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The Urine Color Test with Isoniazid Treatment of Latent Tuberculosis Infection
Abstract & Commentary
Synopsis: Noncompliance with treatment for latent tuberculosis can be monitored with the aid of a special urine test that checks for metabolites of isoniazid.
Source: Eidlitz-Markus T, et al. Chest. 2003;123:736-739.
Tuberculosis continues to be one of the leading causes of mortality and morbidity and still continues to pose a major threat to public health.1 The treatment regimens for tuberculosis are very effective with a 95% cure rate when patients are compliant with the medications. The problem arises when patients are not compliant and endanger their lives and also the lives of those around them due to the infectious nature of the disease. The problem of nonadherence with medications may be even worse in patients being treated for latent tuberculosis. Patients with latent tuberculosis may not perceive themselves as being sick, as they have no symptoms and may be even more reluctant to be compliant with their medications.
The aim of this study was to monitor compliance with isoniazid by a simple urine test—the Arkansas method of detecting metabolites of isoniazid.2 This method has been used for many years but is relatively unknown outside of the United States. It is a simple test, very inexpensive, gives immediate results, and is easy to read. It has a sensitivity of > 97% and a specificity of > 98%.3 Factors that affected compliance with medications were also evaluated in this study.
Patients who were referred to the Tel Aviv Tuberculosis Center and children (younger than 18 years) attending the ambulatory Day Care Center were included in the study. The study was done during the period of September 1999 to April 2000. Only patients on monotherapy with isoniazid were enrolled. Demographic data, dose of isoniazid, duration of therapy, means of administration of therapy (whether self-administered or given by parents in the case of children), and the time of the last dose of isoniazid were collected during interviews with patients or the parents in the case of children. Urine samples were collected on routine analysis, and the urine was checked for metabolites of isoniazid.
The test consisted of placing the urine in a plastic tube containing barbituric acid, N-chlorotoluene-sulfonamide sodium salt solution (Chloramine-T; Sigma; St. Louis, Mo), and potassium cyanide. A positive test resulted in the color of the urine changing from yellow to blue, and a negative test resulted in no change of color.
The study enrolled 105 patients (38 male patients and 67 female patients). The mean age was 26.9 years (range, 1-75 years) and the mean weight was 58.6 kg (range, 9-100 kg). Isoniazid had been prescribed for persons with latent tuberculosis who were at increased risk of developing active tuberculosis as follows: 42 children and adolescents (40%), 25 patients with recent conversion (23.8%), 36 patients with close contact with a patient who had tuberculosis (34.2%), and 2 patients with positive PPD results who had been on prolonged steroid treatment (1.9%) .
The mean dose of isoniazid was 288 mg (range, 100-300 mg) or 5.6 mg/kg (range, 3-15 mg/kg). The mean duration of treatment prior to the study was 2.5 months (range, 2 weeks to 8 months). Adults supervised 77.14% of the children during drug administration. The mean interval between drug intake and the urine test was 14.6 hours (range, 2-48 hours).
The urine test results revealed noncompliance with isoniazid in 30 patients (28.5 %). In the remainder of the patients, the Arkansas test revealed metabolites of isoniazid. There was no statistically significant correlation between compliance and any of the following parameters: age (P = .10), gender (P = .20), diagnosis (P = .55), mode of administration of isoniazid (self-administration or with parent supervision) (P = .27), duration of treatment in months (P = .57), dosage of isoniazid/weight ratio (P = .30), or interval since last dose taken (P = .12).
Repeat urine tests were conducted on 26 patients on follow-up to check for treatment compliance. Noncompliant patients were counseled regarding the importance of compliance with medications. Only 1 of the 6 patients who was found to be noncompliant on the first visit continued to remain noncompliant when tested on the second visit. Three of 20 originally compliant patients were found to be noncompliant on the second visit.
Comment by Najma Usmani, MD, and David Ost, MD
Tuberculosis is a very common disease worldwide. Approximately 8 million new cases of tuberculosis infection and 2.6-2.9 million deaths from this disease occur annually worldwide.4 The major barrier to achieving a cure is not a lack of medications but rather the nonadherence with therapy. This problem with nonadherence is not limited only to patients with active disease but may be even more of a problem in patients being treated for latent tuberculosis, as they are asymptomatic. This study has attempted to address this issue of nonadherence with medications. Information is given on the use of a urine test that is simple, easy to do in the office, gives immediate results, and which may be very helpful. Noncompliant patients can be counseled immediately about the dangers of skipping medications in this potentially fatal disease. Patients who are given clear and comprehensive information regarding the disease demonstrate improved compliance with medications.5
However, this study gives no recommendations on methods of improving compliance due to flaws in the methodology of the study. It did not have a control arm where no testing was done to compare results with the group that was being tested. It draws no conclusions about which groups are at increased risk and need repeated testing for compliance. There is no surrogate marker (improvement in morbidity or mortality) used to demonstrate that repeated testing improves outcome. This study does not give solutions to the issue of noncompliance with medications.
Dr. Usmani is a Fellow, Pulmonary and Critical Care, North Shore University Hospital and Nassau University Medical Center, East Meadow, NY. Dr. Ost is Assistant Professor of Medicine, NYU School of Medicine, and Director of Interventional Pulmonology, Division of Pulmonary and Critical Care Medicine, Northshore University Hospital, Manhasset, NY.
1. Tuberculosis: Strategy and operations, monitoring and evaluation. Geneva, Switzerland: World Health Organization, 2002. Available at: http://www.who.int/gtb.
2. Schraufnagel DE, et al. Chest. 1990;98:314-316.
3. Kilburn JO, et al. Am Respir Rev Dis. 1972;106: 923-924.
4. American Thoracic Society. Diagnostic standards and classification of tuberculosis in adults and children: The official statement of the American Thoracic Society. Am J Respir Crit Care Med. 2000;161:1376-1395.
5. Sbarbaro J. Am J Med. 1985;79(1 suppl):34-37.