© 2004 American Thoracic Society
Side Effects of Antituberculosis DrugsTo the Editor:We read with interest the report by Yee and colleagues (1) who have observed a greater incidence of pyrazinamide-induced hepatotoxicity in patients receiving antituberculosis treatment (ATT) in "routine clinical practice" than previously reported. Pyrazinamide is almost as effective as rifampicin as a sterilizing drug (2). Because the actions of rifampicin and pyrazinamide are synergistic, the treatment could be shortened to 6 months if both these drugs were added to the treatment regimen (3). Failure to administer pyrazinamide for the first 2 months of short-course treatment results in a threefold increase in the risk for relapse (4). The hepatotoxic potential of pyrazinamide is far less in the dosage used in the modern day short-course regimens (5). In India, we treat a large number of patients with active tuberculosis using the directly observed treatment, short-course (DOTS) intermittent chemotherapy regimens, and also the standard daily supervised chemotherapy regimens "individualizing" the drug dosage to suit the needs of the given patient in certain situations. In the published literature, hepatotoxicity seems to be seldom reported when these regimens have been used (5). Because baseline evaluation and subsequent periodic evaluation of liver functions are not mandatory for administering DOTS under program conditions, it is possible that several instances of drug-induced hepatotoxicity are being missed. Therefore, certain methodological issues related to this study (1) need to be clarified because their observations have important implications. It is mentioned that the majority of patients received daily self-administered treatment. However, it is not clear what treatment regimen(s) was used in the remaining patients. Information regarding the treatment regimen(s) used, the duration of treatment for pulmonary and extrapulmonary/disseminated tuberculosis, and whether the drug dosage was individualized according to the body weight of the patient needs to be clarified. Conventionally, in patients with drug-sensitive tuberculosis, pyrazinamide does not give any additional benefit when administered for more than 2 months in short-course regimens (6). Therefore, it also would be interesting to know what time after the initiation of ATT did drug-induced hepatotoxicity develop in the patients in the study by Yee and colleagues (1). Yee and colleagues (1) do not mention the associated comorbid illnesses the patients in their study had and the other medications the patients were receiving together with ATT. It also is not clear whether the human immunodeficiency virus–positive patients with tuberculosis also were receiving antiretroviral treatment concomitantly. These details are required to meaningfully interpret the published results.
a Sri Venkateswara Institute of Medical Sciences Tirupati, India FOOTNOTES Conflict of Interest Statement: A.M. and S.K.S. have no declared conflict of interest. REFERENCES
From the Authors: We agree with Drs. Mohan and Sharma that pyrazinamide (PZA) is an essential component of modern short-course chemotherapy because it accelerates microbiological improvement in the first 2 months, allowing reduction of the total duration of therapy to 2 months (1, 2). In light of recent reports of serious toxicity with the 2-month rifampin (RIF) and PZA regimen for latent tuberculosis (TB) infection (3, 4), information regarding incidence and risk factors of adverse events related to this drug is of great interest. As noted by Drs. Mohan and Sharma, there is little published information on adverse events of first-line anti-TB drugs under operational conditions in developing countries. Whether this is because of underreporting or underrecognition is not clear. To respond to the specific questions proposed by Drs. Mohan and Sharma, all patients received standard short-course therapy if they had drug-sensitive organisms; therapy was prolonged in patients with drug-resistant organisms (1, 2, 5). There were few patients in our study with more serious forms. As stated, only 5% received directly observed therapy; these patients received therapy three times weekly in the continuation phase at doses recommended by the World Health Organization (1). As shown in Table 1 of our article (6), drug dosage was adjusted for body weight as recommended (1, 2, 5) and was not associated with toxicity. As demonstrated in Figures 2 and 3 of our article (6), almost all adverse events occurred in the first 2 months of therapy. As we reported, few of the patients with serious adverse events had comorbid conditions; for example, none of those patients with drug-induced hepatitis had viral hepatitis B or C, one had human immunodeficiency virus (HIV) infection, and none gave a history of alcohol abuse. Patients with HIV coinfection did not receive antiretroviral viral therapy in the first 2 months of TB therapy, when most adverse events occurred. The greater rate of adverse events in our patient population than in Drs. Mohan and Sharma's experience is not explained by greater drug dosage, use of nonstandard regimens, comorbidities, or concomitant medications. The diverse ethnic background and the older age of our patients—which is atypical for developing countries—might have been factors because they were risk factors in our study (6). We believe that PZA toxicity may be underrecognized. A careful assessment of incidence of adverse events from PZA and other anti-TB agents under operational conditions in a developing country would be of great interest.
Montreal Chest Institute Montreal, Quebec, Canada FOOTNOTES Conflict of Interest Statement: D.M. and D.Y. have no declared conflict of interest. REFERENCES
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