Faculty Bibliography

INTRODUCTION: Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the United States (U.S). The United States Drug-Induced Liver Injury Network (DILIN) reported that approximately 15-20% of DILI cases per year could be attributed to herbal and dietary supplements. Khat is a stimulant derived from the leaves of the shrub Catha edulis, which is native to North Yemen and other East African countries. Chewing khat, a drug of abuse, is an established social habit in areas endemic to the shrub. Khat has been associated with clinically relevant acute and chronic liver injury. We present a case of drug induced liver injury related to Khat. CASE DESCRIPTION/METHODS: A 47 year old Yemeni male with no medical history presented with jaundice. He denied prior liver disease, alcohol use or prescription drugs. He reported routine use of Khat. Labwork is shown in Figure 1. MRCP revealed mild hepatosplenomegaly. Viral workup revealed immunity to hepatitis A. The patient presented 3 months later with jaundice and persistently elevated liver enzymes. Abdominal ultrasound was unrevealing. Extensive workup revealed a positive antinuclear antibody 1:320, in homogeneous pattern and an elevated serum immunoglobulin G and was otherwise unrevealing. Liver biopsy revealed mild portal mononuclear infiltration associated with focal interface hepatitis and widespread lobular hepatitis with plasma cell prominence in the infiltrates (Figures 1 and 2). Subsequently the patient was started on a course of Prednisone and Ursodiol with complete resolution of liver injury. DISCUSSION: Liver injury related to Khat typically occurs after years of use and may present acutely with nausea, fatigue, and jaundice or chronically with evidence of portal hypertension. Biochemical injury is typically hepatocellular and liver enzymes may be significantly elevated. Autoantibodies can mimic autoimmune hepatitis. Resolution of liver injury typically occurs with cessation of khat use. Patients may require corticosteroid therapy however the response is typically partial. Liver transplantation due to Khat related liver failure has been reported. Given immigration of individuals from countries endemic to Khat, an extensive history including use of cultural drugs such as Khat and other herbal remedies is critical in making a diagnosis of unexplained liver toxicity. Our case highlights the importance of a complete drug and supplement history and maintaining a high index of suspicion for DILI in the appropriate clinical context. (Table Presented)

Article Title: ACG Clinical Guideline: Hereditary Hemochromatosis.

BACKGROUND & AIMS/OBJECTIVE:Caspase-mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan-caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non-alcoholic steatohepatitis (NASH). METHODS:We performed a multicenter study of 86 patients with cirrhosis (Child-Pugh class A or B; mean score, 6.9; 38% with alcohol-associated cirrhosis, 29% with HCV-associated cirrhosis, and 23% with NASH) and model for end-stage liver disease (MELD) scores of 11-18 (mean, 12.8). Patients were randomly assigned to groups given placebo (n=42) or emricasan (25 mg, n=44), twice daily for 3 months; subjects then received open-label emricasan (25 mg) twice-daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK-18) at month 3. RESULTS:Seventy-four patients completed the 3-month study period (40 given emricasan and 34 given placebo); 69 patients received open-label emricasan for 3 months afterward. At the 3-month timepoint, emricasan significantly reduced mean MELD (P=.003) and Child-Pugh (P=.003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95% CI, -0.2882 to -0.0866) and total bilirubin (95% CI, -1.5069 to -0.0823) vs placebo. There were no significant differences between emricasan and placebo groups in mean MELD (P=.466) or Child-Pugh (P=.124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given emricasan (67%) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20%). Serum levels of full-length CK-18 (P=.02) and caspase 3/7 (P<.001), but not cleaved CK-18 (P=.092), decreased significantly at 3 months in the emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasan's effects were generally maintained or increased after 6 months of treatment. CONCLUSIONS:In a randomized trial of patients with cirrhosis, we found 3 months treatment with emricasan to improve liver function, compared with placebo, reducing MELD and Child-Pugh scores, INR, and total bilirubin in patients with MELD scores ≥15. ClinicalTrials.gov no: NCT002209456.

BACKGROUND:Limited data exist with regard to treatment outcomes in Asian Americans with chronic hepatitis C (CHC). We evaluated sofosbuvir (SOF)-based regimens in a national cohort of Asian Americans. METHODS:Eligible Asian Americans patients with CHC who had posttreatment follow-up of 24 weeks for SOF -based therapies from December 2013 to June 2017 were enrolled from 11 sites across the United States. The primary endpoint was sustained virologic response (SVR) rates at posttreatment weeks 12 and 24. Secondary endpoints were to evaluate safety by tolerability and adverse events (AEs). RESULTS:Among 231 patients screened, 186 were enrolled. At baseline, 31% (57/186) patients were cirrhotic, 34% (63/186) were treatment experienced. Most of the subjects (42%, 79/186) received ledispavir/SOF therapy. The overall SVR12 was 95%, ranging from 86% in genotype (GT) 1b on SOF+ribavirin to 100% in GT 1b patients on ledipasvir/SOF at subgroup analyses. SVR12 was significantly lower in cirrhotic than in noncirrhotic patients [88% (50/57) vs. 98% (126/129), P<0.01]. Stratified by GT, SVR12 were: 96% (43/45) in GT 1a; 93% (67/72) in GT 1b; 100% (23/23) in GT 2; 90% (19/21) in GT 3; 100% (1/1) in GT 4; 83% (5/6) in GT 5; and 100% (16/16) in GT 6. Cirrhotic patients with treatment failure were primarily GT 1, (GT 1a, n=2; GT 1b, n=4) with 1 GT 5 (n=1). Patients tolerated the treatment without serious AEs. Late relapse occurred in 1 patient after achieving SVR12. CONCLUSIONS:In Asian Americans with CHC, SOF-based regimens were well tolerated without serious AEs and could achieve high SVR12 regardless of hepatitis C viral infection GT.

To receive CME/MOC credit for this activity, please go to: http://acgjournalcme.gi.org/Article Title: Refractory Ascites in Liver Cirrhosis.

BACKGROUND & AIMS/OBJECTIVE:We aimed to evaluate the safety and effectiveness of 12 or 24 weeks treatment with ledipasvir and sofosbuvir, with or without ribavirin, in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis in routine clinical practice. Patients were followed in a multi-center, prospective, observational cohort study (HCV-TARGET). METHODS:We collected data from 667 treatment-experienced adults with chronic genotype 1 HCV infection who began treatment with ledipasvir and sofosbuvir, with or without ribavirin, from 2011 through September 15, 2016, according to the regional standards of care, at academic (n = 39) and community (n = 18) centers in the United States, Canada, Germany, and Israel. Information was collected from medical records and abstracted into a unique centralized data core. Independent monitors systematically reviewed data entries for completeness and accuracy. Demographic, clinical, adverse event, and virologic data were collected every 12 weeks during treatment and during the follow-up period. The primary efficacy endpoint was sustained virologic response, defined as a level of HCV RNA below the lower limit of quantification or undetectable at a minimum 64 days after the end of treatment (SVR12). The per-protocol population (n = 610) was restricted to patients who completed 12 or 24 weeks of treatment (±2 weeks) and had final virologic outcomes available. RESULTS:The per-protocol analysis revealed that 579 patients (93.8%) achieved an SVR12, including 50/51 patients who received ledipasvir and sofosbuvir for 12 weeks (98%), 384/408 patients who received ledipasvir and sofosbuvir for 24 weeks (94.1%), 68/70 patients who received ledipasvir and sofosbuvir with ribavirin for 12 weeks (97.1%), and 57/60 patients who received ledipasvir and sofosbuvir with ribavirin for 24 weeks (95%). On multivariate analysis, neither treatment duration nor the addition of ribavirin was associated with SVR12. Compensated cirrhosis (odds ratio [OR] compared to decompensated cirrhosis, 2.41; 95% CI, 1.16-5.02), albumin ≥ 3.5 g/dL (OR, 3.15; 95% CI 1.46-6.80), or total bilirubin ≤ 1.2 mg/dL (OR 3.34; 95% CI, 1.59-7.00) were associated with SVR12. CONCLUSIONS:In an analysis of safety and effectiveness data from the HCV-TARGET study, we found treatment with ledipasvir and sofosbuvir, with or without ribavirin, to be effective and well tolerated by treatment-experienced patients with genotype 1 HCV infection and compensated cirrhosis. There were no significant differences in rate of SVR12 among patients treated with ledipasvir and sofosbuvir for 12 or 24 weeks, with or without ribavirin. Patients with decompensated cirrhosis appear to benefit from the addition of ribavirin or extension of ledipasvir and sofosbuvir treatment to 24 weeks. ClinicalTrials.gov no: NCT10474811.

Treatment of chronic hepatitis C virus (HCV) infection has been revolutionized with the development of direct-acting antiviral agents (DAAs). Eight to twelve weeks of all-oral, once-daily treatments is now the standard of care and viral eradication can be achieved in >95% across different patient populations. Despite these advances, several unresolved issues remain, including treatment of HCV genotype 3, chronic kidney disease, and in patients in whom DAA therapy has failed. Glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) are the most recently approved DAA regimens. Given the overwhelming success of modern DAA-based therapies, GLE/PIB and SOF/VEL/VOX are also likely to represent the last DAAs to be approved. Both are pangenotypic, once-daily, all-oral DAA combinations that have the potential to close the gaps in the current DAA treatment portfolio. Here, we review the challenges associated with current DAAs and how these two regimens may be implemented in existing treatment algorithms.

Chronic hepatitis B virus (HBV) remains a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Because chronic hepatitis B infection is rarely eradicated, preventing mother-to-child transmission (MTCT) is the most effective strategy to eliminate HBV globally. Although immunoprophylaxis strategy is widely available and effective for infants born to mothers with chronic hepatitis B infection, postnatal immunoprophylaxis fails in approximately 5-10 % of infants, and this failure rate goes up to 30 % in infants born to highly viremic mothers. Mothers with HBV DNA levels above 200,000 IU/mL should be managed aggressively with antiviral therapy because viral load is the strongest independent risk factor for immunoprophylaxis failure. Emerging data suggest that initiation of antiviral therapy in late pregnancy in highly viremic mothers can prevent immunoprophylaxis failure in their infants. Reducing viral load to target levels below 200,000 IU/mL at delivery is a practical approach to control MTCT. This review focuses on viral factors in mothers associated with MTCT.