Background: our objective was to determine the incidence of toxicity among veterans initiating isoniazid therapy for latent tuberculosis infection (LTBI) and determine whether advancing age was a risk factor for toxicity. Methods: we performed a retrospective cohort study among all adults initiating isoniazid treatment for LTBI at a Veterans Medical Center from 1999 to 2005. We collected data on patient demographics, co-morbidities, site of initiation, and treatment outcome. Results: 219 patients initiated isoniazid therapy for LTBI during the period of observation, and the completion of therapy was confirmed in 100 patients (46%). Among 18/219 patients (8%) that discontinued therapy due to a documented suspected toxicity, the median time to onset was 3 months (IQR 1–5 months). In an adjusted Cox regression model, there was no association between discontinuation due to suspected toxicity and advancing age (HR 1.03, 95% CI 0.99, 1.07). In contrast, hepatitis C infection was a significant predictor of cessation due to toxicity in the adjusted analysis (HR 3.03, 95% CI 1.08, 8.52). Conclusions: cessation of isoniazid therapy due to suspected toxicity was infrequently observed among a veteran population and was not associated with advancing age. Alternative LTBI treatment approaches should be further examined in the veteran population. 1. Introduction According to World Health Organization estimates, one-third of the world’s population is latently infected with M. tuberculosis, and 10% of immunocompetent individuals will progress from latent to active tuberculosis infection within their lifetimes [1]. Detection and treatment of latent tuberculosis infection (LTBI) remain a cornerstone of the strategy to reduce the incidence of active tuberculosis in the United States. Daily isoniazid therapy for six to 12 months has been shown to significantly reduce the risk of progression from latent to active tuberculosis infection [2]. In the 1970’s, several cases of fatal hepatotoxicity during isoniazid therapy for LTBI raised concerns regarding widespread isoniazid use and led to a reconsideration of its safety in older adults [3]. Subsequent studies of isoniazid toxicity have compared the risk of hepatotoxicity between adults less than and greater than 35 years of age [4–10], and a meta-analysis of these studies demonstrated a small but statistically significant increased risk of hepatotoxicity among adults greater than age 35 [11]. Because of these concerns, providers may be more reluctant to initiate isoniazid therapy in older patients with LTBI, particularly in
References
[1]
C. Dye, S. Scheele, P. Dolin, V. Pathania, and M. C. Raviglione, “Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO global surveillance and monitoring project,” Journal of the American Medical Association, vol. 282, no. 7, pp. 677–686, 1999.
[2]
American Thoracic Society and Centers for Disease Control and Prevention, “Targeted tuberculin testing and treatment of latent tuberculosis infection,” American Journal of Respiratory and Critical Care Medicine, vol. 161, no. S221, S247 pages, 2000.
[3]
D. E. Kopanoff, D. E. Snider, and G. J. Caras, “Isoniazid-related hepatitis: a U.S. Public Health Service cooperative surveillance study,” American Review of Respiratory Disease, vol. 117, no. 6, pp. 991–1001, 1978.
[4]
P. A. LoBue and K. S. Moser, “Use of isoniazid for latent tuberculosis infection in a public health clinic,” American Journal of Respiratory and Critical Care Medicine, vol. 168, no. 4, pp. 443–447, 2003.
[5]
H. Aziz, M. Shubair, V. A. DeBari, M. Ismail, and M. A. Khan, “Assessment of age-related isoniazid hepatotoxicity during treatment of latent tuberculosis infection,” Current Medical Research and Opinion, vol. 22, no. 1, article no. 3148, pp. 217–221, 2006.
[6]
F. F. Fountain, E. Tolley, C. R. Chrisman, and T. H. Self, “Isoniazid hepatotoxicity associated with treatment of latent tuberculosis infection: a 7-year evaluation from a public health tuberculosis clinic,” Chest, vol. 128, no. 1, pp. 116–123, 2005.
[7]
R. Van Hest, H. Baars, S. Kik et al., “Hepatotoxicity of rifampin-pyrazinamide and isoniazid preventive therapy and tuberculosis treatment,” Clinical Infectious Diseases, vol. 39, no. 4, pp. 488–496, 2004.
[8]
C. M. Nolan, S. V. Goldberg, and S. E. Buskin, “Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic,” Journal of the American Medical Association, vol. 281, no. 11, pp. 1014–1018, 1999.
[9]
S. A. Gilroy, M. A. M. Rogers, and D. C. Blair, “Treatment of latent tuberculosis infection in patients aged ≥35 years,” Clinical Infectious Diseases, vol. 31, no. 3, pp. 826–829, 2000.
[10]
A. Fernandez-Villar, B. Sopena, R. Vazquez, et al., “Isoniazid hepatotoxicity among drug users: the role of hepatitis C,” Clinical Infectious Diseases, vol. 36, pp. 293–298, 2003.
[11]
H. Kunst and K. S. Khan, “Age-related risk of hepatotoxicity in the treatment of latent tuberculosis infection: a systematic review,” International Journal of Tuberculosis and Lung Disease, vol. 14, no. 11, pp. 1374–1381, 2010.
[12]
D. J. Sorresso, J. B. Mehta, L. M. Harvill, and S. Bentley, “Underutilization of isoniazid chemoprophylaxis in tuberculosis contacts 50 years of age and older: a prospective analysis,” Chest, vol. 108, no. 3, pp. 706–711, 1995.
[13]
L. Thrupp, S. Bradley, P. Smith et al., “Tuberculosis prevention and control in long-term-care facilities for older adults,” Infection Control and Hospital Epidemiology, vol. 25, no. 12, pp. 1097–1108, 2004.
[14]
J. D. Mancuso and L. W. Keep, “Deployment-related testing and treatment for latent tuberculosis infection, part II,” Military Medicine, vol. 176, pp. 1088–1092, 2011.
[15]
K. R. Page, F. Sifakis, R. Montes De Oca et al., “Improved adherence and less toxicity with rifampin vs isoniazid for treatment of latent tuberculosis: a retrospective study,” Archives of Internal Medicine, vol. 166, no. 17, pp. 1863–1870, 2006.
[16]
R. M. Jasmer, J. J. Saukkonen, H. M. Blumberg et al., “Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a multicenter clinical trial,” Annals of Internal Medicine, vol. 137, no. 8, pp. 640–647, 2002.
