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Dr. Schluger is Associate Professor of Medicine and Public Health, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons.
Correspondence to: Neil W. Schluger, MD, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, PH-8 Center, 622 West 168th St, New York, NY 10032; e-mail: ns311{at}columbia.edu
After an alarming rise in tuberculosis cases in the United States that began in the mid to late 1980s and peaked in 1992, the past 9 years have seen a steady decline in cases (and case rates) of active tuberculosis, which now stand at a historical low. However, the country is far from the goal of elimination of tuberculosis, initially targeted by the federal government in its Healthy People 2000 project for the year 2000 and now pushed back to 2010. (The actual target is one case of tuberculosis per 100,000 persons, less than one fifth the current rate.1 ) What strategies are needed to reach that goal?
The Institute of Medicine last year published "Ending Neglect: the Elimination of Tuberculosis in the United States," a comprehensive and thoughtful analysis of the subject.2 In it, the authors state that "[t]o begin advancing toward the elimination of tuberculosis, aggressive new efforts must be implemented to identify those who are at the greatest risk of disease through targeted programs of tuberculin skin testing coupled with treatment for latent tuberculosis infection." Undoubtedly, those most in need of targeted testing and treatment for latent tuberculosis infection are close contacts of patients with active tuberculosis. Other high priorities include recent skin test converters and HIV-infected persons with evidence of latent infection. Persons who have recently arrived in the United States from high-prevalence countries also contribute a substantial number of cases after their arrival, generally through reactivation of latent infection. The study by Bandyopadhyay and colleagues in this issue of CHEST (see page 1771) addresses a particularly difficult group of patients to target for skin testing and treatment: those who are in and out of short-term correctional facilities. In their study, the authors challenge the notion that screening for latent tuberculosis infection among these individuals should be de-emphasized, since adherence to treatment for latent infection is so poor in patients in that setting. Bandyopadhyay et al conclude that although adherence to treatment in their cohort was in fact low, cost accounting indicates that it is nonetheless money saving in the long run to screen for latent infection in short-term correctional facilities and, on release, to refer persons to the clinic for completion of treatment.
The most recent American Thoracic Society/Centers for Disease Control and Prevention (ATS/CDC) guidelines emphasize targeted screening and treatment.3 Inmates in correctional facilities are generally included in the groups targeted for screening because there have been several well-documented outbreaks of tuberculosis in prisons and jails. However, it is not clear that all such patients in general or in this particular study were in fact at high risk for active tuberculosis. Has there been an outbreak of active tuberculosis in the jail in Hartford (the locale of the study by Bandyopadhyay)? There is no indication as to how many patients in the current article were close contacts of patients with active tuberculosis, or were HIV infected, or recent converters. Patients < 35 years old may have been infected some time ago and may no longer be at high risk for reactivation. In fact, in the current ATS/CDC guidelines, age alone has generally been removed as a criterion for deciding whether to treat latent infection. For these reasons, the present study may overestimate both the number of cases prevented and the cost savings associated with the strategy.
Nonetheless, Bandyopadhyay and colleagues draw attention to a serious problem in treatment of latent tuberculosis infection, namely that of overall low adherence to therapy, which occurs often in populations at great risk for active tuberculosis. Although cost accounting suggests that there still might be a benefit to such treatment, we are clearly not doing well enough. Tulsky et al4 found that only 3.2% of a group of inmates released from jail even presented to the tuberculosis clinic for follow-up, and Nolan et al5 found that only 29% of a group recently released inmates completed self-administered treatment for latent infection. Bock and colleagues6 found that only 20% of a population in Atlanta that included persons seeking health care at public hospitals, released jail inmates, homeless persons, and drug users completed preventive therapy. In New York City, targeting a population with similar characteristics, we achieved similar disappointing results.7
What strategies are available to increase adherence to treatment in at-risk populations, which include recent immigrants from high-prevalence countries, IV drug users, and perhaps most importantly, close contacts of patients with active cases? It is likely that multiple approaches may be desirable and necessary. In several studies, the provision of monetary incentives appeared to increase adherence rates substantially. In two studies examining adherence in drug users, cash incentives of $5 to $10 per visit for twice-weekly supervised therapy with isoniazid increased adherence to between 68% and 89%.8 9 In other populations, supervised therapy has actually been associated with lower adherence. Matteelli and colleagues10 reported that among illegal immigrants in Italy, supervised administration of twice-weekly isoniazid offered a probability of completion of only 7%, compared with a rate of 41% for 6 months of daily, self-administered isoniazid.
It is obvious from the studies cited above, as well as many other experiences, that a range of strategies is needed to improve compliance with or adherence to programs of treatment for latent infection with tuberculosis. In addition to providing incentives and social support to improve adherence, shortening the duration of therapy might also be of great benefit. Most patients in the United States who are treated for latent infection receive either 9 months or 6 months of daily self-administered isoniazid, with 9 months being the preferred regimen for most patients, in accordance with the most recent ATS/CDC guidelines that stress again the improved efficacy of prolonged treatment. However, in the last few years, a number of studies11 12 have examined the potential role of much shorter regimens, some of which consisted of 2 months of rifampin and pyrazinamide (2RZ), which can be administered either daily or intermittently for treatment of latent infection. Randomized, controlled studies of this regimen in patients with HIV infection and positive tuberculin skin test results indicated that it is comparable in efficacy to isoniazid administered daily for 6 to 12 months.12 13 Additionally, the studies generally demonstrated higher treatment completion rates for patients on the shorter regimens. In the largest of these studies,11 adverse events were no more likely to be seen with one regimen than the other, although patients were more likely to discontinue rifampin/pyrazinamide than isoniazid. Based on these studies, the ATS/CDC guidelines recommended 2RZ as the preferred regimen in patients with HIV infection and as a suitable and effective regimen in HIV-negative persons. However soon after these recommendations were made, several deaths were reported in patients who received 2RZ.14 Although it is likely that 2RZ can be used safely in many situations, the reports of deaths associated with this regimen have certainly dampened enthusiasm for its widespread use, and it is unlikely that this regimen will come into common use in most settings.
The Tuberculosis Trials Consortium, a Centers for Disease Control and Prevention-funded clinical research collaboration involving 24 sites (health departments and academic medical centers) in the United States and Canada, has just begun a trial comparing 9 months of daily self-administered isoniazid (270 total doses) to 3 months of once-weekly isoniazid and rifapentine (12 total doses), a long-acting rifamycin, in the treatment of latent tuberculosis infection among persons at high risk for reactivation (mainly close contacts of patients with active cases and HIV-infected individuals). If effective, the 12-dose regimen could have a substantial impact on treatment of latent tuberculosis from a public health standpoint both in the United States and abroad.
Two billion persons around the world have latent tuberculosis infection.15 The reservoir of potential cases is huge. If treatment of latent infection can be made inexpensive, easy to administer and to take, and demonstrably safe, prevention of reactivation can become a more important and realistic goal for tuberculosis control programs in rich and poor countries alike.
References
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