Incidence Of Liver Toxicity Research Articles

Bridge-to-transplant stereotactic body radiation therapy in patients with hepatocellular carcinoma and advanced cirrhosis.

TPS496 Background: Liver cancer is the third most common cause of cancer related death worldwide, and hepatocellular carcinoma (HCC) accounts for 90% of all primary liver cancers, with pre-existing cirrhosis being a very strong risk factor for HCC development. Liver transplantation (LTx) is the best treatment for patients with HCC and advanced cirrhosis as both conditions can be very effectively treated at once. As LTx wait-lists can be many months, liver-directed therapies (LDT), including stereotactic body radiation therapy (SBRT) to one or few lesions are essential as oncologic temporizing measures to bridge patients to LTx and prevent progression outside of LTx criteria. However, due to the fear of further hepatic decompensation, many patients with advanced cirrhosis are excluded from receiving LDT. Rather, recent studies suggest that SBRT be of safe and practical use in this fragile patient population with advanced cirrhosis and HCC, and thereby reduce the rate of transplantation drop-out. This pilot prospective study will assess the feasibility, safety and efficacy of bridge-to-transplantation SBRT for patients with advanced cirrhosis and HCC. Methods: Patients with non-metastatic and unresectable HCC and Child-Pugh (CP)-B8 or worse cirrhosis who are within Milan criteria (one tumor ≤ 5 cm in diameter or no more than 3 tumors each ≤ 3 cm in diameter) and have been listed or recommended to be listed for liver transplantation will be eligible for participation. Eligible participants will undergo SBRT consisting of 40 Gy to be given in 5 fractions every other day to the only or largest lesion, provided that criteria for normal organ constraints are met. In cases where normal organ constraints are not met, the dose will be iteratively de-escalated to two dose levels (35 Gy in 5 fractions, then 30 Gy in 5 fractions). If normal organ constraints are unable to be met at 30 Gy in 5 fractions, the participant will be considered ineligible for SBRT and considered a screen failure. The primary endpoint is the proportion of participants who are transplanted or with localized disease control that meets Milan criteria within a year of SBRT. Secondary endpoints will include localized control rate (mRECIST), incidence of intra- or extra-hepatic progressive disease (mRECIST), overall survival, incidence of liver toxicity per CTCAE v5.0, incidence of non-classical radiation-induced liver disease (defined as CTCAE grade 4 AST/ALT elevation or an increase in CP score of ≥ 2 within 3 months of SBRT) and quality of life scores per QLQ-C30 and FACT-Hep questionnaires. The study is open, aiming to enroll 15 patients with 8 patients enrolled at time of submission. Clinical trial information: NCT03812289.

Histopathologic evaluation of liver metastases from colorectal cancer in patients treated with FOLFOXIRI plus bevacizumab

Background:The FOLFOXIRI regimen produces a high rate of radiological and histopathological responses. Bevacizumab added to chemotherapy showed an improvement in pathological response and necrosis of colorectal liver metastases (CLMs). FOLFOXIRI plus bevacizumab produced promising early clinical results and is under investigation in several randomised trials, although no data are currently available on its effects on response of CLMs and on liver toxicities.Methods:Starting from 499 patients enrolled in first-line phase II/III trials, we selected on the basis of tissue sample availability 18 patients treated with FOLFOXIRI/XELOXIRI and 24 patients treated with FOLFOXIRI plus bevacizumab who underwent secondary resection of CLMs. The 28 untreated patients who underwent primary resection of CLMs were included as control group. Responses of CLMs and chemotherapy-induced toxicities were assessed.Results:Among the patients, 63% of those treated with FOLFOXIRI plus bevacizumab, as compared with 28% of those treated with only FOLFOXIRI/XELOXIRI, showed a histopathological response (P=0.033). In the two groups, 52% and 12.5%, respectively, showed necrosis ⩾50% (P=0.017). The incidence of liver toxicities was not significantly increased in patients treated with FOLFOXIRI plus bevacizumab.Conclusion:The addition of bevacizumab to FOLFOXIRI produces high rates of pathologic responses and necrosis of CLM without increasing liver toxicity.

HIV Co-Infection with Hepatotropic Viruses and Mycobacterial Tuberculosis

HIV Co-infection complicates the natural history, clinical course, therapy and management for HIV. The individuals affected represent a treatment challenge fraught with controversies associated with drug resistance, cross-resistance, hepatotoxicity and suboptimal response. This is a descriptive review of co-infection in HIV positive individuals. Studies have shown that HIV co-infection accelerates the natural course of hepatotropic viruses and increased risk of liver cirrhosis, hepatocellular carcinoma, and decompensated liver disease in co-infected individuals. Studies have equally shown increased risk of progression to acquired immunodeficiency syndrome AIDS and AIDS-related death among HIV/HCV co-infected persons and HCV may affect the management of HIV infection, increasing the incidence of liver toxicity associated with antiretroviral regimens. Dual HBV/ HCV co-infection tend to have more severe liver cirrhosis and hepatitis decompensation, and a higher incidence of hepatocellular carcinoma. HIV is a strong risk factor for TB. High prevalence rates are significantly correlated with high TB incidence rates. Tuberculosis equally accelerates the progression of disease in HIV. Co-infection with HIV is a growing public health problem worldwide. There is need for enlightenment and further researches to highlight the importance of public health follow-up and reduction measures for HIV co-infected individuals in order to prevent subsequent infections.

Nevirapine-associated liver toxicity and hypersensitivity reactions in a cohort of HIV-1-infected patients,clinical analysis

Antiretroviral drug-related liver injury is a common cause of morbidity and treatment discontinuation in HIV-infected patients. Nevirapine is incriminated as one of the liver toxicity inducer especially in patients with high CD4-cells count. The purpose of our study was to analyze the role of CD4 cell count at treatment initiation and that of several co-factors (Hepatitis C or Hepatitis B virus co-infection, concurrent use of protease inhibitors) on the incidence of liver toxicity and hypersensivity reactions induced by Nevirapine in our HIV1-infected patients.

Incidence of Liver Toxicity in Inflammatory Bowel Disease Patients Treated with Methotrexate: A Meta-Analysis of Clinical Trials

Crohn's disease and ulcerative colitis are chronic debilitating diseases for which there are multiple treatment options. There are limited data on methotrexate's efficacy and safety profile. Our aim was to estimate the hepatotoxicity associated with its use in inflammatory bowel diseases (IBDs). We systematically searched the Medline, Cochrane Library, Web of Science, and EMBASE databases and manually examined references in selected articles for trials that used methotrexate as a treatment for IBDs. Thirteen trials that fulfilled the inclusion and exclusion criteria were included in the meta-analysis. Information on trial and patient characteristics, use of methotrexate as well as other treatments or placebo, and levels of hepatic aminotransferase enzymes were abstracted by two independent investigators using a standardized form. A random effects model was used to pool the incidence rates of reported abnormalities in hepatic aminotransferases. The pooled incidence rate of abnormal hepatic aminotransferase levels (defined as up to a 2-fold increase over the upper limit of the normal range) in patients treated with methotrexate for IBD was 1.4 per 100 person-months, while the rate of hepatotoxicity (defined as greater than a 2-fold over the upper limit of the normal range) was 0.9 per 100 person-months. The rate of withdrawal from treatment due to these abnormalities was 0.8 per 100 person-months. The incidence of methotrexate-related hepatotoxicity as measured by elevation in transaminases and drug withdrawal secondary to elevated transaminases is relatively low.

Gastric adenocarcinoma treated with radiation with or without epirubicin-based chemotherapy: Evaluation of radiation-induced liver disease.

110 Background: Anthracycline chemotherapy has been associated with radiation-induced liver disease (RILD). We sought to compare the incidence of liver toxicity among patients with gastric adenocarcinoma treated with radiotherapy (RT) with or without epirubicin-based chemotherapy. Methods: We performed a retrospective analysis of 94 patients with gastric adenocarcinoma treated at Massachusetts General Hospital since November 2005 and the Dana-Farber Cancer Institute since August 1998. All patients underwent definitive surgery and RT (median dose 45 Gray) with a minimum follow up of 6 months. Primary endpoints were development of ascites, radiographic liver change and elevations in liver function tests (LFTs), including alkaline phosphatase (ALP), aspartate transaminase (AST) and alanine transaminase (ALT). Results: In total, 34 patients received epirubicin-based chemotherapy including 9 perioperatively (6 with oxaliplatin and capecitabine [EOX]; 2 with cisplatin and 5-flourouracil [ECF]; 1 with oxaliplatin and 5-flourouracil [EOF]) and 25 postoperatively (2 EOX; 22 ECF; 1 combination). Seven patients were treated with neoadjuvant RT; 87 received adjuvant RT a median of 88 days after surgery (interquartile range 73-108 days). Twenty-one patients developed ascites within 6 months of completing RT, all but one of whom developed peritoneal carcinomatosis or metastatic disease. Among 57 patients that did not develop metastases, maximum elevations in LFTs were similar in patients that received epirubicin-based chemotherapy compared to those who did not (ALP/AST/ALT 150/44/50 vs. 142/41/44, p=0.25/0.36/0.14, respectively), as were rates of radiographic liver change (22% vs. 13%, p=0.44). Conclusions: Epirubicin-based chemotherapy does not significantly increase the risk of RILD in a recent cohort of patients treated with modern RT techniques and dose-constraints. In this setting, treatment of gastric adenocarcinoma with RT and either pre- or postoperative chemotherapy is well tolerated with low rates of liver toxicities. Development of liver toxicity, particularly ascites, within six months of RT may be a harbinger of metastatic disease. No significant financial relationships to disclose.

Management of Pulmonary Arterial Hypertension with Sitaxentan Sodium

Pulmonary arterial hypertension (PAH) is a chronic and progressive disease with a poor prognosis if left untreated. Pathophysiological alterations in this disease lead to vasoconstriction, endothelial and smooth muscle cell proliferation, and in situ thrombosis. Endothelin-1 (one of the most potent vasconstrictors known), has been shown to be increased in PAH, contributing, in part at least, to these abnormalities. Endothelin acts through the binding of two receptors, ETA and ETB. Sitaxentan is a selective ETA endothelin receptor antagonist that has been demonstrated, in several clinical trials, to improve exercise capacity, functional class and hemodynamics. Sitaxentan has a good safety profile, is well tolerated and has a low incidence of liver toxicity.

Liver Toxicity After Switching or Simplifying to Nevirapine-Based Therapy Is Not Related to CD4 Cell Counts: Results of the TOSCANA Study

Purpose:The TOSCANA study aimed to determine the relationship between CD4 cell counts and liver toxicity in patients undergoing treatment simplification or substitution with nevirapine due to the toxicity or poor tolerability of a previous regimen.Methods: A retrospective analysis was conducted of patients with prior viral suppression who were switched to nevirapine.Results: Overall, 221 patients were included, representing 1134.83 patient-years. The median baseline CD4 cell count at the switch was 464 cells/µL, with 75.6% showing high CD4 cell counts (≥250 cells/µL in women or ≥400 cells/µL in men). Hepatotoxicity, defined as liver aminotransferase levels 5 times above the upper limit of normal, was detected in 6.7% of the participants with high CD4 cell counts and 13.0% in those with low counts. The relative risk was 0.51 (95% CI 0.21–1.25), and the incidence rates were 2.63 and 1.26 per 100 patient-years for the low- and high-count subpopulations, respectively. Liver toxicity was mild, reversible upon discontinuation, and more likely to appear after 6 months of nevirapine therapy.Conclusions: Switching to nevirapine was associated with a low incidence of liver toxicity that was unrelated to high CD4 cell counts in patients on prior antiretroviral therapy undergoing simplification or substitution therapy.

Low Rate of Adverse Hepatic Events Associated with Fosamprenavir/Ritonavir-Based Antiretroviral Regimens

Purpose: To appraise the incidence of liver toxicity in a population of patients receiving fosamprenavir/ritonavir (FPV/r) with a high frequency of viral hepatitis co-infection. Method: 636 patients, 341 (54%) with HCV antibodies and 38 (5.6%) bearing serum HBsAg, were recruited. All of them received FPV/r 700/100 twice every day. 93 (27%) patients who tested positive for HCV antibodies showed an AST to platelet ratio index (APRI) higher than 1.5, consistent with significant liver fibrosis. Results: After a median (range) follow-up time of 6.91 (0.46–20.66) months, 3 (0.47%) patients developed grade ⩾3 ALT elevation. All the former patients were hepatitis virus co-infected, 2 with hepatitis C virus and 1 with hepatitis B virus. The frequency of grade ⩾3 ALT elevation in patients with HCV antibodies was 0.58% and in those harbouring HBsAg it was 2.63%. 4 (0.62%) patients suffered from a liver decompensation and 1 died due to a hepatic cause while on follow-up. No patients with APRI equal to or higher than 1.5 showed grade ⩾3 ALT elevation. Conclusion: The incidence of adverse hepatic events in patients receiving FPV/r including combinations seems to be low, even in subjects co-infected with hepatitis virus and in those with significant liver fibrosis.

Hepatotoxicity of Antiretrovirals

Hepatotoxicity is a relevant adverse effect derived from the use of antiretrovirals that may increase the morbidity and mortality among treated HIV-infected patients and challenges the treatment of HIV infection. Although several antiretrovirals have been reported to cause fatal acute hepatitis, they most often cause an asymptomatic elevation of transaminase levels. In addition to ruling out a variety of processes not related to the use of antiretrovirals or to the HIV infection, for appropriate management of the complication it is necessary to deduce the possible pathogenic mechanisms of the hepatotoxicity. Among these mechanisms, direct drug toxicity, immune reconstitution in the presence of hepatitis C virus (HCV) and/or hepatitis B virus (HBV) co-infections, hypersensitivity reactions with liver involvement and mitochondrial toxicity play a major role, although several other pathogenic pathways may be involved. Liver toxicity is more frequent among subjects with chronic HCV and/or HCB co-infections and alcohol users. Complex immune changes that alter the response against hepatitis virus antigens might be involved in the elevation of transaminase levels after suppression of the HIV replication by highly active antiretroviral therapy (HAART) in patients co-infected with HCV/HBV. The contribution of each particular drug to the development of hepatotoxicity in a HAART regimen is difficult to determine. The incidence of liver toxicity is not well known for most of the antiretrovirals. Although it is most often mild, fatal cases of acute hepatitis linked to the use of HAART have been reported across all families of antiretrovirals. Acute hepatitis is related to hypersensitivity reactions in the case of non-nucleosides and to mitochondrial toxicity in the case of nucleoside analogues. Alcohol intake and use of other drugs are other co-factors that increase the incidence of transaminase level elevation among HIV-infected patients. The management of liver toxicity is based mainly on its clinical impact, severity and pathogenic mechanism. Although low-grade HAART-related hepatotoxicity most often spontaneously resolves, severe grades may require discontinuation of the antiretrovirals, for example when there is liver decompensation, hypersensitivity reaction or lactic acidosis.

Delavirdine: a review of its use in HIV infection.

Delavirdine, a bisheteroarylpiperazine derivative, is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that allosterically binds to HIV-1 reverse transcriptase, inhibiting both the RNA- and DNA-directed DNA polymerase functions of the enzyme. Delavirdine in combination with nucleoside reverse transcriptase inhibitors (NRTIs) produced sustained reductions in plasma viral loads and improvements in immunological responses in large randomised, double-blind, placebo-controlled studies of 48 to 54 weeks' duration. In patients with advanced HIV infection, triple therapy with delavirdine, zidovudine and lamivudine, didanosine or zalcitabine for 1 year significantly prolonged the time to virological failure compared with dual therapy (delavirdine plus zidovudine or 2 NRTIs; p < 0.0001). After 50 weeks' treatment, plasma HIV RNA levels were below the limit of detection (LOD; <50 copies/ml) for 40% of patients receiving triple therapy but for only 6% of those receiving dual NRTI therapy. Preliminary results suggest that delavirdine also has beneficial effects on surrogate markers as a component of protease inhibitor-containing triple or quadruple regimens. At 16 to 48 weeks, the minimum mean reduction in plasma viral load from baseline was 2.5 log10 copies/ml and mean CD4+ counts increased by 100 to 313 cells/microl. The proportion of patients with plasma HIV RNAlevels below the LOD (usually 200 to 500 copies/ml) ranged from 48 to 100% after > or = 16 weeks. Delavirdine was also effective as a component of saquinavir soft gel capsule-containing salvage regimens. Since delavirdine shares a common metabolic pathway (cytochrome P450 3A pathway) with other NNRTIs, HIV protease inhibitors and several drugs used to treat opportunistic infections in patients infected with HIV, the drug is associated with a number of pharmacokinetic interactions. Some of these drug interactions are clinically significant, necessitating dosage adjustments or avoidance of co-administration. Delavirdine is not recommended for use with lovastatin, simvastatin, rifabutin, rifampicin, sildenafil, ergot derivatives, quinidine, midazolam, carbamazepine, phenobarbital or phenytoin. Importantly, the drug favourably increases the plasma concentration of several protease inhibitors. Delavirdine is generally well tolerated. Skin rash is the most frequently reported adverse effect, occurring in 18 to 50% of patients receiving delavirdine-containing combination therapy in clinical trials. Although a high proportion of patients developed a rash, it was typically mild to moderate in intensity, did not result in discontinuation or adjustment of treatment in most patients and resolved quickly. The occurrence of Stevens-Johnson syndrome was rare (1 case in 1,000 patients). A retrospective analysis of pooled clinical trial data indicated that there was no significant difference in the incidence of liver toxicity, liver failure or noninfectious hepatitis between delavirdine-containing and non-delavirdine-containing antiretroviral treatment groups. In addition, the incidence of lipodystrophy, metabolic lipid disorders, hyperglycaemia and hypertriglyceridaemia was not significantly different between these 2 treatment groups. In combination with NRTIs. delavirdine produces sustained improvements in surrogate markers of HIV disease and prolongs the time to virological failure in adult patients with HIV infection. Preliminary data of delavirdine as a component of protease inhibitor-containing triple or quadruple highly active antiretroviral therapy regimens indicate that patients achieve marked improvements in virological and immunological markers. The drug is generally well tolerated, with a transient skin rash, typically of mild to moderate intensity, being the most common adverse effect. Delavirdine is an effective component of recommended antiretroviral treatment strategies for adult patients with HIV infection and, in combination with 2 NRTIs as a first-line therapy, the drug has the advantage of sparing protease inhibitors for subsequent use. Since delavirdine favourably increases plasma concentrations of several protease inhibitors, the drug may also be beneficial as a component of salvage therapy in combination with protease inhibitors.

前立腺癌患者に対するフルタミド投与前後の肝機能の検討

The incidence of flutamide-induced liver toxicity was studied in 30 consecutive patients with prostate cancer who were treated with total androgen blockage (TAB) therapy (luteinizing hormone releasing hormone [LHRH] analogue and flutamide) in our hospital during the last 3 years and in 20 consecutive patients with prostate cancer who were treated by partial androgen blockage (PAB) therapy (LHRH analogue alone). Liver function test, including measurement of serum levels of aspartate aminotransferase (AST) alanine aminotransferase (ALT), total cholesterol, total bilirubin, gamma-glutamyl transpeptidase (gamma-GTP), and cholinesterase were performed at regular interval. The incidence of liver toxicity in patients receiving TAB (10 cases of 25 patients) was significantly higher than in patients receiving PAB (2 of 18 patients). Two patients in whom severe liver toxicity developed after receiving TAB were hospitalized. However, after flutamide was discontinued all patients with liver damage recovered with normalization of AST and ALT levels. Levels of total cholesterol and gamma-GTP did not differ significantly in either patient group. In two patients receiving TAB total bilirubin levels showed slight, transient elevations after maximum elevations of AST and ALT. In 80% of patients receiving TAB serum levels of cholinesterase were significantly higher than those in patients receiving PAB. These data suggest that the risk of flutamide-induced liver toxicity is significant in patients receiving TAB. However, this damage can be normalized after flutamide has been discontinued. Serum levels of cholinesterase also increase significantly in patients receiving TAB. This previously unreported phenomenon suggests an unknown effect of flutamide on liver function in patients with prostate cancer.

Isoniazid chemoprophylaxis. Association with detection and incidence of liver toxicity

The hepatotoxicity of isoniazid was studied in a double blind fashion in 120 adult patients receiving the drug for chemoprophylaxis. The incidence of abnormal SGOT values was significantly higher in those on the drug, 18.3% having elevated values as compared to 6.7% of those on placebo during the three-month study period. There was no statistical difference in the frequency of symptoms suggestive of liver diseases between the isoniazid and placebo groups. Furthermore, there was no significant relationship between symptoms and elevated SGOTs. Therefore, symptomatology would not appear to be a sensitive method for detecting early isoniazid liver toxicity. From available evidence, biochemical monitoring would appear to detect liver toxicity at an earlier and more reversible stage.