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Monitored Isoniazid Prophylaxis for Low-Risk Tuberculin Reactors Older Than 35 Years of Age: A Risk-Benefit and Cost-Effectiveness Analysis

Shelley R. Salpeter, MD; Gillian D. Sanders, AB; Edwin E. Salpeter, PhD; and Douglas K. Owens, MD, MSc
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From Santa Clara Valley Medical Center, San Jose, California; Stanford University, Stanford, California; Cornell University, Ithaca, New York; and Veterans Affairs Palo Alto Health Care System, Palo Alto, California. Acknowledgments: The authors thank Robert F. Nease, Thomas G. Kelsey, and Lyn Dupre for comments on the manuscript and Andria Cardinalli for developing cost estimates. Grant Support: In part by the Santa Clara Valley Medical Center, San Jose, California, and by a Career Development Award from the Veterans Affairs Health Services Research and Development Service (Dr. Owens). Requests for Reprints: Shelley R. Salpeter, MD, Santa Clara Valley Medical Center, 2400 Moorpark Avenue, Suite 118, San Jose, CA 95128. Current Author Addresses: Dr. S.R. Salpeter: Santa Clara Valley Medical Center, 2400 Moorpark Avenue, Suite 118, San Jose, CA 95128.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1997;127(12):1051-1061. doi:10.7326/0003-4819-127-12-199712150-00001
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Background: Isoniazid chemoprophylaxis effectively prevents the development of active infectious tuberculosis. Current guidelines recommend withholding this prophylaxis for low-risk tuberculin reactors older than 35 years of age because of the risk for fatal isoniazid-induced hepatitis. However, recent studies have shown that monitoring for hepatotoxicity can significantly reduce the risk for isoniazid-related death.

Objective: To evaluate the effectiveness and cost-effectiveness of monitored isoniazid prophylaxis for low-risk tuberculin reactors older than 35 years of age.

Design: A Markov model was used to compare the health and economic outcomes of prescribing or withholding a course of prophylaxis for low-risk reactors 35, 50, or 70 years of age. Subsequent analyses evaluated costs and benefits when the effect of transmission of Mycobacterium tuberculosis to contacts was included.

Measurements: Probability of survival at 1 year, number needed to treat, life expectancy, and cost per year of life gained for individual persons and total population.

Results: Isoniazid prophylaxis increased the probability of survival at 1 year and for all subsequent years. For 35-year-old, 50-year-old, and 70-year-old tuberculin reactors, life expectancy increased by 4.9 days, 4.7 days, and 3.1 days, respectively, and costs per person decreased by $101, $69, and $11, respectively. When the effect of secondary transmission to contacts was included, the gains in life expectancy per person receiving prophylaxis were 10.0 days for 35-year-old reactors, 9.0 days for 50-year-old reactors, and 6.0 days for 70-year-old reactors. Costs per person for these cohorts decreased by $259, $203, and $100, respectively. The magnitude of the benefit of isoniazid prophylaxis is moderately sensitive to the effect of isoniazid on quality of life. The hypothetical provision of isoniazid prophylaxis for all low-risk reactors older than 35 years of age in the U.S. population could prevent 35 176 deaths and save $2.11 billion.

Conclusions: Monitored isoniazid prophylaxis reduces mortality rates and health care costs for low-risk tuberculin reactors older than 35 years of age, although reductions for individual patients are small. For the U.S. population, however, the potential health benefits and economic savings resulting from wider use of monitored isoniazid prophylaxis are substantial. We should consider expanding current recommendations to include prophylaxis for tuberculin reactors of all ages with no contraindications.


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Figure 1.
The decision model. Top.Bottom.

The square node on the left represents a decision between two treatments: isoniazid prophylaxis and no isoniazid prophylaxis. Circles represent chance nodes. Patients who receive prophylaxis are at risk for death from isoniazid-induced hepatitis. Patients who do not die of hepatitis receive either a complete or an incomplete course of prophylaxis and subsequently enter the tuberculosis-activation subtree. Whether a patient has a complete or an incomplete course of prophylaxis determines the probability that the patient will subsequently develop active tuberculosis. The tuberculosis-activation subtree represents the clinical events that can occur during each 1-year period as a patient is followed throughout remaining life. Each year, a patient is at risk for active tuberculosis. Patients who develop active tuberculosis may die of tuberculosis, may die of other causes, or may remain alive and proceed to a post-tuberculosis state. We also modeled the transmission of tuberculosis organisms to other persons and represent additional deaths from tuberculosis that may occur. Patients who do not develop tuberculosis die of other causes as determined by their age-specific mortality.

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Figure 2.
Sensitivity analyses.Top.Upper middle.Lower middle.Bottom.

The top three panels show sensitivity analyses for the 70-year-old cohort with the benefit of prevention of transmission excluded. This cohort receives the least benefit from isoniazid prophylaxis; therefore, the threshold at which prophylaxis and no prophylaxis provide equal benefit is closer to the base-case estimate for this cohort than for other cohorts. Probability of fatal hepatitis versus life expectancy. Circles represent isoniazid prophylaxis; squares represent no prophylaxis. Efficacy of isoniazid prophylaxis versus life expectancy. Circles represent isoniazid prophylaxis; squares represent no prophylaxis. Average probability of tuberculosis activation versus life expectancy. Circles represent isoniazid prophylaxis; squares represent no prophylaxis. Cost savings obtained with isoniazid prophylaxis for each cohort (transmission excluded) over a range of per-case costs for tuberculosis treatment. Dark solid line represents 70-year-old patients; dashed line represents 50-year-old patients; light solid line represents 35-year-old patients.

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