Tracey G. Simon

Atorvastatin and fluvastatin are associated with dose‐dependent reductions in cirrhosis and hepatocellular carcinoma, among patients with hepatitis C virus: Results from ERCHIVES

Statins are associated with delayed fibrosis progression and a reduced risk of hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV). Limited data exist regarding the most effective type and dose of statin in this population. We sought to determine the impact of statin type and dose upon fibrosis progression and HCC in patients with HCV. Using the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database, we identified all subjects initiated on HCV antibody (anti‐HCV) therapy from 2001 to 2014, and all incident cases of cirrhosis and HCC. Statin use was measured using cumulative defined daily dose (cDDD). Multivariable Coxs proportional hazard regression models were used to examine the relationship between statin use and development of cirrhosis and HCC. Among 9,135 eligible subjects, 1,649 developed cirrhosis and 239 developed incident HCC. Statin use was associated with a 44% reduction in development of cirrhosis (adjusted hazard ratio [HR]: 0.6; 95% confidence interval [CI]: 0.53, 0.68). The adjusted HRs (95% CI) of fibrosis progression with statin cDDD 28‐89, 89‐180, and >180 were 0.74 (0.59, 0.93), 0.71 (0.59, 0.88), and 0.6 (0.53, 0.68), respectively. Mean change in FIB‐4 score with atorvastatin (n = 944) and fluvastatin (n = 34) was ‐0.17 and ‐0.13, respectively (P = 0.04), after adjustment for baseline FIB‐4 score and established predictors of cirrhosis. Statin use was also associated with a 49% reduction in incident HCC (adjusted HR: 0.51; 95% CI: 0.36, 0.72). A similar dose‐response relationship was observed. Conclusion: In patients with chronic HCV, statin use was associated with a dose‐dependent reduction in incident cirrhosis and HCC. Atorvastatin and fluvastatin were associated with the most significant antifibrotic effects, compared with other statins. (Hepatology 2016;64:47–57)

Statin use is associated with a reduced risk of fibrosis progression in chronic hepatitis C

BACKGROUND & AIMS Therapies that slow fibrosis progression in chronic liver disease are needed. Animal models have demonstrated that statins prevent the progression of hepatic fibrosis, but human data is lacking so far. We evaluated the association between statins and fibrosis progression in the HALT-C trial cohort. METHODS Subjects with chronic hepatitis C (CHC) and advanced hepatic fibrosis underwent serial liver biopsies over 3.5 years. The primary outcome was a ⩾ 2-point increase in the Ishak fibrosis score on at least one of two serial biopsies. We used complementary log-log regression analysis to assess the association between statins and fibrosis progression among subjects without baseline cirrhosis. RESULTS Fibrosis progression occurred in 3/29 (10%) statin users and 145/514 (29%) non-users. The unadjusted hazard ratio (HR) for fibrosis progression among statin users compared to non-users was 0.32 (95% CI 0.10-0.99). This association remained significant after adjusting for established predictors of histological outcome, including body mass index, platelets and hepatic steatosis (adjusted HR 0.31; 95% CI 0.10-0.97). The mean change in Ishak fibrosis score over the 3.5 year study period was -0.34 (SE 0.18) for statin users compared to +0.42 (SE 0.07) for non-users (p = 0.006, after adjustment for baseline fibrosis score). CONCLUSIONS Statin use is associated with a reduced risk of fibrosis progression in advanced CHC. Our findings suggest a potential role for statins in preventing liver disease progression.

Effect of addition of statins to antiviral therapy in hepatitis C virus-infected persons: Results from ERCHIVES.

3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) have been variably noted to affect hepatitis C virus (HCV) treatment response, fibrosis progression, and hepatocellular carcinoma (HCC) incidence, with some having a more potent effect than others. We sought to determine the impact of adding statins to antiviral therapy upon sustained virological response (SVR) rates, fibrosis progression, and HCC development among HCV‐infected persons using the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), an established, longitudinal, national cohort of HCV‐infected veterans. Within ERCHIVES, we identified those who received HCV treatment and a follow‐up of >24 months after treatment completion. We excluded those with human immunodeficiency virus coinfection, hepatitis B surface antigen positivity, cirrhosis, and HCC at baseline. Our main outcomes were liver fibrosis progression measured by FIB‐4 scores, SVR rates, and incident HCC (iHCC). Among 7,248 eligible subjects, 46% received statin therapy. Statin use was significantly associated with attaining SVR (39.2% vs. 33.3%; P < 0.01), decreased cirrhosis development (17.3% vs. 25.2%; P < 0.001), and decreased iHCC (1.2% vs. 2.6%; P < 0.01). Statins remained significantly associated with increased odds of SVR (odds ratio = 1.44; 95% confidence interval [CI] = 1.29, 1.61), but lower fibrosis progression rate, lower risk of progression to cirrhosis (hazard ratio [HR] = 0.56; 95% CI = −0.50, 0.63), and of incident HCC (HR = 0.51; 95% CI = 0.34, 0.76) after adjusting for other relevant clinical factors. Conclusions: Statin use was associated with improved virological response (VR) rates to antiviral therapy and decreased progression of liver fibrosis and incidence of HCC among a large cohort of HCV‐positive Veterans. These data support the use of statins in patients with HCV. (Hepatology 2015) Hepatology 2015;62:365–374

Charlson Comorbidity Index predicts patient outcome, in cases of inoperable non-small cell lung cancer treated with radiofrequency ablation.

PURPOSE The Charlson Comorbidity Index (CCI) has been shown to be a significant prognostic indicator in the treatment of many types of cancer. The aim of this study is to evaluate the degree to which the CCI predicts survival in patients with inoperable non-small cell lung cancer (NSCLC) treated with radiofrequency ablation (RFA). MATERIALS AND METHODS Eighty-two (34 men, 48 women) consecutive RFA treatments for medically inoperable NSCLC were performed at our institution from 1/1/2000 to 1/30/2009. With institutional IRB approval and in full HIPAA compliance, the medical records of these patients were examined for data relating to pre-treatment comorbid conditions, and a retrospective analysis was conducted. Survival curves were estimated by the Kaplan-Meier method. Risk factors for mortality were determined by single-factor comparisons of curves using Wilcoxon-weighted chi-square and multiple Cox regressions. RESULTS The patients ranged in age from 59 to 91 years (mean: 75.5). Eighty-eight percent (72 patients) were tumor stage IA or IB. Patients were followed for a total of five years; three-year overall survival was 50.6%. Hospital mortality was 0%. Gender, stage, histology and CCI score were each associated with significantly impaired survival (p<0.001 in all cases). After covarying for age, tumor stage>IB, squamous histology and gender, multiple Cox regressions showed that an increasing CCI score was significantly associated with an increased risk of death (HR 1.3, 95% CI 25.5, 58.2). CONCLUSIONS The CCI is validated as an important, independent predictor of patient survival, in cases of inoperable NSCLC treated with RFA.

Massive intravascular hemolysis from Clostridium perfringens septicemia: a review.

We describe the case of a patient with hemolysis-associated Clostridium perfringens septicemia and review all similar cases published in the literature since 1990, with specific focus on the relationship between treatment strategy and survival. We searched PubMed for all published cases of C. perfringens-associated hemolysis, using the medical subject terms “clostridia,” “clostridial sepsis,” and/or “hemolysis.” All case reports, case series, review articles, and other relevant references published in the English literature since 1990 were included in this study. There were no exclusion criteria. Each case was examined with respect to presenting features of illness, antibiotic regimen, time-to-antibiotic therapy, additional interventions, complications, and patient survival. These variables were entered into a data set and then systematically analyzed with the aid of a statistician, using serial t tests and chi-square analyses. Since 1990, 50 patients of C. perfringens septicemia with hemolysis have been reported. Median age was 61 years (range 31-84), and 58% were male. Mortality was 74%, with a median time to death of 9.7 hours (range 0-96 hours). Of the patients, 35 (70%) were treated medically, while 15 (30%) received antibiotics and surgery. Surgical intervention was associated with significantly improved survival (risk ratio [RR] 0.23, 95% confidence interval [CI] 0.10, 0.53) as was the use of a combination of penicillin and clindamycin (RR of death 0.46, 95% CI 0.25, 0.83). Four patients utilizing hyperbaric oxygen therapy (HBOT) have been reported, and all patients survived. In cases of clostridial sepsis with hemolysis, strong predictors of survival include early initiation of appropriate antibiotics as well as surgical removal of infected foci. The HBOT may also be associated with survival. The disease often progresses rapidly to death, so rapid recognition is critical for the patient survival.

The short‐term incidence of hepatocellular carcinoma is not increased after hepatitis C treatment with direct‐acting antivirals: An ERCHIVES study

Recent studies have reported higher rates of hepatocellular carcinoma (HCC) in individuals treated with direct‐acting antivirals (DAAs). However, making definitive conclusions has been challenging because of the heterogeneous populations and methodologies of these reports. We investigated whether DAA use is associated with higher rates of incident HCC compared to treatment with interferon (IFN)‐based regimens. We performed a retrospective, population‐based cohort study using the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database. In a cohort of 17,836 persons, sustained virological response (SVR) was achieved by 66.6% and 96.2% of the IFN and DAA groups, respectively. Among all treated persons, risk of HCC was not higher in the DAA group compared to the IFN group (hazard ratio, 1.07; 95% confidence interval, 0.55, 2.08). Among persons with cirrhosis who achieved SVR, neither the HCC incidence rate nor HCC‐free survival were significantly different in the DAA group compared to the IFN group (21.2 vs. 22.8 per 1,000 person‐years; P = 0.78 and log‐rank P = 0.17, respectively). Untreated persons with cirrhosis had a significantly higher HCC incidence rate (45.3 per 1,000 person‐years) compared to those treated with either IFN or DAAs (P = 0.03). Both groups of treated persons had significantly lower probability of HCC development compared to untreated persons (log‐rank, P = 0.0004). Conclusion: DAA treatment is not associated with a higher risk of HCC in persons with cirrhosis with chronic HCV infection in the short term. Previously reported higher rates of HCC associated with DAA treatment may be explained by both the presence of relatively fewer baseline HCC risk factors in persons treated with IFN as well as selection bias, given that DAA regimens were used to treat persons at higher risk for developing HCC. (Hepatology 2018;67:2244‐2253).

Lipid dysregulation in hepatitis C virus, and impact of statin therapy upon clinical outcomes

The hepatitis C virus (HCV) is one of the most common causes of chronic liver disease and the leading indication for liver transplantation worldwide. Every aspect of the HCV life cycle is closely tied to human lipid metabolism. The virus circulates as a lipid-rich particle, utilizing lipoprotein cell receptors to gain entry into the hepatocyte. It has also been shown to upregulate lipid biosynthesis and impair lipid degradation, resulting in significant intracellular lipid accumulation and circulating hypocholesterolemia. Patients with chronic hepatitis C (CHC) are at increased risk of hepatic steatosis, fibrosis, and cardiovascular disease including accelerated atherosclerosis. HMG CoA Reductase inhibitors, or statins, have been shown to play an important role in the modulation of hepatic steatosis and fibrosis, and recent attention has focused upon their potential therapeutic role in CHC. This article reviews the hepatitis C viral life cycle as it impacts host lipoproteins and lipid metabolism. It then describes the pathogenesis of HCV-related hepatic steatosis, hypocholesterolemia and atherosclerosis, and finally describes the promising anti-viral and anti-fibrotic effects of statins, for the treatment of CHC.

Effect of Paritaprevir/Ritonavir/Ombitasvir/Dasabuvir and Ledipasvir/Sofosbuvir Regimens on Survival Compared With Untreated Hepatitis C Virus–Infected Persons: Results From ERCHIVES

Background Interferon-based regimens are associated with a substantial survival benefit for persons infected with hepatitis C virus (HCV). Survival data with direct-acting antiviral agents are not available. We conducted this study to quantify the effect of paritaprevir/ritonavir, ombitasvir, dasabuvir (PrOD) and ledipasvir/sofosbuvir (LDV/SOF) regimens upon mortality. Methods In the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), a well-established national cohort of HCV-infected Veterans, we identified HCV-infected persons initiated on PrOD or LDV/SOF, excluding those with human immunodeficiency virus, hepatitis B surface antigen positivity, hepatocellular carcinoma, or missing HCV RNA or FIB-4 scores. For each case, we identified a propensity score-matched control never initiated on treatment. Primary outcome was survival. Outcomes were assessed using frequency of events, Kaplan-Meier curves, and Cox proportional hazards regression analyses. Results We identified 1473 persons on PrOD, 5497 on LDV/SOF, and 6970 propensity score-matched untreated persons. Treated persons were more likely to be obese and have cirrhosis, but less likely to have stage 3-5 chronic kidney disease (CKD), alcohol or drug abuse or dependence diagnosis, and anemia. The proportion of persons who died was higher in the untreated group compared with either treatment group (PrOD, 0.3%; LDV/SOF, 1.4%; untreated controls, 2.5%; P < .001). A significantly larger percentage of treated patients survived to 18 months of follow-up, compared with untreated controls (P < .001). In multivariable Cox regression analysis, treatment with either regimen (hazard ratio [HR], 0.43; 95% confidence interval [CI], .33-.57) and attainment of sustained virologic response (SVR) were associated with significantly lower mortality (HR, 0.57; 95% CI, .33-.99). Conclusions Treatment with PrOD or LDV/SOF and SVR are associated with a significant mortality benefit, apparent within the first 18 months of treatment.

Cardiovascular Risk Reduction in Patients with Nonalcoholic Fatty Liver Disease: The Potential Role of Ezetimibe

Nonalcoholic fatty liver disease (NAFLD) is widely considered to be the hepatic manifestation of the metabolic syndrome and is closely linked to dyslipidemia, obesity, and insulin resistance. Patients with NAFLD have increased mortality when compared to the general population, primarily related to cardiovascular disease or malignancy. The biologic mechanisms that link NAFLD to cardiovascular disease include expansion of visceral adipose tissue, atherogenic dyslipidemia, impaired insulin signaling, systemic inflammation, and endothelial dysfunction. Currently, there are no approved therapies for NAFLD. It has recently been hypothesized that reducing the delivery of dietary cholesterol using the hypolipidemic agent, ezetimibe, could benefit patients with NAFLD. By potently inhibiting the Niemann-Pick C1-Like 1 (NPC1L1) sterol receptor on intestinal enterocytes and within the liver, ezetimibe blocks exogenous cholesterol absorption and has been shown to improve biochemical markers of NAFLD, improve insulin sensitivity and decrease hepatic steatosis. This review summarizes the clinical and epidemiological evidence for the relationship between NAFLD and cardiovascular risk and examines the potential therapeutic role of ezetimibe.

Initial Assessment and Resuscitation in Nonvariceal Upper Gastrointestinal Bleeding

Acute nonvariceal upper gastrointestinal bleeding remains an important cause of hospital admission with an associated mortality of 2-14%. Initial patient evaluation includes rapid hemodynamic assessment, large-bore intravenous catheter insertion and volume resuscitation. A hemoglobin transfusion threshold of 7 g/dL is recommended, and packed red blood cell transfusion may be necessary to restore intravascular volume and improve tissue perfusion. Patients should be risk stratified into low- and high-risk categories, using validated prognostic scoring systems such as the Glasgow-Blatchford, AIMS65 or Rockall scores. Effective early management of acute, nonvariceal upper gastrointestinal hemorrhage is critical for improving patient outcomes.