Incidence Of Hepatotoxicity In Patients Research Articles

Case Reports on Severe Antituberculosis-Drug Induced Hepatotoxicity in Tuberculosis Patients: The Post-Incidence Therapy

Introduction: The first-line regimen for tuberculosis (TB) treatment comprises Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol. However, these drugs are known to potentially cause hepatotoxicity. This study aimed to evaluate hepatotoxicity incidence in patients during intensive phase of anti-tuberculosis treatment focusing on post-incidence therapy. Methods: The study involved pulmonary TB patients who were admitted to the National Lung Health Center due to hepatotoxicity after receiving fixed-dose combination of antituberculosis drugs (FDC-AT) in September-October 2019. Drug-related hepatotoxicity is defined as an increase in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 2.5 times of the normal upper limit (ULN) with an increase in bilirubin level. Results: There were 8 patients admitted to the center due to hepatotoxicity, 4 of them experienced grade 3 (severe) hepatotoxicity, during which the ALT, AST, bilirubin levels increased 5-10 times of the ULN. The post-hepatotoxicity treatment includes the cessation of FDC-AT treatment followed by hepatoprotective supplements. Following two weeks of treatments, the biomarker levels of two out of four patients went back to normal and the AT therapy was resumed. Meanwhile, the other two patients continued to receive the hepatoprotective therapy for up to 8 weeks. However, when the treatment failed to bring the transaminase level back to normal, a different AT regimen was prescribed. Conclusions: The cessation of FDC-AT and the use of hepatoprotective supplements for two to eight weeks were able to alleviate the AT-induced severe hepatotoxicity. A close monitoring of liver biomarkers is warranted to prevent the incidence of hepatotoxicity in patients receiving antituberculosis

A Real-World Assessment of Hepatic Dysfunction Among Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients Receiving First-Line (1L) Tyrosine Kinase Inhibitors (TKIs) in the United States

Introduction:Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the unregulated proliferation of myeloid cells in the bone marrow and their accumulation in the blood. The approval of imatinib (IM) and second-generation TKIs have substantially improved survival for patients with CML. Despite the effectiveness of these TKIs in controlling CML, continuous therapy is necessary for most patients, and may be associated with the development of unfavorable adverse events such as hepatotoxicity. Although patients with elevated liver function tests are excluded from key clinical trials, case reports and small single-center studies have described cases of TKI-associated hepatotoxicity among patients with CML. This study sought to describe the prevalence and incidence of hepatotoxicity in patients with newly diagnosed Philadelphia chromosome-positive chronic-phase (Ph+ CP) CML treated with 1L TKIs in community oncology practices. Methods:This retrospective, observational cohort study identified adult patients newly diagnosed with Ph+ CP CML and treated with 1L dasatinib (DAS), IM, or nilotinib (NIL) within the US Oncology Network (USON) between 1 January 2008 and 30 November 2018. Patients were required to have at least one comprehensive metabolic panel (CMP) within 90 days of treatment start, and ≥ 1 CMP during follow-up. Additionally, patients had to have at least two visits within the USON, no enrollment in any clinical trial during the study period, and no documentation of other primary cancer diagnoses. Descriptive statistics were generated for baseline patient characteristics and prevalence and incidence of hepatotoxicity, and were stratified by 1L TKI treatment initiation. Grades for hepatotoxicity were derived from laboratory data using the Common Terminology Criteria for Adverse Events version 5. Results:A total of 2743 patients with CP-CML were identified. Of those, 730 (26.6%), 1455 (53.0%), and 558 (20.3%) patients were treated with 1L DAS, IM, or NIL, respectively. With the exception of age and region, patient demographic characteristics were well balanced across cohorts. However, baseline hepatic functioning differed across TKIs (Table 1). Prevalence of any-grade liver enzyme elevation was observed in almost one-third (31.9%) of patients, including 246 (33.7%) patients treated with DAS, 416 (28.6%) patients treated with IM, and 213 (38.2%) patients treated with NIL. Among all patients with normal baseline hepatic function, 48.9% developed any-grade hepatotoxicity while on 1L therapy. Across TKI cohorts, significantly more patients treated with NIL developed any-grade hepatotoxicity (70.1%) compared to patients treated with DAS (45.5%) or IM (43.5%) (P< 0.0001). Among all patients receiving 1L treatment, 1.5% to 3.8% of patients experienced grade 3-4 hepatotoxicity. Significant differences in the proportion of patients that developed grade 3-4 hepatotoxicity were observed across treatments and were most common among patients treated with NIL (Table 2). Conclusions:Findings from this analysis suggest that hepatic dysfunction may be common at baseline among patients with CP-CML treated in real-world community oncology settings. Among patients with normal baseline hepatic function, more patients treated with NIL experienced any-grade hepatotoxicity. Patients treated with NIL were also more likely to develop grade 3-4 hepatotoxicity compared to patients treated with DAS or IM. These findings may provide insight into the effects of long-term TKI treatment on hepatic functioning and help to inform treatment choices for patients. Disclosures Kolibaba: AbbVie:Research Funding;Compass Oncology:Ended employment in the past 24 months;Janssen:Research Funding;TG Therapeutics:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;McKesson Life Sciences:Consultancy;Sumitomo Dainippon Pharma Oncology:Consultancy, Other: travel, accommodations, expenses, ;Gilead:Research Funding;Genentech:Research Funding;Cell Therapeutics:Research Funding;Celgene:Research Funding;Acerta:Research Funding;Atara Biotech:Membership on an entity's Board of Directors or advisory committees;Verastem:Honoraria;Seattle Genetics:Research Funding;Novartis:Research Funding;Pharmacyclics:Research Funding.Zhou:McKesson Corporation:Current Employment.Keating:Bristol Myers Squibb:Current Employment.Clark:McKesson Life Sciences:Current Employment, Current equity holder in publicly-traded company.Brokars:Bristol Myers Squibb:Current Employment.Kee:Bristol Myers Squibb:Current Employment.Copher:Bristol Myers Squibb:Current Employment.Stwalley:Bristol Myers Squibb:Current Employment, Current equity holder in publicly-traded company.Jabbour:Adaptive Biotechnologies:Other: Advisory role, Research Funding;Genentech:Other: Advisory role, Research Funding;BMS:Other: Advisory role, Research Funding;Amgen:Other: Advisory role, Research Funding;Pfizer:Other: Advisory role, Research Funding;Takeda:Other: Advisory role, Research Funding;AbbVie:Other: Advisory role, Research Funding.

THU494 - Incidence of hepatotoxicity in patients with hepatocellular carcinoma on treatment with immune checkpoint inhibitors: impact on outcomes and tissue biomarker analysis

THU494 - Incidence of hepatotoxicity in patients with hepatocellular carcinoma on treatment with immune checkpoint inhibitors: impact on outcomes and tissue biomarker analysis

Hepatotoxicity during 6-thioguanine treatment in inflammatory bowel disease and childhood acute lymphoblastic leukaemia: A systematic review.

BackgroundThe recently established association between higher levels of DNA-incorporated thioguanine nucleotides and lower relapse risk in childhood acute lymphoblastic leukaemia (ALL) calls for reassessment of prolonged 6-thioguanine (6TG) treatment, while avoiding the risk of hepatotoxicity.ObjectivesTo assess the incidence of hepatotoxicity in patients treated with 6TG, and to explore if a safe dose of continuous 6TG can be established.Data sourcesDatabases, conference proceedings, and reference lists of included studies were systematically searched for 6TG and synonyms from 1998–2018.MethodsWe included studies of patients with ALL or inflammatory bowel disorder (IBD) treated with 6TG, excluding studies with 6TG as part of an intensive chemotherapy regimen. We uploaded a protocol to PROSPERO (registration number CRD42018089424). Database and manual searches yielded 1823 unique records. Of these, 395 full-texts were screened for eligibility. Finally, 134 reports representing 42 studies were included.Results and conclusionsWe included data from 42 studies of ALL and IBD patients; four randomised controlled trials (RCTs) including 3,993 patients, 20 observational studies including 796 patients, and 18 case reports including 60 patients. Hepatotoxicity in the form of sinusoidal obstruction syndrome (SOS) occurred in 9–25% of the ALL patients in two of the four included RCTs using 6TG doses of 40–60 mg/m2/day, and long-term hepatotoxicity in the form of nodular regenerative hyperplasia (NRH) was reported in 2.5%. In IBD patients treated with 6TG doses of approximately 23 mg/m2/day, NRH occurred in 14% of patients. At a 6TG dose of approximately 12 mg/m2/day, NRH was reported in 6% of IBD patients, which is similar to the background incidence. According to this review, doses at or below 12 mg/m2/day are rarely associated with notable hepatotoxicity and can probably be considered safe.

Adeno-Associated Mediated Gene Transfer for Hemophilia B:8 Year Follow up and Impact of Removing “Empty Viral Particles” on Safety and Efficacy of Gene Transfer

▪Background: We have previously shown that a single intravenous administration of a self-complementary adeno-associated virus (scAAV) vector containing a codon-optimised factor IX gene, under control of a synthetic liver specific promoter and pseudotyped with serotype 8 capsid, (scAAV2/8-LP1-hFIXco) resulted in a dose-dependent increase in plasma FIX levels in all 10 enrolled severe hemophilia B (HB) patients (ClinicalTrials.gov:NCT00979238; Nathwani et al 2011). FIX activity was stably maintained for at least 3 years (Nathwani et al 2014) but concerns over FIX expression declining over time remain. This is because AAV-mediated transgene expression is mediated mainly by episomally retained viral genomes, which may be lost with natural hepatocyte turn-over. The only vector-associated adverse event was an asymptomatic rise in liver enzymes associated with a decline in FIX levels, occurring within 3 months of gene transfer in two-thirds of the patients treated at a dose of 2x1012 vector genomes(vg)/kg. Liver enzymes normalized with corticosteroids without complete loss of transgene expression. There was no long-lasting toxicity over a period of 3 years but further follow-up is required. The vector preparation used contained an excess of empty capsids, which lacked a full-length viral genome, and are therefore, non-functional but capable of provoking an immune response against transduced hepatocytes. Therefore, a new clinical preparation of scAAV2/8-LP1-hFIXco was manufactured from which most of the empty particles were removed by caesium chloride density centrifugation in the hope that this would reduce the risk of hepatotoxicity. We report on the evaluation of this new vector preparation in severe HB patients and provide an update on up to 8 years follow-up of our original cohort of patients.Methods: Ten subjects were recruited in 2010-2012 to the initial dose-escalation/extension study arm, which entailed a single intravenous infusion of scAAV2/8-LP1-hFIXco (full: empty capsid ratio ~1:10) at a dose of either 2x1011vg/kg, 6x1011vg/kg or 2x1012vg/kg. Two severe HB patients (FIX <1%) were enrolled into the first and mid-dose cohorts, with six patients treated at the high dose. In a follow-on study arm, two severe HB subjects received a dose of 2x1012vg/kg of the new scAAV2/8-LP1-hFIXco preparation (full: empty capsid ratio 1:3) whilst the next 2 patients were treated at a dose of 5x1012vg/kg. In both arms, vector was administered without prophylactic immunosuppression but corticosteroids (starting at 60mg/day) were commenced if liver enzymes increased to ≥2 fold over baseline levels after gene transfer.Results: Transgenic FIX activity levels have remained stable in all 10 subjects treated in the initial dose escalation/extension arm over a median follow-up of 6.7±1.0 years with mean levels in the three dose cohorts at the time of reporting of 1.9±0.6, 2.3±0.3 and 5.1±1.4 IU/l respectively. Over this period, annual FIX concentrate usage has dropped by 66% and annual bleed rate has declined by 82% when compared to pre-gene therapy levels. No late toxicity was observed. Neutralising antibodies to FIX were not detected in any patient but anti-AAV8 capsid-specific antibody levels persisted at high titres in 9 of 10 patients. In patients treated with the new preparation of scAAV2/8-LP1-hFIXco (median follow up = 2.1±1.4 years), mean FIX activity in the 2x1012vg/kg dose cohort was 2.6±0.7 IU/l. This is lower than observed previously at this dose level, but the difference is not statistically significant. Mean steady state FIX levels in the 5x1012vg/kg cohort were 17±5 IU/l. FIX antigen to activity ratio was 1:1. Elevation of serum alanine aminotransferase was observed in 3 of 4 patients treated with the new vector preparation, requiring treatment with corticosteroids.Conclusion: This is the first report to demonstrate stable therapeutic expression of FIX in patients with severe HB over a period of 8 years following systemic administration of scAAV2/8-LP1-hFIXco without late toxicities. We show for the first time that reducing the capsid load by removing empty AAV capsids does not appear to reduce the incidence of hepatotoxicity in patients with severe HB suggesting that other factors are involved in the aetiology of this process. DisclosuresNathwani:Freeline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BioMarin: Consultancy, Patents & Royalties; UniQure: Patents & Royalties. Tuddenham:BioMarin: Consultancy, Patents & Royalties; Freeline: Consultancy. Chowdary:Freeline: Consultancy; Baxalta (Shire): Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Swedish Orphan Biovitrum AB (Sobi): Honoraria. McIntosh:Freeline: Consultancy. Recht:Biogen: Research Funding; Shire: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees.

Caspofungin versus micafungin in the incidence of hepatotoxicity inpatients with normal to moderate liver failure.

One of the major adverse events of caspofungin and micafungin is hepatotoxicity, however, there are few reports compared the incidence of hepatotoxicity between caspofungin and micafungin. Herein, the primary objective of this study was to compare the incidence of hepatotoxicity between caspofungin and micafungin treatments for patients with fungal or suspected fungal infection. In total, 201 patients [caspofungin group: 66 patients; micafungin group: 135 patients] treated with echinocandins from April 2014 to November 2015 at Aichi Medical University Hospital. Investigation item were as follows; sex, age, weight, height, duration of treatment, total dose, disease type, clinical isolates, liver enzyme levels, concomitant medications. Liver function was assessed in accordance with Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. We divided into two groups depend on their liver enzyme levels before treated with echinocandins; normal group (liver enzyme levels≤CTCAE Grade 1), abnormal group (liver enzyme levels≥CTCAE Grade 2). The overall incidence of serious hepatotoxicity (Grade 3 or higher) was 6.1% (4/66) in the caspofungin group and 7.4% (10/135) in the micafungin group. The proportion of patients used caspofungin and micafungin showed serious hepatotoxicity were 0% (0/47) and 6.5% (7/108) in normal group (p=0.17), and 21.1% (4/19) and 10.7% (3/28) in abnormal group (p=0.42). There was no notable difference in serious hepatotoxicity between the caspofungin group and the micafungin group, even though in patients with abnormal liver enzyme levels (CTCAE grade 2 or higher).

Association of sustained high plasma trough concentration of voriconazole with the incidence of hepatotoxicity

BackgroundTherapeutic drug monitoring (TDM) of voriconazole is important to optimize efficacy and to minimize toxicity and intolerance. In this study, we evaluated the effect of sustained high plasma trough concentration of voriconazole on the incidence of hepatotoxicity in hospitalized Japanese patients. MethodsThirty-nine patients were divided into 3 groups according to trough concentrations in two consecutive TDMs: <4μg/ml in the first TDM (group A, n=25), >4μg/ml in the first and <4μg/ml in the second TDM (group B, n=8), and >4μg/ml in both first and second TDMs (group C, n=6). ResultsIncidences of hepatotoxicity in groups A, B and C were 16.0, 25.0 and 83.3%, and significant differences were observed between groups A and C and groups B and C. Multiple logistic regression analysis identified the classification into groups A, B and C as an independent variable of hepatotoxicity. ConclusionsThese results suggest that sustained high trough concentration of voriconazole may increase the risk of hepatotoxicity, and decreasing trough concentration to <4μg/ml by dose adjustment after the initial TDM may reduce the incidence of hepatotoxicity in patients treated with voriconazole.

No increased risk of hepatotoxicity in long‐term use of nonnucleoside reverse transcriptase inhibitors in HIV‐infected patients

The aim of this study was to assess the incidence of hepatotoxicity in patients who had used nonnucleoside reverse transcriptase inhibitors (NNRTIs) for at least 3 years. The study group consisted of HIV-infected patients under follow-up at our clinic, who had continuously used an NNRTI-containing regimen (efavirenz or nevirapine) for at least 3 years. Patients who had used protease inhibitors (PIs) for the same time span constituted a control group. Hepatotoxicity was graded according to the modified AIDS Clinical Trial Group grading system, using alanine aminotransferase (ALT) as a marker. One hundred and twenty-two patients on an NNRTI regimen and 54 PI-using patients were included in the analysis. The mean follow-up time was nearly 6 years. Eighteen NNRTI-using patients (14.8%) developed a clinically relevant (≥ grade II) event of hepatotoxicity during treatment; five of them (4.1%) developed severe hepatotoxicity (≥ grade III). No significant difference in the hepatotoxicity rate was seen between NNRTI- and PI-using patients (14.8 vs. 18.5%, respectively; P = 0.52) or between patients using efavirenz and nevirapine (13.8% vs. 16.7%, respectively; P = 0.51). A hepatitis C virus (HCV) coinfection was associated with an increased risk of the development of hepatotoxicity during NNRTI therapy [odds ratio (OR) 1.83; 95% confidence interval (CI) 1.33-4.24; P < 0.01]. Finally, we observed that more hepatotoxic events occurred during the first year of NNRTI therapy compared with the entire period after 1 year (6.6 vs. 2.8 events, respectively, per 100 person-years of treatment; P = 0.04). Long-term NNRTI use was not associated with a higher risk of clinically significant liver toxicity in patients who had been treated with NNRTI for at least 3 years.

Incidence of voriconazole hepatotoxicity during intravenous and oral treatment for invasive fungal infections

Absorption of oral voriconazole is good and in contrast to the intravenous (iv) formulation it can be given in patients with renal insufficiency. Furthermore, the acquisition costs are significantly lower. The aim of this study was to compare the incidence of hepatotoxicity in patients treated with the oral formulation of voriconazole with that in patients treated with the iv formulation. This was a retrospective observational study. A total of 35 patients with haematological disease and an invasive fungal infection were treated with oral voriconazole during the entire regimen. We compared the incidence of hepatotoxicity with that in 11 patients treated intravenously during the first week. The incidence of increased liver enzymes was comparable between both groups. Voriconazole was discontinued in two patients in the oral group and one patient in the iv group because of hepatotoxicity. The incidence of liver enzyme elevations in the entire study cohort of 46 patients was higher than that previously reported in a comparable study population (P < 0.001). However, clinically significant hepatotoxicity was infrequently observed (3/46 or 6.5%). In 35 patients with invasive fungal infections we instituted oral voriconazole therapy from day 1 and found an incidence of hepatotoxicity comparable to 11 controls treated intravenously.

A patient-tailored N-acetylcysteine protocol for acute acetaminophen intoxication

Background: Hepatotoxicity as a result of acetaminophen(APAP) intoxication has become an important problem, but early intervention with N-acetylcysteme (NAC) is effective in preventing hepatic injury. Two NAC regimens are currently approved for acute APAP intoxication: NAC administered orally every 4 hours for 72 hours, and NAC administered intravenously for 20 hours within 8 to 10 hours after ingestion of a potentially hepatotoxic amount of APAP. However, clinical observations suggest that a variable treatment duration may be more appropriate than use of these predetermined, fixed-duration protocols. Objectives: This study investigated the tolerability and efficacy of a patient-tailored NAC protocol for acute APAP intoxication by comparing the incidence of hepatotoxicity in patients receiving this protocol and in historical controls receiving 1 of 2 fixed-duration protocols: oral NAC for 72 hours and intravenous NAC for 20 hours within 8 to 10 hours after ingestion of a potentially hepatotoxic amount of APAP. Methods: This was a retrospective case series study that included all patients admitted through the emergency department (ED) of the National Taiwan University Hospital with a diagnosis of APAP intoxication between October 1997 and October 2002. According to the patient-tailored protocol, which had been used in the ED since 1997, patients with a serum APAP concentration above the limit for possible risk based on a modified Rumack-Matthew nomogram received oral treatment with NAC 140 mg/kg, followed by maintenance doses of 70 mg/kg every 4 hours. NAC treatment was discontinued when the APAP concentration was <10 mg/L and serum aspartate aminotransferase (AST) was <40 IU/L. For the purposes of assessing clinical outcomes, patients were divided into 3 groups based on duration of treatment: the short-course group (≤36 hours), the intermediate-course group (37–72 hours), and the long-course group (≥73 hours). The primary outcome measure was development of hepatotoxicity, defined as a serum AST or alanine aminotransferase concentration >1000 IU/L. Results: Twenty-seven patients were included in thestudy, 17 in the short-course group, 4 in the intermediate-course group, and 6 in the long-course group. The mean (SD) durations of NAC treatment in the respective groups were 22.1 (5.5) hours, 45.0 (8.2) hours, and 97.3 (33.2) hours. All 6 patients (22%) in the long-course group had hepatotoxicity (peak AST range, 1083-9770 IU/L); their treatment duration ranged from 80 to 164 hours. No patients in the short- or intermediate-course group had evidence of hepatotoxicity. One woman in the long-course group in whom initiation of NAC treatment was delayed by 28 hours died of fulminant hepatic failure. The overall incidence of hepatotoxicity was similar to that in the historical controls. Conclusions: In this retrospective case series inpatients who received patient-tailored NAC therapy for acute APAP intoxication, the incidence of hepatotoxicity was low and comparable to that in historical controls who received treatment with 1 of 2 fixed-duration regimens. Use of this protocol may have the potential to shorten hospital stays without increasing the risk to patients. However, the sample size was small, and the findings require confirmation in prospective clinical trials.