Blaire E. Burman

Liver inflammation is a risk factor for prediabetes in at‐risk latinos with and without hepatitis C infection

Early recognition of prediabetes can lead to timely clinical interventions to prevent type 2 diabetes. Both Latino ethnicity and chronic hepatitis C (HCV) have been identified as diabetic risk factors. We aimed to investigate predictors of impaired fasting glucose (IFG), a common prediabetic state, among Latinos with and without HCV.

ACP Journal Club. Adding rifaximin to lactulose increased reversal and decreased mortality in hepatic encephalopathy.

Source Citation Sharma BC, Sharma P, Lunia MK, et al. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopat...

Efficacy and safety of sofosbuvir-based regimens for treatment in chronic hepatitis C genotype 1 patients with moderately impaired renal function

Background/Aims Treatment of chronic hepatitis C virus (HCV) infection in patients with chronic kidney disease (CKD) is essential. The availability of sofosbuvir (SOF) has dramatically improved overall HCV cure rates, however there is insufficient data regarding its use in patients with CKD. We evaluated SOF in patients with hepatitis C genotype 1 (G1) and moderately impaired renal function. Methods We retrospectively reviewed all patients treated with a SOF-based regimen from December 2013 through September 2015 at Virginia Mason Medical Center. Data was then collected for HCV G1 patients with stage 3 CKD. Results A total of 28 patients with HCV G1 and stage 3 CKD were treated with a SOF-based regimen. Twenty-one patients had stage 3A CKD (estimated glomerular filtration rate [eGFR] 45–60 mL/min/1.73m2) and 7 patients had stage 3B CKD (eGFR 30–45 mL/min/1.73m2). The overall rate of sustained virologic response (SVR) 12 weeks after completion of therapy (SVR12) was 85.7% (24/28). SVR12 in stage 3A CKD patients was 81.0% (17/21) and in stage 3B CKD patients, SVR12 was 100% (7/7). Based on the treatment regimen used, the SVR12 was 81.8% (9/11), 92.3% (12/13), and 75.0% (3/4) for SOF/ledipasvir (LDV), SOF/simeprevir (SIM), and SOF/pegylated interferon (PEG)/ribavirin (RBV), respectively. Greater than 30% reduction eGFR was observed in 4 out of 28 patients. Conclusions SOF-based regimens resulted in high SVR12 rates in patients with moderately impaired renal function. During therapy, HCV patients with CKD should be carefully monitored for worsening renal function.

1321 PREDICTORS OF DIRECTLY MEASURED INSULIN RESISTANCE IN AT-RISK LATINOS WITH AND WITHOUT HEPATITIS C (HCV) INFECTION

Background and Aims: HCV is associated with insulin resistance and disproportionately affects Latinos, who in turn have higher rates of diabetes. Factors predictive of insulin resistance in HCVinfected Latinos are not well understood. We aim to compare insulin sensitivity using direct measurements, and assess host and viral factors associated with insulin resistance in Latinos. Methods: 123 non-cirrhotic, non-diabetic Latinos (52 with HCV) were enrolled. All subjects underwent clinical and metabolic evaluation including oral glucose tolerance test and insulin sensitivity by steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Patients in the lowest tertile of SSPG were defined as insulin sensitive (IS) and in the highest tertile as insulin resistant (IR). Results: Overall patient characteristics were: mean age 43±10 years, 64% male, and BMI 27±5 Kg/m. Among HCV-positive patients, 67% were genotype 1, mean log10 HCV viral load was 5.83 IU/mL, and mean ALT 89±73 IU/mL. The mean SSPG in IS (N=40) was of 65±14mg/dL and in IR (N=41) was 239±35mg/dL. On univariable analysis, IS and IR patients were similar with respect to age, family history of diabetes, and tobacco use. However, IR was positively associated with HCV status (OR 1.83, 95%CI 0.7–4.2), female gender (OR 2.38, 95%CI 0.9–5.8), waist circumference (OR 1.21, 95%CI 1.1–1.3), serum LDL (OR 1.02, 95%CI 1.00–1.03), and triglycerides (OR 1.02, 95%CI 1.01–1.04); and negatively associated with HDL (OR 0.93, 95%CI 0.89–0.97), and current alcohol use (OR 0.43, 95%CI 0.97–1.04). On multivariable analysis, controlling for age and family history of diabetes, female gender (OR 13.74, 95%CI 1.99–94.9, p = 0.008), HCV infection (OR 9.13, 95%CI 1.2– 70.1, p = 0.03), waist circumference (OR 1.14, 95%CI 1.04–1.24, p = 0.006), and triglycerides (OR 1.02, 95%CI 1.00–1.04, p = 0.04) were significantly associated with IR. Conclusions: Along with host factors, HCV infection was associated with nine-fold higher odds of directly measured insulin resistance in Latinos. Although male gender is associated with higher diabetic rates, female gender was a strong predictor of insulin resistance among Latinos. The role of other gender-specific factors influencing insulin resistance in this population requires further investigation. Grant support: National Institute of Health, R01-DK074673 (M.K.) and American Diabetes Foundation 1–08-CR-30 (M.K.).

Sa1023 Pre-Diabetes and Chronic Hepatitis C Virus (HCV) Infection: Assessment of Host and Viral Factors in At-Risk Latinos

Introduction: HCC is the third leading cause of cancer-related death worldwide, causing nearly half a million deaths per year. A major risk factor for HCC development is infection with the hepatitis C virus (HCV), which accounts for one-third of HCC cases. Accurate prediction of HCC risk in HCV+ patients has major clinical significance for treatment and screening. Previous studies indicate that serum cytokine profiles may correlate with the risk of viral infection and cancer. Methods: We studied the correlation between 51 cytokine levels and HCC status in 259 patients enrolled at a U.S. university liver clinic. Cytokine levels were measured using a Luminex 200 IS platform. Cytokine levels were normalized to dimensionless values, and differences in median levels between patients with and without HCC were analyzed with half-normal plots. Results: Of the 259 patients in our study, 176 had HCV and 83 had other liver diseases, excluding chronic hepatitis B (HBV). Within the HCV+ group, 45 had HCC and 131 did not; and within the non-HCV group, 14 had HCC and 69 did not. Baseline clinical characteristics for the HCV+ and non-HCV groups were determined for median age (55 vs. 61 years), sex (66% vs. 51% male), race (27% vs. 8% Asian), median ALT (68 vs. 35 U/L), cirrhosis (85% vs. 87%), and mean MELD score (11.4 ± 4.7 vs. 12.2 ± 4.2). Among HCV+ HCC cases, we observed systematic decreases in normalized median cytokine levels compared with HCV+ non-HCC controls (45 of 51 cytokines, P = 1.83 x 10^-8) (Figure 1). Particularly, three cytokines decreased significantly: leptin (2.13 vs. 3.66), tumor necrosis factor beta (TNFb; 6.57 vs. 9.48), and macrophage colony-stimulating factor (M-CSF; 4.98 vs. 6.39). In contrast, for the non-HCV group, we observed a small overall increase in median cytokine levels from non-HCC to HCC (P = 0.024) (Figure 2). Conclusion: Among HCV+ mostly cirrhotic patients, development of HCC is correlated with an overall decrease in serum cytokine levels, most notably in leptin, TNFb, and M-CSF. In contrast, a small increase in cytokine levels is observed in non-HCV nonHBV patients with HCC. Prospective studies are needed to determine whether overall decreases in cytokine levels predict HCC risk in HCV+ patients.

Sa1024 Predictors of Insulin Resistance Using Direct Measurement in At-Risk Latinos With and Without Hepatitis C (HCV) Infection

Background:Host cytoskeletal proteins of the ezrin-moesin-radixin (EMR) family have been shown to modulate single stranded RNA virus (HIV) infection through regulating stable microtubule formation. Previous studies indicate that antibody engagement of CD81, a key receptor regulating HCV infection, induces ezrin phosphorylation. Here we tested the role of EMR proteins in regulating HCV infection and explored their targeting for therapeutic potential. Methods: Gene regulation methods including real-time quantitative PCR, western blot and fluorescent microscopy analysis were used for experimental analysis. Results: We show that proteins of the EMR family differentially regulate HCV infection in the J6/JFH1/Huh7.5 cell system. Moesin and radixin, but not ezrin, expression were decreased in HCV infected compared to uninfected Huh7.5 cells and this was associated with a significant increase in stable microtubules. Over-expression of moesin or radixin or knockdown of ezrin significantly reduced HCV protein expression. In contrast, transient knockdown of moesin or radixin augmented HCV infection. We found that the infectious HCV virus (J6/ JFH-1) induces rapid ezrin and radixin phosphorylation via spleen tyrosine kinase (SYK). SYK phosphorylation contributed to HCV infection because HCV replication was inhibited by a SYK inhibitor (BAY 61-3606). Making use of the Con1 HCV replicon system, we tested the effect of EMR proteins on HCV replication. We found that transient knockdown of moesin increased HCV RNA expression while over-expression of EMR showed no significant effect on HCV replication. Finally, we designed and evaluated the therapeutic potential of a novel moesin-radixin peptide that exhibited anti-HCV properties by blocking HCV infection but not HCV replication. Conclusion: In conclusion, our novel data demonstrate that EMR proteins modulate HCV infection and identify EMR as possible therapeutic targets to inhibit HCV entry. (supported by NIHAAA)