Background and Aims: Consensus guidelines recommend high-dose corticosteroids (1-2 mg/kg/day methylprednisolone equivalents) for treating grade ≥3 immune checkpoint inhibitor (ICI) hepatitis. We examined the effect of corticosteroid dosing on time to alanine aminotransferase (ALT) normalization, need for additional immunosuppression, and steroid-related complications. Approach and Results:We conducted a retrospective cohort study of 215 ICI-treated patients from 2010 to 2020 who developed grade ≥3 (ALT > 200 U/L) ICI hepatitis. Patients were grouped by initial corticosteroid dose (≥1.5 mg/kg or <1.5 mg/kg methylprednisolone equivalents).Propensity scores were calculated predicting the risk of receiving the higher steroid dose and used in inverse probability of treatment weighted (IPTW) logistic or Cox regression. The 87 patients in the ≥1.5 mg/kg group received higher initial (2.0 vs. 0.8 mg/kg/day, p < 0.001) and maximum (2.0 vs. 1.0 mg/kg/day, p < 0.001) steroid doses than the 128 patients in the <1.5 mg/kg group. There was no difference between the higher versus lower-dose groups in development of steroid-refractory hepatitis (OR 1.22, 95% CI 0.79-1.89, p = 0.365) on IPTW-logistic regression. In patients with steroid-responsive disease, there was no difference between the two groups in time to ALT normalization using either standard Cox regression (HR 1.02, 95% CI 0.72-1.45, p = 0.903) or IPTW-Cox regression (HR 1.09, 95% CI 0.78-1.51, p = 0.610). The ≥1.5 mg/kg group had longer exposure to corticosteroids (median 60 vs. 44 days, p = 0.005) and higher incidences of infection (18.4% vs. 7.0%, relative risk [RR] 2.6, 95% CI 1.2-5.6, p = 0.011) and hyperglycemia requiring treatment (23.3% vs.
Background In the current study, the authors assessed the risks and outcomes of immune checkpoint inhibitor (ICI) rechallenge in patients with resolved grade 3 to 4 ICI hepatitis because current guidelines recommend permanent ICI discontinuation in these patients. Methods The authors performed a retrospective cohort study from 2010 through 2019 of patients with melanoma who were treated with ≥1 ICIs and who recovered from grade 3 to 4 ICI hepatitis. The primary outcome was hepatitis recurrence and the secondary outcome was the development of any immune‐related adverse event (irAE) requiring the discontinuation of ICI rechallenge. Best overall response and time to all‐cause death were compared between the patients who did and those who did not undergo ICI rechallenge. Grading was performed using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Results Of the 102 patients with melanoma who developed high‐grade ICI hepatitis, 31 underwent ICI rechallenge. Although 15 of 31 patients (48%) developed an irAE of any grade, only 6 patients (19%) required ICI discontinuation due to irAE severity (4 of 29 patients [14%] rechallenged with anti–PD‐1 or anti‐PD‐L1 and 2 of 2 patients [100%] rechallenged with ipilimumab). Recurrent hepatitis accounted for 4 of these 6 cases. Rechallenged patients who did not require ICI discontinuation were found to be significantly less likely to receive ipilimumab rather than anti–PD‐1 or anti‐PD‐L1 monotherapy (0% vs 33%; relative risk (RR), 0.1 [95% CI, 0.1‐0.3; P = .032]) and significantly less likely to be rechallenged with their original ICI (8% vs 50%; RR, 0.2 [95% CI, 0.1‐0.7; P = .038]). There was no difference noted with regard to best overall response or time to death between rechallenged and non‐rechallenged patients. Conclusions ICI therapy can be resumed in patients with melanoma who have recovered from grade 3 to 4 ICI hepatitis with a modest risk of serious irAEs. It remains unclear whether ICI retreatment improves clinical outcomes.
The utility of liver biopsy in diagnosis and management of immune checkpoint inhibitor (ICI) hepatitis is uncertain. [1][2][3] We examined the association of histology with management and outcomes of high-grade ICI hepatitis.
Despite scant evidence, current guidelines indicate that esophageal varices are a relative contraindication to transesophageal echocardiography (TEE). The aim of this study is to compare the risk of gastrointestinal bleeding following TEE among cirrhotic patients with and without endoscopically-documented esophageal varices. This is a retrospective analysis of patients with cirrhosis who underwent upper endoscopy within 4 years of TEE at five institutions between January 2000 and March 2020. Primary outcome was overt gastrointestinal bleeding. Secondary outcomes were hemoglobin decline by at least 2 g/dL or blood transfusion within 48 hours following TEE. Of the 191 patients, 79 (41.4%) had esophageal varices (30.4% large). No patient experienced a primary outcome. Secondary outcomes occurred in 52 (27.2%): 28 (35.4%) with esophageal varices and 24 (21.4%) without varices. After propensity-score covariate adjustment, the odds ratio for a secondary outcome in patients with esophageal varices was 1.49 (95% confidence interval 0.74-2.99). Restricting analysis to those who underwent endoscopy within 1 year of TEE did not significantly alter results. The risk of a secondary outcome was identical between patients who had upper endoscopy prior (27.5%) versus subsequent (26.7%; P = 1.00) to TEE. Conclusions: Among patients with cirrhosis, there was no overt gastrointestinal bleeding after TEE. The likelihood of a 2 g/dL decline in hemoglobin or blood transfusion within 48 hours following TEE was not significantly higher in patients with esophageal varices after controlling for confounders. Patients who underwent upper endoscopy before TEE did not manifest a lower risk of secondary outcomes versus those who had endoscopy after TEE, suggesting that routine preprocedural endoscopy is of marginal utility. (Hepatology Communications 2020;0:1-10).
BACKGROUND: Serum bilirubin is inversely associated with cardiovascular risk. Atazanavir, an HIV protease inhibitor that competitively inhibits bilirubin conjugation, provides a unique opportunity to examine whether selectively increasing bilirubin is cardioprotective. We sought to determine whether patients receiving atazanavir manifest a reduced risk of cardiovascular disease compared with those receiving darunavir, an HIV protease inhibitor that does not increase serum bilirubin. METHODS AND RESULTS: This was a retrospective cohort study of 1020 patients with HIV. The main outcome was time to myocardial infarction or ischemic stroke. Mean follow‐up was 6.6±3.4 years, with 516 receiving atazanavir and 504 darunavir. Atazanavir patients exhibited significantly higher serum total bilirubin (1.7 versus 0.4 mg/dL; P <0.001) and longer mean time to ischemic event (10.2 versus 9.4 years; P <0.001). On Cox regression, atazanavir treatment (hazard ratio [HR], 0.38; 95% CI, 0.21–0.71; P =0.002) and serum bilirubin (HR, 0.60; 95% CI, 0.41–0.89; P =0.011) were independently associated with a lower risk of an ischemic event. Notably, when atazanavir and bilirubin were included together in the Cox regression model, atazanavir lost significance (HR, 0.55; 95% CI, 0.24–1.29; P =0.169) consistent with bilirubin being an intermediate variable on the causal pathway between atazanavir and its effect on cardiovascular disease. Patients on atazanavir also had a significantly lower risk of developing new cardiovascular disease (HR, 0.53; 95% CI, 0.33–0.86; P =0.010) and longer mean time to death (12.2 versus 10.8 years; P <0.001). CONCLUSIONS: Patients with HIV on atazanavir manifest a decreased risk of cardiovascular disease when compared with those on darunavir, an effect that appears to be mediated by serum bilirubin.
Background: We evaluated the impact of gastroenterology/hepatology consultation, as recommended by guidelines, on the management of severe immune checkpoint inhibitor (ICI)–induced hepatitis. Methods: We conducted a multicenter, retrospective cohort study of 294 patients who developed grade ≥3 (alanine aminotransferase [ALT] >200 U/L) ICI-induced hepatitis, with early gastroenterology/hepatology consultation defined as occurring within 7 days of diagnosis. The primary outcome was time to ALT normalization (≤40 U/L), and the secondary outcome was time to ALT improvement to ≤100 U/L. Results: A total of 117 patients received early consultation. In the 213 patients with steroid-responsive hepatitis, early consultation was not associated with faster ALT normalization (hazard ratio [HR], 1.12; 95% CI, 0.83–1.51; P=.453). A total of 81 patients developed steroid-refractory hepatitis, with 44 (54.3%) receiving early consultation. In contrast to the patients whose hepatitis responded to steroid treatment, early consultation in those with steroid-refractory disease was associated with faster ALT normalization (HR, 1.89; 95% CI, 1.12–3.19; P=.017) and ALT improvement to ≤100 U/L (HR, 1.72; 95% CI, 1.04–2.84; P=.034). Notably, additional immunosuppressive therapy for steroid-refractory disease was initiated sooner after diagnosis in the early consult group (median 7.5 vs 13.0 days; log-rank P=.001). When time to additional immunosuppression was added as a covariate to the Cox model in mediation analysis, early consultation was no longer associated with time to ALT normalization (HR, 1.39; 95% CI, 0.82–2.38; P=.226) or with time to ALT improvement to ≤100 U/L (HR, 1.25; 95% CI, 0.74–2.11; P=.404). Time to additional immunosuppression remained associated with faster ALT normalization and faster ALT improvement to ≤100 U/L in the model, suggesting that the faster hepatitis resolution in the early consultation group was primarily attributable to earlier initiation of additional immunosuppression. Conclusions: Early gastroenterology/hepatology consultation is associated with faster resolution of biochemical abnormalities in patients with steroid-refractory hepatitis. This beneficial effect appears to be mediated by earlier initiation of additional immunosuppressive therapy in those receiving early consultation.
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