James F. Trotter, M.D.

Fallahzadeh, M. A. and J. F. Trotter (2020). “An Experiment of Nature: HBV-naive Recipients Receiving Liver Grafts With HBV Core Antibody-positive Donors Without Antiviral Prophylaxis.” Transplantation 104(8): e245-e246.

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Transplantation of livers from donors who are hepatitis B core antibody (HBcAb) positive and hepatitis B surface antigen (HBsAg) negative is a standard practice occurring in about 5% of the US liver transplants (LTs).1,2 Current guidelines recommend lifelong oral antiviral prophylaxis to prevent viral reactivation reported in up to 78% of untreated recipients.1,3 We report a series of HBsAg-negative LT recipients who received an organ from HBcAb-positive donors without receiving antiviral prophylaxis through an administrative error. [No abstract; excerpt from article].

Asrani, S. K., L. W. Jennings, W. R. Kim, P. S. Kamath, J. Levitsky, M. K. Nadim, G. Testa, M. D. Leise, J. F. Trotter and G. Klintmalm (2020). “MELD-GRAIL-Na: Glomerular Filtration Rate and Mortality on Liver-Transplant Waiting List.” Hepatology 71(5): 1766-1774.

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BACKGROUND AND AIMS: Among patients with cirrhosis awaiting liver transplantation, prediction of wait-list (WL) mortality is adjudicated by the Model for End Stage Liver Disease-Sodium (MELD-Na) score. Replacing serum creatinine (SCr) with estimated glomerular filtration rate (eGFR) in the MELD-Na score may improve prediction of WL mortality, especially for women and highest disease severity. APPROACH AND RESULTS: We developed (2014) and validated (2015) a model incorporating eGFR using national data (n = 17,095) to predict WL mortality. Glomerular filtration rate (GFR) was estimated using the GFR assessment in liver disease (GRAIL) developed among patients with cirrhosis. Multivariate Cox proportional hazard analysis models were used to compare the predicted 90-day WL mortality between MELD-GRAIL-Na (re-estimated bilirubin, international normalized ratio [INR], sodium, and GRAIL) versus MELD-Na. Within 3 months, 27.8% were transplanted, 4.3% died on the WL, and 4.7% were delisted for other reasons. GFR as estimated by GRAIL (hazard ratio [HR] 0.382, 95% confidence interval [CI] 0.344-0.424) and the re-estimated model MELD-GRAIL-Na (HR 1.212, 95% CI 1.199-1.224) were significant predictors of mortality or being delisted on the WL within 3 months. MELD-GRAIL-Na was a better predictor of observed mortality at highest deciles of disease severity (>/= 27-40). For a score of 32 or higher (observed mortality 0.68), predicted mortality was 0.67 (MELD-GRAIL-Na) and 0.51 (MELD-Na). For women, a score of 32 or higher (observed mortality 0.67), the predicted mortality was 0.69 (MELD-GRAIL-Na) and 0.55 (MELD-Na). In 2015, use of MELD-GRAIL-Na as compared with MELD-Na resulted in reclassification of 16.7% (n = 672) of patients on the WL. CONCLUSION: Incorporation of eGFR likely captures true GFR better than SCr, especially among women. Incorporation of MELD-GRAIL-Na instead of MELD-Na may affect outcomes for 12%-17% awaiting transplant and affect organ allocation.

Kowdley, K. V., R. Vuppalanchi, C. Levy, A. Floreani, P. Andreone, N. F. LaRusso, R. Shrestha, J. Trotter, D. Goldberg, S. Rushbrook, G. M. Hirschfield, T. Schiano, Y. Jin, R. Pencek, L. MacConell, D. Shapiro and C. L. Bowlus (2020). “A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis.” J Hepatol Mar 9. pii: S0168-8278(20)30160-4. [Epub ahead of print].

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BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC. METHODS: AESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) >/=2xULN and total bilirubin <2.5xULN. Patients were randomized 1:1:1 to receive placebo, OCA 1.5-3 mg, or OCA 5-10 mg once daily for a 24-week double-blind phase followed by a 2-year, long-term safety extension (LTSE). Primary endpoints were change in ALP from baseline to week 24, and safety. RESULTS: The intent-to-treat population comprised 76 patients randomized to placebo (n=25), OCA 1.5-3 mg (n=25), and OCA 5-10 mg (n=26). At week 24, serum ALP was significantly reduced with OCA 5-10 mg vs. placebo: least-square (LS) mean difference = 83.4 (standard error [SE]=40.3) U/L, 95% CI: -164.28, -2.57; p=0.043. Serum ALP was not significantly reduced with OCA 1.5-3 mg vs. placebo at week 24 (LS mean [SE] difference = -78.29 [41.81] U/L, 95% CI: -162.08, 5.50; p=0.067). Total bilirubin remained comparable to baseline in all groups. The most common treatment-emergent adverse event was dose-related pruritus (placebo, 46%; OCA 1.5-3 mg, 60%; OCA 5-10 mg, 67%). Reductions in ALP were maintained during the LTSE, and no new safety signals emerged. CONCLUSIONS: Treatment with OCA 5-10 mg reduced serum ALP in patients with PSC. Mild to moderate dose-related pruritus was the most common adverse event.

Asrani, S. K., J. Trotter, J. Lake, A. Ahmed, A. Bonagura, A. Cameron, A. DiMartini, S. Gonzalez, G. Im, P. Martin, P. Mathurin, J. Mellinger, J. P. Rice, V. H. Shah, N. Terrault, A. Wall, S. Winder and G. Klintmalm (2020). “Meeting Report: The Dallas Consensus Conference on Liver Transplantation for Alcohol Associated Hepatitis.” Liver Transpl 26(1): 127-140.

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Liver transplantation (LT) for alcohol associated hepatitis (AH) remains controversial. We convened a consensus conference to examine various aspects of LT for AH. The goal was not to unequivocally endorse LT for AH; instead, it was to propose recommendations for programs that perform or plan to perform LT for AH. Criteria were established to determine candidacy for LT in the setting of AH and included the following: (1) AH patients presenting for the first time with decompensated liver disease that are nonresponders to medical therapy without severe medical or psychiatric comorbidities; (2) a fixed period of abstinence prior to transplantation is not required; and (3) assessment with a multidisciplinary psychosocial team, including a social worker and an addiction specialist/mental health professional with addiction and transplantation expertise. Supporting factors included lack of repeated unsuccessful attempts at addiction rehabilitation, lack of other substance use/dependency, acceptance of diagnosis/insight with a commitment of the patient/family to sobriety, and formalized agreement to adhere to total alcohol abstinence and counseling. LT should be avoided in AH patients who are likely to spontaneously recover. Short-term and longterm survival comparable to other indications for LT must be achieved. There should not be further disparity in LT either by indication, geography, or other sociodemographic factors. Treatment of alcohol-use disorders should be incorporated into pre- and post-LT care. The restrictive and focused evaluation process described in the initial LT experience for AH worldwide may not endure as this indication gains wider acceptance at more LT programs. Transparency in the selection process is crucial and requires the collection of objective data to assess outcomes and minimize center variation in listing. Oversight of program adherence is important to harmonize listing practices and outcomes.

Younossi, Z. M., V. Ratziu, R. Loomba, M. Rinella, Q. M. Anstee, Z. Goodman, P. Bedossa, A. Geier, S. Beckebaum, P. N. Newsome, D. Sheridan, M. Y. Sheikh, J. Trotter [ . . . ] and A. J. Sanyal (2019). “Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.” Lancet 394(10215): 2184-2196.

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BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. METHODS: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (>/=1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. FINDINGS: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0.045), and 71 (23%) in the obeticholic acid 25 mg group (p=0.0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0.18], and 36 [12%] in the obeticholic acid 25 mg group [p=0.13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). INTERPRETATION: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes. FUNDING: Intercept Pharmaceuticals.