A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis.

BACKGROUND: Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator-activated receptor delta agonist, has potential benefits. METHODS: In this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus). RESULTS: Of the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, -3.2 vs. -1.7; least-squares mean difference, -1.5; 95% CI, -2.5 to -0.5, P = 0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively. CONCLUSIONS: In this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733; EudraCT number, 2020-004348-27.).

Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis.

BACKGROUND: Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown. METHODS: In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). RESULTS: A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P = 0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (-1.93 vs. -1.15; difference, -0.78; 95% CI, -1.99 to 0.42; P = 0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting. CONCLUSIONS: Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.).

Immunopathogenesis of Primary Biliary Cholangitis, Primary Sclerosing Cholangitis and Autoimmune Hepatitis: Themes and Concepts.

Autoimmune liver diseases include primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis, a family of chronic immune-mediated disorders that target hepatocytes and cholangiocytes. Treatments remain nonspecific, variably effective, and noncurative, and the need for liver transplantation is disproportionate to their rarity. Development of effective therapies requires better knowledge of pathogenic mechanisms, including the roles of genetic risk, and how the environment and gut dysbiosis cause immune cell dysfunction and aberrant bile acid signaling. This review summarizes key etiologic and pathogenic concepts and themes relevant for clinical practice and how such learning can guide the development of new therapies for people living with autoimmune liver diseases.

Fazirsiran for Adults with Alpha-1 Antitrypsin Deficiency Liver Disease: A Phase 2 Placebo Controlled Trial (SEQUOIA).

BACKGROUND & AIMS: Homozygous ZZ alpha-1 antitrypsin (AAT) deficiency produces mutant AAT (Z-AAT) proteins in hepatocytes, leading to progressive liver fibrosis. We evaluated the safety and efficacy of an investigational RNA interference therapeutic, fazirsiran, that degrades Z-AAT mRNA, reducing deleterious protein synthesis. METHODS: This ongoing, phase 2 study randomized 40 patients to subcutaneous placebo or fazirsiran 25/100/200 mg. The primary endpoint was percentage change in serum Z-AAT concentration from baseline to Week 16. Patients with fibrosis on baseline liver biopsy received treatment on Day 1, Week 4, and then every 12 weeks, and had a second liver biopsy at or after Weeks 48, 72, or 96. Patients without fibrosis received two doses on Day 1 and Week 4. RESULTS: At Week 16, least-squares mean percent declines in serum Z-AAT concentration were -61%, -83% and -94% with fazirsiran 25/100/200 mg, respectively, versus placebo (all P< .0001). Efficacy was sustained through Week 52. At post-dose liver biopsy, fazirsiran reduced median liver Z-AAT concentration by 93% compared with an increase of 26% with placebo. All fazirsiran-treated patients had histological reduction from baseline in hepatic globule burden. Portal inflammation improved in 5/12 and 0/8 patients with baseline score >0 in the fazirsiran and placebo groups, respectively. Histological METAVIR score improved by >1 point in 7/14 and 3/8 patients with fibrosis >F0 at baseline in the fazirsiran and placebo groups, respectively. No adverse events led to discontinuation and pulmonary function tests remained stable. CONCLUSIONS: Fazirsiran reduced serum and liver concentrations of Z-AAT in a dose dependent manner and reduced hepatic globule burden (NCT03945292).

Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study.

BACKGROUND AND AIMS: ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA). APPROACH AND RESULTS: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events. CONCLUSIONS: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.

Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report.

Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition.

Systematic review of response criteria and endpoints in autoimmune hepatitis by the International Autoimmune Hepatitis Group.

BACKGROUND & AIMS: Autoimmune hepatitis (AIH) has been well characterised and codified through the development of diagnostic criteria. These criteria have been adapted and simplified and are widely used in clinical practice. However, there is a need to update and precisely define the criteria for both treatment response and treatment. METHODS: A systematic review was performed and a modified Delphi consensus process was used to identify and redefine the response criteria in autoimmune hepatitis. RESULTS: The consensus process initiated by the International Autoimmune Hepatitis Group proposes that the term 'complete biochemical response' defined as 'normalization of serum transaminases and IgG below the upper limit of normal' be adopted to include a time point at 6 months after initiation of treatment. An insufficient response by 6 months was a failure to meet the above definition. Non-response was defined as '<50% decrease of serum transaminases within 4 weeks after initiation of treatment'. Remission is defined as liver histology with a Hepatitis Activity Index <4/18. Intolerance to treatment was agreed to stand for 'any adverse event possibly related to treatment leading to potential drug discontinuation'. CONCLUSIONS: These definitions provide a simple and reproducible framework to define treatment response and non-response, irrespective of the therapeutic intervention. A consensus on endpoints is urgently required to set a global standard for the reporting of study results and to enable inter-study comparisons. Future prospective database studies are needed to validate these endpoints. LAY SUMMARY: Consensus among international experts on response criteria and endpoints in autoimmune hepatitis is lacking. A consensus on endpoints is urgently required to set a global standard for the reporting of study results and to enable the comparison of results between clinical trials. Therefore, the International Autoimmune Hepatitis Group (IAIHG) herein presents a statement on 5 agreed response criteria and endpoints: complete biochemical response, insufficient response, non-response, remission, and intolerance to treatment, which can be used to guide future reporting.

A phase II, randomized, open-label, 52-week study of seladelpar in patients with primary biliary cholangitis.

BACKGROUND & AIMS: We examined the efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, in adults with primary biliary cholangitis (PBC) at risk of disease progression (alkaline phosphatase [ALP] ≥1.67xupper limit of normal [ULN]) who were receiving or intolerant to ursodeoxycholic acid. METHODS: In this 52-week, phase II, dose-ranging, open-label study, patients were randomized (1:1) to seladelpar 5 mg/day (n = 53) or 10 mg/day (n = 55) or assigned to 2 mg/day (n = 11; United Kingdom sites after interim analysis) for 12 weeks. Doses could then be uptitrated to 10 mg/day. The primary efficacy endpoint was ALP change from baseline to Week 8. RESULTS: Mean baseline ALP was 300, 345, and 295 U/L in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Twenty-one percent of patients had cirrhosis, 71% had pruritus. At Week 8, mean ± standard error ALP reductions from baseline were 26 ± 2.8%, 33 ± 2.6%, and 41 ± 1.8% in the 2 mg (n = 11), 5 mg (n = 49), and 10 mg (n = 52) cohorts (all p ≤0.005), respectively. Responses were maintained or improved at Week 52, after dose escalation in 91% and 80% of the 2 mg and 5 mg cohorts, respectively. At Week 52, composite response (ALP <1.67xULN, ≥15% ALP decrease, and normal total bilirubin) rates were 64%, 53%, and 67%, and ALP normalization rates were 9%, 13%, and 33% in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Pruritus visual analog scale score was decreased in the 5 mg and 10 mg cohorts. There were no treatment-related serious adverse events, and 4 patients discontinued due to adverse events. CONCLUSIONS: Seladelpar demonstrated robust, dose-dependent, clinically significant, and durable improvements in biochemical markers of cholestasis and inflammation in patients with PBC at risk of disease progression. Seladelpar appeared safe and well tolerated and was not associated with any increase in pruritus. GOV NUMBER: NCT02955602 CLINICALTRIALSREGISTER. EU NUMBER: 2016-002996-91 LAY SUMMARY: Current treatment options for patients living with primary biliary cholangitis (PBC) are not optimal due to inadequate effectiveness or undesirable side effects. Patients with PBC who took seladelpar, a new treatment being developed for PBC, at increasing doses (2, 5, or 10 mg/day) for 1 year had clinically significant, dose-dependent improvements in key liver tests. Treatment appeared safe and was not associated with any worsening in patient self-reported itch scores.

A randomized placebo-controlled trial of elafibranor in patients with primary biliary cholangitis and incomplete response to UDCA.

BACKGROUND & AIMS: Patients with primary biliary cholangitis (PBC) who have an incomplete response to ursodeoxycholic acid remain at risk of disease progression. We investigated the safety and efficacy of elafibranor, a dual PPARα/δ agonist, in patients with PBC. METHODS: This 12-week, double-blind phase II trial enrolled 45 adults with PBC who had incomplete response to ursodeoxycholic acid (alkaline phosphatase levels ≥1.67-fold the upper limit of normal (ULN). Patients were randomly assigned to elafibranor 80 mg, elafibranor 120 mg or placebo. The primary endpoint was the relative change of ALP at 12 weeks (NCT03124108). RESULTS: At 12 weeks, ALP was reduced by -48.3±14.8% in the elafibranor 80 mg group (p <0.001 vs. placebo) and by -40.6±17.4% in the elafibranor 120 mg group (p <0.001) compared to a +3.2±14.8% increase in the placebo group. The composite endpoint of ALP ≤1.67-fold the ULN, decrease of ALP >15% and total bilirubin below the ULN was achieved in 67% patients in the elafibranor 80 mg group and 79% patients in the elafibranor 120 mg group, vs. 6.7% patients in the placebo group. Levels of gamma-glutamyltransferase decreased by 37.0±25.5% in the elafibranor 80 mg group (p <0.001) and 40.0±24.1% in the elafibranor 120 mg group (p <0.01) compared to no change (+0.2±26.0%) in the placebo group. Levels of disease markers such as IgM, 5'-nucleotidase or high-sensitivity C-reactive protein were likewise reduced by elafibranor. Pruritus was not induced or exacerbated by elafibranor and patients with pruritus at baseline reported less pruritic symptoms at the end of treatment. All possibly drug-related non-serious adverse events were mild to moderate. CONCLUSION: In this randomized phase II trial, elafibranor was generally safe and well tolerated and significantly reduced levels of ALP, composite endpoints of bilirubin and ALP, as well as other markers of disease activity in patients with PBC and an incomplete response to ursodeoxycholic acid. LAY SUMMARY: Patients with primary biliary cholangitis (a rare chronic liver disease) that do not respond to standard therapy remain at risk of disease progression toward cirrhosis and impaired quality of life. Elafibranor is a nuclear receptor agonist that we tested in a randomized clinical trial over 12 weeks. It successfully decreased levels of disease activity markers, including alkaline phosphatase. Thus, this study is the foundation for a larger prospective study that will determine the efficacy and safety of this drug as a second-line therapy. CLINICAL TRIAL REGISTRATION NUMBER: Clinical Trials.gov NCT03124108.

Glecaprevir-Pibrentasvir for 8 or 12 Weeks in HCV Genotype 1 or 3 Infection.

BACKGROUND: Glecaprevir and pibrentasvir are direct-acting antiviral agents with pangenotypic activity and a high barrier to resistance. We evaluated the efficacy and safety of 8-week and 12-week courses of treatment with 300 mg of glecaprevir plus 120 mg of pibrentasvir in patients without cirrhosis who had hepatitis C virus (HCV) genotype 1 or 3 infection. METHODS: We conducted two phase 3, randomized, open-label, multicenter trials. Patients with genotype 1 infection were randomly assigned in a 1:1 ratio to receive once-daily glecaprevir-pibrentasvir for either 8 or 12 weeks. Patients with genotype 3 infection were randomly assigned in a 2:1 ratio to receive 12 weeks of treatment with either glecaprevir-pibrentasvir or sofosbuvir-daclatasvir. Additional patients with genotype 3 infection were subsequently enrolled and nonrandomly assigned to receive 8 weeks of treatment with glecaprevir-pibrentasvir. The primary end point was the rate of sustained virologic response 12 weeks after the end of treatment. RESULTS: In total, 1208 patients were treated. The rate of sustained virologic response at 12 weeks among genotype 1-infected patients was 99.1% (95% confidence interval [CI], 98 to 100) in the 8-week group and 99.7% (95% CI, 99 to 100) in the 12-week group. Genotype 3-infected patients who were treated for 12 weeks had a rate of sustained virologic response at 12 weeks of 95% (95% CI, 93 to 98; 222 of 233 patients) with glecaprevir-pibrentasvir and 97% (95% CI, 93 to 99.9; 111 of 115) with sofosbuvir-daclatasvir; 8 weeks of treatment with glecaprevir-pibrentasvir yielded a rate of 95% (95% CI, 91 to 98; 149 of 157 patients). Adverse events led to discontinuation of treatment in no more than 1% of patients in any treatment group. CONCLUSIONS: Once-daily treatment with glecaprevir-pibrentasvir for either 8 weeks or 12 weeks achieved high rates of sustained virologic response among patients with HCV genotype 1 or 3 infection who did not have cirrhosis. (Funded by AbbVie; ENDURANCE-1 and ENDURANCE-3 ClinicalTrials.gov numbers, NCT02604017 and NCT02640157 .).

Inter- and Intra-individual Variation, and Limited Prognostic Utility, of Serum Alkaline Phosphatase in a Trial of Patients With Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: Serum alkaline phosphatase (ALP) and the enhanced liver fibrosis (ELF) score are used as endpoints in trials of patients with primary sclerosing cholangitis (PSC). We aimed to quantify inter- and intra-individual variation in levels of ALP and the ELF score over time, and evaluated their association with fibrosis progression. METHODS: We analyzed data from 234 patients with large-duct PSC enrolled in a 2-year, phase 2b placebo-controlled trial of simtuzumab. Participants were assessed by laboratory tests every 4 weeks, and liver biopsies collected at time of screening, week 48, and week 96. RESULTS: Serum levels of ALP and ELF scores did not differ significantly between simtuzumab and placebo groups, so the data were pooled. Median per-patient variations in ALP between clinic visits were approximately 12% over 12 weeks, 20% over 48 weeks, and 20% over 96 weeks. Reductions, unrelated to study intervention, of more than 40% in ALP were observed in 10.9% of patients with baseline activity greater than 2-fold the upper limit of normal (ULN) and 12.5% of patients with more than 3-fold the ULN at 1 year. At 2 years, reductions of more than 40% in ALP were observed in 15.8% of patients with baseline activity greater than 2-fold the ULN and 17.9% of patients with more than 3-fold the ULN. Among the 209 patients with Ishak fibrosis stage 0-4 at baseline, serum ALP activity did not associate with development of cirrhosis or with a 2-point increase in fibrosis stage at 2 years. In contrast, the median per-patient variation in ELF scores between clinic visits was approximately 3% over 12 weeks, 4% over 48 weeks, and 4% over 96 weeks. Elevated ELF scores at baseline and at weeks 12, 24 and 48, each associated with development of cirrhosis at 2 years (odds ratio >2.75; P < .01 for all timepoints). ELF scores at baseline and weeks 12, 24 and 48, also associated with a 2-point increase in fibrosis stage at 2 years (odds ratios all greater than 2; P < .01 for all timepoints). CONCLUSIONS: In an analysis of data from patients with large-duct PSC enrolled in a prospective trial, we found large interindividual and intraindividual variations in serum ALP activity. Serum ALP activity did not associate with disease progression over a 2-year period. Variations in ELF score were smaller, and scores determined at multiple timepoints associated with fibrosis progression and development of cirrhosis.

Presentation and Outcomes of Autoimmune Hepatitis Type 1 and Type 2 in Children: A Single-center Study.

OBJECTIVE: Autoimmune hepatitis (AIH) is designated as type 1 or 2 (AIH-1/2) on the basis of serum autoantibody (Ab) profiles. In children, AIH may present as acute or chronic liver failure or cirrhotic AIH (ALF/CLF/CAIH) with or without overlap sclerosing cholangitis (SC). The aim of this study was to compare demographics, presentation, and outcomes between groups in children. METHODS: A retrospective electronic chart review of children with AIH who met standard diagnostic criteria with histologic confirmation at Texas Children's Hospital was performed, with de novo AIH after liver transplant (LT) excluded. Patients were identified and divided into AIH-1, AIH-2, ALF, CAIH, AIH-SC, and LT and compared using chi-square analysis, Student t-test, and Mood median test. RESULTS: Among 91 children with AIH, 72 (79.1%) had AIH-1, 19 (20.9%) had AIH-2, 13 (14.3%) had ALF, 25 (27.5%) had CAIH, and 14 (15.4%) had AIH-SC. Both AIH-1/2 had female and Hispanic predominance (72.2/89.5%, 40.3/57.9%). AIH-2 presented at younger mean age in years than AIH-1 (6.8, 12.1, P < 0.05). Both AIH-1/2 had low rates of remission after 1 year of IS (25.4, 35.7%) and most recent (30.6, 54.5%) follow-up. Twenty-two (24.2) patients received LT: 16 had AIH-1 (72.7%), 6 had AIH-2 (27.3%), 9 (40.9%) had ALF, and 13 (59.1%) had CAIH. One-year patient and graft survivals were 100%. CONCLUSIONS: The epidemiology and clinical presentation of AIH-1 and -2 had a few subtle differences. AIH-1 was associated with more complications after LT. More data are needed to better characterize the 2 as separate disease entities.

Donor and transplant candidate selection for solid organ transplantation during the COVID-19 pandemic.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel coronavirus responsible for a worldwide pandemic has forced drastic changes in medical practice in an alarmingly short period of time. Caregivers must modify their strategies as well as optimize the utilization of resources to ensure public and patient safety. For organ transplantation, in particular, the loss of lifesaving organs for transplantation could lead to increased waitlist mortality. The priority is to select uninfected donors to transplant uninfected recipients while maintaining safety for health care systems in the backdrop of a virulent pandemic. We do not yet have a standard approach to evaluating donors and recipients with possible SARS-CoV-2 infection. Our current communication shares a protocol for donor and transplant recipient selection during the coronavirus disease 2019 (COVID-19) pandemic to continue lifesaving solid organ transplantation for heart, lung, liver, and kidney recipients. The initial results using this protocol are presented here and meant to encourage dialogue between providers, offering ideas to improve safety in solid organ transplantation with limited health care resources. This protocol was created utilizing the guidelines of various organizations and from the clinical experience of the authors and will continue to evolve as more is understood about SARS-CoV-2 and how it affects organ donors and transplant recipients.

Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection.

BACKGROUND: Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options. METHODS: We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. In POLARIS-4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir-voxilaprevir (163 patients) or sofosbuvir-velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. RESULTS: In the three active-treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir-velpatasvir-voxilaprevir, as compared with 0% with placebo. In POLARIS-4, the rate of response was 98% with sofosbuvir-velpatasvir-voxilaprevir and 90% with sofosbuvir-velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower. CONCLUSIONS: Sofosbuvir-velpatasvir-voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed. (Funded by Gilead Sciences; POLARIS-1 and POLARIS-4 ClinicalTrials.gov numbers, NCT02607735 and NCT02639247 .).

Best practices for detection, assessment and management of suspected immune-mediated liver injury caused by immune checkpoint inhibitors during drug development.

Immune checkpoint inhibitors (ICIs) have shown significant efficacy in patients with various malignancies, however, they are associated with a wide range of immune-related toxicities affecting many organs, including the liver. Immune-mediated liver injury caused by checkpoint inhibitors (ILICI) is a distinctive form of drug induced liver injury (DILI), that differs from most DILI types in presumed underlying mechanism, incidence, and response to therapeutic interventions. Despite increased awareness of ILICI and other immune-related adverse effects of ICIs reflected by recent guidelines for their management in post marketing clinical practice, there is lack of uniform best practices to address ILICI risk during drug development. As efforts to develop safer and more effective ICIs for additional indications grow, and as combination therapies including ICIs are increasingly investigated, there is a growing need for consistent practices for ILICI in drug development. This publication summarizes current best practices to optimize the monitoring, diagnosis, assessment, and management of suspected ILICI in clinical trials using ICI as a single agent and in combination with other ICIs or other oncological agents. It is one of several publications developed by the IQ DILI Initiative in collaboration with DILI experts from academia and regulatory agencies. Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, ILICI detection, approach to a suspected ILICI signal, causality assessment, hepatic discontinuation rules and additional medical treatment.

Safety and tolerability of elbasvir/grazoprevir in chronic hepatitis C virus therapy: Integrated analysis from clinical trials.

Direct-acting antiviral treatments for chronic hepatitis C virus (HCV) infection are generally safe; however, understanding the safety profile of each regimen is essential for their continued use. Safety data were pooled from 12 clinical trials of elbasvir/grazoprevir (EBR/GZR) that enrolled adult participants with HCV infection. Pooled analyses are presented for participants receiving EBR/GZR for 12 weeks and those receiving EBR/GZR plus ribavirin (RBV) for 16-18 weeks. Safety data are also presented for participants with comorbidities receiving EBR/GZR for 12 weeks in individual clinical trials (chronic kidney disease [CKD] stage 4/5, inherited blood disorders [IBLD] or receiving opioid agonist therapy [OAT]). Among 1743 participants receiving EBR/GZR for 12 weeks, 1068 (61.3%) reported ≥1 adverse event (AE) and 491 had AEs (28.2%) considered drug-related. The most frequent AEs were headache (10.6%), fatigue (8.7%), nasopharyngitis (5.8%), nausea (5.1%) and diarrhoea (5.0%). Serious AEs were reported by 37 participants (2.1%), and 12 (0.7%) discontinued treatment due to an AE. In populations with CKD 4/5 or IBLD or receiving OAT, safety was similar in participants receiving EBR/GZR for 12 weeks and those receiving placebo. Some AEs occurred at higher frequencies in participants receiving RBV compared with those receiving EBR/GZR alone: fatigue (32.7% vs 8.7%); headache (21.6% vs 10.6%); and nausea (15.8% vs 5.1%). Safety was similar in participants with and those without cirrhosis. Grade 3/4 alanine aminotransferase elevations were reported in 0.7% participants. EBR/GZR is a safe treatment option for individuals with HCV genotype (GT) 1 or GT4 infections, even those with challenging comorbidities such as CKD or IBLD and those receiving OAT.

A learning curve in using orphan liver allografts for transplantation.

Given the critical shortage of donor livers, marginal liver allografts have potential to increase donor supply. We investigate trends and long-term outcomes of liver transplant using national share allografts transplanted after rejection at the local and regional levels. We studied a cohort of 75 050 candidates listed in the Organ Procurement and Transplantation Network for liver transplantation between 2002 and 2016. We compared patients receiving national share and regional/local share allografts from 2002-2006, 2007-2011, and 2012-2016, performing multivariate Cox regression for graft survival. Recipient and center-level covariates that were not significant (P < .05) were removed. Graft survival of national share allografts improved over time. National share allografts had a 26% increased risk for graft failure in 2002-2006 but no impact on graft survival in 2007-2011 and 2012-2016. The cold ischemia time (CIT) of national share allografts decreased from 10.4 to 8.0 hours. We demonstrate that CIT had significant impact on graft survival using national share allografts (CIT <6 hours: hazard ratio 0.75 and CIT >12 hours: hazard ratio 1.25). Despite a trend toward sicker recipients and poorer quality allografts, graft survival outcomes using national share allografts have improved to benchmark levels. Reduction in cold ischemia time is a possible explanation.

Aggressive utilization of liver allografts: Improved outcomes over time.

BACKGROUND: Aggressive acceptance of liver allografts has driven utilization of marginal allografts. Our aim was to assess the impact of the aggressive phenotype on transplant center outcomes over time. METHODS: We used a cohort of 148 361 candidates from the Organ Procurement and Transplantation Network for liver transplantation between 2002 and 2016 in 134 centers. Using the Discard Risk Index, we designated high probability discard allografts by the top 10th percentile for likelihood of discard. Aggressive phenotype was defined by usage of high probability discard (HPD) allografts (top 10th percentile). Our analysis of survival on waitlist and graft survival after transplantation included a comprehensive list of center level covariates across three equal time periods (2002-2006, 2007-2011, and 2012-2016). RESULTS: After adjusting for recipient and center-level factors, aggressive centers had improving graft survival over time. Aggressive vs non-aggressive centers: 2002-2006 HR 1.12 (1.05-1.19), 2007-2011 HR 1.13 (1.05-1.22), 2012-2016 HR 0.99 (0.89-1.10). Aggressive centers had improved waitlist survival compared with non-aggressive centers after adjusting for allograft disparity. CONCLUSIONS: Aggressive phenotype had a positive impact on waitlist survival, and graft survival in aggressive centers have improved to benchmark levels over time. These findings serve as justification for aggressive utilization of allografts.

Pediatric length-of-stay index following liver transplantation.

BACKGROUND: PELD scores are used to reduce waitlist mortality, but they do not accurately predict likelihood of prolonged length-of-stay or higher costs associated with it. This study aims to create a pediatric length-of-stay (LOS) index to predict increased risk of prolonged stay following liver transplantation. METHODS: The scoring system generated predicts length-of-stay following pediatric liver transplantation. With univariate and multivariate analyses on data from 5669 pediatric liver transplant recipients, independent recipient/donor risk factors for prolonged stay (>30 days) were identified. Multiple imputations accounted for missing variables. RESULTS: The most significant factors were ICU admission (OR 2.92, CI 2.27-3.75), recipient bilirubin >32 (OR 2.35, CI 1.70-3.25), and hemodialysis 1 week before transplantation (OR 2.27, CI 1.57-3.27). The LOS index assigns weighted scoring points to factors to predict prolonged stay (C-statistic of .72). The index demonstrated discrimination across the population after dividing it into quartiles for prolonged stay. CONCLUSIONS: The pediatric LOS index, utilizing 13 donor/recipient factors, can assess the risk for pediatric liver transplantation prolonged stay. Important predictive factors are hemodialysis, ICU admission, recipient weight and bilirubin, and recipient life support status.