Prognostic factors of unresectable hepatocellular carcinoma treated with yttrium-90 radioembolization: results from a large cohort over 13 years at a single center.

BACKGROUND: A previous study of patients with unresectable hepatocellular carcinoma (HCC) was extended to further examine factors associated with overall survival (OS) after selective internal radiation therapy with yttrium-90 resin microspheres (Y90 SIRT). METHODS: Data from patients of any age diagnosed with unresectable HCC and treated with Y90 SIRT at our institution from 2004 through 2017 were retrospectively analyzed. Among other criteria, patients had to have Eastern Cooperative Oncology Group performance status 0 to 2, not have received Y90 SIRT previously, and not have extrahepatic disease. Primary outcome was OS; secondary outcomes included tumor response and adverse events (AEs). Kaplan-Meier survival analyses and multivariable Cox proportional hazards models were used to evaluate prognostic factors for OS. RESULTS: Of the 226 patients, 59% were White, 77% were male, and the mean age at first SIRT procedure was 65.1±9.4 years. More than half had received previous treatment for HCC. The most common etiology was hepatitis C (n=138/224 available, 62%), followed by alcohol use (n=45, 20%), and nonalcoholic steatohepatitis (n=27, 12%). The mean model for end-stage liver disease score at baseline was 8.8±2.2. Patients were followed-up for a median of 12.2 months (95% CI, 0.0-62.6). Median OS was 16.6 months (95% CI, 13.1 to not reached). Bilobar disease, higher albumin-bilirubin score at baseline, prior treatment with sorafenib, alcohol use etiology, and higher administered dose were associated with shorter survival, whereas subsequent liver transplant [in 26 patients (11.5%)] was associated with longer survival. Of the 186 patients with AEs data, 75 (40.3%) patients reported an event and, of these, 13 (17.3%) patients had grade 4 bilirubin values. CONCLUSIONS: In a large, diverse population treated at a single center over 13 years, Y90 SIRT produced a median OS of 16.6 months in patients with unresectable HCC and enabled subsequent transplantation in a subset of patients. Factors affecting the length of survival should be considered when making treatment decisions for unresectable HCC.

Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity cause chronic necroinflammation and direct hepatocellular injury resulting in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emricasan is a pan-caspase inhibitor that inhibits excessive apoptosis and inflammation; it has also been shown to decrease portal pressure and improve synthetic function in mice with carbon tetrachloride-induced cirrhosis. METHODS: This double-blind, placebo-controlled study randomized 217 individuals with decompensated NASH cirrhosis 1:1:1 to emricasan (5 mg or 25 mg) or placebo. Patients were stratified by decompensation status and baseline model for end-stage liver disease-sodium (MELD-Na) score. The primary endpoint comprised all-cause mortality, a new decompensation event (new or recurrent variceal hemorrhage, new ascites requiring diuretics, new unprecipitated hepatic encephalopathy ≥grade 2, hepatorenal syndrome, spontaneous bacterial peritonitis), or an increase in MELD-Na score ≥4 points. RESULTS: There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 1.02 (95% CI 0.59-1.77; p = 0.94) and 1.28 (95% CI 0.75-2.21; p = 0.37) for 5 mg and 25 mg of emricasan, respectively. MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level or Child-Pugh score. Emricasan was generally safe and well-tolerated. CONCLUSIONS: Emricasan was safe but ineffective for the treatment of decompensated NASH cirrhosis. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis. LAY SUMMARY: Patients with decompensated cirrhosis related to non-alcoholic steatohepatitis are at high risk of additional decompensation events and death. Post hoc analyses in previous pilot studies suggested that emricasan might improve portal hypertension and liver function. In this larger randomized study, emricasan did not decrease the number of decompensation events or improve liver function in patients with a history of decompensated cirrhosis related to non-alcoholic steatohepatitis. CLINICALTRIALS. GOV IDENTIFIER: NCT03205345.

A Cross-Sectional Study of Stress and the Perceived Style of Decision-Making in Clinicians and Patients With Cancer.

BACKGROUND AND AIMS: Perceived stress and mindfulness can impact medical decision-making in both patients and clinicians. The aim of this study was to conduct a cross-sectional evaluation of the relationships between stress, mindfulness, self-regulation, perceptions of treatment conversations, and decision-making preferences among clinicians. Also, perceptions of treatment conversations and decision-making preferences among patients with cancer were evaluated. METHODOLOGY: Survey instruments were developed for clinicians and patients incorporating previously published questions and validated instruments. Institutional review board approval was obtained. Patients, physicians, and advanced practice providers from a tertiary referral center were asked to complete surveys. Continuous variables were evaluated for normality and then bivariate relationships between variables were evaluated using χ2, Fisher's exact test, Cochran-Mantel-Haenszel (CMH) row mean scores differ statistic, or Kruskal-Wallis tests, where appropriate. Significance was defined at P < .05. All tests were conducted using SAS v.9.4. RESULTS: 77 patients and 86 clinicians (60.1% and 43% response rates, respectively) participated in the surveys. More clinicians who reported feeling "great/good" said they always/sometimes had enough time to spend with patients (66.1%) compared to those that hardly ever/never had enough time (26.3%), χ2(1, N = 75) = 6.62, P = .0101; CMH row mean scores differ statistic). Interestingly, 40.3% of patients preferred a paternalistic style of decision-making compared to 6.3% of clinicians, χ2(2, N = 146) = 27.46, P < .0001; χ2 test. Higher levels of dispositional mindfulness (Mindful Attention Awareness Scale) were found among clinicians who reported they felt "great/good" (median = 4.5) as compared to those who reported that they were "definitely stressed/stressed out" (3.3), χ2(2, N = 80) = 10.32, P = .0057; Kruskal-Wallis test. Higher levels of emotional self-regulation (Emotional Regulation Questionnaire-Cognitive Reappraisal facet) were found among clinicians who reported they felt "great/good" (median = 31.0) compared to those who reported that they were "definitely stressed/stressed out" (20.0), χ2(2, N = 79) = 8.88, P = .0118; Kruskal-Wallis test. CONCLUSION: In order to have meaningful conversations about treatment planning, an understanding of mental well-being and its relationship to decision-making preferences is crucial for both oncology patients and clinicians. Our results show that for clinicians, lower perceived stress was associated with higher levels of mindfulness (experiencing the present moment), emotional self-regulation, and spending more time with patients. Larger prospective studies are needed to validate these findings.

Efficacy and Safety of Ombitasvir/Paritaprevir/Ritonavir in Patients With Hepatitis C Virus Genotype 1 or 4 Infection and Advanced Kidney Disease.

INTRODUCTION: Hepatitis C virus (HCV) infection is common in patients with end-stage renal disease. We investigated the safety and efficacy of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) ± dasabuvir (DSV) ± ribavirin (RBV) in 2 phase 3, open-label, multicenter studies in patients with stage 4 or 5 chronic kidney disease (CKD). METHODS: RUBY-I, Cohort 2 enrolled treatment-naïve or -experienced patients with HCV genotype (GT) 1a or 1b infection, with or without cirrhosis. Patients received 12 weeks (24 weeks for GT1a patients with cirrhosis) of OBV/PTV/r + DSV; all GT1a patients received RBV. RUBY-II enrolled treatment-naïve patients with GT1a or GT4 infection without cirrhosis. All patients received 12 weeks of RBV-free treatment: OBV/PTV/r + DSV for GT1a-infected patients; OBV/PTV/r for GT4-infected patients. The primary endpoint was sustained virologic response at posttreatment week 12 (SVR12). RESULTS: RUBY-I, Cohort 2 and RUBY-II enrolled 66 patients, including 50 (76%) on dialysis; 15 (23%) had compensated cirrhosis. Overall, the SVR12 rate was 95% (63/66); 1 patient had virologic failure. There were 3 discontinuations due to adverse events. Seventy-three percent (27/37) of patients receiving RBV had adverse events leading to RBV dose modification. The RBV-free RUBY-II study had no hemoglobin-associated adverse events. CONCLUSION: Treatment with OBV/PTV/r ± DSV ± RBV was well tolerated and patients with HCV GT1 or 4 infection and stage 4 or 5 CKD had high SVR12 rates, including patients with compensated cirrhosis and/or prior treatment experience.

Longitudinal correlations between MRE, MRI-PDFF, and liver histology in patients with non-alcoholic steatohepatitis: Analysis of data from a phase II trial of selonsertib.

BACKGROUND & AIMS: Non-invasive tools for monitoring treatment response and disease progression in non-alcoholic steatohepatitis (NASH) are needed. Our objective was to evaluate the utility of magnetic resonance (MR)-based hepatic imaging measures for the assessment of liver histology in patients with NASH. METHODS: We analyzed data from patients with NASH and stage 2 or 3 fibrosis enrolled in a phase II study of selonsertib. Pre- and post-treatment assessments included centrally read MR elastography (MRE)-estimated liver stiffness, MR imaging-estimated proton density fat fraction (MRI-PDFF), and liver biopsies evaluated according to the NASH Clinical Research Network classification and the non-alcoholic fatty liver disease activity score (NAS). RESULTS: Among 54 patients with MRE and biopsies at baseline and week 24, 18 (33%) had fibrosis improvement (≥1-stage reduction) after undergoing 24 weeks of treatment with the study drug. The area under the receiver operating characteristic curve (AUROC) of MRE-stiffness to predict fibrosis improvement was 0.62 (95% CI 0.46-0.78) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRE had 67% sensitivity, 64% specificity, 48% positive predictive value, 79% negative predictive value. Among 65 patients with MRI-PDFF and biopsies at baseline and week 24, a ≥1-grade reduction in steatosis was observed in 18 (28%). The AUROC of MRI-PDFF to predict steatosis response was 0.70 (95% CI 0.57-0.83) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRI-PDFF had 89% sensitivity and 47% specificity, 39% positive predictive value, and 92% negative predictive value. CONCLUSIONS: These preliminary data support the further evaluation of MRE-stiffness and MRI-PDFF for the longitudinal assessment of histologic response in patients with NASH. LAY SUMMARY: Liver biopsy is a potentially painful and risky method to assess damage to the liver due to non-alcoholic steatohepatitis (NASH). We analyzed data from a clinical trial to determine if 2 methods of magnetic resonance imaging - 1 to measure liver fat and 1 to measure liver fibrosis (scarring) - could potentially replace liver biopsy in evaluating NASH-related liver injury. Both imaging methods were correlated with biopsy in showing the effects of NASH on the liver.

Glecaprevir/Pibrentasvir Treatment in Liver or Kidney Transplant Patients With Hepatitis C Virus Infection.

Well-tolerated, ribavirin-free, pangenotypic hepatitis C virus (HCV) treatments for transplant recipients remain a high priority. Once-daily glecaprevir/pibrentasvir demonstrates high rates of sustained virologic response at 12 weeks posttreatment (SVR12) across all major HCV genotypes (GTs). This trial evaluated the safety and efficacy of glecaprevir/pibrentasvir for patients with chronic HCV GT1-6 infection who had received a liver or kidney transplant. MAGELLAN-2 was a phase 3, open-label trial conducted in patients who were ≥3 months posttransplant. Patients without cirrhosis who were HCV treatment-naive (GT1-6) or treatment-experienced (GT1, 2, 4-6; with interferon-based therapy with or without sofosbuvir, or sofosbuvir plus ribavirin) received glecaprevir/pibrentasvir (300/120 mg) once daily for 12 weeks. The primary endpoint compared the percentage of patients receiving glecaprevir/pibrentasvir with SVR12 to a historic SVR12 rate based on the standard of care. Safety of glecaprevir/pibrentasvir was assessed. In total, 80 liver transplant and 20 kidney transplant patients participated in the trial. Most patients had no or minimal fibrosis (80% had fibrosis scores F0-F1) and were infected with HCV GT1 (57%) or GT3 (24%). The overall SVR12 was 98% (n/N = 98/100; 95% confidence interval, 95.3%-100%), which exceeded the prespecified historic standard-of-care SVR12 threshold of 94%. One patient experienced virologic failure. One patient discontinued because of an adverse event considered to be unrelated to treatment; this patient achieved SVR12. Adverse events were mostly mild in severity, and laboratory abnormalities were infrequent. CONCLUSION: Once-daily glecaprevir/pibrentasvir for 12 weeks is a well-tolerated and efficacious, ribavirin-free treatment for patients with chronic HCV GT1-6 infection who have received a liver or kidney transplant. (ClinicalTrials.gov NCT02692703.) (Hepatology 2018; 00:000-000).

Efficacy of Glecaprevir/Pibrentasvir for 8 or 12 Weeks in Patients With Hepatitis C Virus Genotype 2, 4, 5, or 6 Infection Without Cirrhosis.

BACKGROUND & AIMS: Hepatitis C virus (HCV) has high genotypic diversity and global distribution. Agents that are effective against all major HCV genotypes, with shorter treatment duration, are needed to reduce disease burden. Glecaprevir (an NS3/4A protease inhibitor) and pibrentasvir (an NS5A inhibitor) have a high barrier to resistance and synergistic antiviral activity. We evaluated the safety and efficacy of 8 and 12 weeks' treatment with glecaprevir/pibrentasvir in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis in 3 separate phase 3 trials. METHODS: We performed 2 open label, single-arm studies (SURVEYOR-II, Part 4 and ENDURANCE-4) and a randomized, double-blind, placebo-controlled study (ENDURANCE-2). In the ENDURANCE-2 study, adult patients with untreated or previously treated HCV genotype 2 infection without cirrhosis were randomly assigned (2:1) to groups given once-daily oral glecaprevir/pibrentasvir (n = 202; 300 mg/120 mg) or placebo (n = 100) for 12 weeks. In the SURVEYOR-II, Part 4 and ENDURANCE-4 studies, adult patients with untreated or previously treated patients with HCV genotype 2, genotype 4, genotype 5, or genotype 6 infection, without cirrhosis, were given once-daily oral glecaprevir/pibrentasvir (n = 121 in ENDURANCE-4 and n = 145 in SURVEYOR-II) for 12 or 8 weeks, respectively. In all studies the primary endpoint was sustained virologic response at 12 weeks after treatment (SVR12) in the intention-to-treat population. RESULTS: Among patients receiving glecaprevir/pibrentasvir for 8 weeks, rates of SVR12 were 98% (95% CI, 94.1-99.3) in those infected with HCV genotype 2 and 93% (95% CI, 83.6-97.3) in those infected with HCV genotypes 4, 5, or 6. Among patients receiving glecaprevir/pibrentasvir for 12 weeks, rates of SVR12 were 99.5% (95% CI, 98.5-100) in those infected with HCV genotype 2 and 99% (95% CI, 97.6-100) in those infected with HCV genotype 4, 5, or 6. No virologic failures occurred in patients with HCV genotype 4, 5, or 6 infections. The frequency and severity of adverse events in patients receiving glecaprevir/pibrentasvir were similar to those of patients who received placebo. CONCLUSION: In 3 Phase 3 studies, 8 weeks' treatment with glecaprevir/pibrentasivr produced an SVR12 in at least 93% of patients with chronic HCV genotype 2, 4, 5, or 6 infection without cirrhosis, with virologic failure in less than 1%. The drug combination had a safety profile comparable to 12 week's treatment with glecaprevir/pibrentasvir. ClinicalTrials.gov numbers: NCT02640482 (ENDURANCE-2), NCT02636595 (ENDURANCE-4), and NCT02243293 (SURVEYOR-II).

The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial.

Inhibition of apoptosis signal-regulating kinase 1, a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis. We evaluated the safety and efficacy of selonsertib, a selective inhibitor of apoptosis signal-regulating kinase 1, alone or in combination with simtuzumab, in patients with nonalcoholic steatohepatitis and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 weeks of open-label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once-weekly injections of 125 mg of simtuzumab or simtuzumab alone. The effect of treatment was assessed by paired pretreatment and posttreatment liver biopsies, magnetic resonance elastography, magnetic resonance imaging-estimated proton density fat fraction, quantitative collagen content, and noninvasive markers of liver injury. Due to the lack of effect of simtuzumab on histology or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. After 24 weeks of treatment, the proportion of patients with a one or more stage reduction in fibrosis in the 18-mg selonsertib group was 13 of 30 (43%; 95% confidence interval, 26-63); in the 6-mg selonsertib group, 8 of 27 (30%; 95% confidence interval, 14-50); and in the simtuzumab-alone group, 2 of 10 (20%; 95% confidence interval, 3-56). Improvement in fibrosis was associated with reductions in liver stiffness on magnetic resonance elastography, collagen content and lobular inflammation on liver biopsy, as well as improvements in serum biomarkers of apoptosis and necrosis. There were no significant differences in adverse events between the treatment groups. Conclusion: These findings suggest that selonsertib may reduce liver fibrosis in patients with nonalcoholic steatohepatitis and stage 2-3 fibrosis. (Hepatology 2018;67:549-559).

Ledipasvir/sofosbuvir for treatment of hepatitis C virus in sofosbuvir-experienced, NS5A treatment-naïve patients: Findings from two randomized trials.

BACKGROUND & AIMS: We report data from two similarly designed studies that evaluated the efficacy, safety, and optimal duration of ledipasvir/sofosbuvir (LDV/SOF) ± ribavirin (RBV) for retreatment of chronic hepatitis C virus (HCV) in individuals who failed to achieve sustained virological response (SVR) with prior SOF-based, non-NS5A inhibitor-containing regimens. METHODS: The RESCUE study enrolled HCV mono-infected adults with genotype (GT) 1 or 4. Non-cirrhotic participants were randomized to 12 weeks of LDV/SOF or LDV/SOF + RBV. Compensated cirrhotic participants were randomized to LDV/SOF + RBV (12 weeks) or LDV/SOF (24 weeks). The AIDS Clinical Trials Group A5348 study randomized genotype 1 adults with HCV/HIV co-infection to LDV/SOF + RBV (12 weeks) or LDV/SOF (24 weeks). Both studies used SVR at 12 weeks post-treatment (SVR12) as the primary endpoint. RESULTS: In the RESCUE study, 82 participants were randomized and treated, and all completed treatment. Overall, SVR12 was 88% (72/82); 81-100% in non-cirrhotic participants treated with LDV/SOF or LDV/SOF + RBV for 12 weeks and 80-92% in cirrhotic participants treated with LDV/SOF + RBV for 12 weeks or LDV/SOF for 24 weeks. Adverse events (AEs), mostly mild-to-moderate in severity, were experienced by 78% of participants, with headache and fatigue most frequently reported. One serious AE, not related to treatment, was observed. No premature discontinuations of study drug, or deaths occurred. In the A5348 study, seven participants were randomized (cirrhotic n = 1; GT1a n = 5) and all attained SVR12, with no serious AEs or premature discontinuations. CONCLUSIONS: In this SOF-experienced, NS5A inhibitor-naïve population, which included participants with cirrhosis or HCV/HIV co-infection, high SVR12 rates were achieved.

Selective internal radiation therapy using yttrium-90 resin microspheres in patients with unresectable hepatocellular carcinoma: a retrospective study.

BACKGROUND: Selective internal radiation therapy (SIRT) with yttrium-90 resin (Y-90 resin) microspheres has been used as a locoregional therapy for patients with unresectable hepatocellular carcinoma (HCC). We examined patient and disease characteristics that might affect survival after Y-90 resin, as well as treatment tolerability. METHODS: Data from patients with unresectable HCC treated with Y-90 resin at a single institution were reviewed retrospectively. Survival was assessed with Kaplan-Meier curves and log-rank tests. Response was evaluated with the response evaluation criteria in solid tumors (RECIST) criteria. Adverse events (AEs) were noted, and laboratory values were graded with CTCAE v3.0. RESULTS: Data from 111 patients were analyzed. AEs occurred in 23 patients at 1 week after treatment and in 46 at 3 months. At 6 months, 13 patients had a complete response and 13 had a partial response. Factors associated with longer overall survival (OS) included early-stage disease [27.8 months for patients with Barcelona-Clinic Liver Cancer (BCLC) A vs. 9.2 months for BCLC C]; treatment with other locoregional therapies (69.0 vs. 11.4 months); and lack of bilobar disease (23.5 vs. 9.4 months), portal vein thrombosis (16.2 vs. 8.6 months), ascites (16.6 vs. 10.3 months), and treatment with sorafenib (17.2 vs. 10.3 months). In six patients, Y-90 resin was used as a bridge to liver transplantation, which greatly improved survival (69.0 vs. 12.1 months). CONCLUSIONS: Several characteristics may prove useful for selecting patients likely to respond well to Y-90 resin. These results should be confirmed in prospective studies.

Efficacy of Direct-Acting Antiviral Combination for Patients With Hepatitis C Virus Genotype 1 Infection and Severe Renal Impairment or End-Stage Renal Disease.

BACKGROUND & AIMS: Although hepatitis C virus (HCV) infection is common in patients with end-stage renal disease, highly efficacious, well-tolerated, direct-acting antiviral regimens have not been extensively studied in this population. We investigated the safety and efficacy of ombitasvir co-formulated with paritaprevir and ritonavir, administered with dasabuvir (with or without ribavirin) in a prospective study of patients with stage 4 or 5 chronic kidney disease (CKD). METHODS: We performed a single-arm, multicenter study of treatment-naïve adults with HCV genotype 1 infection, without cirrhosis and with CKD stage 4 (estimated glomerular filtration rate, 15-30 mL/min/1.73 m(2)) or stage 5 (estimated glomerular filtration rate, <15 mL/min/1.73 m(2) or requiring hemodialysis). Twenty patients were given ombitasvir co-formulated with paritaprevir and ritonavir, administered with dasabuvir for 12 weeks. Patients with HCV genotype 1a infections also received ribavirin (n = 13), whereas those with genotype 1b infection did not (n = 7). The primary end point was sustained virologic response (serum HCV RNA <25 IU/mL) 12 weeks after treatment ended (SVR12). We collected data on on-treatment adverse events (AEs), serious AEs, and laboratory abnormalities. RESULTS: All 20 patients completed 12 weeks of treatment. Eighteen of the 20 patients achieved SVR12 (90%; 95% confidence interval: 69.9-97.2). One patient death after the end of the treatment (unrelated to the treatment) and 1 relapse accounted for the 2 non-SVRs. Adverse events were primarily mild or moderate, and no patient discontinued treatment due to an AE. Four patients experienced serious AEs; all were considered unrelated to treatment. Ribavirin therapy was interrupted in 9 patients due to anemia; 4 received erythropoietin. No blood transfusions were performed. CONCLUSIONS: In a clinical trial, the combination of ombitasvir, paritaprevir, and ritonavir, administered with dasabuvir, led to an SVR12 in 90% of patients with HCV genotype 1 infection and stage 4 or 5 CKD. The regimen is well tolerated, though RBV use may require a reduction or interruption to manage anemia. ClinicalTrials.gov ID NCT02207088.

Dasabuvir (ABT333) for the treatment of chronic HCV genotype I: a new face of cure, an expert review.

Hepatitis C virus (HCV) affects nearly 1.3% of US population and around 2% of people worldwide. It is associated with serious complication of Cirrhosis and Hepatocellular carcinoma leading to significant morbidity and mortality. Until now the only treatment option for this serious disease was interferon based therapy which had poor tolerance and at best SVR (Sustained virological response) in only 50% of cases. With the introduction of other direct - acting antiviral agents the treatment of HCV has been revolutionized with significantly high rates of cure. Among novel Direct acting antivirals are non-nucleoside inhibitor NS5B which is highly effective in treatment of HCV genotype 1 a and 1b including those with compensated cirrhosis achieving high cure rates with SVR more than 97 % in pooled analysis from six different phase 3 trials. This review will discuss the DAA - Dasabuvir, a non - nucleoside NS5B inhibitor, its mechanism of action, efficacy, safety & tolerance, and drug resistance. Dasabuvir is approved by FDA in combination with other DAA agents called as the 3D(Viekira Pak) in various interferon free regimens achieving high cure rates (SVR >95%) with low adverse effects. In Europe, it is approved by European medicines agency for use in combination with Ombitasvir, Paritaprevir, and ritonavir with or without ribavirin. The drug is used in treatment naive as well as previously treated patient with high success rates. It is also approved in patients with compensated cirrhosis, patients with HIV co-infection and liver transplant recipients which were in the past were excluded from treatment with interferon based therapy. Dasabuvir is extensively evaluated in large clinical trials and shown excellent SVR among HCV genotype1 patient population in combination with other oral DAAs, with good safety profile and tolerance. Its drawback is its genotype restriction, need for ribavirin (RBV) for 1a genotype, low resistance barrier and high cost. It is well tolerated with less than 1 % of patients permanently discontinuing treatment and 2% of patient experiencing a serious adverse reaction. It is contraindicated in patients with known hypersensitivity to ritonavir (e.g. Steven - Johnson syndrome) and strong inducers of CYP3A and CYP2CB.

An interferon-free antiviral regimen for HCV after liver transplantation.

BACKGROUND: Hepatitis C virus (HCV) infection is the leading indication for liver transplantation worldwide, and interferon-containing regimens are associated with low response rates owing to treatment-limiting toxic effects in immunosuppressed liver-transplant recipients. We evaluated the interferon-free regimen of the NS5A inhibitor ombitasvir coformulated with the ritonavir-boosted protease inhibitor ABT-450 (ABT-450/r), the nonnucleoside NS5B polymerase inhibitor dasabuvir, and ribavirin in liver-transplant recipients with recurrent HCV genotype 1 infection. METHODS: We enrolled 34 liver-transplant recipients with no fibrosis or mild fibrosis, who received ombitasvir-ABT-450/r (at a once-daily dose of 25 mg of ombitasvir, 150 mg of ABT-450, and 100 mg of ritonavir), dasabuvir (250 mg twice daily), and ribavirin for 24 weeks. Selection of the initial ribavirin dose and subsequent dose modifications for anemia were at the investigator's discretion. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment. RESULTS: Of the 34 study participants, 33 had a sustained virologic response at post-treatment weeks 12 and 24, for a rate of 97% (95% confidence interval, 85 to 100). The most common adverse events were fatigue, headache, and cough. Five patients (15%) required erythropoietin; no patient required blood transfusion. One patient discontinued the study drugs owing to adverse events after week 18 but had a sustained virologic response. Blood levels of calcineurin inhibitors were monitored, and dosages were modified to maintain therapeutic levels; no episode of graft rejection was observed during the study. CONCLUSIONS: Treatment with the multitargeted regimen of ombitasvir-ABT-450/r and dasabuvir with ribavirin was associated with a low rate of serious adverse events and a high rate of sustained virologic response among liver-transplant recipients with recurrent HCV genotype 1 infection, a historically difficult-to-treat population. (Funded by AbbVie; CORAL-I ClinicalTrials.gov number, NCT01782495.).

Small-bowel masses found and missed on capsule endoscopy for obscure bleeding.

OBJECTIVE: Data on the nature of small-bowel tumors found or missed by capsule endoscopy (CE) are limited. The aim of this study was to review the CE findings in patients with small-bowel tumors presenting as obscure gastrointestinal (GI) bleeding. MATERIAL AND METHODS: We retrospectively reviewed the medical records of the first 300 patients who underwent CE for obscure bleeding (non-diagnostic EGD and colonoscopy) at our institution. RESULTS: Ten (3%) confirmed small-bowel masses were found in 9 patients. CE findings included distinct mass (n=4), focal irregular (ulcerated or nodular) mucosa (n=2), focal blood without clear lesion (n=1), proximal angiodysplasia with obscuring distal melena (n=1), incomplete distal examination with normal proximal images (n=1), and normal findings (n=1). Most (80%) of the lesions were potentially malignant: adenocarcinoma (n=4), neuroendocrine carcinoma (n=1), leiomyosarcoma (n=1), and GI stroma cell tumors (GISTs) (n=2). Benign lesions included inflammatory fibroid polyp (n=1) and lipoma (n=1). Three duodenal masses were missed on a previous EGD; one was missed by CE as well. CE findings led directly to tumor diagnosis in 7 of the 10 cases. Capsule retention occurred in 2 of the 10 cases, with one patient requiring urgent surgery for acute obstruction. CONCLUSIONS: Small-bowel tumors are a rare but serious source of obscure GI bleeding. Our large single-center experience shows that most lesions are of malignant potential. Tumors can have an atypical appearance including focal ulceration, nodularity, or active bleeding without a clear lesion. Mass lesions in the duodenum are particularly elusive and can be missed by both EGD and CE.

Capsule endoscopy for obscure GI bleeding: therapeutic yield of follow-up procedures.

Positive findings on capsule endoscopy (CE) often prompt a follow-up procedure with therapeutic intent. Our purpose was to review the therapeutic yield of subsequent procedural interventions based on positive CE findings. The medical records of all patients who underwent CE between June 2002 and February 2005 for obscure bleeding were retrospectively reviewed. Fifty-two patients had follow-up procedures based on positive capsule findings. In this group, angiodysplasia was the most common CE finding (n=30), with therapeutic intervention performed in 16 cases (53%). Fresh blood without clear lesion was the second most common finding (n=9), with therapeutic intervention performed in 6 cases (67%). Overall, a therapeutic intervention was performed in 33 of the 52 follow-up procedures (63%). Positive capsule findings directed further procedural investigation in 52 cases, with a high therapeutic yield of 63% in those cases. The long-term efficacy of such interventions warrants further investigation.

What we have learned from 5 cases of permanent capsule retention.

BACKGROUND: Capsule endoscopy allows the direct visualization of the entire small bowel. There is limited data on the clinical significance of permanent capsule retention. OBJECTIVE: Our purpose was to document the frequency, findings, risk factors, management, and outcomes of permanent capsule retention. DESIGN: Retrospective, case series. SETTING: Single tertiary referral center, outpatient. RESULTS: Permanent capsule retention occurred in 2% of our cases (5/245). The following pathologies caused insufficient capsule passage: adenocarcinoma in a patient with hereditary nonpolyposis colorectal cancer (1), idiopathic stenosis (1), stricturing Crohn's disease (2), and adhesions (1). Capsule retention lead to a symptomatic small-bowel obstruction in only 1 of these cases (0.4%). As a consequence, 2 cases had successful endoscopic retrieval; 3 cases required surgical intervention. Four of 5 patients had a clear clinical benefit resulting from the capsule findings or the secondary procedure. CONCLUSIONS: Permanent capsule retention is rare. Even though this event may lead to the necessity of an endoscopic or surgical intervention, a clear benefit for the patient in respect to the underlying disease resulted in 4 of 5 patients.

Liver transplantation in sickle cell anemia: a case of acute sickle cell intrahepatic cholestasis and a case of sclerosing cholangitis.

Very few cases of liver transplantation in patients with sickle cell disease have been reported in peer-reviewed literature. We reviewed the medical records of two patients with sickle cell disease that received liver transplantation at our institution. The first patient was a 27-year-old female who presented with encephalopathy and cholestatic jaundice with a Hemoglobin S (HbS) level of 69.6%. She was diagnosed with acute sickle cell intrahepatic cholestasis. The second patient was a 26-year-old female with sclerosing cholangitis who presented with encephalopathy, bleeding, and cholestatic jaundice. Her HbS level was normal. Both patients underwent liver transplantation successfully but died in the postoperative period from multiorgan failure. We report a rare case of liver transplantation for acute sickle cell intrahepatic cholestasis and a novel case of transplantation in a patient with sickle cell disease and sclerosing cholangitis. Liver transplantation did not lead to a successful outcome in either case.