Risk factors for liver enzyme elevation with remdesivir use in the treatment of paediatric COVID-19.

AIM: Remdesivir (RDV) causes liver enzyme elevation in adults; however, the frequency of this elevation in children and the associated risk factors are largely unknown. Therefore, we aimed to examine risk factors for liver enzyme elevation in hospitalised paediatric patients who received RDV. METHODS: This was a retrospective case-control study of all patients aged <18 years who were diagnosed with coronavirus disease 2019 and received RDV at a tertiary care hospital between February 2022 and September 2023. Demographic and clinical data were retrieved from the medical records and analysed. Patients with liver enzyme elevation were defined as cases, while those with no liver enzyme elevation were defined as controls. The two groups were compared and analysed for possible risk factors for liver enzyme elevation with RDV use. RESULTS: Sixty-six patients were treated with RDV, 12 (18.2%) of whom developed liver enzyme elevation. Liver enzyme elevation was associated with the median duration of RDV administration (7.5 days vs. 3 days, P = 0.012), median total RDV dose (17.7 mg/kg vs. 10.3 mg/kg, P = 0.017) and acetaminophen use (67% vs. 22%) (odds ratio = 4.34; 95% confidence interval, 1.05-19.97, P = 0.023). All patients showed improvement, except three who had no liver enzyme measurements after having the highest aspartate aminotransferase and alanine aminotransferase values during the observation period. CONCLUSION: Liver enzyme elevation was reversible after discontinuing RDV use. Overall, RDV can be considered safe in children with careful monitoring.

Prevalence of hepatotoxicity among HIV-infected patients in Ethiopia: a systematic review and meta-analysis.

BACKGROUND: Globally, the human immunodeficiency virus has been recognized as a major public health concern. The direct toxicity of antiretroviral medicines or their active metabolites causes liver cell destruction by different mechanisms, inducing immune-mediated inflammation, oxidative stress, and other mechanisms. On the other hand, the virus itself also produces hepatotoxicity. Therefore, this systematic review and meta-analysis aimed to assess the pooled prevalence of hepatotoxicity among HIV-infected patients in Ethiopia. METHODS: PubMed, Science Direct, Cochrane Library, Web of Science, and ResearchGate databases were used to find relevant articles. As well, various professional associations were searched to retrieve grey literature. The Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of recruited studies. The data were extracted using Microsoft Excel, and the meta-analysis was carried out using STATA 14 software. I2 and Cochran's Q test were employed to assess the presence of heterogeneity between studies. A random effect model was used. The funnel plot and Egger's statistics were used to assess publication bias. Moreover, subgroup analysis and sensitivity analysis were also done. RESULTS: The pooled prevalence of hepatotoxicity among HIV patients in Ethiopia was 25.45% (95% CI = 20.06-30.84%). There was high heterogeneity, with an I2 value of 93.7%. Subgroup analysis by HAART status showed a higher pooled prevalence of hepatotoxicity among HIV patients taking HAART (23.63%) than among HAART naive patients (7.29%). In subgroup analysis, the pooled prevalence of hepatotoxicity among HIV/Tb co-infected and HIV mono-infected patients was 26.3% and 17.94%, respectively. CONCLUSION: The current systematic review and meta-analysis showed a high prevalence of hepatotoxicity among HIV-infected patients. Therefore, regular monitoring of hepatotoxicity among HIV-infected patients is required in order to avoid liver damage and other complications. Systematic review registration PROSPERO (2022:CRD42022334704).

Hepatotoxicity and Liver-Related Mortality in Women of Childbearing Potential Living With Human Immunodeficiency Virus and High CD4 Cell Counts Initiating Efavirenz-Containing Regimens.

BACKGROUND: Severe hepatotoxicity in people with human immunodeficiency virus (HIV) receiving efavirenz (EFV) has been reported. We assessed the incidence and risk factors of hepatotoxicity in women of childbearing age initiating EFV-containing regimens. METHODS: In the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, ART-naive pregnant women with HIV and CD4 count ≥ 350 cells/µL and alanine aminotransferase ≤ 2.5 the upper limit of normal were randomized during the antepartum and postpartum periods to antiretroviral therapy (ART) strategies to assess HIV vertical transmission, safety, and maternal disease progression. Hepatotoxicity was defined per the Division of AIDS Toxicity Tables. Cox proportional hazards models were constructed with covariates including participant characteristics, ART regimens, and timing of EFV initiation. RESULTS: Among 3576 women, 2435 (68%) initiated EFV at a median 121.1 weeks post delivery. After EFV initiation, 2.5% (61/2435) had severe (grade 3 or higher) hepatotoxicity with an incidence of 2.3 (95% confidence interval [CI], 2.0-2.6) per 100 person-years. Events occurred between 1 and 132 weeks postpartum. Of those with severe hepatotoxicity, 8.2% (5/61) were symptomatic, and 3.3% (2/61) of those with severe hepatotoxicity died from EFV-related hepatotoxicity, 1 of whom was symptomatic. The incidence of liver-related mortality was 0.07 (95% CI, .06-.08) per 100 person-years. In multivariable analysis, older age was associated with severe hepatotoxicity (adjusted hazard ratio per 5 years, 1.35 [95% CI, 1.06-1.70]). CONCLUSIONS: Severe hepatotoxicity after EFV initiation occurred in 2.5% of women and liver-related mortality occurred in 3% of those with severe hepatotoxicity. The occurrence of fatal events underscores the need for safer treatments for women of childbearing age.

Exposure-safety analyses of nintedanib in patients with chronic fibrosing interstitial lung disease.

BACKGROUND: Nintedanib reduces the rate of decline in forced vital capacity in patients with idiopathic pulmonary fibrosis (IPF), other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype and systemic sclerosis-associated ILD (SSc-ILD). The recommended dose of nintedanib is 150 mg twice daily (BID). METHODS: Data from Phase II and III trials in IPF and Phase III trials in SSc-ILD and progressive fibrosing ILDs other than IPF were analyzed to investigate the relationship between nintedanib plasma concentrations (exposure) and safety (liver enzyme elevations [defined as transaminase elevations equal or greater than 3 times the upper limit of normal] and diarrhea). RESULTS: Using data from 1403 subjects with IPF treated with 50-150 mg nintedanib BID, a parametric time-to-first-event model for liver enzyme elevations was established. Besides exposure, gender was a significant covariate, with a three-fourfold higher exposure-adjusted risk in females than males. Subsequent analysis of combined data from IPF, SSc-ILD (n = 576) and progressive fibrosing ILD (n = 663) studies suggested a consistent exposure-liver enzyme elevation relationship across studies. No exposure-diarrhea relationship was found using data from the various fibrosing ILDs, but diarrhea risk was dependent on dose administered. CONCLUSIONS: The positive correlation between exposure and risk of liver enzyme elevations was consistent across nintedanib studies in IPF, SSc-ILD and progressing fibrosing ILDs other than IPF. The effect size does not warrant a priori dose adjustment in patients with altered plasma exposure (excluding hepatic impairment patients, where there are specific labelling recommendations). For diarrhea, dose administered was a better predictor than exposure.

Chronic Liver Enzyme Elevation and Use of Contemporary ARVs Among People With HIV.

Background: While use of some older antiretroviral drugs (ARVs) is associated with chronic liver enzyme elevation (cLEE), the impact of newer ARVs remains unknown. Methods: People with HIV enrolled in the RESPOND cohort who started an ARV after January 1, 2012 were included (baseline). The primary outcome was first cLEE individuals were censored at first of cLEE, last visit, death, or December 31, 2021. Incidence rates (IRs; events/1000 person-years) were calculated for each ARV overall and by ARV exposure (6-12 months, 1-2 years, and 2+ years). Poisson regression was used to estimate the incidence rate ratio (IRR) of cLEE and its association with individual ARVs and ARV class. Results: Of 17 106 individuals included contributing 87 924 person-years of follow-up, 1932 (11.3%) experienced cLEE (incidence rate [IR], 22.0; 95% CI, 21.0-23.0). There was no evidence of a cumulative ARV effect on cLEE incidence, (6-12 months: IR, 45.8; 95% CI, 41.4-50.19; 1-2 years: IR, 34.3; 95% CI, 31.5-37.4; and 2+ years: IR, 18.5; 95% CI, 17.4-19.7). Any use (vs no prior use) of non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a class and tenofovir disoproxil fumarate (TDF) was independently associated with an increased IRR of cLEE, and any use of darunavir (DRV) was associated with a decreased risk of cLEE. Conclusions: cLEE is common and more frequent during the first year after initiating new ARVs. With a >5-year median follow-up, we found no short-term liver safety concerns with the use of INSTIs. Use of NNRTIs and TDF was associated with an increased cLEE risk, while DRV was associated with lower risk.

Elevated Liver Enzymes With Positive Hepatitis B Serology After Intravenous Immunoglobulin Treatment of Guillain-Barré Syndrome.

Intravenous immunoglobulin (IVIG) is used to treat multiple conditions, one of which is Guillain-Barré syndrome. Despite its multiple benefits, IVIG can cause a wide variety of side effects, most of which resolve with supportive care. We present a case in which a patient with new-onset Guillain-Barré syndrome was treated with IVIG and subsequently developed an acute elevation in liver enzymes with positive hepatitis B serology.

Esophageal achalasia with severe malnutrition and liver enzyme elevation.

A 70-year-old woman presented dysphagia and postprandial vomiting, and weight loss of about 15 kg in one year. She was markedly emaciated with a body mass index of 12.4 kg/m2 and had difficulty in movement. Esophagogastroduodenoscopy and computed tomography revealed stenosis of the esophagogastric junction (EGJ) with no malignant findings. Additionally, based on the findings of the esophagogram and high-resolution manometry, the patient was diagnosed with esophageal achalasia. The patient also had an elevation in liver enzymes but was ruled out alcoholic, drug-induced, viral, or other hepatitis. It was considered that malnutrition caused by esophageal achalasia led to a rise in liver enzymes. After the onset of nutritional therapy, the liver enzyme elevation deteriorated, electrolyte abnormalities and hypoglycemic attacks occurred frequently. She had developed the refeeding syndrome, thus feeding was reduced, but the condition deteriorated further and the liver enzymes reached a peak. These findings were assumed to be due to persistent malnutrition, and normalized with gradually increased nutrition. After improving the general condition, per-oral endoscopic myotomy (POEM) was performed. After POEM, her dysphagia disappeared and nutritional state completely improved. Careful nutritional therapy improved her general condition, and POEM improved gastrointestinal symptoms and prevented the recurrence of malnutrition.

Risk Factors Associated With Chronic Liver Enzyme Elevation in Persons With HIV Without Hepatitis B or C Coinfection in the Combination Antiretroviral Therapy Era.

BACKGROUND: As morbidity due to viral coinfections declines among HIV-infected persons, changes in liver-related morbidity are anticipated. We examined data from the US Military HIV Natural History Study (NHS), a cohort of military beneficiaries, to evaluate incidence and risk factors associated with chronic liver enzyme elevation (cLEE) in HIV-monoinfected patients in the combination antiretroviral therapy (cART) era. METHODS: Participants who were hepatitis B virus and hepatitis C virus seronegative with follow-up after 1996 were included. We defined chronic liver enzyme elevation (cLEE) as alanine aminotransferase elevations ≥1.25 times the upper limit of normal on at least 2 visits, for a duration of ≥6 months within 2 years. We used multivariate Cox proportional hazards models to examine risk factors for cLEE. RESULTS: Of 2779 participants, 309 (11%) met criteria for cLEE for an incidence of 1.28/100 PYFU (1.28-1.29/100 PYFU). In an adjusted model, cLEE was associated with Hispanic/other ethnicity (reference Caucasian: hazard ratio [HR], 1.744; 95% CI, 1.270-2.395), non-nucleoside reverse transcriptase inhibitor-based cART (reference boosted protease inhibitors: HR, 2.232; 95% CI, 1.378-3.616), being cART naïve (HR, 6.046; 95% CI, 3.686-9.915), or having cART interruptions (HR, 8.671; 95% CI, 4.651-16.164). African American race (HR, 0.669; 95% CI, 0.510-0.877) and integrase strand transfer inhibitor (INSTI)-based cART (HR, 0.222; 95% CI, 0.104-0.474) were protective. CONCLUSIONS: Our findings demonstrate that initiation and continued use of cART are protective against cLEE and support the hypothesis that HIV infection directly impacts the liver. INSTI-based regimens were protective and could be considered in persons with cLEE.

Risk Factors for Postoperative Liver Enzyme Elevation After Laparoscopic Gastrectomy for Gastric Cancer.

BACKGROUND/AIM: Laparoscopic gastrectomy (LG) is more frequently associated with postoperative liver enzyme elevation (PLEE) than open gastrectomy in phase III clinical trials for Japanese gastric cancer patients. The aim of this study was to determine the risk factors for PLEE after LG for gastric cancer. PATIENTS AND METHODS: This study enrolled 153 consecutive patients with gastric cancer who underwent LG. The patient characteristics, the liver retraction method [silicone disc (SD) or Nathanson liver retractor (NLR)], and perioperative outcomes were compared between patients with and without PLEE. RESULTS: PLEE was observed in 26 patients (17%). The patients with PLEE exhibited longer operative times (p=0.005) and more frequent use of the NLR for liver retraction (p=0.022). In the multivariate analysis, liver retraction using the NLR (p=0.003) and aberrant left hepatic artery (ALHA) ligation (p=0.042) were independent risk factors of PLEE. CONCLUSION: Liver retraction with the SD during LG was shown to be the safer method that is less likely to cause postoperative liver dysfunction. ALHA preservation may contribute to avoiding postoperative liver dysfunction.

Long-term safety and tolerability of atabecestat (JNJ-54861911), an oral BACE1 inhibitor, in early Alzheimer's disease spectrum patients: a randomized, double-blind, placebo-controlled study and a two-period extension study.

BACKGROUND: Atabecestat, a potent brain-penetrable inhibitor of BACE1 activity that reduces CSF amyloid beta (Aß), was developed for oral treatment for Alzheimer's disease (AD). The long-term safety and effect of atabecestat on cognitive performance in participants with predementia AD in two phase 2 studies were assessed. METHODS: In the placebo-controlled double-blind parent ALZ2002 study, participants aged 50 to 85 years were randomized (1:1:1) to placebo or atabecestat 10 or 50 mg once daily (later reduced to 5 and 25 mg) for 6 months. Participants entered ALZ2004, a 12-month treatment extension with placebo or atabecestat 10 or 25 mg, followed by an open-label phase. Safety, changes in CSF biomarker levels, brain volume, and effects on cognitive performance were assessed. RESULTS: Of 114 participants randomized in ALZ2002, 99 (87%) completed, 90 entered the ALZ2004 double-blind phase, and 77 progressed to the open-label phase. CSF Aß fragments and sAPPß were reduced dose-proportionately. Decreases in whole brain and hippocampal volumes were greater in participants with mild cognitive impairment (MCI) due to AD than in preclinical AD, but were not affected by treatment. In ALZ2004, change from baseline in RBANS trended toward worse scores for atabecestat versus placebo. Elevated liver enzyme adverse events reported in 12 participants on atabecestat resulted in dosage modification and increased frequency of safety monitoring. Treatment discontinuation normalized ALT or AST in all except one with pretreatment elevation, which remained mildly elevated. No case met ALT/AST > 3× ULN and total bilirubin > 2× ULN (Hy's law). CONCLUSION: Atabecestat was associated with trend toward declines in cognition, and elevation of liver enzymes. TRIAL REGISTRATION: ALZ2002: ClinicalTrials.gov, NCT02260674, registered October 9, 2014; ALZ2004: ClinicalTrials.gov, NCT02406027, registered April 1, 2015.

Liver damage in patients living with HIV on antiretroviral treatment with normal baseline liver function and without HBV/HCV infection: an 11-year retrospective cohort study in Guangxi, China.

OBJECTIVE: To characterise the association between duration of exposure to antiretroviral treatment (ART) and liver damage in HIV patients with an initially normal baseline liver function and without hepatitis B virus (HBV)/hepatitis C virus (HCV) infection. METHODS: A retrospective cohort study was conducted in HIV-infected individuals with normal liver function parameters at ART initiation and without HBV/HCV infection, from 14 April 2004 to 13 April 2015 in Guigang city, Guangxi, China. The association between duration of ART and liver damage (grade II-IV liver enzyme elevation [LEE] and/or total bilirubin elevation [TBE]), was analysed. Cox regression was used to examine the factors related to liver damage. RESULTS: Of 2119 eligible patients, 12.41% (263/2119) developed liver damage (grade II-IV LEE/TBE) and contributed 4.11/100 person-years crude incidence rate. The highest liver damage incidence was observed in patients with 6-12 months' ART (15.16/100 person-years). The incidence decreased to 5.56/100 person-years in patients with 12-18 months' ART and 3.13/100 person years in patients with 18-24 months' ART, and then maintained at a relatively low and stable level in patients with 2 years' ART or longer (average of 3.65/100 person-years). Cox regression analysis revealed that current WHO disease stage II, III or IV (compared with stage I) were the risk factors for liver damage, while baseline disease stage II, III (compared with stage I) and current regimen 3TC+AZT+NVP were the protective factors for liver damage. CONCLUSIONS: Liver damage always exists among HIV-infected patients on ART with normal baseline liver function and without HBV/HCV infection. Nevertheless, cumulative ART duration does not increase the risk of liver damage. ART could tend to be long-term, however, monitoring and management of liver damage among patients on ART are also important in clinical therapy.

Liver enzyme elevation in patients taking HAART compared with treatment naïve controls at Debre Berhan Referral Hospital: a comparative cross-sectional study, Northeast Ethiopia.

OBJECTIVE: HAART had significantly improved the quality of life of HIV patients. However, it results different adverse effects such as: hepatotoxicity, nephrotoxicity, lipodystrophy, anemia, diarrhea, psychiatric disorder and others. Therefore, this comparative cross sectional study was designed to investigate liver enzyme elevation in patients taking HAART compared with treatment naïve controls at Debre Berhan Referral Hospital. RESULT: A total of 152 individuals (76 cases and 76 controls) were included in this study. The mean ages of treatment and control groups were 37.37 and 36.38 respectively. The mean values of liver enzymes (ALT, AST and ALP), total bilirubin and direct bilirubin were significantly higher (p < 0.05) while, total protein and creatinine were significantly lower in patients taking HAART compared with treatment naïve controls. In this study, about 19 (25%) of clients in HAART treated groups and 7 (9.2%) of treatment naïve controls had showed liver enzyme changes. Moreover, 23.7% and 1.3% of the HAART treated groups developed mild and moderate liver enzyme elevation or hepatotoxicity, respectively. In this study, significant difference was observed in liver enzyme elevation between ART and pre-ART patients. As a result, regular clinical and laboratory monitoring of liver function will be necessary to prevent severe form of liver injury.

Direct oral anticoagulant successfully used to treat an adult nephrotic patient complicated with portal vein thrombosis.

Thromboembolism is a major complication of nephrotic syndrome, with the renal vein being the most frequent site. However, the incidence of portal vein thrombosis (PVT) in patients with nephrotic syndrome is rare. We report a case of a relapsed steroid-dependent minimal change disease with incidental PVT. A 38-year-old man presented with anasarca. Elevated liver enzymes were discovered during routine blood testing within days after commencing treatment. Although drug-induced liver injuries are frequently observed with mild aminotransferase abnormality during therapy with steroid or immune-suppressive agents, imaging revealed a massive thrombus of the portal vein, which was treated by anticoagulant therapy with edoxaban. Treatment with anticoagulant therapy could normalize liver function. Two months after the initiation of treatment with edoxaban, the follow-up CT scan and ultrasound showed the disappearance of PVT. Our case suggests that much attention should be paid to PVT as a cause of liver enzyme elevation when treating patients with nephrotic syndrome.

Modelling hepatotoxicity and antiretroviral therapeutic effect in HIV/HBV coinfection.

Enzyme alanine aminotransferase (ALT) elevation which reflects hepatocellular injury is a current challenge in people infected with human immunodeficiency virus (HIV) on antiretroviral therapy (ART). One of the factors that enhance the risk of hepatotoxicity is underlying diseases such as hepatitis caused by hepatitis B virus (HBV). HIV/HBV coinfected patients stand a greater risk of hepatotoxicity because all ART are toxic and liver cells (hepatocytes) that are responsible for metabolising the toxic ART, support all stages of HIV and HBV viral production. Mathematical models coupled with numerical simulations are used in this study with the aim of investigating the optimal combination of ART in HIV/HBV coinfection. Emtricitabine, tenofovir and efavirenz is the optimal combination that maximises the therapeutic effect of therapy and minimises the toxic response to medication in HIV/HBV coinfection.

Assessing risk of liver enzyme elevation in patients with immune-mediated diseases and different hepatitis B virus serostatus receiving anti-TNF agents: a nested case-control study.

BACKGROUND: Liver enzyme elevation is an important and common adverse effect among patients with immune-mediated diseases who receive tumour necrosis factor inhibitors (anti-TNF), and has various causes. Hence, we evaluated the relative risks of developing liver enzyme elevation in anti-TNF users with differing hepatitis B virus (HBV) infection status. METHODS: At a hospital in central Taiwan, 407 patients with rheumatoid arthritis, ankylosing spondylitis, or psoriasis/psoriatic arthritis received anti-TNF therapy between 1 January 2004 and 30 June 2012. We performed a nested case-control study (n = 368) of cases with serum alanine aminotransferase (ALT) > 40 international units/L ≤ 12 months after starting anti-TNF therapy, and corresponding controls without liver enzyme elevation. Conditional logistic regression was used to evaluate associations between liver enzyme elevation and HBV serostatus, as well as other risk factors. RESULTS: Thirty cases were compared to 338 controls. After adjustment for potential confounders, HBV surface antigen-positive (HBsAg+) serostatus was associated with substantially higher likelihood of developing elevated ALT (adjusted odds ratio 7.91, 95% confidence interval (CI) 2.16-31.31) relative to those with an uninfected HBV status; no such association was observed among HBsAg-negative/HBV core antibody-positive (HBsAg-/HBcAb+) patients (adjusted odds ratio 1.00, 95% CI 0.33-3.25). Increased risk of ALT elevation was associated with methotrexate used alone, without folic acid (adjusted odds ratio 11.60, 95% CI 2.52-56.46), and history of ALT elevation (adjusted odds ratio 13.71, 95% CI 4.32-45.75). CONCLUSIONS: HBsAg+ patients with immune-mediated diseases who received anti-TNF therapy had an approximately eight-fold higher likelihood of liver enzyme elevation than those without HBV infection, whereas patients with HBsAg-/HBcAb+ serostatus had a risk similar to that of uninfected patients.