Incidence Of Liver Enzyme Elevations Research Articles

Safety and Dose-Response of Vidofludimus Calcium in Relapsing Multiple Sclerosis: Extended Results of a Placebo-Controlled Phase 2 Trial.

Vidofludimus calcium suppressed MRI disease activity compared with placebo in patients with relapsing-remitting multiple sclerosis (RRMS) in the first cohort of the phase 2 EMPhASIS study. Because 30 mg and 45 mg showed comparable activity on multiple end points, the study enrolled an additional low-dose cohort to further investigate a dose-response relationship. In a randomized, placebo-controlled, phase 2 trial, patients with RRMS, aged 18-55 years, and with ≥2 relapses in the last 2 years or ≥1 relapse in the last year, and ≥1 gadolinium-enhancing brain lesion in the last 6 months. Patients were randomly assigned (1:1:1) vidofludimus calcium (30 or 45 mg) or placebo in cohort 1 and vidofludimus calcium (10 mg) or placebo (4:1) in cohort 2 for 24 weeks. The primary end point was the cumulative number of combined unique active (CUA) lesions at week 24. Secondary end points were clinical outcomes and safety. Across cohorts 1 and 2, 268 patients were randomized to placebo (n = 81), 10 mg (n = 47) vidofludimus calcium, 30 mg (n = 71) vidofludimus calcium, or 45 mg (n = 69) vidofludimus calcium. The mean cumulative CUA lesions over 24 weeks was 5.8 (95% CI 4.1-8.2) for placebo, 5.9 (95% CI 3.9-9.0) for 10 mg treatment group, 1.4 (95% CI 0.9-2.1) for 30 mg treatment group, and 1.7 (95% CI 1.1-2.5) for 45 mg treatment group. Serum neurofilament light chain decreased in a dose-dependent manner. The number of patients with confirmed disability worsening after 24 weeks was 3 (3.7%) patients receiving placebo and 3 (1.6%) patients receiving any dose of vidofludimus calcium. Treatment-emergent adverse events occurred in 35 (43%) placebo patients compared with 11 (23%) and 71 (37%) patients in the 10 mg or any dose of vidofludimus calcium groups, respectively. The incidence of liver enzyme elevations and infections were similar between placebo and any dose of vidofludimus calcium. No new safety signals were observed. Compared with placebo, vidofludimus calcium suppressed the development of new brain lesions with daily doses of 30 mg and 45 mg, but not 10 mg, establishing the lowest efficacious dose is 30 mg. This study provides Class II evidence that among adults with active RRMS and≥1 Gd+ brain lesion in the past 6 months, the cumulative number of active lesions decreased with vidofludimus calcium. ClinicalTrials.gov (NCT03846219) and EudraCT (2018-001896-19).

The Impact of 131I-Metaiodobenzylguanidine as a Conditioning Regimen of Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation for High-Risk Neuroblastoma.

The optimal conditioning regimen of tandem high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) for high-risk neuroblastoma (HR-NBL) has not been established. The efficacy of 131I-MIBG therapy is under exploration in newly diagnosed HR-NBL patients. Here, we compared the outcomes of tandem HDC/ASCT between the 131I-MIBG combination and non-MIBG groups. We retrospectively analyzed the clinical data of 33 HR-NBL patients who underwent tandem HDC/ASCT between 2007 and 2021 at the Seoul National University Children's Hospital. The median age at diagnosis was 3.6 years. 131I-MIBG was administered to 13 (39.4%) of the patients. Thirty patients (90.9%) received maintenance therapy after tandem HDC/ASCT, twenty-two were treated with isotretinoin ± interleukin-2, and eight received salvage chemotherapy. The five-year overall survival (OS) and event-free survival (EFS) rates of all patients were 80.4% and 69.4%, respectively. Comparing the 131I-MIBG combined group and other groups, the five-year OS rates were 82.1% and 79.7% (p = 0.655), and the five-year EFS rates were 69.2% and 69.6% (p = 0.922), respectively. Among the adverse effects of grade 3 or 4, the incidence of liver enzyme elevation was significantly higher in the non-131I-MIBG group. Although tandem HDC/ASCT showed promising outcomes, the 131I-MIBG combination did not improve survival rates.

Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study

Neurokinin 3 receptor antagonists are potential non-hormonal therapies for the treatment of vasomotor symptoms in menopausal women as options are scarce for those who cannot or do not want to take hormone therapy. Fezolinetant is one of the first non-hormonal neurokinin 3 receptor antagonists in development for the treatment of vasomotor symptoms due to menopause. This study investigated the safety and efficacy of fezolinetant for the treatment of moderate-to-severe vasomotor symptoms associated with menopause. SKYLIGHT 1 is a randomised, double-blind, placebo-controlled, 12-week, phase 3 trial with a 40-week active treatment extension. This trial was done at 97 facilities across the USA, Canada, Czech Republic, Hungary, Poland, Spain, and the UK. Women aged 40-65 years with an average of seven or more moderate-to-severe hot flashes per day were randomly assigned (1:1:1) to once-daily exact-matched placebo, fezolinetant 30 mg, or fezolinetant 45 mg. Randomisation was done using a web-based interactive response system and investigators, project team members, clinical staff, and participants were masked to treatment assignment. Coprimary endpoints were mean change in frequency and severity of vasomotor symptoms from baseline to weeks 4 and 12. The efficacy and safety analyses comprised all randomly assigned participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT04003155) and is completed. Between July 11, 2019, and Aug 11, 2021, 2205 women were recruited of whom 175 were assigned to placebo, 176 to fezolinetant 30 mg, and 176 to fezolinetant 45 mg (175 in the placebo group, 174 in the fezolinetant 30 mg group, and 173 in the fezolinetant 45 mg received at least one dose [safety analysis set]). One participant randomly assigned to fezolinetant 45 mg received fezolinetant 30 mg in error, so the efficacy analysis set (full analysis set) consisted of 173 in the fezolinetant 30 mg group and 174 in the fezolinetant 45 mg group. 23 participants in the placebo group, 31 in the fezolinetant 30 mg group, and 13 in the fezolinetant 45 mg group discontinued treatment before week 12, mostly due to adverse events or participant withdrawal. Compared with placebo, fezolinetant 30 mg and fezolinetant 45 mg significantly reduced the frequency of vasomotor symptoms at week 4 (difference in change in least squares mean -1·87 [SE 0·42; p<0·001], -2·07 [SE 0·42; p<0·001]) and week 12 (-2·39 [SE 0·44; p<0·001], -2·55 [SE 0·43; p<0·001]). Compared with placebo, fezolinetant 30 mg and 45 mg significantly reduced the severity of vasomotor symptoms at week 4 (-0·15 [0·06; p=0·012], -0·19 [0·06; p=0·002]) and week 12 (-0·24 [0·08; p=0·002], -0·20 [0·08; p=0·007]). Improvements in frequency and severity of vasomotor symptoms were observed after 1 week and maintained over 52 weeks. During the first 12 weeks, treatment-emergent adverse events occurred in 65 (37%) of 174 women in the fezolinetant 30 mg group, 75 (43%) of 173 in the fezolinetant 45 mg group, and 78 (45%) of 175 in the placebo group. The incidence of liver enzyme elevations was low (placebo n=1; fezolinetant 30 mg n=2; fezolinetant 45 mg n=0) and these events were generally asymptomatic, transient, and resolved while on treatment or after treatment discontinuation. Data support the clinical use of fezolinetant as a non-hormonal treatment for vasomotor symptoms associated with menopause. The study was placebo-controlled for 12 weeks followed by a 40-week blinded extension to assess the maintenance of effect. Furthermore, the population studied was diverse and representative of the potential target population for fezolinetant therapy. Further characterisation of the benefit of fezolinetant on quality of life, including on symptoms of mood and sexual wellbeing, merits investigation. Astellas Pharma.

Liver enzyme elevation in patients with ankylosing spondylitis treated with tumor necrosis factor inhibitors: a single-center historical cohort study.

Background/AimsTumor necrosis factor inhibitors (TNFi) have been known to induce liver enzyme elevation, sometimes associated with viral reactivation or toxic hepatitis. We evaluated the incidence and risk factors of TNFi-associated liver enzyme elevation in Korean ankylosing spondylitis (AS) patients who previously had normal liver enzymes.MethodsRetrospectively, we collected data from the records of 363 AS patients treated with TNFi at a tertiary hospital from 2003 to 2017. Liver enzyme elevation was defined as abnormal elevation of aspartate aminotransferase and/or alanine aminotransferase levels on two or more consecutive visits. Patients with previously diagnosed liver disease were excluded.ResultsThe incidence of liver enzyme elevation was 23.7% (occurring in 86 of 363 patients). The median duration of TNFi exposure before liver enzyme elevation was 3.72 months (interquartile range, 1.77 to 12.51). There was no difference in the occurrence of liver enzyme elevation with concomitant disease-modifying anti-rheumatic drugs and TNFi compared to TNFi alone (23.9% vs. 23.6%). In multivariate analysis, the hazard ratios for liver enzyme elevation were 4.62 (95% confidence interval [CI], 1.43 to 15.01) for male sex, 4.06 (95% CI, 2.11 to 7.84) for underlying non-alcoholic fatty liver disease, and 2.53 (95% CI, 1.38 to 4.64) for hyperlipidemia. After switching to another TNFi, the liver enzyme elevation was not normalized in nine of 13 patients.ConclusionsLiver enzyme elevation was observed in a quarter of patients with AS receiving a TNFi. Male sex, non-alcoholic fatty liver disease, and hyperlipidemia were independent risk factors for liver enzyme elevation. Switching to another TNFi had a limited effect on restoring normal liver enzyme levels.

Incidence and risk factors for liver enzymes elevations in highly treatment-experienced patients switching from enfuvirtide to raltegravir: a sub-study of the ANRS-138 EASIER trial.

BackgroundIn the ANRS EASIER trial where treatment-experienced patients switched from enfuvirtide (ENF) to raltegravir (RAL), a high incidence of transaminase elevation was reported in the RAL arm.MethodsWe compared the incidence of emergent liver enzyme elevations (LEE) of grade 2 or more among patients randomized to the maintenance ENF arm or the switch RAL arm up to W24. We also assessed the overall incidence of LEE over the 48-week duration of the trial and baseline risk factors for grade 2 or more alanine aminotransferase (ALT) elevation using univariate and multivariate analyses.ResultsDuring the first 24 weeks, 6/84 (7.1 %) and 2/85 patients (2.4 %) presented with ALT elevation of grade 2 or more in the RAL and ENF arms, respectively (p = 0.21). Grade 2 or more γGT and ALP elevations were seen in 18 and 11 % (p = 0.35), and 5 and 1 % (p = 0.14) of patients in the RAL and ENF arms, respectively. The 48-week incidence of grade 2 or more LEE was 11.6 per 100-pts-years for ALT, 24.5 per 100-pts-years for γ-GT and 4.5 per 100-pts-years for ALP, respectively. In the multivariate analysis, tipranavir/ritonavir use (OR 3.66; 95 % CI [1.20–11.1], p = 0.022) and elevated ALT at baseline (OR 10.3; 95 % CI [2.67–39.6], p < 10−3) were significantly associated with a grade 2 or more ALT elevation during follow-up.ConclusionThe incidence of LEE was relatively high in these highly treatment-experienced patients switching to a RAL-based regimen. Both tipranavir/ritonavir use and high baseline ALT levels were associated with an increased risk of ALT.Trial registration: ClinicalTrials.gov identifier: NCT00454337

Prevalence and incidence of liver enzyme elevations in a pooled oncology clinical trial cohort

Few epidemiologic studies describe longitudinal liver chemistry (LC) elevations in cancer patients. A population-based retrospective cohort was identified from 31 Phase 2–3 oncology trials (excluding targeted therapies) conducted from 1985 to 2005 to evaluate background rates of LC elevations in patients (n = 3998) with or without liver metastases. Patients with baseline liver metastases (29% of patients) presented with a 3% prevalence of alanine transaminase (ALT) ≥ 3x upper limits normal (ULN) and 0.2% prevalence of bilirubin ≥ 3xULN. During follow-up, the incidence (per 1000 person-months) of new onset ALT elevations ≥3xULN was 6.1 (95% CI: 4.5, 8.0) and 2.2 (95% CI: 0.9, 4.5) in patients without and with liver metastases, respectively. No new incident cases of ALT and bilirubin elevations suggestive of severe liver injury occurred among those with liver metastases; a single case occurred among those without metastasis. Regardless of the presence of liver metastases, LC elevations were rare in cancer patients during oncology trials, which may be due to enrollment criteria. Our study validates uniform thresholds for detection of LC elevations in oncology studies and serves as an empirical referent point for comparing liver enzyme abnormalities in oncology trials of novel targeted therapies. These data support uniform LC stopping criteria in oncology trials.

Liver dysfunction in patients with severe anorexia nervosa.

Evaluation of liver dysfunction in patients with severe anorexia nervosa (AN) has typically been limited to small case series. We report an investigation into the admission characteristics and clinical outcomes associated with liver dysfunction in a large cohort of adults hospitalized for medical stabilization of severe AN. We retrospectively evaluated electronic medical records to quantify the cumulative incidence of elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT). We compared mean (±SD), frequencies (%), and median (IQR) values of clinical covariates of interest by incidence of liver enzyme elevation. The study included 181 adults, admitted for medical stabilization of AN, from October 1, 2008 to December 31, 2013. AST and ALT were mildly elevated in 27.6% of patients and severely elevated (more than three times the upper limit of normal) in 35.4% of patients. On admission, patients with severely elevated liver enzymes had a lower body mass index (BMI) (11.9 ± 1.8 kg/m(2) vs.13.3 ± 1.7 kg/m(2)), lower percentage ideal body weight (56.5% ± 7.7% vs. 63.5% ± 8.3%), and lower prealbumin (64% vs. 37%) compared with the rest of the cohort (p < 0.001). While hospitalized, patients with severely elevated liver enzymes more often developed hypoglycemia, hypophosphatemia, and experienced longer lengths of stay (p < 0.001). Elevated liver enzymes are common in our patient population with severe AN. Liver enzymes reached near normal values by the time of discharge. Severely elevated liver enzymes were associated with a lower BMI and the development of hypoglycemia.

Pattern of liver enzyme elevations in acute ST-elevation myocardial infarction

Liver enzyme elevations occur with ST-segment elevation myocardial infarction (STEMI); however, their significance in the modern era is not well-defined. The incidence of liver enzyme elevations in STEMI, temporal trends, correlations with creatine kinase-MB (CK-MB), and associations with clinical outcomes were evaluated. The Complement Inhibition in Myocardial Infarction Treated with Angioplasty and Complement Inhibition in Myocardial Infarction Treated with Thrombolytics trials evaluated 1903 patients with STEMI. A core lab analyzed liver enzymes at baseline, days 1, 6, and 14, and CK-MB measured sequentially over 72 h. The GUSTO model for 30-day mortality was used to predict clinical endpoints. A total of 1783 patients were included in the analysis. Aspartate transaminase (AST) was elevated above the upper limit of normal in 85.6% and alanine transaminase (ALT) was elevated in 48.2% of patients at baseline or day 1. CK-MB area under the curve correlated with maximum AST (r=0.727) and maximum ALT (r=0.456). Both AST and ALT elevations were independent predictors of worse outcomes in multivariable adjusted analysis, even after adjustment for CK-MB. Hazard ratios and 95% confidence intervals of AST elevation were 1.12 (1.05-1.19) for all-cause mortality, and 1.08 (1.02-1.13) for the composite endpoint of death, congestive heart failure, shock, or stroke. Hazard ratios and 95% confidence intervals of ALT elevation were 1.15 (1.04-1.27) for mortality and 1.47 (1.10-1.98) for the composite endpoint. AST and ALT elevations are common in STEMI. Both markers are correlated with CK-MB area under the curve, but independently associated with worse mortality and clinical outcomes.

Safety and Efficacy of Ambrisentan in the Treatment of Pulmonary Arterial Hypertension

Three different classes of specific therapy exist for pulmonary arterial hypertension. Ambrisentan belongs to the endothelin receptor antagonist (ERA) class of drugs, which inhibit the action of Endothelin-1; a potent vasoconstrictor and mitogen. Unlike bosentan and sitaxentan, it has a propanoic-acid based structure and like sitaxentan it has selective affinity for type A Endothelin receptors. Two large randomized controlled trials (ARIES-1 and ARIES-2) have demonstrated clinical benefit with ambrisentan in pulmonary arterial hypertension by repeated measurement of 6-minute walk distance. The most common adverse effect associated with ambrisentan use is peripheral edema, the incidence of liver enzyme elevation seen is lower than for other ERAs. Ambrisentan is safe in combination with warfarin and sildenafil. It offers further flexibility in the treatment of PAH as monotherapy and in combination. Although encouraging, trial data do not exhibit improved efficacy compared with other ERAs or sildenafil and there are no direct comparison studies. Long-term outcome data, including subgroup analysis are awaited to see if there are particular benefits of this therapy in PAH.

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.

Short Communication: Changes in Nevirapine Plasma Concentrations Over Time and Its Relationship with Liver Enzyme Elevations

Liver enzyme elevations are frequently seen in patients treated with nevirapine (NVP). Both elevated NVP plasma levels and hepatitis C virus (HCV) infection seem to favor the development of NVP-related liver toxicity. We have examined variation on NVP C(trough) over time, as well as the impact of NVP C(trough) concentrations and the role of chronic hepatitis C on the incidence of liver enzyme elevations over a 48-week study period in HIV-infected patients on NVP therapy. Thirty-seven patients who initiated a triple regimen of NVP (200 mg bid) plus two nucleoside reverse transcriptase inhibitors (NRTI) were analyzed. A significant increase in serum transaminase levels occurred progressively over time. However, no significant variations in NVP plasma C(trough) were noticed in 48 weeks. In total population, maximum fold increase (MFI) in serum AST, ALT, and GGT was correlated with 24 week NVP C(trough). In HCV+ subjects, 12-week NVP C(trough) was closely correlated with maximum transaminase elevations, whereas in HCV- patients, 24-week concentrations were correlated with maximum transaminase increase. However, no differences in either NVP plasma C(trough) or in MFI in transaminase levels could be determined when comparing patients with and without hepatitis C at any time point.

Hepatic Reactions During Treatment of Multiple Sclerosis with Interferon-??-1a

Hepatic dysfunction, manifested as liver enzyme elevations, occurs frequently in patients who are treated with interferon, however, data for patients with multiple sclerosis are limited. To retrospectively assess the safety profile of interferon-beta-1a therapy with respect to liver function during clinical trials and postmarketing surveillance in the treatment of multiple sclerosis. Adverse effects and laboratory abnormalities were analysed from six randomised, controlled clinical trials (five of which were placebo-controlled) that assessed the use of interferon-beta-1a in patients with multiple sclerosis. Treatment data were collected for 2819 patients for up to 12 months, of whom 1995 received interferon-beta-1a (337 [12%] received Avonex intramuscular therapy, and 1658 [59%] received Rebif subcutaneous therapy), and 824 (29%) received placebo. Data for 2 years were collated for 1178 patients (from two studies). Total weekly interferon doses were 22-132 microg. Postmarketing surveillance data were also analysed. In patients receiving interferon-beta-1a, there were significant elevations of alanine aminotransferase (ALT) levels, of all grades of severity, in up to 59% of patients at 6 months, up to 64% of patients at 12 months and up to 67% of patients at 24 months; ALT elevations were asymptomatic and dose related. More than 50% of elevations in liver enzymes occurred during the first 3 months of treatment, and more than 75% occurred during the first 6 months. Elevated enzyme levels resolved spontaneously or with dosage adjustment. Although the overall incidence of liver enzyme elevation was high during the early months of therapy, after 2 years, the proportion of patients with abnormal liver enzyme levels was 11% of those receiving Rebif 44 microg three times weekly compared with 6% of placebo-treated patients. Only 0.4% of patients discontinued interferon-beta-1a treatment because of hepatic adverse effects. Serious symptomatic interferon-related hepatic toxicity occurs, but is uncommon. Concomitant medication use was not associated with increased risk. Asymptomatic hepatic dysfunction is common in patients with multiple sclerosis who are treated with interferon-beta-1a, and is dose related. Adverse effects are mainly mild and transient, with little impact on adherence to therapy, although rare serious events can occur. Regular liver function monitoring during the first 6 months is recommended.

Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy.

This retrospective cohort study investigated whether particular antiretroviral agents are associated with a higher risk for developing grade 4 liver enzyme elevations (LEEs) in patients with human immunodeficiency virus (HIV) type 1 infection who are starting to receive highly active antiretroviral therapy (HAART). Grade 4 LEE was defined as aminotransferase levels >10 times the upper limit of normal and >200 U above baseline levels. A multivariate Cox model was used to identify risk factors. The incidence of LEE was 6.3%. No patients died of LEE consequences. Risk factors were higher baseline alanine aminotransferase levels, chronic hepatitis B or C virus infection, antiretroviral therapy-naive patients undergoing their first HAART regimen, recent start of a regimen of nevirapine or high-dose ritonavir, and female sex. In hepatitis B virus (HBV)-coinfected patients, discontinuing lamivudine (3TC) use was a risk factor. In 97% of cases, >or=1 risk factor was present. In HBV-coinfected patients using 3TC, continued use of 3TC should be considered, even if 3TC-resistant HIV strains develop.