Richard Gilroy

Sofosbuvir and Ribavirin for Treatment of Compensated Recurrent Hepatitis C Virus Infection After Liver Transplantation

BACKGROUND & AIMS Interferon alfa-based regimens used to treat recurrent hepatitis C virus (HCV) infection after liver transplantation are poorly tolerated, associated with generally modest efficacy, and can interact with immunosuppressive agents. We evaluated the efficacy and safety of an interferon-free regimen of the nucleotide polymerase inhibitor sofosbuvir combined with ribavirin for 24 weeks in treating post-transplantation HCV infection. METHODS In a prospective, multicenter, open-label pilot study, we enrolled patients with compensated recurrent HCV infection of any genotype after a primary or secondary liver transplantation. All patients received 24 weeks of sofosbuvir 400 mg daily and ribavirin starting at 400 mg daily, which was adjusted according to creatinine clearance and hemoglobin values. The primary end point was sustained virologic response 12 weeks after treatment. RESULTS Of the 40 patients enrolled and treated, 78% were male, 85% were white, 83% had HCV genotype 1, 40% had cirrhosis (based on biopsy), and 88% had been previously treated with interferon. Sustained virologic response 12 weeks after treatment was achieved by 28 of 40 patients (70%; 90% confidence interval: 56%-82%). Relapse accounted for all cases of virologic failure. No patients had detectable viral resistance during or after treatment. The most common adverse events were fatigue (30%), diarrhea (28%), and headache (25%). In addition, 20% of the subjects experienced anemia. Two patients discontinued study treatment because of adverse events, which were considered unrelated to study treatment. No deaths, graft losses, or episodes of rejection occurred. No interactions with any concomitant immunosuppressive agents were reported. CONCLUSIONS Sofosbuvir and ribavirin combination therapy for 24 weeks is an effective and well-tolerated interferon-free treatment for post-transplantation HCV infection. EudraCT, Number: 2012-002417-19; ClinicalTrials.gov, Number: NCT01687270.

Randomised placebo-controlled trial of teduglutide in reducing parenteral nutrition and/or intravenous fluid requirements in patients with short bowel syndrome

Background and aims Teduglutide, a GLP-2 analogue, may restore intestinal structural and functional integrity by promoting repair and growth of the mucosa and reducing gastric emptying and secretion, thereby increasing fluid and nutrient absorption in patients with short bowel syndrome (SBS). This 24-week placebo-controlled study evaluated the ability of teduglutide to reduce parenteral support in patients with SBS with intestinal failure. Methods In 83 patients randomised to receive subcutaneous teduglutide 0.10 mg/kg/day (n=32), 0.05 mg/kg/day (n=35) or placebo (n=16) once daily, parenteral fluids were reduced at 4-week intervals if intestinal fluid absorption (48 h urine volumes) increased ≥10%. Responders were subjects who demonstrated reductions of ≥20% in parenteral volumes from baseline at weeks 20 and 24. The primary efficacy end point, a graded response score (GRS), took into account higher levels and earlier onset of response, leading to longer duration of response. The intensity of the response was defined as a reduction from baseline in parenteral volume (from 20% to 100%), and the duration of the response was considered the response at weeks 16, 20 and 24. The results were tested according to a step-down procedure starting with the 0.10 mg/kg/day dose. Results Using the GRS criteria, teduglutide in a dose of 0.10 mg/kg/day did not have a statistically significant effect compared with placebo (8/32 vs 1/16, p=0.16), while teduglutide in a dose of 0.05 mg/kg/day had a significant effect (16/35, p=0.007). Since parenteral volume reductions were equal (353±475 and 354±334 ml/day), the trend towards higher baseline parenteral volume (1816±1008 vs 1374±639 ml/day, p=0.11) in the 0.10 mg/kg/day group compared with the 0.05 mg/kg/day group may have accounted for this discrepancy. Three teduglutide-treated patients were completely weaned off parenteral support. Serious adverse events were distributed similarly between active treatment groups and placebo. Villus height, plasma citrulline concentration and lean body mass were significantly increased with teduglutide compared with placebo. Conclusions Teduglutide was safe, well tolerated, intestinotrophic and suggested pro-absorptive effects facilitating reductions in parenteral support in patients with SBS with intestinal failure. ClinicalTrials.gov number NCT00172185.

Safety and Efficacy of Teduglutide After 52 Weeks of Treatment in Patients With Short Bowel Intestinal Failure

BACKGROUND & AIMS Although home parenteral nutrition (PN) can save the lives of patients with massive bowel loss that results in short-bowel syndrome and intestinal failure, quality of life is impaired by PN and its complications. We examined the 12-month tolerability and efficacy of teduglutide to reduce PN dependency. METHODS Patients who received teduglutide (0.05 or 0.10 mg/kg/d) for 24 weeks in a randomized controlled trial were eligible for a 28-week double-blind extension study; 52 patients were given 52 weeks of the same doses of teduglutide. We investigated the safety, tolerability, and clinical efficacy (defined as a clinically meaningful ≥20% reduction in weekly PN volume from baseline) at week 52. RESULTS The most common adverse events reported included headache (35%), nausea (31%), and abdominal pain (25%); 7 patients withdrew because of adverse events (gastrointestinal disorders in 4). Both groups had progressive reduction in PN. At week 52, 68% of the 0.05-mg/kg/d and 52% of the 0.10-mg/kg/d dose group had a ≥20% reduction in PN, with a reduction of 1 or more days of PN dependency in 68% and 37%, respectively. Four patients achieved complete independence from PN. CONCLUSIONS For patients with short-bowel syndrome intestinal failure, the efficacy of teduglutide was maintained over 52 weeks and the safety profile was sufficient for it to be considered for long-term use. Further studies are needed to determine whether these effects will translate into improved quality of life and reduced PN complications. ClinicalTrials.gov number, NCT00172185.

Nrf2 Inhibits LXRα-Dependent Hepatic Lipogenesis by Competing with FXR for Acetylase Binding

AIMS The nuclear receptor liver X receptor-α (LXRα) stimulates lipogenesis, leading to steatosis. Nuclear factor erythroid-2-related factor-2 (Nrf2) contributes to cellular defense mechanism by upregulating antioxidant genes, and may protect the liver from injury inflicted by fat accumulation. However, whether Nrf2 affects LXRα activity is unknown. This study investigated the inhibitory role of Nrf2 in hepatic LXRα activity and the molecular basis. RESULTS A deficiency of Nrf2 enhanced the ability of LXRα agonist to promote hepatic steatosis, as mediated by lipogenic gene induction. In hepatocytes, Nrf2 overexpression repressed gene transactivation by LXR-binding site activation. Consistently, treatment of mice with sulforaphane (an Nrf2 activator) suppressed T0901317-induced lipogenesis, as confirmed by the experiments using hepatocytes. Nrf2 activation promoted deacetylation of farnesoid X receptor (FXR) by competing for p300, leading to FXR-dependent induction of small heterodimer partner (SHP), which was responsible for the repression of LXRα-dependent gene transcription. In human steatotic samples, the transcript levels of LXRα and SREBP-1 inversely correlated with those of Nrf2, FXR, and SHP. INNOVATION Our findings offer the mechanism to explain how decrease in Nrf2 activity in hepatic steatosis could contribute to the progression of NAFLD, providing the use of Nrf2 as a molecular biomarker to diagnose NAFLD. As certain antioxidants have the abilities to activate Nrf2, clinicians might utilize the activators of Nrf2 as a new therapeutic approach to prevent and/or treat NAFLD. CONCLUSION Nrf2 activation inhibits LXRα activity and LXRα-dependent liver steatosis by competing with FXR for p300, causing FXR activation and FXR-mediated SHP induction. Our findings provide important information on a strategy to prevent and/or treat steatosis.

Increasing the Number of Organ Transplants in the United States by Optimizing Donor Authorization Rates.

While recent policies have focused on allocating organs to patients most in need and lessening geographic disparities, the only mechanism to increase the actual number of transplants is to maximize the potential organ supply. We conducted a retrospective cohort study using OPTN data on all “eligible deaths” from 1/1/08 to 11/1/13 to evaluate variability in donor service area (DSA)‐level donor authorization rates, and to quantify the potential gains associated with increasing authorization rates. Despite adjustments for donor demographics (age, race/ethnicity, cause of death) and geographic factors (rural/urban status of donor hospital, statewide participation in deceased‐donor registries) among 52 571 eligible deaths, there was significant variability (p < 0.001) in donor authorization rates across the 58 DSAs. Overall DSA‐level adjusted authorization rates ranged from 63.5% to 89.5% (median: 72.7%). An additional 773–1623 eligible deaths could have been authorized, yielding 2679–5710 total organs, if the DSAs with authorization rates below the median and 75th percentile, respectively, implemented interventions to perform at the level of the corresponding reference DSA. Opportunities exist within the current organ acquisition framework to markedly improve DSA‐level donor authorization rates. Such initiatives would mitigate waitlist mortality while increasing the number of transplants.

Alteration of hepatic nuclear receptor‐mediated signaling pathways in hepatitis C virus patients with and without a history of alcohol drinking

The current study tests a hypothesis that nuclear receptor signaling is altered in chronic hepatitis C patients and that the altered pattern is specific to alcohol drinking history. The expression of a panel of more than 100 genes encoding nuclear receptors, coregulators, and their direct/indirect targets was studied in human livers. Gene expression pattern was compared between 15 normal donor livers and 23 hepatitis C virus (HCV) genotype 1–positive livers from patients without a drinking history (matched for age, sex, and body mass index). HCV infection increased the expression of nuclear receptors small heterodimer partner and constitutive androstane receptor (CAR) as well as genes involved in fatty acid trafficking, bile acid synthesis and uptake, and inflammatory response. However, the expression of retinoid X receptor (RXR) α, peroxisomal proliferator‐activated receptor (PPAR) α and β as well as steroid regulatory element‐binding protein (SREBP)‐1c was decreased in HCV‐infected livers. Gene expression pattern was compared in chronic hepatitis C patients with and without a drinking history. Alcohol drinking increased the expression of genes involved in fatty acid uptake, trafficking, and oxidation, but decreased the expression of genes responsible for gluconeogenesis. These changes were consistent with reduced fasting plasma glucose levels and altered expression of upstream regulators that include RXRα, PPARα, and CAR. The messenger RNA levels of fibroblast growth factor 21, interleukin‐10, and fatty acid synthase, which are all regulated by nuclear receptors, showed independent correlation with hepatic HCV RNA levels. Conclusion: Our findings suggest that those genes and pathways that showed altered expression could potentially be therapeutic targets for HCV infection and/or alcohol drinking‐induced liver injury. (HEPATOLOGY 2011)

Maintenance of parenteral nutrition volume reduction, without weight loss, after stopping teduglutide in a subset of patients with short bowel syndrome.

BACKGROUND Teduglutide was discontinued after being tested for ≥ 24 weeks in patients with parenteral nutrition (PN) -dependent short bowel syndrome in a clinical trial for efficacy to reduce PN volume. This study was describes change in body mass index (BMI) and PN volume over 12 months in patients who stopped drug after the clinical trial. METHODS Prescribed PN volume, weight, and complications were reported. Patients with stable (NEUT, n = 15) or decreased (DEC, n = 7) PN volume by 12 months after stopping drug (NEUT/DEC, n = 22) were compared to those who had increased PN volume (INC, n = 15). With drug response defined by ≥ 20% reduction from pre-drug PN volume to end of drug therapy, 12 INC and 13 NEUT/DEC patients were drug responders. RESULTS Eleven of 20 eligible sites reported data for 39 of 53 eligible study participants, with follow-up data for 37. INC patients had shorter colon and less frequently had colon in continuity than NEUT/DEC. BMI was decreased at 3, 6, and 12 months relative to the first off-drug visit in INC patients (P = .001), but not in NEUT/DEC patients. Change in BMI off-drug was predicted by colon and small bowel length, baseline BMI, and on-drug change in PN volume (adjusted R2 = 0.708). CONCLUSIONS Gastrointestinal anatomy, baseline BMI, and PN volume reduction on-drug predicted change in BMI off-drug. Whether this response would be maintained for a longer time or in the context of a challenging clinical situation has not been evaluated.

Donor PNPLA3 rs738409 genotype affects fibrosis progression in liver transplantation for hepatitis C

The rs738409 G>C single nucleotide polymorphism occurring in the patatin‐like phospholipase 3 gene has been identified as a novel genetic marker for hepatic steatosis. Recent studies also associated rs738409 with fibrosis in hepatitis C (HCV). Therefore, we sought to determine the impact of donor and recipient rs738409 genotype on the progression of fibrosis after liver transplantation for HCV. This cohort study included 101 patients infected with HCV who underwent liver transplantation between January 2008, and June 2011. Donor and recipient rs738409 genotypes were determined from donor wedge biopsies and recipient explants. The time to Ishak stage 3 fibrosis, or HCV‐related mortality/graft loss was analyzed by the Cox model adjusting for HCV‐Donor Risk Index, warm ischemic time, pretransplant Model for Endstage Liver Disease (MELD) and viral load. The rs738409 CC variant was present in 56% of donors and 57% of recipients. The median follow‐up period was 620 days. A total of 39 patients developed the primary outcome of ≥stage 3 fibrosis or HCV‐related mortality/graft loss, the time to which differed by donor (P = 0.019) but not recipient (P = 0.89) genotype. In the multivariate model, donor GC or GG variants had 2.53 times the risk (95% confidence interval [CI] 1.25‐5.02, P = 0.008) compared to CC variants. In the alternative endpoint: stage 3 fibrosis or all‐cause mortality/graft loss, the effect of donor genotype was attenuated but remained significant at 1.98 (95% CI 1.11‐3.53). Conclusions: The rs738409 genotype is an important predictor of posttransplant outcome in HCV. Liver, and not adipocytes, is the site at which this effect occurs. Our finding may be useful in donor selection for liver transplantation with HCV, and may guide decisions regarding early antiviral treatment. (Hepatology 2014;59:453–460)

Emergency department visits for gastrointestinal bleeding in children: Results from the Nationwide Emergency Department Sample 2006-2011

Abstract Objective: To describe the epidemiology and trends in pediatric gastrointestinal (GI) bleeding associated emergency department (ED) visits in the US. Methods: Estimates of GI bleeding associated ED visits were calculated in children from birth to 19 years of age using the Nationwide Emergency Department Sample (NEDS). Results: From 2006 to 2011, there were an estimated total of 437,283 ED visits associated with diagnosis of GI bleeding. Specifically, there were 88,675 cases of upper GI bleeding, 132,102 cases of lower GI bleeding and 217,008 cases of unspecified GI bleeding. GI bleeding associated ED visits increased from 82.2/100,000 children in 2006 to 93.9/100,000 children in 2011 (14.3% increase; P < 0.01). The rate of increase was chiefly noted for lower GI bleeding (31.3%) followed by unspecified GI bleeding (10.4%) with a relatively minor increase in upper GI bleeding (1.1%). The greatest number of visits occurred in children 15–19 years of age (39.2%). A majority of patients underwent routine discharge (80.8%). Risk factors independently associated with an increased rate of hospital admission included ≥3 comorbid conditions (adjusted odds ratio [aOR] 112.2; 95% CI 103.4–121.7), presentation to a teaching hospital (aOR 3.2; 95% CI 3.1–3.2), the presence of upper GI bleeding (aOR 3.1; 95% 3.0–3.2), health coverage with private insurance (aOR 1.6; 95% CI 1.6–1.7) and children <5 years of age (aOR 1.3; 95% CI 1.2–1.3). Conclusion: Our results indicate that there has been an increasing incidence of GI bleeding associated ED visits in children from 2006 to 2011 with cases of lower GI bleeding accounting for the largest increase. Only a small number of children merited admission to the hospital, suggesting that a majority of visits involved non-life-threatening bleeds. These data represent important complementary information to the overall study of pediatric GI bleeding in the US.

Regulation of the Human Hydroxysteroid Sulfotransferase (SULT2A1) by RORα and RORγ and Its Potential Relevance to Human Liver Diseases

The retinoid-related orphan receptors (RORs) were postulated to have functions in tissue development and circadian rhythm. In this study, we revealed a novel function of RORα (NR1F1) and RORγ (NR1F3) in regulating the human hydroxysteroid sulfotransferase (SULT2A1), a phase II conjugating enzyme known to sulfonate bile acids, hydroxysteroid dehydroepiandrosterone, and related androgens. A combination of promoter reporter gene assay and EMSA and chromatin immunoprecipitation (ChIP) assays showed that both RORα and RORγ transactivated the SULT2A1 gene promoter through their binding to a ROR response element found in the SULT2A1 gene promoter. Interestingly, this ROR response element overlaps with a previously reported constitutive androstane receptor response element on the same promoter. Down-regulation of RORα and/or RORγ by small interfering RNA inhibited the expression of endogenous SULT2A1. In primary human hepatocytes and human livers, we found a positive correlation between the expression of SULT2A1 and RORs, which further supported the regulation of SULT2A1 by RORs. We also found that the expression of RORα and RORγ was impaired in several liver disease conditions, such as steatosis/steatohepatitis, fibrosis, and hepatocellular carcinoma. The positive regulation of human SULT2A1 by RORs is opposite to the negative regulation of Sult2a1 by RORs in rodents. In summary, our results established SULT2A1 as a novel ROR target gene. The expression of RORs is a potential predictor for the expression of SULT2A1 as well as disease conditions.