should be incorporated in the evaluation and management of RT candidates with HCV. Recent surveys with long-term follow-up have documented adverse effects of HCV on patient and graft survival. Use of renal grafts from HCV-infected donors in recipients with HCV does not appear to result in a greater burden of liver disease albeit with short-term follow-up. There is only limited data about interferon (IFN) therapy in chronic dialysis patients, although sustained responses are reported. Preliminary data on IFN plus ribavirin therapy in dialysis patients with hepatitis C have given encouraging results, but randomized trials are needed. Interferon remains contraindicated post-RT because of concern about precipitating graft dysfunction.

Sofosbuvir (SOF) in combination with ribavirin (RBV) for 12 or 24 weeks is the current standard of care for patients infected with hepatitis C virus (HCV) genotypes 2 and 3, respectively. However, in clinical trials treatment-experienced patients, particularly those with cirrhosis, had suboptimal sustained virological response (SVR) rates. We assessed the efficacy and safety of sofosbuvir plus peginterferon and ribavirin (SOF+Peg-IFN+RBV) administered for 12 weeks to treatment-experienced patients with HCV genotypes 2 and 3, with and without cirrhosis. We enrolled 47 patients in this open-label, nonrandomized, uncontrolled phase 2 study. The primary endpoint was the proportion of patients with SVR at 12 weeks after cessation of study treatment (SVR12). The overall rate of SVR12 was 89% (95% confidence interval [CI]: 77-97). Rates of SVR12 were higher in patients with genotype 2 than in those with genotype 3, 96% (95% CI: 78-100) and 83% (95% CI: 62-95), respectively. Rates of SVR12 were similar in patients with and without cirrhosis: for genotype 2, 93% of patients with cirrhosis and 100% of patients without cirrhosis achieved SVR12, and for genotype 3, the SVR12 rate was 83% in patients both with and without cirrhosis. One patient discontinued study treatment because of an adverse event and four patients experienced serious adverse events. The most common adverse events were influenza-like illness, fatigue, anemia, and neutropenia. Conclusion: In treatment-experienced patients with HCV genotypes 2 and 3, 12-week administration of SOF+Peg-IFN+RBV provided high SVR rates, irrespective of cirrhosis status. No safety concerns were identified. (Hepatology 2015;61:769–775)

International audience; BACKGROUND & AIMS:HCV-infected cirrhotics may urgently need therapy but are often under-represented in clinical trials resulting in limited data to guide their management. We performed a meta-analysis of well-compensated cirrhotic patients from five Phase 3 trials.METHODS:Patients received P/R (peginterferon/ribavirin; 4 weeks) followed by BOC (boceprevir)/P/R or P/R for 24, 32, or 44 weeks. Sustained virologic response (SVR) rates were calculated by Metavir score. Multivariate logistic regression (MLR) models identified baseline and on-treatment predictors of SVR. Safety was evaluated by adverse-event (AE) reporting and laboratory monitoring.RESULTS:Pooled meta-estimates for SVR rates (95% confidence interval) in 212 F4 (cirrhotic) patients were 55% (43, 66) with BOC/P/R vs.17% (0, 41) with P/R. MLR identified 4 predictors of SVR in F3/F4 patients: undetectable HCV-RNA at treatment week (TW) 8; ⩾ 1 log10 decline in HCV-RNA from baseline at TW4; male; and baseline HCV-RNA ⩽ 800,000 IU/ml. SVR rate was 89% (65/73) in F4 patients who were HCV-RNA undetectable at TW8. No F3 (0/5) or F4 (0/17) patients with

Pegylated interferon (peginterferon) alfa 2a or 2b plus ribavirin regimens were the standard of care in patients with hepatitis C virus (HCV) infection, but the sustained virological response can be suboptimum in patients with HCV genotype 1 infection. The efficacy, safety, and tolerability of the combination of simeprevir, a one-pill, once-daily, oral HCV NS3/4A protease inhibitor versus placebo, plus peginterferon alfa 2a or 2b plus ribavirin was assessed in treatment-naive patients with HCV genotype 1 infection.In the QUEST-2, phase 3 study, done at 76 sites in 14 countries (Europe, and North and South Americas), patients with confirmed chronic HCV genotype 1 infection and no history of HCV treatment were randomly assigned with a computer-generated allocation sequence in a ratio of 2:1 and stratified by HCV genotype 1 subtype and host IL28B genotype to receive simeprevir (150 mg once daily, orally), peginterferon alfa 2a (180 μg once weekly, subcutaneous injection) or 2b (according to bodyweight; 50 μg, 80 μg, 100 μg, 120 μg, or 150 μg once weekly, subcutaneous injection), plus ribavirin (1000-1200 mg/day or 800-1400 mg/day, orally; simeprevir group) or placebo (once daily, orally), peginterferon alfa 2a or 2b, plus ribavirin (placebo group) for 12 weeks, followed by just peginterferon alfa 2a or 2b plus ribavirin. Total treatment duration was 24 weeks or 48 weeks (simeprevir group) based on criteria for response-guided therapy (ie, HCV RNA25 IU/mL undetectable or detectable at week 4 and undetectable week 12) or 48 weeks (placebo). Patients, study personnel, and the sponsor were masked to treatment assignment. The primary efficacy endpoint was sustained virological response at 12 weeks after the planned end of treatment (SVR12). Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01290679. Results from the primary (SVR12, week 60) analysis are presented.209 (81%) of 257 patients in the simeprevir group and 67 (50%) of 134 in the placebo group had SVR12 (adjusted difference 32·2%, 95% CI 23·3-41·2; p0·0001). The incidences of adverse events were similar in the simeprevir and placebo groups at 12 weeks (246 [96%] vs 130 [97%]) and for the entire treatment (249 [97%] vs 132 [99%]), irrespective of the peginterferon alfa used. The most common adverse events were headache, fatigue, pyrexia, and influenza-like illness at 12 weeks (95 [37%) vs 45 [34%], 89 [35%] vs 52 [39%], 78 [30%] vs 48 [36%], and 66 [26%] vs 34 [25%], respectively) and for the entire treatment (100 [39%] vs 49 [37%], 94 [37%] vs 56 [42%], 79 [31%] vs 53 [40%], and 66 [26%] vs 35 [26%], respectively). Rash and photosensitivity frequencies were higher in the simeprevir group than in the placebo group (61 [24%] vs 15 [11%] and ten [4%] vs one [1%], respectively). There was no difference in the prevalence of anaemia between the simeprevir and placebo groups (35 [14%] vs 21 [16%], respectively, at 12 weeks, and 53 [21%] vs 37 [28%], respectively, during the entire treatment).Addition of simeprevir to either peginterferon alfa 2a or peginterferon alfa 2b plus ribavirin improved SVR in treatment-naive patients with HCV genotype 1 infection, without worsening the known adverse events associated with peginterferon alfa plus ribavirin.Janssen Infectious Diseases-Diagnostics.

This pooled analysis of five Phase IIb and III studies evaluated the safety and tolerability of simeprevir, a once daily, oral hepatitis C virus (HCV) NS3/4A protease inhibitor. Data were summarised for patients who received simeprevir 150 mg once daily (n = 924) or placebo (n = 540) plus pegylated interferon-α/ribavirin for 12 weeks. During the first 12 weeks of treatment, few patients discontinued simeprevir or placebo due to adverse events (AEs) (both 2.2%). Pruritus (23.8% vs 17.4%), rash (any; 22.9% vs 16.7%) and photosensitivity (3.2% vs 0.6%) [Correction added on 16 January 2015, after first online publication: In the above sentence, the values in 'Photosensitivity' were previously incorrect and have now been changed to 3.2% vs 0.6%.] were more prevalent in the simeprevir vs the placebo groups. Most AEs were grade 1/2 (72.4% for simeprevir vs 71.3% for placebo). All grade 3/4 AEs occurred in

Background & Aims Triple therapy with peginterferon/ribavirin (PR) plus an NS3 protease inhibitor has emerged as the standard-of-care for patients with chronic hepatitis C genotype-1. We provide a detailed safety analysis comparing PR to boceprevir plus PR (BOC/PR) across three phase 2/3 studies. Methods SPRINT-1 was an open-label phase 2 study in 595 treatment-naive patients. In the two phase 3 studies, 1500 patients (1097 treatment-naive, SPRINT-2; 403 treatment-failure, RESPOND-2) were randomized to receive PR alone, or one of two regimens where BOC was added to PR after a 4-wk PR lead-in. In this analysis, the respective BOC/PR and PR arms were combined for all three trials. The benefit of shortened duration of treatment using response-guided therapy (RGT) was also explored in the SPRINT-2 trial. Results Only two adverse events, anaemia and dysgeusia, occurred 20% more often with the BOC-containing regimens compared with PR. Nausea, diarrhoea and neutropenia were the only other common events with an incidence of at least 5% greater when BOC was added to the PR backbone. The proportions of patients reporting serious adverse events (AE), life-threatening AEs, and study drug discontinuation because of an AE were similar in the PR and BOC/PR arms. In treatment-naive patients, RGT generally did not result in a lower frequency of common AEs; however, RGT led to decreased exposure to all 3 study drugs and to a decrease in the mean duration of several clinically relevant AEs such as anaemia, neutropenia, fatigue and depression, as well as earlier normalization of haemoglobin and neutrophil counts. Conclusions The safety profile of BOC combination therapy largely reflects the known profile of peginterferon and ribavirin, with incremental haematolgical effects and dysgeusia. Shorter treatment duration with RGT significantly reduced the duration of AEs.

International audience; BACKGROUND & AIMS:Boceprevir with peginterferon/ribavirin (BOC/PR) leads to significantly higher sustained virological response (SVR) rates in patients with chronic hepatitis C and partial response or relapse after prior treatment with peginterferon/ribavirin. We studied the efficacy of BOC/PR in patients with prior treatment failure, including those with a null response (2 weeks after end-of-treatment in the prior study received PR for 4 weeks before adding boceprevir.RESULTS:Of 168 patients enrolled, four discontinued from the PR lead-in and 164 received BOC/PR. Baseline viral load was >800,000 IU/ml in 77% of patients; 62% had HCV genotype 1a, and 10% were cirrhotic. In the ITT analysis (all 168 patients), SVR was achieved in 20 (38%) of 52 patients with prior null response, 57 (67%) of 85 with prior partial response, and 27 (93%) of 29 with prior relapse. In the mITT analysis (164 BOC/PR-treated patients), SVR rates were 41% (20/49), 67% (57/85), and 96% (27/28), respectively. SVR was achieved by 48% of patients with

Portopulmonary hypertension (PPHTN) is no longer an absolute contraindication to orthotopic liver transplantation (OLT). The pre-OLT management of patients with PPHTN requires early diagnosis and chronic therapy with intravenous epoprostenol to decrease pulmonary vascular resistance (PVR). Close follow-up is necessary to reassess pulmonary artery pressures (PAPs) and evaluate right ventricular (RV) function. This assists in the optimal timing of OLT. Successful management also necessitates reassessment of pulmonary artery hemodynamics just before OLT, with clearly defined parameters used to determine whether to proceed. Even with the intraoperative and postoperative availability of potent pulmonary vasodilators, clinical management may be suboptimal in reducing PAP. Adequate reduction in PVR and improvement in RV function in response to chronic epoprostenol therapy may facilitate successful OLT. We present a case report and review the limited experience with this treatment.

Summary Background Interferon-based treatment is not suitable for many patients with hepatitis C virus (HCV) infection because of contraindications such as psychiatric illness, and a high burden of adverse events. We assessed the efficacy and safety of an interferon-free regimen—a fixed-dose combination of the nucleotide polymerase inhibitor sofosbuvir (400 mg) and the HCV NS5A inhibitor ledipasvir (90 mg), with and without ribavirin—in patients with genotype-1 hepatitis C infection who were treatment-naive or previously treated with a protease-inhibitor regimen. Methods For this open-label study, we enrolled 100 adult patients (>18 years) with HCV infection at a centre in the USA between Nov 2, 2012, and Dec 21, 2012. In cohort A, we used a computer-generated sequence to randomly assign (1:1:1; stratified by HCV genotype [1a vs 1b]) 60 non-cirrhotic, treatment-naive patients to receive sofosbuvir plus ledipasvir for 8 weeks (group 1), sofosbuvir plus ledipasvir and ribavirin for 8 weeks (group 2), or sofosbuvir plus ledipasvir for 12 weeks (group 3). In cohort B, we randomly allocated (1:1; stratified by genotype and presence or absence of cirrhosis) 40 patients who previously had virological failure after receiving a protease inhibitor regimen to receive sofosbuvir plus ledipasvir for 12 weeks (group 4) or sofosbuvir plus ledipasvir and ribavirin for 12 weeks (group 5). 22 (55%) of 40 patients in cohort B had compensated cirrhosis. The primary endpoint was sustained virological response 12 weeks after treatment (SVR12), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01726517. Findings In cohort A, SVR12 was achieved by 19 (95%) of 20 patients (95% CI 75–100) in group 1, by 21 (100%) of 21 patients (84–100) in group 2, and by 18 (95%) of 19 patients (74–100) in group 3. In cohort B, SVR12 was achieved by 18 (95%) of 19 patients (74–100) in group 4 and by all 21 (100%) of 21 patients (84–100) in group 5. Two patients had viral relapse; one patient was lost to follow-up after achieving sustained virological response 8 weeks after treatment. The most common adverse events were nausea, anaemia, upper respiratory tract infection, and headache. One patient in group five had a serious adverse event of anaemia, thought to be related to ribavirin treatment. Interpretation These findings suggest that the fixed-dose combination of sofosbuvir-ledipasvir alone or with ribavirin has the potential to cure most patients with genotype-1 HCV, irrespective of treatment history or the presence of compensated cirrhosis. Further clinical trials are needed to establish the best treatment duration and to further assess the contribution of ribavirin. Funding Gilead Sciences.

Immunoprophylaxis using intravenous (IV) hepatitis B immune globulin (HBIG) decreases the recurrence of hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT). However, IV HBIG is expensive, has significant side effects, and is inconvenient to administer. An alternative approach for prophylaxis using intramuscular (IM) HBIG and oral lamivudine was prospectively evaluated in this study. Ten consecutive patients with cirrhosis with HBV infection who underwent OLT were included in this study. Nine of 10 patients received lamivudine, 150 mg/d, for an average duration of 8.6 months before OLT. Two of 10 patients with detectable HBV DNA at the time of OLT received 10,000 U (45 mL) of IV HBIG daily for 7 consecutive days, followed by 5 mL of IM HBIG weekly for the next 3 weeks, then every 3 weeks. The other 8 patients were HBV DNA negative at OLT and received one dose of IV HBIG (45 mL) during surgery, followed by 5 mL of IM HBIG weekly for 4 weeks, then every 3 weeks. All patients received lamivudine, 150 mg/d, after OLT. During a mean follow-up of 15.6 months, 9 of 10 patients achieved a protective hepatitis B surface antibody (HBsAb) titer greater than 200 IU/L and had no evidence of HBV recurrence. One patient failed to develop an adequate HBsAb titer and developed histological and virological evidence of recurrence. One patient died unrelated to HBV recurrence. Our preliminary data suggest that this combination prophylaxis with IM HBIG and lamivudine is effective and potentially cost saving.

O005 RETREATMENT OF PATIENTS WHO FAILED 8 OR 12 WEEKS OF LEDIPASVIR/SOFOSBUVIR-BASED REGIMENS WITH LEDIPASVIR/SOFOSBUVIR FOR 24 WEEKS E. Lawitz, S. Flamm, J.C. Yang, P.S. Pang, Y. Zhu, E. Svarovskaia, J.G. McHutchison, D. Wyles, P. Pockros. Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, Feinberg School of Medicine, Northwestern University, Chicago, IL, Gilead Sciences, Foster City, CA, University of California, San Diego, CA, Scripps Clinic, La Jolla, CA, United States E-mail: jenny.yang@gilead.com

Objective: With the continued shortage of deceased donor grafts, living donor liver transplantation has become an option for adult liver transplant candidates. In the non-transplant setting, liver biopsy is typically carried out to evaluate clinical or biochemical hepatic dysfunction. In living donor liver transplantation, assessment of histological abnormalities that are undetectable by serological, biochemical and radiological methods might play an important role in donor and recipient outcome. Methods: Seventy consecutive liver biopsies carried out as part of our evaluation of potential donor candidates for adult-to-adult or adult-to-child living donor liver transplants were analyzed. Results: Of the 70 potential donor candidates who underwent liver biopsy for evaluation for living donor liver transplantation, 67% had an unexpected abnormality, of which steatosis was the most common abnormality (38.5%). A variety of other histopathological abnormalities were found including granulomas of unknown etiology (7%), chronic hepatitis (6%) and a microabscess. None of the histological abnormalities had been suspected despite extensive clinical, serological or radiological investigation. Conclusions: Among the 70 potential donor candidates for living donor liver transplantation, 34% had unremarkable liver biopsies. The most common abnormality was steatosis (38.5%). These findings suggest that all potential candidates for living donor liver transplants should undergo screening liver biopsies. The precise significance of these changes remains to be determined, including which of these changes are contraindications to liver transplantation. These findings may also have implications in the non-transplant setting as changes ascribed to specific etiologies for liver disease might include changes occurring in apparently healthy individuals.

Objectives: Evaluate the ability of two bone alkaline phosphatase (ALP B ) immunoassays (Ostase, Hybritech Inc and Alkphase-B, Metra Biosystems) to clinically differentiate between osseous and non-osseous ALP sources. Design and Methods: Specimens from patients with either liver or bone disease (Paget’s disease or metastatic cancer) were analyzed by both methods. Results: There was a good correlation between these two assays. Values for ALP B , whether determined as a concentration by the Ostase assay or as an activity by the Alkphase-B assay, were similar for subjects with liver disease or bone disease. However, total ALP (ALP T ) activity was higher in liver disease compared to bone. When ALP B was expressed in relation to ALP T , ratios were significantly greater in subjects with bone disease than in those with liver disease. ALP B /ALP T ratios improved the specificity of the Ostase assay from 52% to 86% and the Alkphase-B assay from 58% to 74%. Conclusions: These two ALP B assays have good analytical performance and their clinical utility can be enhanced by expressing ALP B values in relation to ALP T activity.