James F. Trotter, M.D.

Modi, A. A., H. Nazario, J. F. Trotter, M. Gautam, J. Weinstein, P. Mantry, M. Barnes, A. Habib, J. McAfee, O. Teachenor, L. Tujague and S. Gonzalez (2016). “Safety and efficacy of simeprevir plus sofosbuvir with or without ribavirin in patients with decompensated genotype 1 hepatitis C cirrhosis.” Liver Transpl 22(3): 281-286

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Combination antiviral therapy involving sofosbuvir (SOF) and simeprevir (SIM) is a treatment option in patients with genotype 1 chronic hepatitis C; however, the safety of this regimen in patients with decompensated cirrhosis is not established. Data from a combined treatment cohort of 2 large hepatology referral centers were evaluated to assess for safety and efficacy of SIM plus SOF with or without ribavirin (RBV) in patients with Child B or C cirrhosis. All (n = 42) patients included in the analysis had Child B (n = 35) or C (n = 7) cirrhosis and received 400 mg daily of SOF plus 150 mg daily of SIM, with (n = 7) or without (n = 35) RBV, for 12 weeks. Of the 42 patients in this cohort, 31 (74%) were male, 22 (52%) had failed prior treatments, and 28 (67%) were genotype 1a. Prior decompensating events included encephalopathy (57%), fluid overload (88%), or variceal hemorrhage (24%). Median Model for End-Stage Liver Disease score was 12 (range, 6-25). Treatment was well tolerated overall with more than one-half (57%) reporting no adverse events. In those reporting adverse events, the most common were fatigue (n = 6), insomnia (n = 4), headache (n = 5), nausea (n = 4), and grade 1 rash (n = 1). One patient developed chemical pancreatitis that did not require treatment discontinuation. Three of 7 patients who received RBV developed anemia, with 2 requiring blood transfusions and 1 requiring a dose reduction. No episodes of decompensation requiring hospitalization or deaths occurred on treatment. Of 42 patients, 38 (90%) patients had negative viral load at end of treatment (EOT), and 31 of 42 patients (74%) achieved sustained virological response 12 weeks after EOT; 10 of 10 patients (100%) with HCV genotype 1b achieved sustained virological response for 12 weeks (SVR12). In conclusion, SOF plus SIM was very well tolerated in patients with advanced Child B/C decompensated cirrhosis. Overall, 74% of patients achieved SVR12; 100% of patients with genotype 1b decompensated cirrhosis achieved SVR12.

Loomba, R., R. Mohseni, K. J. Lucas, J. A. Gutierrez, R. G. Perry, J. F. Trotter, R. S. Rahimi, S. A. Harrison, V. Ajmera, J. D. Wayne, M. O’Farrell, W. McCulloch, K. Grimmer, M. Rinella, V. Wai-Sun Wong, V. Ratziu, G. J. Gores, B. A. Neuschwander-Tetri and G. Kemble (2021). “TVB-2640 (FASN Inhibitor) for the Treatment of Nonalcoholic Steatohepatitis: FASCINATE-1, a Randomized, Placebo-Controlled Phase 2a Trial.” Gastroenterology 161(5): 1475-1486.

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BACKGROUND & AIMS: Increased de novo lipogenesis creates excess intrahepatic fat and lipotoxins, propagating liver damage in nonalcoholic steatohepatitis. TVB-2640, a fatty acid synthase inhibitor, was designed to reduce excess liver fat and directly inhibit inflammatory and fibrogenic pathways. We assessed the safety and efficacy of TVB-2640 in patients with nonalcoholic steatohepatitis in the United States. METHODS: 3V2640-CLIN-005 (FASCINATE-1) was a randomized, placebo-controlled, single-blind study at 10 US sites. Adults with ≥8% liver fat, assessed by magnetic resonance imaging proton density fat fraction, and evidence of liver fibrosis by magnetic resonance elastography ≥2.5 kPa or liver biopsy were eligible. Ninety-nine patients were randomized to receive placebo or 25 mg or 50 mg of TVB-2640 (orally, once-daily for 12 weeks). The primary end points of this study were safety and relative change in liver fat after treatment. RESULTS: Liver fat increased in the placebo cohort by 4.5% relative to baseline; in contrast TVB-2640 reduced liver fat by 9.6% in the 25-mg cohort (n = 30; least squares mean: -15.5%; 95% confidence interval, -31.3 to -0.23; P = .053), and 28.1% in the 50-mg cohort (n = 28; least squares mean: -28.0%; 95% confidence interval, -44.5 to -11.6; P = .001). Eleven percent of patients in the placebo group achieved a ≥30% relative reduction of liver fat compared to 23% in the 25-mg group, and 61% in the 50-mg group (P < .001). Secondary analyses showed improvements of metabolic, pro-inflammatory and fibrotic markers. TVB-2640 was well tolerated; adverse events were mostly mild and balanced among the groups. CONCLUSIONS: TVB-2640 significantly reduced liver fat and improved biochemical, inflammatory, and fibrotic biomarkers after 12 weeks, in a dose-dependent manner in patients with nonalcoholic steatohepatitis. ClinicalTrials.gov, Number NCT03938246.

Kasiske, B. L., Y. S. Ahn, M. Conboy, M. A. Dew, C. Folken, M. L. Levan, A. Humar, A. K. Israni, D. L. Rudow, J. F. Trotter, A. B. Massie and D. Musgrove (2021). “Outcomes of living liver donor candidate evaluations in the Living Donor Collective pilot registry.” Clin Transplant Aug 3. [Epub ahead of print].

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BACKGROUND: To gather information on long-term outcomes after living donation, the Scientific Registry of Transplant Recipients (SRTR) conducted a pilot on the feasibility of establishing a comprehensive donor candidate registry. METHODS: A convenience sample of 6 US living liver donor programs evaluated 398 consecutive donor candidates in 2018, ending with the March 12, 2020, COVID-19 emergency. RESULTS: For 333/398 (83.7%), the donor or program decided whether to donate; 166/333 (49.8%) were approved, and 167/333 (50.2%) were not or opted out. Approval rates varied by program, from 27.0% to 63.3% (median, 46%; intraquartile range, 37.3-51.1%). Of those approved, 90.4% were white, 57.2% were women, 83.1% were < 50 years, and 85.5% had more than a high school education. Of 167 candidates, 131 (78.4%) were not approved or opted out because of: medical risk (10.7%); chronic liver disease risk (11.5%); psychosocial reasons (5.3%); candidate declined (6.1%); anatomical reasons increasing recipient risk (26.0%); recipient-related reasons (33.6%); finances (1.5%); or other (5.3%). CONCLUSIONS: A comprehensive national registry is feasible and necessary to better understand candidate selection and long-term outcomes. As a result, the US Health Resources and Services Administration asked SRTR to expand the pilot to include all US living donor programs.

Wey, A., S. Noreen, S. Gentry, M. Cafarella, J. Trotter, N. Salkowski, D. Segev, A. Israni, B. Kasiske, R. Hirose and J. Snyder (2021). “The effect of acuity circles on deceased donor transplant and offer rates across MELD and exception statuses.” Liver Transpl Sep 5. [Epub ahead of print].

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Acuity circles (AC), the new liver allocation system, was implemented on February 4, 2020. Difference-in-differences analyses estimated the effect of AC on adjusted deceased donor transplant and offer rates across pediatric and adult models for end-stage liver disease (P/MELD) categories and types of exception statuses. The offer rates were the number of first offers, top 5 offers, and top 10 offers on the match run per person-year. Each analysis adjusted for candidate characteristics, and only used active candidate time on the waiting list. The before-AC period was February 4, 2019, to February 3, 2020, and the after-AC period was February 4, 2020, to February 3, 2021. P/MELD 29-32 and P/MELD 33-36 candidates had higher transplant rates than P/MELD 15-28 candidates after AC compared to before (transplant rate ratios: P/MELD 29-32, (2.34) 3.32(4.71) ; P/MELD 33-36, (1.70) 2.51(3.71) ). P/MELD 29 or higher candidates had higher offer rates than P/MELD 15-28 candidates, and P/MELD 29-32 candidates had the largest difference (offer rate ratios [ORR]: 1(st) offers, (2.77) 3.95(5.63) ; top 5 offers, (3.90) 4.39(4.95) ; top 10 offers, (4.85) 5.30(5.80) ). Candidates with exceptions had lower offer rates than candidates without exceptions for offers in the top 5 (ORR: hepatocellular carcinoma [HCC], (0.68) 0.77(0.88) ; non-HCC, (0.73) 0.81(0.89) ) and top 10 (ORR: HCC, (0.59) 0.65(0.71) ; non-HCC, (0.69) 0.75(0.81) ). P/MELD 15-28 and HCC exception recipients received a larger proportion of donation after circulatory death (DCD) donors after AC than before, although the differences in the liver donor risk index was comparatively small. Thus, P/MELD 29-34 and non-exception candidates had better access to transplant after AC, and donor quality did not notably change beyond the proportion of DCD donors.

Singapura, P., Ma, T.W., Sarmast, N., Gonzalez, S., Durand, F., Maiwall, R., Nadim, M.K., Fullinwider, J., Saracino, G., Francoz, C., Sartin, R., Trotter, J. and Asrani, S.K. (2021). “Estimating glomerular filtration rate in cirrhosis using creatinine- and cystatin C- based equations: systematic review and meta-analysis.” Liver Transpl Jun 18. [Epub ahead of print].

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BACKGROUND AND AIMS: Accurate estimation of kidney function in cirrhosis is crucial for prognosis and decisions regarding dual organ transplantation. Several estimating glomerular filtration rate (GFR) equations are used, however, most overestimate kidney function. APPROACH AND RESULTS: We performed a systematic review/meta-analysis to assess the performance of creatinine and cystatin C-based GFR estimating (eGFR) equations as compared to measured GFR (mGFR) in patients with cirrhosis. Standardized mean difference (SMD) of each eGFR equation was compared to mGFR. Twenty-five studies (n= 4,565, 52.0years, 37.0% female) comprising 18 equations met the inclusion criteria. All GFR: Creatinine-based equations overestimated GFR (SMD 0.51, 95% CI0.31-0.71) and cystatin C-based equations underestimated GFR (SMD -0.3, 95% CI-0.6- -0.02). Equations based on both creatinine and cystatin C were the least biased (SMD -0.14, 95% CI -0.46-0.18). CKD-Epi-sCr-CysC was the least biased but had low precision and underestimated GFR by -3.6 ml/min/1.73m(2) (95% CI -17.4-10.3). GFR<60ml/min/1.73m(2) : All equations significantly overestimated GFR (+21.7 ml/min/1.73m(2) , 95% CI17.7-25.7); of these, CKD-Epi-CysC (10.3 ml/min/1.73m(2) , 95% CI2.1-18.4) and GFR Assessment in Liver disease (GRAIL) (12.6 ml/min/1.73m(2) , 95%CI 7.2-18.0) were the least biased followed by Royal Free Hospital (RFH) (15 ml/min/1.73m(2) , 95%CI 5.5-24.6) and MDRD-6 (15.7 ml/min/1.73m(2) , 95%CI 10.6-20.8).; however there was overlap in the precision of estimates and studies were limited. Ascites: Overestimation of GFR was common (+8.3 ml/min/1.73m(2) , 95%CI -3.1-19.7). CONCLUSION: CKD-Epi-sCr-CysC may be acceptable across the spectrum of GFR. However, overestimation of GFR by 10-20 ml/min/1.73m(2) is common in patients with cirrhosis with most equations, especially in conjunction with ascites and/or kidney dysfunction. There is wide overlap in confidence intervals/precision. A tailored approach is required based on clinical scenario, especially for decisions regarding dual organ transplantation.