Safety and Pharmacokinetics of Glecaprevir/Pibrentasvir in Adults With Chronic Genotype 1-6 Hepatitis C Virus Infections and Compensated Liver Disease.

BACKGROUND: Untreated, chronic hepatitis C virus (HCV) infection may lead to progressive liver damage, which can be mitigated by successful treatment. This integrated analysis reports the safety, efficacy, and pharmacokinetics (PK) of the ribavirin-free, direct-acting, antiviral, fixed-dose combination of glecaprevir/pibrentasvir (G/P) in patients with chronic HCV genotype 1-6 infections and compensated liver disease, including patients with chronic kidney disease stages 4 or 5 (CKD 4/5). METHODS: Data from 9 Phase II and III clinical trials, assessing the efficacy and safety of G/P treatment for 8-16 weeks, were included. The presence of cirrhosis was determined at screening using a liver biopsy, transient elastography, or serum biomarkers. The objectives were to evaluate safety, the rate of sustained virologic response at post-treatment week 12 (SVR12), and steady-state PK by cirrhosis status. RESULTS: Among 2369 patients, 308 (13%) were Child-Pugh Class A, including 20 with CKD 4/5. Overall, <1% of patients experienced an adverse event (AE) that led to G/P discontinuation or G/P-related serious AEs (SAEs). The most common AEs were headache and fatigue, occurring at similar frequencies with and without cirrhosis. SAEs were more common in patients with CKD 4/5, but all were unrelated to G/P. There were no cases of drug-induced liver injury or clinically relevant hepatic decompensation. SVR12 rates were 96.4% (297/308) with compensated cirrhosis and 97.5% (2010/2061) without cirrhosis. PK analysis demonstrated a 2.2-fold increase in glecaprevir exposure, but not pibrentasvir exposure, in patients with compensated cirrhosis. CONCLUSIONS: G/P was safe and efficacious in patients with compensated liver disease, including those with CKD 4/5. CLINICAL TRIALS REGISTRATION: NCT02243280, NCT02243293, NCT02604017, NCT02640482, NCT02640157, NCT02636595, NCT02642432, NCT02651194, and NCT02446717.

Transient elastography to assess liver stiffness in patients with inflammatory bowel disease.

BACKGROUND: Liver injury during inflammatory bowel disease (IBD) is primarily diagnosed by liver biopsy, which has a small but serious risk of severe complications. The aim of this study was to assess liver stiffness, and subsequently the prevalence and associations of liver fibrosis in IBD patients with thiopurine therapy and other clinical factors, by using transient elastography (TE). METHODS: In this prospective, international two-center study, included IBD-patients underwent TE measurements. Laboratory results and medication reports, radiology results and historical liver biopsy results were extracted from the patient charts. RESULTS: Transient elastography results of 168 patients were presented. Moderate and severe fibrosis were detected in 4% (7/168) and 1% (1/168) of the cohort, respectively. Factors contributing to lower liver stiffness were female gender and (historical) exposure to azathioprine. Further, there was a statistical trend towards lower liver stiffness in patients using thiopurines overall (4.7 vs. 5.2kPa, p=0.07). Liver stiffness correlated positively with waist circumference, liver enzyme tests, hemoglobin and 6-methylmercaptopurine concentration and negatively with platelet count. CONCLUSION: Exposure to thiopurine therapy was not associated with higher liver stiffness, although no clinical difference in severity of fibrosis was detected. Further research should robustly determine the accuracy of TE as an evaluation of liver fibrosis in IBD patients.

Impact of improved treatment on disease burden of chronic hepatitis C in New Zealand.

BACKGROUND: We describe the burden of HCV infection and estimate the effect of four different treatment strategies to reduce HCV-related morbidity and mortality. METHODS: Baseline model parameters were based upon literature review and expert consensus, focusing on New Zealand data. Four scenarios were modelled: Scenario 1 estimated the impact of increased treatment efficacy, while Scenario 2 estimated the effect of increased treatment efficacy and gradual increases in numbers treated. Scenarios 3 and 4 estimated the impact of deferred introduction of new DAAs for either 1 or 2 years. RESULTS: Prevalence of HCV infection peaked in 2010 (50,480 cases). Peak prevalence of cirrhosis and HCC will occur after 2030. Scenario 2 resulted in sizeable decreases in HCV-related morbidity and mortality. The impact of Scenario 1 was smaller. Deferring funding for new DAA treatments for a further 1 or 2 years resulted in an 18-36% increase in liver-related deaths in 2030. CONCLUSIONS: While prevalence of chronic HCV infection may have peaked, disease burden continues to grow. Increased treatment uptake and efficacy combined with efforts to reduce disease transmission, will help prevent advanced liver disease and deaths.

Mortality and the risk of malignancy in autoimmune liver diseases: a population-based study in Canterbury, New Zealand.

UNLABELLED: Population-based quantitative data on the mortality and cancer incidence of autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC) are scarce. Our aim was to systematically investigate the survival and risk of malignancy on population-based cohorts of AIH, PBC, and PSC in Canterbury, New Zealand. Multiple case-finding methods were employed, including searches of all public and private, adult and pediatric outpatient clinics, hospital notes, laboratory, radiology, and pathology reports. Cases that fulfilled standardized diagnostic criteria were included. Kaplan-Meier survival estimates, standardized mortality ratios (SMR), and standard incidence ratios (SIR) for malignancy were calculated. A total of 130 AIH, 70 PBC, and 81 PSC patients were included contributing to 1,156, 625, and 613 person-years at risk, respectively. For AIH, PBC, and PSC cohorts, SMRs for all-cause mortality were 2.1 (95% confidence interval [CI] 1.4-3.1), 2.7 (95% CI 1.7-4.0), and 4.1 (95% CI 2.6-6.3), SMRs for hepatobiliary mortality were 42.3 (95% CI 20.3-77.9), 71.2 (95% CI 30.7-140.3), and 116.9 (95% CI 66.8-189.8), SIRs for all cancers were 3.0 (95% CI 2.0-4.3), 1.6 (95% CI 0.8-2.9), and 5.2 (95% CI 3.3-7.8), and SIRs for extrahepatic malignancy were 2.7 (95% CI 1.8-3.9), 1.6 (95% CI 0.8-2.9), and 3.0 (95% CI 1.6-5.1), respectively. CONCLUSION: This is the first population-based study to examine and compare the survival and cancer incidence in AIH, PBC, and PSC in the same population. The mortality for all three cohorts was significantly increased due to liver-related death, demonstrating the inadequacy of current management strategies. The risk of hepatic and extrahepatic malignancy was significantly increased in AIH and PSC patients.

Inflammatory bowel disease is associated with poor outcomes of patients with primary sclerosing cholangitis.

BACKGROUND & AIMS: Little is known about the exact etiology of primary sclerosing cholangitis (PSC); epidemiologic data are scarce. We performed a population-based epidemiologic study of PSC in Canterbury, New Zealand. METHODS: By using multiple case-finding methods, we searched public and private adult and pediatric outpatient clinics, hospital discharge summaries, and radiology and pathology reports to identify all cases of PSC in the region. Cases were included if PSC was identified by endoscopic retrograde cholangiography, magnetic resonance cholangiography, or liver biopsy analysis (n = 79). RESULTS: The incidence of PSC in 2008 was 1.6 per 100,000 persons (95% confidence interval [CI], 0.5-2.7). The point prevalence on December 31, 2008, was 11.7 per 100,000 persons (95% CI, 8.7-14.8). The mean and median ages at diagnosis were 50 years (95% CI, 46-53 years) and 49 years (range, 17-80 years), respectively. Patients who had inflammatory bowel disease (IBD) presented with PSC earlier than those without IBD (P = .003), were more likely to develop serious malignant complications (P = .017), and were more likely to require liver transplantation or die (P = .03). CONCLUSIONS: In a population-based epidemiology study of PSC in Canterbury, New Zealand, we observed large differences between PSC patients with or without concurrent IBD in age at diagnosis, development of cancer, mortality, and requirement for liver transplantation. IBD therefore affects outcomes of patients with PSC, an important observation that requires further study.

Allopurinol might improve response to azathioprine and 6-mercaptopurine by correcting an unfavorable metabolite ratio.

BACKGROUND AND AIM: Allopurinol potentiates azathioprine and 6-mercaptopurine (6-MP) by increasing 6-thioguanine nucleotide (6-TGN) metabolite concentrations. The outcome might also be improved by adding allopurinol in individuals who preferentially produce 6-methylmercaptopurine nucleotides (6-MMPN), rather than 6-TGN. The aim of the present study was to investigate the effect of allopurinol on concentrations of 6-MMPN and 6-TGN in individuals with a high ratio of these metabolites (>20), which is indicative of a poor thiopurine response. METHODS: Sixteen individuals were identified who were taking azathioprine or 6-MP, and were commenced on allopurinol to improve a high 6-MMPN:TGN ratio. Metabolite concentrations were compared before and after commencing allopurinol, and markers of disease control were compared. RESULTS: The addition of 100-300 mg allopurinol daily and thiopurine dose reduction (17-50% of the original dose) resulted in a reduction of the median (and range) 6-MMPN concentration, from 11,643 (3,365-27,832) to 221 (55-844) pmol/8×10(8) red blood cells (RBC; P=0.0005), increased 6-TGN from 162 (125-300) to 332 (135-923) pmol/8×10(8) RBC (P=0.0005), and reduced the 6-MMPN:6-TGN ratio from 63 (12-199) to 1 (0.1-4.5) (P=0.0005). There was a significant reduction in steroid dose requirements at 12 months (P=0.04) and trends for improvement in other markers of disease control. One patient developed red cell aplasia that resolved upon stopping azathioprine and allopurinol. CONCLUSIONS: In those with a high 6-MMPN:6-TGN ratio (>20), response to thiopurine treatment might be improved by the addition of allopurinol, together with a reduced thiopurine dose and close hematological monitoring.

Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury.

Cholestasis is associated with accumulation of bile acids and lipids, and liver injury. The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic nuclear receptors that coordinate protective hepatic responses to potentially toxic stimuli, including bile acids. We investigated the role of these receptors in the regulation of bile acid and lipid metabolism in a bile duct ligation (BDL) model of cholestasis applied to receptor knockout mice. Hepatic damage from bile acid accumulation was increased in both CAR knockout (CARKO) and PXR knockout mice, but bile acid concentrations were lower in CARKO mice. High-density lipoprotein (HDL) cholesterol was elevated in CARKO mice, and serum total cholesterol increased less in CARKO or PXR knockout mice than WT mice after BDL. Gene expression analysis of the BDL knockout animals demonstrated that, in response to cholestasis, PXR and CAR both repressed and induced the specific hepatic membrane transporters Oatp-c (organic anion transporting polypeptide C) and Oatp2 (Na+-dependent organic anion transporter 2), respectively. Induction of the xenobiotic transporter multidrug resistance protein 1 in cholestasis was independent of either PXR or CAR, in contrast to the known pattern of induction of multidrug resistance protein 1 by xenobiotics. These results demonstrate that CAR and PXR influence cholesterol metabolism and bile acid synthesis, as well as multiple detoxification pathways, and suggest their potential role as therapeutic targets for the treatment of cholestasis and lipid disorders.

Feed-forward regulation of bile acid detoxification by CYP3A4: studies in humanized transgenic mice.

Bile acids are potentially toxic end products of cholesterol metabolism and their concentrations must be tightly regulated. Homeostasis is maintained by both feed-forward regulation and feedback regulation. We used humanized transgenic mice incorporating 13 kb of the 5' regulatory flanking sequence of CYP3A4 linked to a lacZ reporter gene to explore the in vivo relationship between bile acids and physiological adaptive CYP3A gene regulation in acute cholestasis after bile duct ligation (BDL). Male transgenic mice were subjected to BDL or sham surgery prior to sacrifice on days 3, 6, and 10, and others were injected with intraperitoneal lithocholic acid (LCA) or vehicle alone. BDL resulted in marked hepatic activation of the CYP3A4/lacZ transgene in pericentral hepatocytes, with an 80-fold increase in transgene activation by day 10. Individual bile acids were quantified by liquid chromatography/mass spectrometry. Serum 6beta-hydroxylated bile acids were increased following BDL, confirming the physiological relevance of endogenous Cyp3a induction to bile acid detoxification. Although concentrations of conjugated primary bile acids increased after BDL, there was no increase in LCA, a putative PXR ligand, indicating that this cannot be the only endogenous bile acid mediating this protective response. Moreover, in LCA-treated animals, 5-bromo-4-chloro-3-indolyl-beta-d-galactopyranoside staining showed hepatic activation of the CYP3A4 transgene only on the liver capsular surface, and minimal parenchymal induction, despite significant liver injury. This study demonstrates that CYP3A up-regulation is a significant in vivo adaptive response to cholestasis. However, this up-regulation is not dependent on increases in circulating LCA and the role of other bile acids as regulatory molecules requires further exploration.