Duloxetine hepatotoxicity: a case-series from the drug-induced liver injury network

Aliment Pharmacol Ther 2010; 32: 1174–1183Case reports suggest that duloxetine hepatotoxicity may arise, but risk factors, presenting features and clinical course are not well-described.To describe the presenting features and outcomes of seven well-characterized patients with suspected duloxetine hepatotoxicity.Patients enrolled in the Drug-Induced Liver Injury Network Prospective Study underwent an extensive laboratory and clinical evaluation to exclude competing aetiologies of liver injury as well as a standardized assessment for causality and disease severity.Between 1/2006 and 9/2009, six of the seven cases of DILI attributed to duloxetine were assessed as definite or very likely. Median patient age was 49 years, six (86%) were women and the median latency from drug initiation to DILI onset was 50 days. Six patients developed jaundice and the median peak alanine aminotransferase in the five patients with acute hepatocellular injury was 1633 IU/L. Ascites developed in one patient and acute renal dysfunction in two others (29%). All patients recovered without liver transplantation even though three had pre-existing chronic liver disease. Liver histology in four cases demonstrated varying patterns of liver injury.Duloxetine hepatotoxicity developed within 2 months of drug intake and led to clinically significant liver injury. A spectrum of laboratory, histological and extra-hepatic features were noted at presentation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79147/1/j.1365-2036.2010.04449.x.pd

Detection and management of latent tuberculosis in liver transplant patients

The optimal means for detecting and managing liver transplantation (LT) patients with latent tuberculosis (TB) are not well defined. Our study aims were to (1) determine the frequency and risk factors of latent TB in a large cohort of consecutive adult LT candidates and (2) determine the safety and efficacy of isoniazid treatment in LT recipients with latent TB. A review of patients assessed for latent TB by skin testing using purified protein derivative (PPD; January 2004 to September 2008) or with the interferon-γ release assay QuantiFERON-TB Gold (QFT; March 2008 to October 2009) was undertaken. The baseline clinical features and outcomes of subjects with latent TB and subjects without latent TB were compared. Twenty-five of 420 subjects (6.0%) were positive for PPD. In comparison, 11 of 119 subjects (9.2%) had a positive QFT assay, and 15 others (13%) had indeterminate results. Both PPD-positive and QFT-positive subjects were less likely to be Caucasian than subjects without latent TB ( p < 0.001). The 3-year survival rate of the 25 LT recipients with latent TB was similar to that of the 296 LT recipients without latent TB (78.7% versus 74.6%, P = 0.58). Fifteen of the 25 latent TB patients received isoniazid at a mean of 0.67 months after LT. Although isoniazid was discontinued in 8 subjects because of possible side effects, none of the 25 latent TB patients developed TB reactivation after transplantation with a mean follow-up of 33 months. In conclusion, both QFT testing and PPD testing demonstrate similar rates of detecting latent TB infection in American LT candidates, but QFT testing also leads to a moderate rate of indeterminate test results. Early isoniazid chemoprophylaxis after LT is poorly tolerated and is frequently discontinued. Liver Transpl, 2011. © 2011 AASLD.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83174/1/22203_ftp.pd

Tuberculosis screening of travelers to higher-incidence countries: A cost-effectiveness analysis

Abstract Background Travelers to countries with high tuberculosis incidence can acquire infection during travel. We sought to compare four screening interventions for travelers from low-incidence countries, who visit countries with varying tuberculosis incidence. Methods Decision analysis model: We considered hypothetical cohorts of 1,000 travelers, 21 years old, visiting Mexico, the Dominican Republic, or Haiti for three months. Travelers departed from and returned to the United States or Canada; they were born in the United States, Canada, or the destination countries. The time horizon was 20 years, with 3% annual discounting of future costs and outcomes. The analysis was conducted from the health care system perspective. Screening involved tuberculin skin testing (post-travel in three strategies, with baseline pre-travel tests in two), or chest radiography post-travel (one strategy). Returning travelers with tuberculin conversion (one strategy) or other evidence of latent tuberculosis (three strategies) were offered treatment. The main outcome was cost (in 2005 US dollars) per tuberculosis case prevented. Results For all travelers, a single post-trip tuberculin test was most cost-effective. The associated cost estimate per case prevented ranged from $21,406 for Haitian-born travelers to Haiti, to$161,196 for US-born travelers to Mexico. In all sensitivity analyses, the single post-trip tuberculin test remained most cost-effective. For US-born travelers to Haiti, this strategy was associated with cost savings for trips over 22 months. Screening was more cost-effective with increasing trip duration and infection risk, and less so with poorer treatment adherence. Conclusion A single post-trip tuberculin skin test was the most cost-effective strategy considered, for travelers from the United States or Canada. The analysis did not evaluate the use of interferon-gamma release assays, which would be most relevant for travelers who received BCG vaccination after infancy, as in many European countries. Screening decisions should reflect duration of travel, tuberculosis incidence, and commitment to treat latent infection.</p

The benefits and risks of bacille Calmette-Guérin vaccination among infants at high risk for both tuberculosis and severe combined immunodeficiency: assessment by Markov model

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccine is given to Canadian Aboriginal neonates in selected communities. Severe reactions and deaths associated with BCG have been reported among infants born with immunodeficiency syndromes. The main objective of this study was to estimate threshold values for severe combined immunodeficiency (SCID) incidence, above which BCG is associated with greater risk than benefit. METHODS: A Markov model was developed to simulate the natural histories of tuberculosis (TB) and SCID in children from birth to 14 years. The annual risk of tuberculous infection (ARI) and SCID incidence were varied in analyses. The model compared a scenario of no vaccination to intervention with BCG. Appropriate variability and uncertainty analyses were conducted. Outcomes included TB incidence and quality-adjusted life years (QALYs). RESULTS: In sensitivity analyses, QALYs were lower among vaccinated infants if the ARI was 0.1% and the rate of SCID was higher than 4.2 per 100,000. Assuming an ARI of 1%, this threshold increased to 41 per 100,000. In uncertainty analyses (Monte Carlo simulations) which assumed an ARI of 0.1%, QALYs were not significantly increased by BCG unless SCID incidence is 0. With this ARI, QALYs were significantly decreased among vaccinated children if SCID incidence exceeds 23 per 100,000. BCG is associated with a significant increase in QALYs if the ARI is 1%, and SCID incidence is below 5 per 100,000. CONCLUSION: The possibility that Canadian Aboriginal children are at increased risk for SCID has serious implications for continued BCG use in this population. In this context, enhanced TB Control – including early detection and treatment of infection – may be a safer, more effective alternative

Tuberculosis Prevention in South Africa

Background South Africa has one of the highest per capita rates of tuberculosis (TB) incidence in the world. In 2012, the South African government produced a National Strategic Plan (NSP) to control the spread of TB with the ambitious aim of zero new TB infections and deaths by 2032, and a halving of the 2012 rates by 2016. Methods We used a transmission model to investigate whether the NSP targets could be reached if immediate scale up of control methods had happened in 2014. We explored the potential impact of four intervention portfolios; 1) “NSP” represents the NSP strategy, 2) “WHO” investigates increasing antiretroviral therapy eligibility, 3) “Novel Strategies” considers new isoniazid preventive therapy strategies and HIV “Universal Test and Treat” and 4) “Optimised” contains the most effective interventions. Findings We find that even with this scale-up, the NSP targets are unlikely to be achieved. The portfolio that achieved the greatest impact was “Optimised”, followed closely by “NSP”. The “WHO” and “Novel Strategies” had little impact on TB incidence by 2050. Of the individual interventions explored, the most effective were active case finding and reductions in pre-treatment loss to follow up which would have a large impact on TB burden. Conclusion Use of existing control strategies has the potential to have a large impact on TB disease burden in South Africa. However, our results suggest that the South African TB targets are unlikely to be reached without new technologies. Despite this, TB incidence could be dramatically reduced by finding and starting more TB cases on treatment

Adverse events with isoniazid preventive therapy: experience from a large trial.

OBJECTIVES: We describe isoniazid-related adverse events in Thibela TB, a cluster-randomized study of community-wide isoniazid preventive therapy (IPT) among gold miners in South Africa, where HIV prevalence is estimated at 30%. METHODS: Consenting employees were screened prior to IPT for active tuberculosis and increased risk of isoniazid toxicity using a questionnaire and chest radiograph. Study-defined IPT-related adverse events were sought at each study visit: liver function tests were only performed if clinically indicated. In a substudy, we questioned consecutive participants at baseline and months 1, 3, and 6 concerning minor IPT-related adverse events. RESULTS: Among 24,221 participants (95.2% men, median age 40 years), 130 individuals had 132 study-defined adverse events (0.54%); 61 (0.25%) possible hypersensitivity rash, 50 (0.21%) peripheral neuropathy, 17 (0.07%) clinical hepatotoxicity, and four (0.02%) convulsions. Four events (two hepatotoxicity, one fatal, and two convulsions) fulfilled criteria for seriousness. Clinical hepatotoxicity was associated with consumption of alcohol [0.11 vs. 0.03% if no alcohol consumed, odds ratio 3.9 (95% confidence interval 1.2-12.1)], but not with sex, age, weight, or concurrent antiretroviral therapy. In the substudy, 324 of 498 (65.1%) participants reported better health since starting IPT; 180 of 324 (55.6%) reported that this was because of increased appetite. The frequency of specific minor symptoms was low among those taking IPT, and all symptoms were reported less often than at baseline. CONCLUSION: The risk of adverse events, particularly hepatotoxicity, was very low in this population. Our data suggest that clinical criteria can safely be used for screening prior to and monitoring during IPT