© 2003 American Thoracic Society
Isoniazid for Latent Tuberculosis InfectionApproaching 40 and Reaching Its PrimePublic Health Seattle and King County Seattle, Washington Isoniazid preventive therapy for latent tuberculosis infection was introduced to clinical practice 38 years ago, in 1965, after a series of superb clinical trials (1) showed its efficacy in preventing tuberculosis in a wide variety of settings. Instead of hastening the decline in the incidence of tuberculosis in the United States as it was expected to do, however, isoniazid found itself in a 4-decade struggle for survival, from which it is now emerging. The pitfall was the almost immediate report of cases of fatal hepatotoxicity (2), a side effect not anticipated from results of the clinical trials. This ominous complication doomed isoniazid preventive therapy as it was originally intended, a curative treatment for every person in the United States with latent tuberculosis infection. What followed was a lengthy series of debates in the medical literature: Should isoniazid ever be used as preventive therapy? Who should receive it? How should it be monitored (3–5)? Alternative therapies were sought, and one, a 2-month regimen of rifampin and pyrazinamide, was recommended in 2000 as a shorter, isoniazid-free alternative regimen for treatment of latent tuberculosis infection (6). The tide has gradually turned in isoniazid's favor. A feasible process for selecting and monitoring patients on isoniazid preventive therapy was adopted in 1983 (7). In the 1990s, two surveys of public health tuberculosis clinics reported that the intervention was being used with increasing confidence (8) and that the risk of death with isoniazid treatment of latent tuberculosis infection was negligible (9). The report of our clinic's experience verified that isoniazid usage under current guidelines was safe, and we attempted to reconcile the older and more recent literature (10). The article in this issue of AJRCCM (pp. 443–447) by LoBue and Moser (11) adds additional data to substantiate the safety of isoniazid therapy. These authors reported a rate of hepatotoxicity of only 0.3% among 3,788 patients starting isoniazid treatment for latent tuberculosis infection, with no hospitalizations or deaths. This publication also extends the understanding of the safety profile of isoniazid by reporting that only 6.8% of persons who failed to complete isoniazid treatment did so because of an adverse drug effect; most persons were lost to follow-up or simply lost interest in continuing the lengthy course of treatment. As isoniazid treatment of latent tuberculosis infection approaches 40 years of clinical usage, it appears to have grown beyond its troubled youth and to be reaching its prime. Experts who have drafted proposals for progressing toward the elimination of tuberculosis in the United States (12) and in Western Europe (13), where the disease now occurs with low incidence, have included isoniazid preventive therapy as one of the key strategies: it offers the only possibility of preventing the future occurrence of tuberculosis in persons with latent infection, whose estimated number is between 5–10 million in the United States alone. In addition, for the first time, there is interest in isoniazid preventive therapy as a weapon in the global battle against epidemic tuberculosis. Isoniazid is now recommended for worldwide use to prevent tuberculosis in two particularly vulnerable groups: persons with human immunodeficiency virus infection, and children in the household of adults with pulmonary tuberculosis. The studies by LoBue and Moser (11) and others that verify isoniazid's safety is important in restoring confidence in isoniazid treatment of latent tuberculosis infection because to exert an impact on the incidence of tuberculosis, in other words to serve as an effective public health tool, this intervention must be expanded beyond its current scope. Through the years, public health programs that provide clinical services have been the stalwarts of isoniazid usage for the prevention of tuberculosis. Although data are not readily available, it is believed that this preventive intervention has been used only modestly in the nonpublic health sector. A call has been made to employ preventive therapy more widely (14), and there are encouraging reports of preventive therapy programs in such diverse sites as syringe exchange units, jails, neighborhood health clinics, homeless shelters, and schools. Isoniazid is not the perfect regimen for the treatment of latent tuberculosis infection. A shorter and even safer drug regimen would likely lead to greater physician acceptance and patient adherence. In an ironic twist of fate the rifampin–pyrazinamide regimen, which was found to be quite safe in clinical trials with human immunodeficiency virus seropositive patients, was almost immediately shown on clinical usage to be associated with severe, fatal hepatotoxicity (15). A 4-month course of rifampin is currently recommended as an alternative regimen (15), but there is very little experience with its use. Isoniazid and rifampin are routinely used together in a 3-month regimen in Britain. The Centers for Disease Control–sponsored Tuberculosis Clinical Trials Consortium is currently conducting a clinical trial that compares the efficacy of a once-weekly directly observed dose of isoniazid and rifapentine, a long-acting rifamycin, for 3 months with that of a 9-month course of isoniazid. There is also a need for better understanding of the biology of the latent stage of infection with Mycobacterium tuberculosis (16) to devise novel strategies for preventing progression from latent infection to active tuberculosis. Best of all, of course, would be the development of a vaccine that could prevent such progression, a postinfection (postexposure) vaccine. That is the best hope for the great majority of persons throughout the world—estimated at two billion at the present time—that are living with latent tuberculosis infection. Until then, it will likely be necessary to depend on drug therapy, and isoniazid remains the clear drug of choice. As the article by LoBue and Moser (11) indicates, isoniazid, when used with proper monitoring, is safe, has been long known to be efficacious (1), and deserves and needs to be more widely used. Acknowledgments C.M.N. has no declared conflict of interest. REFERENCES
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