Increased frequency of hepatic steatosis and fibrosis in patients with gout detected by transient elastography.

OBJECTIVES: It has been suggested that gout is associated with non-alcoholic fatty liver disease (NAFLD). Our aim was to assess NAFLD in gout patients using the validated non-invasive imaging technique, transient elastography (FibroScan). METHODS: FibroScans in consecutive gout patients in a single centre from 11/1/2016 to 11/1/2021 and reviewed retrospectively. FibroScan results include the E- score (kPA), measuring liver stiffness, and controlled attenuation parameter (CAP) score (dB/m), assessing steatosis. In addition, a FIB-4 fibrosis score was calculated. RESULTS: 47 gout patients (7 females, 14.9%; 40 males, 85.1%) underwent FibroScans. The mean age was 59.8 years, the mean body mass index (BMI) was 30.95 kg/m2, and gout duration 0-49 years. Tophi were present in 11 (26.2%). Comorbidities included dyslipidaemia (86.7%), diabetes mellitus (31.1%), known liver disease (33.3%), current alcohol consumption (46.8%), ALT or AST elevations (54.4%), and hyperuricaemia (53.7%). FibroScan results revealed hepatic steatosis (CAP >238 dB/m) in 40 (85.1%) and were significantly associated with BMI (r=0.53, p=0.0001) but not age, serum urate (SU), glucose, triglycerides, ALT, AST. FibroScan also revealed fibrosis (E score >7) in 9 (19.1%); severe fibrosis (cirrhosis) in 8. Fibrosis was significantly associated with age (p=0.03) and known liver disease (p=0.003) but not BMI, SU, or comorbidities. The FIB-4 score was significantly associated with the fibrosis score (r2=0.24, p=0.0009) but not with CAP, ALT, or AST. CONCLUSIONS: Despite not being associated with common gout comorbidities, fatty liver and liver fibrosis were common in this gout cohort, suggesting FibroScan screening in gout patients to assess NAFLD, irrespective of serum transaminase levels.

Outcomes and risk factors for mortality in clostridioides difficile infection in patients with NAFLD and NASH.

INTRODUCTION AND OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and can progress to non-alcoholic steatohepatitis (NASH) and, ultimately, cirrhosis. Clostridioides difficile is the most common nosocomial cause of diarrhea and is associated with worse clinical outcomes in other liver diseases, including cirrhosis, but has not been extensively evaluated in concomitant NAFLD/NASH. MATERIALS AND METHODS: We conducted a retrospective cohort study using the National Inpatient Sample database from 2015 to 2017. Patients with a diagnosis of CDI, NAFLD, and NASH were identified using International Classification of Diseases (Tenth Revision) codes. The outcomes of our study include length of stay, hospitalization cost, mortality, and predictors of mortality. RESULTS: The CDI and NASH cohort had a higher degree of comorbidity burden and prevalence of peptic ulcer disease, congestive heart failure, diabetes mellitus, and cirrhosis. Patients with NASH and CDI had a significantly higher mortality rate compared to the CDI only cohort (mortality, 7.11 % vs. 6.36 %; P = 0.042). Patients with CDI and NASH were at increased risk for liver-related complications, acute kidney injury, and septic shock (P < 0.001) compared to patients with CDI only. Older age, intestinal complications, pneumonia, sepsis and septic shock, and liver failure conferred an increased risk of mortality among the CDI and NASH cohort. CONCLUSIONS: Patients with NASH had a higher rate of liver-related complications, progression to septic shock, and mortality rate following CDI infection compared to the CDI only cohort.

Improvement in hepatic fibrosis estimated by Fibrosis-4 index in pegloticase treated chronic refractory gout patients.

OBJECTIVES: To determine whether lowering serum urate (SU) affects the course of non-alcoholic fatty liver disease (NAFLD). METHODS: Retrospective data analysis from chronic refractory gout patients who participated in two 6-month pegloticase randomised clinical trials compared patients who received pegloticase biweekly to those who received placebo. Patients with persistent urate-lowering to <1 mg/dL in response to biweekly pegloticase (responders, n=36) were compared to those who received placebo (n=43). NAFLD was assessed using the Fibrosis-4 (Fib-4) index. Comparisons between groups were carried out using 2 sample Wilcoxon tests or regression analysis. RESULTS: At baseline the mean (standard deviation [SD]) Fib-4 values were 1.40 (0.86) in pegloticase responders, and 1.04 (0.53) in patients receiving placebo. Patients receiving placebo exhibited a change of 0.26 (0.41) in Fib-4 score over 6 months vs 0.13 (0.62) for pegloticase responders (p=0.048). When only patients with a Fib-4 value >1.3 were considered (n=27), a significant difference in the change in the Fib-4 values between pegloticase responders vs. placebo was observed (-0.15 [0.67] vs. 0.7 [0.42], p=0.04). The correlation between the SU area under the curve (AUC) over the 6-month trial period and the change in Fib-4 value was R=0.33 (p=0.0004). Multivariable analysis indicated SU AUC was the only significant contributor to the change in Fib-4 values (p=0.018). CONCLUSIONS: Persistent lowering of SU significantly reduced Fib-4 scores, implying a possible effect on NAFLD progression. These results support the consideration of a complete analysis of the impact of profound urate-lowering on NAFLD as measured by the Fib-4 index.

Bariatric Surgery Reduces Cancer Risk in Adults With Nonalcoholic Fatty Liver Disease and Severe Obesity.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and increased risk of cancer. The impacts of bariatric surgery on cancer risk in NAFLD patients are unknown. We investigated the effect of bariatric surgery on cancer risk in patients with NAFLD and severe obesity using the MarketScan database. METHODS: We conducted a retrospective cohort study of 18 to 64 years old newly diagnosed NAFLD patients with severe obesity between 2007 and 2017. We used Cox proportional hazard models to examine the association between bariatric surgery, modeled as a time-varying covariate, and the risks of any cancer and obesity-related cancer, while accounting for confounding using inverse probability of treatment weighting (IPTW). RESULTS: A total of 98,090 patients were included in the study, 33,435 (34.1%) received bariatric surgery. In those without surgery, 1898 incident cases of cancer occurred over 115,890.11 person-years of follow-up, compared with 925 cancer cases over 67,389.82 person-years among surgery patients (crude rate ratio, 0.84; 95% CI, 0.77- 0.91). The IPTW-adjusted risk of any cancer and obesity-related cancer was reduced by 18% (hazard ratio, 0.82; 95% CI, 0.76-0.89) and 25% (hazard ratio, 0.65; 95% CI, 0.56-0.75), respectively, in patients with versus without bariatric surgery. The adjusted risks of any cancer and obesity-related cancer were significantly lower in cirrhotic versus non-cirrhotic patients who underwent surgery. In cancer-specific models, bariatric surgery was associated with significant risk reductions for colorectal, pancreatic, endometrial, thyroid cancers, hepatocellular carcinoma, and multiple myeloma. CONCLUSION: Bariatric surgery was associated with significant reductions in the risks of any cancer and obesity-related cancer in NAFLD patients with severe obesity.

The relationship between metabolic syndrome severity and the risk of mortality in gout patients: a population-based study.

OBJECTIVES: To examine Metabolic Syndrome (MetS) severity using a recently validated Metabolic Syndrome Severity Score (MetSSS) in order to explore the overall associations between MetSSS and the risk of mortality related to all-causes, heart disease, diabetes mellitus, and hypertension amongst American adults with gout. METHODS: Mortality-linked data for 12,101 adults aged 18 to 90 years who participated in the National Health and Nutrition Examination Survey III by gout status was analysed. All 5 metabolic features were used to calculate gender-race/ethnicity-specific MetSSS Z-scores in gout patients. The calculated Z-scores are a continuous representation of all MetS conditions while accounting for gender-race/ethnicity disparities. RESULTS: A total of 3,381 deaths were observed, of which 215 had gout. The prevalence amongst adults was 2.59%. Moderate to high MetS severity was significantly prevalent amongst gout patients (47.33% vs. 21.16 % no gout; p-value <0.0001). The mean MetSSS Zscore for gout patients was significantly higher than those without gout (0.71 vs. -0.04 no gout; p-value <0.0001). A one-unit increase in MetSSS score was associated with significant increases in the risk of all-cause mortality, heart disease, diabetes- and hypertension-related mortalities. CONCLUSIONS: Moderate to high MetSSS is significantly prevalent amongst gout patients. A one-unit increase in MetSSS score was associated with significant increases in the risk of all-cause mortality, heart disease, diabetes- and hypertension-related mortalities. MetS is a clinically accessible tool for predicting mortality risks in gout patients with MetS.

Safety and Efficacy of Thrombin for Bleeding Gastric Varices: A Systematic Review and Meta-Analysis.

INTRODUCTION: The optimal therapy for bleeding-related gastric varices is still a controversial topic. There is a paucity of literature that comprehensively summarizes the available literature regarding safety and efficacy of thrombin in bleeding gastric varices. METHODS: Four independent reviewers performed a comprehensive review of all original articles published from inception to October 2020, describing the use of thrombin for management of bleeding gastric varices. Primary outcomes were (1) pooled early and late rebleeding rate, (2) pooled gastric variceal related mortality rate, (3) pooled rescue therapy rate, and (4) pooled adverse event rate with the use of thrombin in bleeding gastric varices. The meta-analysis was performed and the statistics were two-tailed. Finally, probability of publication bias was assessed using funnel plots and with Egger's test. RESULTS: Eleven studies were included in the analysis after comprehensive search. This yielded a pooled early rebleeding rate of 9.3% (95% CI 4.9-17) and late rebleeding rate 13.8% (95% CI 9-20.4). Pooled rescue therapy rate after injecting thrombin in bleeding gastric varices was 10.1% (95% CI 6.1-16.3). The pooled 6-week gastric variceal-related mortality rate after injecting thrombin in bleeding gastric varices was 7.6% (95% CI 4.5-12.5). There were a total of four adverse events out of a total of 222 patients with pooled adverse event rate after injecting thrombin in bleeding gastric varices was 5.6% (95% CI 2.9-10.6). CONCLUSION: In summary, the systematic review and meta-analysis on the use of thrombin for bleeding gastric varices suggest low rates of rebleeding and minimal rates of adverse events. While, early and late rebleeding rate and rescue therapy rate are similar to cyanoacrylate-based therapy, the minimal rates of adverse events are perhaps the most important benefit of thrombin. Thus, the current data suggest that thrombin is a very promising therapeutic alternative with low risk of adverse events for bleeding gastric varices.

Economic and Health Care Burdens of Hepatitis Delta: A Study of Commercially Insured Adults in the United States.

BACKGROUND AND AIMS: The paucity of data regarding the extent of hepatitis delta virus (HDV) associated health care burden in the United States is an important obstacle to assessing the cost-effectiveness of potential intervention strategies. In this study, we characterized the health care use and cost burdens of HDV in the United States using real-world claims data. APPROACH AND RESULTS: We conducted a case-control study using the Truven Health MarketScan Commercial Claims databases from 2011-2014. A total of 2,727 HDV cases were matched 1:1 by sociodemographic characteristics and comorbidities to chronic hepatitis B virus (HBV) controls using propensity scores. The HDV group had significantly higher prevalence of substance abuse, sexually transmitted diseases, decompensated cirrhosis, cirrhosis, and hepatitis C virus compared to patients with chronic HBV. First HDV diagnosis was associated with significant increases in the total number of health care claims (25.61 vs. 28.99; P < 0.0001) and total annual health care costs ($19,476 vs. $23,605; P < 0.0001) compared with pre-HDV baseline. The case-control analysis similarly indicated higher total claims (28.99 vs. 25.19; P < 0.0001) and health care costs ($23,605 vs. $18,228; P < 0.0001) in HDV compared with HBV alone. Compared with HBV controls, HDV cases had an adjusted incident rate ratio of 1.16 (95% confidence interval: 1.10, 1.22) times the total number of annual claims and an adjusted incident rate ratio 1.32 (95% confidence interval 1.17, 1.48) times the total annual health care cost. CONCLUSIONS: HDV is associated with higher health care use and cost burden than HBV alone, underscoring the need for improved screening and treatment.

Renal Failure is Associated With Increased Mortality and Hospital Utilization in Patients Admitted With Nonalcoholic Steatohepatitis.

GOALS: We aimed to investigate the mortality and hospital utilization outcomes of hospitalized nonalcoholic steatohepatitis (NASH) patients with and without kidney failure in a nationwide cohort. BACKGROUND: NASH is a common medical condition associated with significant morbidity and mortality. A paucity of data exists regarding the impact of kidney failure (defined as acute and chronic kidney failure) on outcomes of NASH hospitalizations. MATERIALS AND METHODS: We conducted a retrospective cohort study using the 2016 Nationwide Inpatient Sample dataset of adult patients hospitalized for NASH, stratified for the presence of renal failure. The primary outcome was inpatient mortality, predictors were analyzed using multivariate logistic regression. Secondary outcomes were the length of stay and mean total hospitalization charges. RESULTS: The overall sample included 7,135,090 patients. Among 6855 patients admitted for NASH, 598 or 8.7% had comorbid kidney failure. After multivariate regression analysis, NASH patients with renal failure had increased in-hospital mortality [odds ratio=28.72, 95% confidence interval (CI): 8.99-91.73], length of stay (ß=3.02, 95% CI: 2.54-3.5), total hospital charges (ß=$37,045, 95% CI: $31,756.18-$42,335.62). Positive predictors of mortality in the renal failure group were Charlson Comorbidity Index ≥3 [adjusted odds ratio (aOR)=3.46, 95% CI: 1.04-11.51], variceal bleeding (aOR=3.02, 95% CI: 1.06-8.61), and hepatic encephalopathy (aOR=26.38, 95% CI: 1.29-540.56). Predictors of decreased mortality were Medicaid (aOR=0.047, 95% CI: 0.28-0.79) and private insurance (aOR=0.56, 95% CI: 0.38-0.83). CONCLUSIONS: The prevalence of renal failure in NASH hospitalizations is associated with markedly increased mortality, hospital costs, and length of stay. As a result, clinicians should be vigilant in treating kidney failure in this population.

Drug-induced liver injury associated with antiseizure medications from the FDA Adverse Event Reporting System (FAERS).

PURPOSE: Treatment with antiseizure medications (ASMs) confers a risk of drug-induced liver injury (DILI), especially for older ASMs. We sought to quantify recent reports of DILI attributed to both older and newer generation ASMs and survey newly marketed ASMs for hepatotoxicity in a large post-marketing database. METHODS: We queried over 2.6 million adverse event reports made to the FDA Adverse Event Reporting System (FAERS) database between July 1, 2018 and March 31, 2020 for DILI due to ASMs commonly used in clinical practice. Patient characteristics and outcomes were assessed. We calculated the reporting odds ratio (ROR) of DILI for each individual ASM versus all non-ASM reports. RESULTS: A total of 2175 DILI cases were attributed to an ASM during the study period. 97.2% of these were designated as serious reactions, which include death, hospitalization, disability, and other life-threatening outcomes. A number of older and newer generation ASMs were associated with DILI, specifically: carbamazepine (ROR 2.92), phenobarbital (ROR 2.91), oxcarbazepine (ROR 2.58), phenytoin (ROR 2.40), valproate (ROR 2.22), lamotrigine (ROR 2.06), clobazam (ROR 1.67), levetiracetam (ROR 1.56), and diazepam (ROR 1.53). However, increased odds of DILI were not seen with zonisamide, perampanel, stiripentol, lacosamide, clonazepam, pregabalin, felbamate, eslicarbazepine, cannabidiol, topiramate, gabapentin, ethosuximide, brivaracetam, or primidone. Vigabatrin, tiagabine, and rufinamide all had zero reports of DILI. CONCLUSIONS: The majority of newer generation ASMs were not significantly associated with DILI. Future studies utilizing FAERS in conjunction with other data sources will be critical for the ongoing surveillance of DILI, particularly as newly marketed ASMs continue to enter into widespread clinical use.

Predictors of do-not-resuscitate order utilization in decompensated cirrhosis hospitalized patients: A nationwide inpatient cohort study.

INTRODUCTION AND OBJECTIVES: Decompensated cirrhosis carries high inpatient morbidity and mortality. Consequently, advance care planning is an integral aspect of medical care in this patient population. Our study aims to identify do-not-resuscitate (DNR) order utilization and demographic disparities in decompensated cirrhosis patients. PATIENTS OR MATERIALS AND METHODS: Nationwide Inpatient Sample was used to extract the cohort of patients from January 1st, 2016 to December 31st, 2017, based on the most comprehensive and recent data. The first cohort included hospitalized patients with decompensated cirrhosis. The second cohort included patients with decompensated cirrhosis with at least one contraindication for liver transplantation. RESULTS: A cohort of 585,859 decompensated cirrhosis patients was utilized. DNR orders were present in 14.2% of hospitalized patients. DNR utilization rate among patients with relative contraindication for liver transplantation was 15.0%. After adjusting for co-morbid conditions, disease severity, and inpatient mortality, African-American and Hispanic patient populations had significantly lower DNR utilization rates. There were regional, and hospital-level differences noted. Moreover, advanced age, advanced stage of decompensated cirrhosis, inpatient mortality, and relative contraindications for liver transplantation (metastatic neoplasms, dementia, alcohol misuse, severe cardiopulmonary disease, medical non-adherence) were independently associated with increased DNR utilization rates. CONCLUSIONS: The rate of DNR utilization in patients with relative contraindications for liver transplantation was similar to patients without any relative contraindications. Moreover, there were significant demographic and hospital-level predictors of DNR utilization. This information can guide resource allocation in educating patients and their families regarding prognosis and outcome expectations.

The Microbiome and Hepatocellular Carcinoma.

The human microbiome is a vast and complex system encompassing all of the microbes and their genes that occupy the environmentally exposed surfaces of the human body. The gut microbiota and its associated microbiome play an integral role in mammalian metabolism and immune tolerance as well as in immunocompetence. Disruptions in the human gut microbiome are associated with a cycle of hepatocyte injury and regeneration characteristic of chronic liver disease. The persistence of this inflammation has been shown to induce the accumulation of genetic and epigenetic changes leading to hepatocellular carcinoma (HCC). Therefore, the importance and prognostic influence of the gut microbiome on hepatocarcinogenesis has been increasingly studied in recent years. This review discusses the mechanisms by which imbalances in the gut microbiome disturb the gut-liver axis to impact hepatocarcinogenesis, including disruption of the intestinal barrier, changes in bile acid metabolism, and reduction in tumor-suppressing microRNA. Furthermore, this review summarizes recent advances in potential microbiome-based therapeutic opportunities in HCC.

One-year risk of opioid use disorder after index hospitalization for inflammatory bowel disease.

PURPOSE: Patients with inflammatory bowel disease are commonly prescribed opiates for pain. We sought to determine the incidence of opiate use disorder after inflammatory bowel disease (IBD) admission over a 1-year period as well as its impact on mortality and hospital resource utilization. METHODS: The Nationwide Readmission Database 2016 was used to identify adult patients with a principal diagnosis of IBD who were subsequently readmitted with a primary diagnosis of opioid use disorder. The primary outcome was 1-year readmission rate for opiate use disorder. Predictors were analyzed using multivariate logistic regression. Secondary outcomes were mortality rate, length of stay, and total hospital costs and charges. RESULTS: Among the 6340 index hospitalizations for IBD, 4.7% (6.0% Crohn's and 2.6% ulcerative colitis) were readmitted within 1 year for opiate use disorder. Readmission hospitalizations were associated with additional mortality (0.32%) and hospital utilization (length of stay 4.80 days, mean total costs $9503, and mean total charges $38,288). Ulcerative colitis had significantly higher mortality and hospital utilization costs compared with Crohn's disease. In multivariable analysis, odds of readmission were associated with female sex (OR 1.51, CI 1.19-1.92), private insurance (OR 0.20, CI 0.11-0.37), Charlson Comorbidity Index (OR 0.20, CI 0.11-0.37), anxiety (OR 1.65, CI 1.02-2.63), and depression (OR 2.07, CI 1.28-3.34). On stratification analysis, psychiatric comorbidities were associated with both Crohn's and ulcerative colitis. CONCLUSION: Patients with IBD were often readmitted for opiate use disorder and sustained significant mortality and hospital costs. Psychiatric comorbidities, gender, and insurance status impacted the odds of readmission and represent targets for intervention.

Increased serum selenium levels are associated with reduced risk of advanced liver fibrosis and all-cause mortality in NAFLD patients: National Health and Nutrition Examination Survey (NHANES) III.

INTRODUCTION AND OBJECTIVES: Selenium supplementation has been shown to have therapeutic value in chronic liver disease. We aimed to investigate the association between serum selenium, severity of liver fibrosis, and mortality in patients with Nonalcoholic Fatty Liver Disease (NAFLD). PATIENTS OR MATERIAL AND METHODS: A total of 33,944 patients were identified from the Third National Health and Nutrition Examination Survey. NAFLD was diagnosed by hepatic ultrasound after the exclusion of other forms of liver diseases. The severity of liver fibrosis was determined by NAFLD Fibrosis Score >0.676. Multivariate logistic regression analysis was used to investigate the relationship between serum selenium level and liver fibrosis. Association between serum selenium and all-cause mortality in NAFLD patients was also evaluated. RESULTS: Multivariate logistic regression analysis demonstrated odds ratio of advanced liver fibrosis (NFS > 0.676) was significantly reduced with increasing serum selenium levels; OR 0.55, [95% CI 0.32-0.94] in the highest selenium quartile. On stratification analysis, the following populations had a significantly reduced risk of advanced liver fibrosis: non-Hispanic white = OR 0.41 [0.24,0.68]; female = OR 0.32 [0.15-0.66] and age >47 = OR 0.47 [0.28-0.79]. The relationship was significant regardless of BMI as noted by BMI ≤ 30 Kg/m2= OR 0.42 [0.19-0.91] and BMI > 30 Kg/m2=OR 0.52 [0.28-0.97]. Hazard ratio for all-cause mortality was HR 0.72 [0.56-0.95]. CONCLUSIONS: The risk of advanced liver fibrosis is inversely associated with serum selenium levels, particularly in older patients, Caucasians, and females. All-cause mortality decreased with increased selenium levels. Selenium may play a role in the prevention of liver fibrosis in NAFLD.

Blood lead level is associated with advanced liver fibrosis in patients with non-alcoholic fatty liver disease: A nationwide survey (NHANES 2011-2016).

INTRODUCTION AND OBJECTIVES: Non-Alcoholic Fatty Liver Disease (NAFLD) is linked to obesity and metabolic syndrome, but increasing evidence also implicates environmental toxins. In this study, we aim to show that in elevated blood Lead levels in NAFLD patients result in worsening liver fibrosis. MATERIALS AND METHODS: 30,172 patients from NHANES 2011-2016 met inclusion criteria. 2499 patients ages 20-74 were identified with NAFLD as determined by the Fatty Liver Index score, and 425 with advanced liver fibrosis were identified using the NAFLD Fibrosis Score. Simple linear regression, Student's T-test, and Rao-Scott Chi-Square test was used for continuous and categorical variables. Multivariate regression analysis was used to adjust for confounders to determine odds of Advanced Fibrosis. RESULTS: Increased serum Lead level was independently associated with increased risk of Advanced Fibrosis (OR 5.93, 95% CI 2.88-12.24) in the highest Lead quartile (Q4). In subgroup analysis stratified by BMI, a significant association between advanced liver fibrosis and blood Lead levels was consistently present, Q4 (OR 5.78, 95% CI 0.97-33.63) and Q4 (OR 6.04, 95% CI 2.92-12.48) in BMI <30 and >30, respectively. Increased Lead exposure was also evident in patients who were older, less educated, male, and drank alcohol and smoked tobacco. CONCLUSIONS: Our findings show that advanced liver fibrosis is up to six times more likely in NAFLD patients with increased Lead exposure.

Microbiota and the liver.

The gut microbiome outnumbers the human genome by 150-fold and plays important roles in metabolism, immune system education, tolerance development, and prevention of pathogen colonization. Dysbiosis has been associated with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and alcoholic liver disease (ALD) as well as cirrhosis and complications. This article provides an overview of this relationship. Liver Transplantation 24 539-550 2018 AASLD.

Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.

BACKGROUND: High rates of sustained virologic response were observed among patients with hepatitis C virus (HCV) infection who received 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor ledipasvir. This study examined 8 weeks of treatment with this regimen. METHODS: In this phase 3, open-label study, we randomly assigned 647 previously untreated patients with HCV genotype 1 infection without cirrhosis to receive ledipasvir and sofosbuvir (ledipasvir-sofosbuvir) for 8 weeks, ledipasvir-sofosbuvir plus ribavirin for 8 weeks, or ledipasvir-sofosbuvir for 12 weeks. The primary end point was sustained virologic response at 12 weeks after the end of therapy. RESULTS: The rate of sustained virologic response was 94% (95% confidence interval [CI], 90 to 97) with 8 weeks of ledipasvir-sofosbuvir, 93% (95% CI, 89 to 96) with 8 weeks of ledipasvir-sofosbuvir plus ribavirin, and 95% (95% CI, 92 to 98) with 12 weeks of ledipasvir-sofosbuvir. As compared with the rate of sustained virologic response in the group that received 8 weeks of ledipasvir-sofosbuvir, the rate in the 12-week group was 1 percentage point higher (97.5% CI, -4 to 6) and the rate in the group that received 8 weeks of ledipasvir-sofosbuvir with ribavirin was 1 percentage point lower (95% CI, -6 to 4); these results indicated noninferiority of the 8-week ledipasvir-sofosbuvir regimen, on the basis of a noninferiority margin of 12 percentage points. Adverse events were more common in the group that received ribavirin than in the other two groups. No patient who received 8 weeks of only ledipasvir-sofosbuvir discontinued treatment owing to adverse events. CONCLUSIONS: Ledipasvir-sofosbuvir for 8 weeks was associated with a high rate of sustained virologic response among previously untreated patients with HCV genotype 1 infection without cirrhosis. No additional benefit was associated with the inclusion of ribavirin in the regimen or with extension of the duration of treatment to 12 weeks. (Funded by Gilead Sciences; ION-3 ClinicalTrials.gov number, NCT01851330.).

Cost-effectiveness of new antiviral regimens for treatment-naïve U.S. veterans with hepatitis C.

UNLABELLED: Recently approved, interferon-free medication regimens for treating hepatitis C are highly effective, but extremely costly. We aimed to identify cost-effective strategies for managing treatment-naïve U.S. veterans with new hepatitis C medication regimens. We developed a Markov model with 1-year cycle length for a cohort of 60-year-old veterans with untreated genotype 1 hepatitis C seeking treatment in a typical year. We compared using sofosbuvir/ledipasvir or ombitasvir/ritonavir/paritaprevir/dasabuvir to treat: (1) any patient seeking treatment; (2) only patients with advanced fibrosis or cirrhosis; or (3) patients with advanced disease first and healthier patients 1 year later. The previous standard of care, sofosbuvir/simeprevir or sofosbuvir/pegylated interferon/ribavirin, was included for comparison. Patients could develop progressive fibrosis, cirrhosis, or hepatocellular carcinoma, undergo transplantation, or die. Complications were less likely after sustained virological response. We calculated the incremental cost per quality-adjusted life year (QALY) and varied model inputs in one-way and probabilistic sensitivity analyses. We used the Veterans Health Administration perspective with a lifetime time horizon and 3% annual discounting. Treating any patient with ombitasvir-based therapy was the preferred strategy ($35,560; 14.0 QALYs). All other strategies were dominated (greater costs/QALY gained than more effective strategies). Varying treatment efficacy, price, and/or duration changed the preferred strategy. In probabilistic sensitivity analysis, treating any patient with ombitasvir-based therapy was cost-effective in 70% of iterations at a $50,000/QALY threshold and 65% of iterations at a $100,000/QALY threshold. CONCLUSION: Managing any treatment-naïve genotype 1 hepatitis C patient with ombitasvir-based therapy is the most economically efficient strategy, although price and efficacy can impact cost-effectiveness. It is economically unfavorable to restrict treatment to patients with advanced disease or use a staged treatment strategy. (Hepatology 2016;63:428-436).

Safety and Efficacy of Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir With or Without Ribavirin in HCV-Infected Patients Taking Concomitant Acid-Reducing Agents.

OBJECTIVES: Acid-reducing agents (ARAs) and proton-pump inhibitors (PPIs) that increase gastric pH can alter the bioavailability of antiviral drugs, particularly relevant in patients with advanced liver disease caused by chronic hepatitis C virus (HCV) infection seeking therapy. Using integrated data from six phase 3 studies, we report the safety and efficacy of the 3-direct-acting antiviral (DAA) regimen containing ombitasvir (OBV, an NS5A inhibitor), ritonavir-boosted paritaprevir (PTV/r, an NS3/4A protease inhibitor), and dasabuvir (DSV, an NS5B polymerase inhibitor) with or without ribavirin (RBV) for HCV genotype 1 patients taking concomitant ARAs and PPIs. METHODS: Treatment-naïve or peginterferon/RBV treatment-experienced patients with or without compensated cirrhosis received OBV/PTV/r and DSV with or without weight-based RBV. Rates of sustained virologic response (SVR), defined as HCV RNA below the lower limit of quantification, 12 weeks post-treatment (SVR12) and safety were evaluated in patients who were receiving concomitant ARAs. RESULTS: Among 2,053 patients enrolled and dosed with study drug, 410 (20%) were receiving concomitant ARAs; of these, 308 (15%) were taking concomitant PPIs. Rates of SVR12 were 95.9% (95% confidence interval (CI) 93.5-97.4%) among patients receiving an ARA, and 96.3% (95% CI 95.3-97.2%) in patients not receiving a concomitant ARA. Similarly, among patients receiving a PPI or not, SVR12 was achieved in 95.1% (95% CI 92.1-97.0%) and 96.4% (95% CI 95.5-97.2%), respectively. Response rates were high regardless of treatment regimen (with or without RBV), and among patients receiving a standard or high dose of PPIs. Regarding safety, adverse events and serious adverse events were more frequently reported in patients taking concomitant ARAs, though baseline population differences may have played a role. CONCLUSIONS: In phase 3 trials of OBV/PTV/r plus DSV and RBV in HCV genotype 1-infected patients, SVR12 rates were high regardless of ARA/PPI use or PPI dose. These data support the co-administration of this regimen with ARAs including PPIs.

Daclatasvir + asunaprevir + beclabuvir ± ribavirin for chronic HCV genotype 1-infected treatment-naive patients.

BACKGROUND AND AIMS: This phase-2b study examined the safety and efficacy of an all-oral, interferon-free combination of the NS5A replication complex inhibitor daclatasvir (DCV), the NS3 protease inhibitor asunaprevir (ASV), and the nonnucleoside NS5B polymerase inhibitor beclabuvir (BCV) with or without ribavirin in patients with HCV genotype (GT) 1 infection. METHODS: A total of 187 patients received 12 weeks of DCV 30 mg BID plus ASV 200 mg BID and BCV 150 mg BID (n = 86) or 75 mg BID with (n = 21) or without (n = 80) weight-based ribavirin BID. The primary endpoint was HCV RNA <25 IU/ml at post-treatment week 12 (SVR12). RESULTS: Overall, 90% of patients (169/187) in the combined treatment groups achieved SVR on or after post-treatment week 12. SVR rates were similar across subgroups (by mITT analysis), i.e. patients with cirrhosis (88%, 14/16), HCV GT-1a (90%, 137/155), and IL28B non-CC genotype (90%, 115/128). There were no drug-related serious AEs or grade 4 AEs. The most frequently reported AEs were headache, diarrhoea, fatigue and nausea. Addition of ribavirin to DCV+ASV+BCV was associated with decreased haemoglobin, compared with DCV+ASV+BCV alone. There were six grade 3/4 laboratory abnormalities noted, all unrelated to the study drugs. Viral breakthrough occurred in 2.5-4.8% of patients across groups and appeared unrelated to BCV dose or ribavirin inclusion. CONCLUSIONS: Results support phase 3 evaluation of a twice-daily, fixed-dose formulation of this DCV+ASV+BCV regimen with or without ribavirin in HCV GT-1-infected patients.