CHEST. 2003;123(3) 

In This Article

Urine Color Test to Monitor Isoniazid Compliance

May we say this in a prominent medical journal such as CHEST? Is it audacity or truthful metaphor? For the two of us from Brooklyn, the phrase "pissin' in the wind" means doing something that is essentially futile and possibly detrimental. Our third colleague assures us that the Japanese equivalent, "spitting in the sky," also holds the same meaning. (Does all deep philosophy reduce down to body fliuds?) However it may be, in discussing an article where urine drug screening reveals nonadherence to therapy, we believe the phrase is apt.

In this issue of CHEST, as in other journals, there are articles that discuss the search for an etiology, definitive diagnosis, or treatment of medical conditions for which these answers are at present un-known. While this is exciting and even essential for patient health, an equally important axiom is often overshadowed in these same journals: no matter how effective the medical regimen may be, if the patient does not adhere to medical therapy then, miracles aside, they will not be cured of their disease.

Tuberculosis (TB) should be the envy of every disease for which the cause and treatment remain elusive. For > 120 years, we have known the etiologic agent of TB. For > 100 years, we have known how to effectively diagnose the disease, and for > 50 years, we have had treatment regimens with a 95% cure rate when taken correctly and completely. Yet despite this almost uniquely fortuitous set of circumstances, TB continues to be one of the leading causes of mortality and morbidity in the world,[1] and still poses a major threat to public health. Needless to say, TB medications are effective only when patients take their pills as prescribed. Not unique to TB, patient nonadherence to therapy has been observed in a variety of settings[2,3]; however, this failure to comply with the treatment of a potentially fatal communicable disease is particularly important from a public health perspective, as nonadherence to treatment not only affects the afflicted individuals, but also increasingly endangers those around them through prolonged infectivity and possible development of drug resistance

Among the most challenging and unique aspects of TB are the inordinate number of medications and prolonged length of treatment necessary to achieve a cure. Historically, adherence to TB medication therapy, when left to self-administration, has resulted in poor completion rates accompanied by high rates of relapse and the development of drug resistance.[4] Treatment success rates of multidrug resistant tuberculosis (that is, resistant to at least isoniazid and rifampin) may fall to as low as 50%, with the cost of successful therapy rising to ≥ $400,000 (unpublished data; A.G. Holley State Hospital; Lantana, FL), as compared to approximately $1,500 for a drug-sensitive case.[5] Therefore, given the documentation that nonadherent patients with TB can spread their disease to as many as 30 other people,[6] from a public health as well as an economic standpoint, it is best to cure individuals with TB before they acquire resistance and spread the resistant strain to many others.

The major barrier to achieving a cure in patients with TB lies neither in medications nor therapeutics, but rather in the lack of adherence to therapy. It has been widely recognized that directly observed therapy (DOT), where a health-care worker or other individual observes a patient taking their medications, improves the completion rate of treatment in patients with TB.[4] Even DOT, however, is not a perfect solution,[7] and we have occasionally encountered challenging medication delivery problems, such as "cheeking" or regurgitating pills after they are given, despite direct observation by medical or outreach workers, and pharmacokinetic drug monitoring (personal observation; A.G. Holley State Hospital). Moreover, it has been considered futile to try to predict which patient will be nonadherent to therapy[8] (except in the case of medical personnel, who are notoriously poor compliers).

This problem of nonadherence is not solely limited to those with active TB disease. As might be inferred from treatment completion rates, there may be an even higher prevalence of nonadherence to therapy in individuals with latent TB infection (LTBI). Patients with LTBI are asymptomatic for TB and generally are informed of the potential side effects of the medications even before starting treatment for an infection few may actually perceive themselves to have. The use of DOT in the treatment of LTBI would be exemplary, resources permitting, in order to maximize adherence and thereby significantly increase completion rates and decrease new cases of TB disease. Regrettably, the use of DOT for all cases of LTBI would be impractical, as one third of the population of the world is infected by Mycobacterium tuberculosis. DOT might be considered, however, in those patients with LTBI at greatest risk for developing active TB disease. Even concentrating on this group, though, would be difficult without a system of community-based collaboration and support. The questions of screening for LTBI, delivery of LTBI therapy, and to whom, has of late been one of the major issues for TB control programs.[9,10]

The article by Eidlitz-Markus et al in this issue of CHEST (see page 736) reminds clinicians of the importance of patient adherence to medical therapy. The study used the urine color test to detect the taking of isoniazid within the prior 48 h. This test can be accurate, easy to administer in various settings, and may increase patient adherence to therapy. In the study, if nonadherence was found on testing, patients were told the results and the implications of their actions explained. Almost one third of the patients tested were found to be nonadherent with isoniazid therapy on at least one of two separate occasions. While disappointing, these results are not unexpected. What if patients had been tested on more occasions? Would more nonadherence have been discovered? Fifteen percent of those patients found to test positive for isoniazid the first time tested negative the second time, and one of the six patients initially found to have a negative urine color test result continued to test negative on the second test despite educational intervention.

The long-term effect of this testing needs further study. Does periodically checking a urine color test in patients receiving therapy for LTBI increase adherence, and ultimately decrease the rate of progression to active TB disease? Some clinicians might argue that a patient does not need to have taken 100% of the required doses of isoniazid for it to be effective. There has been a report of considerable reduction (52%) in TB rates in patients receiving medication for ≥ 10 months, but with only a 40 to 59% compliance rate.[11] However, the differences between our current TB patient populations and that of Alaska in the 1960s may make this finding inapplicable to our present circumstances.

We still face many challenges in our efforts to reduce and eventually eliminate tuberculosis, among them diagnosing and treating infectious cases, appropriate and effective contact investigations, and the screening and treatment of LTBI. Sheer numbers alone make these tasks truly daunting, but ones that could be accomplished if patient adherence to treatment were either not a factor, or an insignificant one. As DOT may not be, at the present time, either available or possible in many parts of the world, the urine color test might be used to check and hopefully improve adherence in patients with TB disease on combination-pill medications, or those receiving treatment of LTBI with isoniazid alone.

The role of the periodic testing of adherence to self-administered therapy may not only be important to TB, but also have a broader application to any chronic illness. No medication, regardless of its efficacy, will work if not taken. Therefore, studies looking at improving adherence to medical therapy, without the use of DOT, will be important for pubic health and cost-effective disease management.

In the fight against tuberculosis, as nonadherence leads to drug resistance and the loss of effective medical weapons for the disease, we cannot afford to be complacent about this issue. If we are to truly control and eventually eradicate this disease, we need methods of treatment and prevention that will improve patient compliance, whether it is shorter and simpler regimens or medication adherence monitoring. If not, despite all the tools at hand, we may just be "pissin' in the wind."

Elena S. Hollender, MD, David Ashkin, MD, FCCP, Masahiro Narita, MD, Lantana, FL

Drs. Ashkin and Hollender are from A. G. Holley State Tuberculosis Hospital, the Florida Department of Health. In addition, Drs. Ashkin and Narita are Clinical Assistant Professors, Division of Pulmonary and Critical Care Medicine, University of Miami School of Medicine. Dr. Narita is now with the Tuberculosis Control Program, Public Health -- Seattle and King County, Washington.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: David Ashkin, MD, FCCP, A. G. Holley State Hospital, 1199 W. Lantana Rd, Lantana, FL 33462; E-mail: David_Ashkin@doh.state.fl.us.

  1. Tuberculosis: strategy and operations, monitoring and evaluation. Geneva, Switzerland: World Health Organization, 2002. Available at: http://www.who.int/gtb. Accessed February 6, 2003

  2. Bender BG. Overcoming barriers to nonadherence in asthma treatment. J Allergy Clin Immunol 2002; 109(6 Suppl):S554 - S559

  3. Wang PS, Bohn RL, Knight E et al. Noncompliance with antihypertensive medications. J Gen Intern Med 2002; 17: 504-511

  4. Chaulk CP, Kazandjian VA. Directly observed therapy for treatment completion of pulmonary tuberculosis: consensus statement of the Public Health Tuberculosis Guidelines Panel. JAMA 1998; 279:943-948

  5. Iseman MD, Cohn DL, Sbarbaro JA. Directly observed treatment of tuberculosis: we can't afford not to try it. N Engl J Med 1993; 328:576-578

  6. Small PM, Hopewell PC, Singh SP, et al. The epidemiology of tuberculosis in San Francisco: a population-based study using conventional and molecular methods. N Engl J Med 1994; 330:1703-1709

  7. Davidson BL. A controlled comparison of directly observed therapy vs self-administered therapy for active tuberculosis in the urban United States. Chest 1998; 114:1239-1243

  8. Sbarbaro JA, Earnest M. Tuberculosis: adherence to regimens and directly observed therapy. In: Rom WN, Garay SM, eds. Tuberculosis. New York, NY: Little, Brown and Company, 1995; 927-934

  9. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Morb Mortal Wkly Rep 2000; 49(RR-6):1-51

  10. Institute of Medicine CotEoTitUS. Ending neglect: the elimination of tuberculosis in the United States. Washington DC: National Academy Press, 2000; 86-121

  11. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis: a general review. Adv Tuberc Res 1970; 17:28-106