https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(09)60918-1.pdf

Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial

Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs either as a predictable event when an individual is exposed to toxic doses of some compounds or as an unpredictable event with many drugs in common use. Drugs can be harmful to the liver in susceptible individuals owing to genetic and environmental risk factors. These risk factors modify hepatic metabolism and excretion of the DILI-causative agent leading to cellular stress, cell death, activation of an adaptive immune response and a failure to adapt, with progression to overt liver injury. Idiosyncratic DILI is a relative rare hepatic disorder but can be severe and, in some cases, fatal, presenting with a variety of phenotypes, which mimic other hepatic diseases. The diagnosis of DILI relies on the exclusion of other aetiologies of liver disease as specific biomarkers are still lacking. Clinical scales such as CIOMS/RUCAM can support the diagnostic process but need refinement. A number of clinical variables, validated in prospective cohorts, can be used to predict a more severe DILI outcome. Although no pharmacological therapy has been adequately tested in randomized clinical trials, corticosteroids can be useful, particularly in the emergent form of DILI related to immune-checkpoint inhibitors in patients with cancer.

/pdf/drug-induced-liver-injury-3n62mwaml0.pdf

Drug-induced liver injury

Objectives: To determine the influence of cytochrome P450 2B6 (CYP2B6) genotype on the rate of oxidative efavirenz metabolism in human liver microsomes. Materials & methods: Formation rates of 8-hydroxyefavirenz, 7-hydroxyefavirenz and 8,14-dihydroxyefavirenz were determined in vitro with efavirenz as a substrate (10 µM) in a large panel of human liver microsomes (n = 87) that were genotyped for variants of the CYP2B6 gene and phenotyped for CYP2B6 protein expression and bupropion hydroxylation. Results: Efavirenz 8-hydroxylation, the major route of efavirenz clearance, was detected in all samples, exhibiting an overall interindividual variability of 44.7-fold; 8,14-dihydroxyefavirenz and 7-hydroxyefavirenz were also detected in most samples. The formation rate of 8-hydroxyefavirenz correlated significantly with CYP2B6 protein (Spearman’s rS = 0.54; p < 0.0001) and bupropion hydroxylase activity (rS  = 0.73; p < 0.0001). Compared with the *1/*1 genotype, efavirenz 8-hydroxylation was significantly lower i...

Impact of CYP2B6 polymorphism on hepatic efavirenz metabolism in vitro.

Antibiotics used by general practitioners frequently appear in adverse-event reports of drug-induced hepatotoxicity. Most cases are idiosyncratic (the adverse reaction cannot be predicted from the drug's pharmacological profile or from pre-clinical toxicology tests) and occur via an immunological reaction or in response to the presence of hepatotoxic metabolites. With the exception of trovafloxacin and telithromycin (now severely restricted), hepatotoxicity crude incidence remains globally low but variable. Thus, amoxicillin/clavulanate and co-trimoxazole, as well as flucloxacillin, cause hepatotoxic reactions at rates that make them visible in general practice (cases are often isolated, may have a delayed onset, sometimes appear only after cessation of therapy and can produce an array of hepatic lesions that mirror hepatobiliary disease, making causality often difficult to establish). Conversely, hepatotoxic reactions related to macrolides, tetracyclines and fluoroquinolones (in that order, from high to low) are much rarer, and are identifiable only through large-scale studies or worldwide pharmacovigilance reporting. For antibiotics specifically used for tuberculosis, adverse effects range from asymptomatic increases in liver enzymes to acute hepatitis and fulminant hepatic failure. Yet, it is difficult to single out individual drugs, as treatment always entails associations. Patients at risk are mainly those with previous experience of hepatotoxic reaction to antibiotics, the aged or those with impaired hepatic function in the absence of close monitoring, making it important to carefully balance potential risks with expected benefits in primary care. Pharmacogenetic testing using the new genome-wide association studies approach holds promise for better understanding the mechanism(s) underlying hepatotoxicity.

/pdf/hepatic-safety-of-antibiotics-used-in-primary-care-3xfdfrcbqc.pdf

Hepatic safety of antibiotics used in primary care

In patients infected by HIV, the efficacy of highly active antiretroviral (ARV) therapy through the blockade of different steps of the retrovirus life cycle is now well established. As HIV is a retrovirus that replicates within the cells of the immune system, intracellular drug concentrations are important to determine ARV drug efficacy and toxicity. Indeed, nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs), newly available integrase inhibitors and protease inhibitors (PIs) act on intracellular targets. NRTIs are prodrugs that require intracellular anabolic phosphorylation to be converted into their active form of triphosphorylated NRTI metabolites, most of which have longer plasma half-lives than their parent compounds. The activity of intracellular kinases and the expression of uptake transporters, which may depend on cell functionality or their activation state, may greatly influence intracellular concentrations of triphosphorylated NRTI metabolites. In contrast, NNRTIs and PIs are not prodrugs, and they exert their activity by inhibiting enzyme targets directly. All PIs are substrates of cytochrome P450 3A, which explains why most of them display poor pharmacokinetic properties with intensive presystemic first-pass metabolism and short elimination half-lives. There is evidence that intracellular concentrations of PIs depend on P-glycoprotein and/or the activity of other efflux transporters, which is modulated by genetic polymorphism and coadministration of drugs with inhibiting or inducing properties. Adequate assay of the intracellular concentrations of ARVs is still a major technical challenge, together with the isolation and counting of peripheral blood mononuclear cells (PBMCs). Furthermore, intracellular drug could be bound to cell membranes or proteins; the amount of intracellular ARV available for ARV effectiveness is never measured, which is a limitation of all published studies. In this review, we summarize the findings of 31 studies that provided results of intracellular concentrations of ARVs in HIV-infected patients. Most studies also measured plasma concentrations, but few of them studied the relationship between plasma and intracellular concentrations. For NRTIs, most studies could not establish a significant relationship between plasma and triphosphate concentrations. Only eight published studies reported an analysis of the relationships between intracellular concentrations and the virological or immunological efficacy of ARVs in HIV patients. In prospective studies that were well designed and had a reasonable number of patients, virological efficacy was found to correlate significantly with intracellular concentrations of NRTIs but not with plasma concentrations. For PIs, the only prospectively designed trial of lopinavir found that virological efficacy was influenced by both trough plasma concentrations and intracellular concentrations. ARVs are known to cause important adverse effects through interference with cellular endogenous processes. The relationship between intracellular concentrations of ARVs and their related toxicity was investigated in only four studies. For zidovudine, the relative strength of the association between a decrease in haemoglobin levels and plasma zidovudine concentrations, as compared with intracellular zidovudine triphosphate concentrations, is still unknown. Similarly, for efavirenz and neuropsychological disorders, methodological differences confound the comparison between studies. In conclusion, intracellular concentrations of ARVs play a major role in their efficacy and toxicity, and are influenced by numerous factors. However, the number of published clinical studies in this area is limited; most studies have been small and not always adequately designed. In addition, standardization of assays and PBMC counts are warranted. Larger and prospectively designed clinical studies are needed to further investigate the links between intracellular concentrations of ARVs and clinical endpoints.

https://www.hal.inserm.fr/inserm-00461125/document

Intracellular Pharmacokinetics of Antiretroviral Drugs in HIV-Infected Patients, and their Correlation with Drug Action

Background Data on long-term central nervous system (CNS) toxicity associated with efavirenz therapy are scarce, and risk factors remain largely unknown. We aimed to determine whether monitoring the plasma concentration of efavirenz could predict neuropsychiatric adverse events associated with long-term therapy with efavirenz. Methods We performed a longitudinal study involving 17 consecutive human immunodeficiency virus (HIV)-infected subjects with virological suppression after at least 6 months of antiretroviral therapy with an efavirenz-containing regimen. Efavirenz plasma concentrations were measured at study entry and at different time points through an 18-month study period. Results Median duration of efavirenz therapy before study entry was 18 months (range, 6-27 months). Ten (58.8%) of the patients experienced CNS-related adverse effects, ranging from insomnia and abnormal dreams to depression with suicidal ideation. In 4 (23.5%) of the cases, CNS toxicity led to efavirenz discontinuation. Mean (+/- standard deviation) plasma levels were higher for patients experiencing neuropsychiatric symptoms (5.10 +/- 2.15 microg/mL vs. 2.79 +/- 1.31 microg/mL; P = .024). A plasma level of 2.74 microg/mL had a sensitivity of 90.9% and specificity of 72% to predict CNS toxicity (area under the curve, 0.839; 95% confidence interval, 0.73-0.95; P 2.74 microg/mL at any time point of the study were 5.68 times more likely to experiencing CNS toxicity than were other patients (95% confidence interval, 1.97-16.37). Conclusions In patients with HIV infection receiving long-term therapy with efavirenz-containing antiretroviral regimens, CNS toxicity is related to efavirenz plasma levels. Patients achieving higher plasma levels are at increased risk of experiencing neuropsychiatric adverse events.

Prediction of Neuropsychiatric Adverse Events Associated with Long-Term Efavirenz Therapy, Using Plasma Drug Level Monitoring

Disulfiram is widely used in the treatment of chronic alcoholism. Adverse drug reactions with fatal outcome following disulfiram therapy are infrequent, and hepatic failure accounts for most of them. Since disulfiram is a cytochrome P450 (CYP450) enzyme system inhibitor, numerous interactions with several drugs metabolized in the liver have been reported. Like disulfiram, clarithromycin inhibits a CYP450 isoenzyme, but, despite its widespread use for the treatment of respiratory tract infections, no interactions with disulfiram have been described as yet. We report a case of fatal toxic epidermal necrolysis (Lyell disease) and fulminant hepatitis shortly after starting treatment with clarithromycin in a patient who was receiving disulfiram. This is the first case of such a severe dermatosis in a patient receiving either disulfiram or clarithromycin therapy. The temporal relationship between drug administration and clinical symptoms in this case suggests a probable interaction between the 2 drugs.

Fulminant hepatitis and fatal toxic epidermal necrolysis (Lyell disease) coincident with clarithromycin administration in an alcoholic patient receiving disulfiram therapy.

Joaquín Borrás

Papers

Prediction of Neuropsychiatric Adverse Events Associated with Long-Term Efavirenz Therapy, Using Plasma Drug Level Monitoring

Fulminant hepatitis and fatal toxic epidermal necrolysis (Lyell disease) coincident with clarithromycin administration in an alcoholic patient receiving disulfiram therapy.