Dynamics of SARS-CoV-2 RT-PCR positivity and seroprevalence among high-risk healthcare workers and hospital staff.

Staff working in units that were highly exposed to coronavirus disease 2019 were invited to participate in a 6-month study on the carriage and seroprevalence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The results from visits on Day 1 and Day 15 show that 41 cases of SARS-CoV-2 infection were confirmed by reverse transcriptase polymerase chain reaction and/or serology in 326 participants (overall infection rate 12.6%). The presence of comorbidities or symptoms at the time of sample collection was a risk factor for infection, but working as a physician/nurse was not a risk factor. Universal screening in high-risk units, irrespective of symptoms, allowed the identification of asymptomatic and potentially contagious infected workers, enabling them to self-isolate for 7 days.

Meropenem-clavulanate for drug-resistant tuberculosis: a follow-up of relapse-free cases.

BACKGROUND: Extensively drug-resistant tuberculosis (XDR-TB), defined as TB caused by a Mycobacterium strain resistant to at least rifampicin, isoniazid, any fluoroquinolone and one of the injectable anti-tuberculosis drugs, remains a worldwide public health threat. Among repurposed drugs empirically used for XDR-TB cases, carbapenems have been studied in vitro and in animal models, with encouraging results. However, only short-term follow-up data from clinical studies are currently available. OBJECTIVES: To study the long-term follow-up of XDR-TB cases treated with a regimen containing meropenem-clavulanate (M/Clav). DESIGN: Retrospective observational case series study at a single hospital. METHODS: All hospitalised drug-resistant TB patients who received M/Clav as part of their treatment from 2009 to 2016 were included. Demographic and clinical data were extracted from medical records. RESULTS: Eighteen XDR-TB patients were included in the analysis. The successful outcome and mortality rates were respectively 83.3% and 11.1%. No relapses were observed in cured patients after a median follow-up of 4 years. No specific adverse events were attributed to treatment with M/Clav. CONCLUSION: The rate of sustained successful treatment outcome observed here is far higher than the 26% observed in the 2014 World Health Organization XDR-TB cohort, suggesting that carbapenems may be beneficial for the treatment of difficult-to-treat TB cases.

[Professional fatigue syndrome (burnout) : Part 2 : from therapeutic management]. / Syndrome de fatigue professionnelle (burnout) 2ème partie : de la prise en charge thérapeutique.

Burnout or professional fatigue syndrome is the result of exposure to a situation in which the strategies of the subject who are supposed to manage the stresses of the environment become outdated and inoperative. An imbalance is created between the demands and the material, operational and psychological resources to cope with them. Many health professions are confronted with the challenge of managing burnout, but the general practitioner is very often on the front line. After a first article devoted to the epidemiology, diagnosis, causes and consequences of the burnout, this second article is focusing on its therapeutic management, through listening, sick leave, dietary supplements, antidepressants, behavioural and cognitive therapy, professional coaching and multidisciplinary approach.

on disponible Résumé : Le burnout ou syndrome de fatigue professionnelle est le résultat de l'exposition à une situation durant laquelle les stratégies du sujet, qui sont censées gérer les stress de l'environnement, deviennent dépassées et inopérantes. Un déséquilibre se crée entre l'exigence des demandes et les ressources matérielles, opérationnelles et psychologiques pour y faire face. De nombreuses professions de santé se trouvent confrontées au défi de la prise en charge du burnout, dont le médecin généraliste. Après un premier article dédié à l'épidémiologie, au diagnostic, aux causes et aux conséquences du burnout, ce second article est consacré à la prise en charge de ce syndrome. Il se centre sur la prise en charge thérapeutique par l'écoute, l'interruption du temps de travail, les compléments alimentaires, les antidépresseurs, la thérapie comportementale et cognitive, le coaching professionnel et l'approche multidisciplinaire.

[Professional fatigue syndrome (burnout). Part 1 : identification by the general practitioner]. / Syndrome de fatigue professionnelle (burnout) 1ère partie : de l'identification par le médecin généraliste.

Burnout or professional fatigue syndrome has never been more talked about than in recent times. It is the result of exposure to a situation in which the strategies of the subject who are supposed to manage the stresses of the environment become outdated and inoperative. An imbalance is created between the demands and the material, operational and psychological resources to cope with them. Many health professions are confronted with the challenge of managing burnout. Among them, the general practitioner is very often on the front line. This paper is dedicated to him in priority. In its first part, it deals successively with the classification of the pathology (ICD-10 and DSM-5), its prevalence, its socio-economic impacts, its clinical picture (three stages), its diagnosis (by clinic and questionnaires), its causes, its evolution (from denial to acceptance), and its long-term consequences in the absence of treatment.

Le burnout ou syndrome de fatigue professionnelle n'a jamais autant fait parler de lui que ces derniers temps. Il est le résultat de l'exposition à une situation durant laquelle les stratégies du sujet, qui sont censées gérer les stress de l'environnement, deviennent dépassées et inopérantes. Un déséquilibre se crée entre l'exigence des demandes et les ressources matérielles, opérationnelles et psychologiques pour y faire face. De nombreuses professions de santé se trouvent confrontées au défi de la prise en charge du burnout. Parmi celles-ci, le médecin généraliste est très souvent en première ligne. Cet article s'adresse à lui en priorité. Dans ce premier volet, il traite successivement de la classification de la pathologie (ICD-10 et DSM-5), de sa prévalence, de ses impacts socio-économiques, de son tableau clinique (trois stades), de son diagnostic (par la clinique et les questionnaires), de ses causes, de son évolution (du déni à l'acceptation) et de ses conséquences à long terme en l'absence de traitement.

Isolation unit for multidrug-resistant tuberculosis patients in a low endemic country, a step towards the World Health Organization End TB Strategy.

Tuberculosis (TB) remains a threat to public health and is the second cause of death due to a single infectious agent after HIV/AIDS. The worldwide distribution of TB is heterogeneous. The incidence is decreasing in most high-income regions, but the situation remains worrying in many parts of the world. The emergence of Mycobacterium tuberculosis strains resistant to key agents used in treatment (rifampin and isoniazid) contributes to TB transmission around the world. To achieve TB elimination, both high and low endemic countries must upscale their efforts to decrease disease transmission and improve cure rates. Management of drug-resistant TB is of particular importance. In this paper, we discuss the different models of care of multidrug-resistant TB (MDR-TB), the ethical considerations and the specific constraints present in high income countries. The management model chosen by the Belgian TB specialists in accordance with public health authorities as well as building of a specific MDR/XDR-TB isolation unit are also discussed.

Auditing HIV Testing Rates across Europe: Results from the HIDES 2 Study.

European guidelines recommend the routine offer of an HIV test in patients with a number of AIDS-defining and non-AIDS conditions believed to share an association with HIV; so called indicator conditions (IC). Adherence with this guidance across Europe is not known. We audited HIV testing behaviour in patients accessing care for a number of ICs. Participating centres reviewed the case notes of either 100 patients or of all consecutive patients in one year, presenting for each of the following ICs: tuberculosis, non-Hodgkins lymphoma, anal and cervical cancer, hepatitis B and C and oesophageal candidiasis. Observed HIV-positive rates were applied by region and IC to estimate the number of HIV diagnoses potentially missed. Outcomes examined were: HIV test rate (% of total patients with IC), HIV test accepted (% of tests performed/% of tests offered) and new HIV diagnosis rate (%). There were 49 audits from 23 centres, representing 7037 patients. The median test rate across audits was 72% (IQR 32-97), lowest in Northern Europe (median 44%, IQR 22-68%) and highest in Eastern Europe (median 99%, IQR 86-100). Uptake of testing was close to 100% in all regions. The median HIV+ rate was 0.9% (IQR 0.0-4.9), with 29 audits (60.4%) having an HIV+ rate >0.1%. After adjustment, there were no differences between regions of Europe in the proportion with >0.1% testing positive (global p = 0.14). A total of 113 patients tested HIV+. Applying the observed rates of testing HIV+ within individual ICs and regions to all persons presenting with an IC suggested that 105 diagnoses were potentially missed. Testing rates in well-established HIV ICs remained low across Europe, despite high prevalence rates, reflecting missed opportunities for earlier HIV diagnosis and care. Significant numbers may have had an opportunity for HIV diagnosis if all persons included in IC audits had been tested.

Week 96 analysis of rilpivirine or efavirenz in HIV-1-infected patients with baseline viral load ≤ 100 000 copies/mL in the pooled ECHO and THRIVE phase 3, randomized, double-blind trials.

OBJECTIVES: These 96-week, ECHO/THRIVE pooled analyses evaluated data for antiretroviral treatment-naïve, HIV-1-infected adults with viral load (VL) ≤ 100 000 HIV-1 RNA copies/mL receiving rilpivirine or efavirenz. METHODS: ECHO and THRIVE were phase 3, randomized, double-blind trials. Patients received rilpivirine 25 mg once daily (qd) or efavirenz 600 mg qd, with a fixed (ECHO) or investigator-chosen (THRIVE) nucleoside/tide reverse transcriptase inhibitor (N[t]RTI) background regimen. Response rate (the percentage of patients with VL < 50 copies/mL, using an intent-to-treat-population, time-to-loss-of-virological-response algorithm), virological failure (VF), resistance development, safety and tolerability were evaluated. RESULTS: Baseline characteristics were comparable between the rilpivirine (n = 368) and efavirenz (n = 329) groups. At week 96, response rates [84% for rilpivirine vs. 80% for efavirenz; difference 4.0%; 95% confidence interval (CI) -1.7% to 9.7%] and incidences of VF for the resistance analysis (VFres) (8% for rilpivirine vs. 6% for efavirenz; P = 0.46) were similar in the two groups. Among patients with VFres , a comparable proportion in each group developed nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutations (RAMs). Among those with VFres , more patients in the rilpivirine group than in the efavirenz group developed N[t]RTI RAMs, mostly M184I/V. The mean (95% CI) CD4 cell count increased from baseline to week 96 by 224 (208-240) cells/µL in the rilpivirine group and by 206 (188-225) cells/µL in the efavirenz group. Treatment-related grade 2-4 overall adverse events, any rash and dizziness were less frequent for rilpivirine than for efavirenz (P < 0.0001). CONCLUSIONS: Rilpivirine demonstrated antiviral efficacy similar to that of efavirenz in antiretroviral treatment-naïve adults with baseline VL ≤ 100 000 copies/mL over 96 weeks. Frequencies of VFres and emergent NNRTI RAMs in each group were similar. More patients with VFres in the rilpivirine group than in the efavirenz group developed N[t]RTI RAMs (mostly M184I/V). Rilpivirine had a more favourable safety/tolerability profile than efavirenz.

Meningitis and splenic infarction due to disseminated Mycobacterium genavense infection in an HIV patient. Case report and review of the literature.

We report a case of disseminated infection with Mycobacterium genavense in a 58 year old HIV positive woman presenting with fever, diarrhea, abdominal pain and weight loss. She had a striking hepatosplenomegaly, abdominal lymphadenopathy, anaemia and thrombopenia. Direct smears and cultures of blood, stool, sputum, urine and bone marrow were negative for common and opportunistic microorganisms. Splenectomy revealed numerous acid fast bacill. Lumbar puncture also showed acid fast bacilli at direct examination. Specific PCR and 16s rRNA gene sequencing identified M. genavense. The outcome was fatal despite antimycobacterial therapy. M. genavense must be included in the differential diagnosis of fever, weight loss, lymphadenopathy and splenomegaly in immunocompromised patients. Prompt diagnosis is based on molecular biology methods. Empirical therapy, using at least three antimycobacterial agents, including clarithromycin should be introduced in case of high clinical suspicion.

Feasibility and acceptability of HIV screening through the use of rapid tests by general practitioners in a Brussels area with a substantial African community.

OBJECTIVES: To assess:1) if HIV screening with rapid tests in neighbourhoods with a substantial African community is feasible and acceptable among GPs and patients; 2) HIV seroprevalence. METHODS: Multicenter prospective study with 10 trained physicians. Use of HIV standard test and INSTI Ultrarapid test. INCLUSION CRITERIA: MSM, sex worker, multiple sexual partners, having returned or coming from a country with high HIV prevalence, IVDU, Indicator conditions as defined by HIV Indicator Diseases across Europe Study, having an AIDS-defining illness, having had a recent pregnancy or abortion; or presenting other risks. RESULTS: From August 2010 to August 2011, 10 trained GPs offered an HIV test to 224 patients: 51% ♀, 48% ♂, 43% Caucasians, 45% Africans. INCLUSION CRITERIA: 32% "high risk group", 9% returning from an endemic country, 29% with an indicator condition; 12 patients (6%) refused the standard test. The INSTI was offered to 217(97%), 197 performed with 2 reactive rapid tests confirmed. The seroprevalence according to ethnic origin was 0% among Caucasians and 2.2% among Africans and was 1.5% among patients with an indicator condition. 1087 consecutive consultations of the same GPs were recorded: 42% patients had ≥ 1 inclusion criteria among which 41% of offered tests, that is to say 59% of "missed opportunities". The reasons for not offering the test as recorded for 55% of patients:"not indicated" 44.5%, "no time" 33%, "impossible to propose" 15%, test completed previously 11%, known HIV-positive 4%. CONCLUSIONS: Standard and rapid tests are well received by patients but were usually not offered by doctors who have been trained.

Epidemiology of MDR-TB in a Belgian infectious diseases unit: a 15 years review.

INTRODUCTION: For the last 20 years the world has seen the emergence of a growing epidemic of MDR-TB, followed by the appearance of XDR-TB. Both require longer, more expensive and more toxic treatments. MDR-TB and especially XDR-TB are associated with a lower cure rate than non MDR-TB. MATERIALS AND METHODS: We reviewed retrospectively all cases of MDR-and XDR-TB managed at St Pierre University Hospital between 1996 and 2010. Epidemiological, clinical, bacteriological, treatment, follow up and outcome were collected and analysed. RESULTS: We recorded 73 instances of MDR-TB and 11 XDR-TB for a total of 78 patients. All but 4 patients were of non Belgian origin. 10 patients were co-infected with HIV. A median of 4 active drugs (1-5) were used for a median of 448 days (329-616). 41 MDR-TB (56%) and 1 XDR-TB (1%) were considered as cured and 20 are still on treatment. Since 2007, increasing resistance to second line injectable drugs, fluoroquinolones and even linezolid (1 case) is observed. Extensive resistance was mainly found in patients who had previously been mismanaged with second line agents. CONCLUSIONS: This study illustrates the growing epidemic of MDR and XDR-TB, it emphasizes the importance of proper diagnosis and adequate management of TB in patients at risk for resistance and stresses the need for new therapies.

The MONET trial: week 144 analysis of the efficacy of darunavir/ritonavir (DRV/r) monotherapy versus DRV/r plus two nucleoside reverse transcriptase inhibitors, for patients with viral load < 50 HIV-1 RNA copies/mL at baseline.

BACKGROUND: In the MONotherapy in Europe with Tmc114 (MONET) trial, darunavir/ritonavir (DRV/r) monotherapy showed noninferior efficacy vs. two nucleoside reverse transcriptase inhibitors (NRTIs) plus DRV/r at the primary 48-week analysis. The trial was continued to week 144 to assess the durability of the results. METHODS: A total of 256 patients with viral load < 50 HIV-1 RNA copies/mL on current highly active antiretroviral therapy (HAART) for at least 6 months switched to DRV/r 800/100 mg once daily, either as monotherapy (n=127) or with two NRTIs (n=129). Treatment failure was defined as two consecutive HIV RNA levels above 50 copies/mL [time to loss of virological response (TLOVR)] by week 144, or discontinuation of study drugs. RESULTS: Eighty-one per cent of patients were male and 91% were Caucasian, and they had a median baseline CD4 count of 575 cells/uL. More patients in the DRV/r monotherapy arm had hepatitis C virus coinfection at baseline than in the control arm (18% vs. 12%, respectively). By week 144, the percentage of patients with HIV RNA < 50 copies/mL [intent to treat (ITT), TLOVR, switch=failure method] was 69% vs. 75% in the DRV/r monotherapy and triple therapy arms [difference= -5.9%; 95% confidence interval (CI) -16.9%, +5.1%]; by a strict ITT analysis (switches not considered failures), the percentage of patients with HIV RNA < 50 copies/mL was 84% vs. 83.5%, respectively (difference= +0.5%; 95% CI -8.7%, +9.7%). Twenty-one and 13 patients had two consecutive HIV RNA results above 50 copies/mL in the DRV/r monotherapy arm and triple therapy arm, respectively, of whom 18 of 21 (86%) and 10 of 13 (77%) had HIV RNA < 50 copies/mL at week 144. CONCLUSIONS: In this study, for patients with HIV RNA < 50 copies/mL at baseline, switching to DRV/r monotherapy showed noninferior efficacy to DRV/r plus two NRTIs in a strict ITT (switches not considered failures) analysis, but not in a TLOVR switch equals failure analysis.

Clinical use of the meropenem-clavulanate combination for extensively drug-resistant tuberculosis.

Mycobacterium tuberculosis strains resistant to almost all available anti-tuberculosis drugs are an increasing threat to public health worldwide. Among existing drugs with potential antimycobacterial effects, the combination of meropenem with clavulanate has been shown to have potent in vitro bactericidal activity against extensively drug-resistant tuberculosis (XDR-TB). To explore its potential clinical efficacy, a meropenem-clavulanate-containing salvage regimen was started in six patients with severe pulmonary XDR-TB, in association with the only one or two remaining active second-line drugs. Encouraging preliminary data are detailed and discussed.

Virological response with fully active etravirine: pooled results from the DUET-1 and DUET-2 trials.

The objective of this subanalysis of the Phase III DUET trials was to examine virological response to an etravirine-containing regimen in patients harbouring virus fully sensitive to etravirine. Full etravirine sensitivity was defined as fold change in 50% effective concentration (FC) ≤3 or weighted genotypic score ≤2. At Week 48 in the etravirine group, 74% of patients with etravirine FC ≤3 and 77% with etravirine genotypic score ≤2 had viral load <50 HIV-1 RNA copies/mL, versus 48% and 46%, respectively, in the placebo group (P < 0.0001). Response rates increased with baseline phenotypic sensitivity score, but were consistently higher with etravirine (56-82%) than placebo (2-72%). Similar observations were made in patients harbouring virus with full etravirine and darunavir sensitivity. Our findings support current recommendations to include three active agents in treatment-experienced patients' regimens.

[The struggle against AIDS: between new paradigms and inertia]. / La lutte contre le Sida; entre nouveaux paradigmes et inerties.

Recent statistics on the global HIV epidemic illustrate that HIV incidence continues to increase and provide stark reminders of the urgent need for new and more effective HIV prevention tools. The new paradigm of HIV prevention strategies consists on a biomedical approach including circumcision, vaginal microbicides, pre and post exposure prophylaxis and the treatment of the infected individual. The goal of the ARV therapy is to reach level of plasma HIV indetectability. At less than 20c/ml the risk of sexual transmission is equal to zero. A mathematical model shows that by universal testing associated with immediate therapy the epidemic could be driven towards elimination by the year 2020. It is anticipated that there will be substantial barriers to making biomedical HIV prevention tools available to individuals who are the highest risk of infection. Operationalizing biomedical approaches will require tight links between HIV testing and treatment programs, as HIV testing will be the common entry point for people to receive either biomedical prevention tools or treatment.

Risk factors of osteopenia in HIV-infected women: no role of antiretroviral therapy.

OBJECTIVES: Osteopenia and osteoporosis are more frequent in HIV-infected patients. Whether antiretroviral therapy induces a bone mineral density (BMD) loss remains controversial and few data are available in women. This cross-sectional study of 89 pre-menopausal HIV-infected women evaluates the relationship between BMD and antiretroviral treatment. METHODS: Three groups of women were compared: women never treated (n=37), women treated with nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors and never treated with protease inhibitor (PI) (n=25) and women treated with a PI-containing regimen (n=27). Their lumbar spine and hip BMD was measured by dual-energy X-ray absorptiometry. We assessed also demographic parameters, body mass index (BMI), habits, history of HIV infection and treatment, lipodystrophy and metabolic and hormonal parameters. RESULTS: 83% were African women. Mean age was 37 years. Median duration of HIV treatment was 3.5 years. The overall prevalence of osteopenia/porosis was 31.5%. No difference was found between the three groups. Using logistic regression, low BMI was the only factor associated with osteopenia/porosis. CONCLUSION: Osteopenia/porosis was highly prevalent among these HIV-infected pre-menopausal women, mainly of African origin. BMD loss was not associated with antiretroviral therapy (containing PI or not) but was associated with a low BMI.

Working conditions predict incidence of long-term spells of sick leave due to depression: results from the Belstress I prospective study.

BACKGROUND: During the last few years, a high incidence of sick leave due to depression has been reported, resulting in important economic and social impacts. Only a limited number of studies investigating the influence of psychosocial working conditions on sick leave have been prospective and have utilised a valid methodology, while none have studied sick leave due to depression. In this study, the impact of adverse psychosocial working conditions is analysed on the risk for long-term sick leave due to depression. METHODS: This study resulted from the large-scale Belstress I study on the relationship between perceived job stress and health problems. Subjects were Belgian employees selected from 11 large companies (n = 9396). Using a longitudinal design, the association between the three Karasek stress dimensions (job control, psychological demand, and social support) was explored, separately and combined according to the demand-control and demand-control-support models and the incidence of long-term sick leave for depression as diagnosed by the family physician. RESULTS: After adjusting for age, occupational categories, living situation, and baseline depression score, 'passive jobs' (OR 2.67; 95% CI 1.15 to 6.19) and 'high strain' jobs (OR 3.23; 95% CI 1.40 to 7.43) predicted sick leave due to depression at follow-up in men. Job control predicted sick leave due to depression in both men (OR 2.43; 95% CI 1.27 to 4.66) and women (OR 2.21; 95% CI 1.05 to 4.68). CONCLUSIONS: This study provides evidence that the psychosocial working environment influences long-term sick leave due to depression. Efforts to improve skill discretion and decision authority at work could help prevent depression.

Indicator disease-guided testing for HIV--the next step for Europe?

HIV should preferably be diagnosed in its earlier stages. To optimize the chances of doing so, HIV testing in patients presenting with one of several indicator diseases and conditions is recommended. Patients presenting with tuberculosis and other AIDS-defining conditions should be tested. Patients with sexually transmitted diseases should be offered an HIV test, as should patients with certain types of cancers and laboratory abnormalities. Governments should consider adopting opt-out testing for pregnant women. These recommendations should be considered for implementation by all types of health professionals across Europe, and audits to study the extent of their being followed, conducted and reported to the European AIDS Clinical Society webpage (http://www.eacs.eu).

European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of HIV-infected adults.

A working group of the European AIDS Clinical Society (EACS) have developed these guidelines for European clinicians to help them in the treatment of adults with HIV infection. This third version of the guidelines includes, as new topics, the assessment of patients at initial and subsequent clinic visits as well as post-exposure prophylaxis. A revision of the 2005 guidelines based on current data includes changes in the sections on primary HIV infection, when to initiate therapy, which drug combinations are preferred as initial combination regimens for antiretroviral-naïve patients, how to manage virological failure and the treatment of HIV during pregnancy. In Europe, there is a wide range of clinical practices in antiretroviral therapy depending on various factors such as drug registration, national policies, local availability, reimbursement and access to treatment. These can vary greatly from one country to another, especially in Central and Eastern parts of Europe. These guidelines are intended to help clinicians achieve the best care for their patients. In some countries, particularly where the quality of and access to care are not optimal, these guidelines should help AIDS societies and physicians or patient group organizations to negotiate with their national health authorities with a view to implementing what should be the standard of care for HIV-infected patients all over Europe.

Hepatotoxicity observed in clinical trials of aplaviroc (GW873140).

Aplaviroc (APL) was a new CCR5 antagonist that was investigated in two dose-ranging studies with antiretroviral therapy-naïve, human immunodeficiency virus-infected adults: ASCENT, in which 147 subjects were randomized 2:2:1 to receive zidovudine-lamivudine (ZDV-3TC) plus APL 600 mg twice a day (BID), APL 800 mg BID, or efavirenz (EFV), respectively, and EPIC, in which 195 subjects were randomized 2:2:2:1 to receive lopinavir-ritonavir (LPV-RTV) plus APL 200 mg BID, APL 400 mg BID, APL 800 mg once a day, or ZDV-3TC BID, respectively. Both studies (and, ultimately, the clinical development of APL) were discontinued after a mean of 14 weeks of therapy because of higher than anticipated severe liver toxicity; grade 2 or higher treatment-emergent elevations in alanine aminotransferase (ALT) levels were observed in 17/281 (6.0%) APL recipients but only 2/55 (3.6%) control recipients, while grade 2 or higher elevations in total bilirubin levels occurred in 29/281 (10.3%) APL recipients but only 4/55 (7.3%) controls. Two APL recipients developed grade 3 or higher treatment-emergent elevations in both ALT and total bilirubin levels, and one of these individuals had a severe case of hepatic cytolysis that was attributed to APL. Despite the high intersubject variability in APL plasma exposures, a Pearson correlation analysis of the combined study data did not reveal any significant associations between plasma concentrations and the liver enzyme elevations observed during the study. The mechanism for the idiosyncratic hepatotoxicity observed in the clinical trials of APL is unknown but is likely intrinsic to the molecule rather than its novel mechanism of action.