Hepatitis C Virus Antiviral Drug Resistance and Salvage Therapy Outcomes Across Australia.

Background: Hepatitis C virus (HCV) infection can now be cured with well-tolerated direct-acting antiviral (DAA) therapy. However, a potential barrier to HCV elimination is the emergence of resistance-associated substitutions (RASs) that reduce the efficacy of antiviral drugs, but real-world studies assessing the clinical impact of RASs are limited. Here, an analysis of the impact of RASs on retreatment outcomes for different salvage regimens in patients nationally who failed first-line DAA therapy is reported. Methods: We collected data from 363 Australian patients who failed first-line DAA therapy, including: age, sex, fibrosis stage, HCV genotype, NS3/NS5A/NS5B RASs, details of failed first-line regimen, subsequent salvage regimens, and treatment outcome. Results: Of 240 patients who were initially retreated as per protocol, 210 (87.5%) achieved sustained virologic response (SVR) and 30 (12.5%) relapsed or did not respond. The SVR rate for salvage regimens that included sofosbuvir/velpatasvir/voxilaprevir was 94.3% (n = 140), sofosbuvir/velpatasvir 75.0% (n = 52), elbasvir/grazoprevir 81.6% (n = 38), and glecaprevir/pibrentasvir 84.6% (n = 13). NS5A RASs were present in 71.0% (n = 210) of patients who achieved SVR and in 66.7% (n = 30) of patients who subsequently relapsed. NS3 RASs were detected in 20 patients (20%) in the SVR group and 1 patient in the relapse group. NS5B RASs were observed in only 3 patients. Cirrhosis was a predictor of relapse after retreatment, as was previous treatment with sofosbuvir/velpatasvir. Conclusions: In our cohort, the SVR rate for sofosbuvir/velpatasvir/voxilaprevir was higher than with other salvage regimens. The presence of NS5A, NS5B, or NS3 RASs did not appear to negatively influence retreatment outcomes.

Inflammatory Bowel Disease Environmental Risk Factors: A Population-Based Case-Control Study of Middle Eastern Migration to Australia.

BACKGROUND & AIMS: The incidences of the inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis (UC) are increasing, indicating gene-environment interactions. Migrants from low-IBD-prevalence countries to a high-prevalence country may help identify the relative contribution of environmental risk factors compared with native Caucasians. METHODS: This prospective case-control study evaluated IBD environmental risk factors of Middle Eastern migrants (MEM) in Australia compared with matched Caucasian IBD subjects, MEM controls, Caucasian controls, and controls in the Middle East using adjusted odds ratios (aOR). RESULTS: A total of 795 subjects were recruited: 154 MEM cases (75 CD; 79 UC), 153 MEM controls, 162 Caucasian cases (85 CD; 77 UC), 173 Caucasian controls, and 153 controls in Lebanon. Smoking increased CD risk in MEM and Caucasians and reduced UC risk in Caucasians (aOR, 0.77; 95% CI, 0.41-0.98) but not MEM (aOR, 1.45; 95% CI, 0.80-2.62). Antibiotic use reduced the risk of MEM CD (aOR, 0.27; 95% CI, 0.11-0.67) and UC (aOR, 0.38; 95% CI, 0.18-0.80), but increased the risk in Caucasians (CD: aOR, 5.24; 95% CI, 2.13-12.90; and UC: aOR, 6.82; 95% CI, 2.67-17.38). Most hygiene markers (rural dwelling, pet ownership, pet feeding, and farm animal contact) reduced CD and UC risk in MEM (P < .05). In contrast, in Caucasians these hygiene markers lacked significance. Other significant risk factors include IBD family history, appendectomy, tonsillectomy, and breastfeeding. CONCLUSIONS: Differential IBD environmental risk factors exist between migrants and native Caucasians, indicating a dynamic interplay between environmental factors and IBD risk for immigrants that is distinct to those factors most relevant in native Caucasians.

Non-invasive estimation of liver fibrosis in non-alcoholic fatty liver disease using the 13 C-caffeine breath test.

BACKGROUND AND AIM: Fibrotic progression in non-alcoholic fatty liver disease (NAFLD) is associated with impaired hepatic function. The (13) C-caffeine breath test (CBT) is a non-invasive, quantitative test of liver function. We sought to determine the utility of the CBT in detecting hepatic fibrosis in NAFLD. METHODS: The CBT was applied to 48 patients with NAFLD. CBT results were compared to clinical, biochemical and histological data. Twenty-four healthy subjects served as controls. RESULTS: Patients with simple steatosis had similar CBT values (2.28 ± 0.71 Δ‰ per 100 mg caffeine) to controls (2.31 ± 0.85, P = 1.0). However, CBT was significantly reduced in patients with non-alcoholic steatohepatitis (1.59 ± 0.65, P = 0.005) and cirrhosis (1.00 ± 0.73, P < 0.001). CBT significantly correlated with Brunt's fibrosis score (r = -0.49, P < 0.001) but not with steatosis (P = 0.23) or inflammation (P = 0.08). CBT also correlated with international normalized ratio (r = -0.61, P < 0.001), albumin (r = 0.37, P = 0.009), aspartate aminotransferase/alanine aminotransferase (r = -0.34, P = 0.018) and platelets (r = 0.31, P = 0.03). On multivariate analysis, age (odds ratio 1.12, 95% confidence interval 1.042-1.203, P = 0.002) and CBT (OR 0.264, 95% CI 0.084-0.822, P = 0.02) were independent predictors of significant fibrosis (F ≥ 2). CBT yielded an area under the receiver operating characteristic curve of 0.86 for the diagnosis of cirrhosis. CONCLUSIONS: The CBT reflects the extent of hepatic fibrosis in NAFLD and represents a non-invasive predictor of fibrosis severity in this condition.

Validity of the 13C-caffeine breath test as a noninvasive, quantitative test of liver function.

The properties of caffeine render it an ideal substrate for a quantitative test of liver function. The aim of this study was to determine whether the caffeine breath test (CBT) using orally administered 13C-caffeine correlates reliably with plasma caffeine clearance and reflects varying degrees of liver dysfunction. The CBT was performed in 25 healthy controls; 20 subjects with noncirrhotic, chronic hepatitis B or C; and 20 subjects with cirrhosis. Plasma caffeine clearance was assayed simultaneously with the CBT in a cohort of these subjects. Over a broad range of caffeine clearances, the CBT exhibited a highly significant correlation with plasma clearance (r = 0.85, P <.001). Cirrhotic patients were characterized by significantly reduced CBT values (1.15 +/- 0.75 delta per thousand mg(-1)) compared with controls (2.23 +/- 0.76; P =.001) and hepatitic patients (1.83 +/- 1.05; P =.04). There was a significant inverse relationship between the CBT and Child-Pugh score (r = -.74, P =.002). The intraclass correlation coefficient between repeated CBTs in 20 subjects with normal and cirrhotic livers was 0.89. Although smoking was associated with an 86% to 141% increase in CBT in all groups, the CBT was able to distinguish control, hepatitic, and cirrhotic smokers (5.36 +/- 0.82, 3.63 +/- 1.21, and 2.14 +/- 1.14, respectively, P =.001). Multivariate analysis revealed that only smoking (P <.001) and disease state (P =.001) were significant predictors of the CBT. In conclusion, the 13C-CBT represents a valid indicator of plasma caffeine clearance and correlates reproducibly with hepatic dysfunction.