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Use of Intermittent Rifampin and Pyrazinamide Therapy for Latent Tuberculosis Infection in a Targeted Tuberculin Testing Program

  1. David H. Priest1,
  2. Louis F. Vossel Jr.2,
  3. Elizabeth A. Sherfy2,
  4. Debbie P. Hoy2, and
  5. Connie A. Haley1,2
  1. 1Vanderbilt University School of Medicine, Nashville, Tennessee
  2. 2Tennessee Department of Health, Nashville, Tennessee
  1. Reprints or correspondence: Dr. Connie A. Haley, State of Tennessee Dept. of Health, 4th Fl., Cordell Hull Bldg., 425 5th Ave. N., Nashville, TN 37247-4911 (connie.haley{at}state.tn.us).
 
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Abstract

Background. To determine the rates of hepatotoxicity and treatment completion associated with intermittent rifampin and pyrazinamide (RZ) therapy for latent tuberculosis infection, we evaluated a cohort of patients from a targeted tuberculin testing site in Tennessee.

Methods. From 4 February 2000 through 9 November 2001, a total of 423 patients with latent tuberculosis infection received directly observed preventive therapy (DOPT) with RZ given twice weekly for 2 months. Most of the patients were young, Hispanic males who had recently immigrated to the United States.

Results. During treatment, hepatotoxicity developed in 29 patients (6.9%; hereafter refered to as “case patients”), and peak alanine aminotransferase (ALT) levels that were >10 times the upper limit of normal were noted in 18 case patients. Of the case patients, 14 had asymptomatic hepatotoxicity, and 2 required hospitalization; none of the case patients died. Hepatotoxicity developed after the receipt of 12 doses in more than half of the case patients, and 4 case patients received all 16 doses. The risk of RZ-associated hepatotoxicity was independently associated with older age (odds ratio [OR], 1.07 per year; P = .01). In total, 352 patients (83.2%) completed RZ therapy. The strongest predictors for noncompletion of RZ treatment were the development of a clinical symptom (OR, 9.73; P < .001) and older age (OR, 1.08 per year; P = .001).

Conclusions. Despite the use of DOPT, intermittent dosing, and vigilant monitoring throughout therapy, RZ was associated with an unacceptable risk of hepatotoxicity.

Although tuberculosis incidence in the United States has decreased during the past decade, the proportion of cases in high-risk populations is increasing [1]. In 2002, more than half of the tuberculosis cases in the United States occurred among foreign-born individuals, for whom the tuberculosis case rate was >8 times higher than that among US-born individuals [1]. Targeted tuberculin testing and treatment have been recommended as a strategy to focus limited public health resources on the identification of high-risk individuals, such as foreign-born individuals, who would most benefit from treatment for latent tuberculosis infection (LTBI) [2].

The cornerstone of a targeted tuberculin testing program is to ensure that treatment for LTBI is completed in a safe manner. Although isoniazid (INH) treatment is effective in the prevention of tuberculosis and has relatively low associated toxicity [18–20]. Of interest, lower hepatotoxicity rates have been reported in studies conducted in correctional facilities where intermittent or daily RZ therapy was provided through the use of directly observed preventive therapy (DOPT) [16, 17]. To determine whether treatment safety and completion rates could be enhanced by the provision of intermittent therapy, DOPT, and frequent monitoring, we evaluated the use of RZ in a highly supervised targeted tuberculin testing setting. We also examined factors that might predict drug-related toxicity or failure to complete RZ therapy.

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Methods

Background. From October 1999 through August 2001, a total of 6 active tuberculosis cases were reported among employees of a food processing plant in Tennessee. Although these individuals with tuberculosis were not epidemiologically linked, all were recent immigrants from Mexico and Central America. Contact investigation demonstrated a high rate of positive tuberculin skin test results among employees and found that most employees were recent immigrants from countries where tuberculosis is endemic. Concerned with the potential for additional tuberculosis cases, the plant instituted a policy that required tuberculin skin tests for all employees at the time they were hired and annually thereafter.

In collaboration with plant administrators, the regional health department initiated a targeted tuberculin testing program to identify and treat employees who had tuberculosis or LTBI. Between 4 February 2000 and 9 November 2001, a total of 2268 employees were tested, and 598 received a diagnosis of LTBI. Of these 598 employees, 91 were not treated, including 86 employees who were >35 years of age (nontreatment of persons in this age group was a practice that was later discontinued), 2 employees who were pregnant, and 3 employees who had been previously treated. A total of 423 employees with LTBI were prescribed treatment with RZ given twice weekly, and 84 employees with LTBI were prescribed INH. A retrospective review of the public health records of patients who were treated with RZ was performed in March and April of 2003 to determine rates of toxicity and treatment completion.

Evaluation of patients. Regional health department staff and the occupational nurses who worked at the plant performed tuberculin skin tests for employees by use of the Mantoux method. Employees with a result that was positive according to ATS/CDC criteria [2] (i.e., induration of ⩾5 mm for employees who had known contact with an individual with tuberculosis and induration of ⩾10 mm for all other employees) were referred to the regional health department for evaluation. The plant administrators granted administrative leave for employees to attend the clinic and frequently provided the employees' transportation to the clinic. A single pulmonologist who was experienced in the management of tuberculosis and LTBI performed clinical and radiographic evaluations of all patients. The following data were recorded in the regional health department record for each individual: demographic information; previous treatment for tuberculosis or LTBI; past medical history, including reported HIV infection and history of hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, or other liver disease; current medications; risk factors for tuberculosis infection; and use of alcohol or illicit drugs. Alcohol use was characterized as “less than one drink per day on average,” “one or more drinks per day on average,” or “binge use.” Individuals were classified as having engaged in “binge use” only if this specific term was documented. Serum liver enzyme levels were measured at baseline and were considered to be elevated if ALT levels were >2 times the ULN (i.e., >80 U/L). Serologic HIV testing was offered to all patients. Spanish interpreters were used to aid in the provision of all patient education, clinical evaluation, and treatment for and monitoring of LTBI.

Treatment regimen. Patients were prescribed therapy with RZ given twice weekly for 8 weeks (for a total of 16 doses). The dose of rifampin was 600 mg for all patients, except for 2 patients who weighed <50 kg and were prescribed doses of 300 mg. The dose of pyrazinamide was ∼50 mg/kg of body weight, with a maximum dose of 4000 mg. For patients with elevated ALT levels at baseline, the decision to initiate or defer treatment was made by the pulmonologist after he discussed the risks and benefits of both options with each patient. RZ therapy was provided at the plant as strict DOPT. “Treatment completion” was defined as a patient being observed to swallow 16 doses of RZ.

Monitoring during treatment. Patients were required to provide photographic identification at all encounters. Clinical monitoring for hepatotoxocity or clinical symptoms besides those suggestive of hepatotoxocity was performed prior to the administration of each dose. The frequency of laboratory monitoring during treatment was altered during the study to remain consistent with changing ATS/CDC recommendations [2, 19]. Specifically, the frequency of laboratory monitoring changed from monitoring at baseline only to monitoring monthly and, then, biweekly, so that equal monitoring was not performed for all patients. Dates of implementation of these changes were not clearly defined. Treatment was withheld or discontinued at the discretion of the pulmonologist and in consideration of patient preference. “Hepatotoxicity” was defined by (1) an ALT level of >3 times the ULN (i.e., 120 U/L) as well as 1 or more clinical signs or symptoms of hepatotoxocity, including nausea, vomiting, abdominal pain, or jaundice, or (2) an ALT level of >5 times the ULN (i.e., 200 U/L), regardless of hepatotoxocity symptoms.

Statistical analysis. Analyses were performed using Stata statistical software, version 8.0 (Stata) and SPSS software, version 11.5 (SPSS). Differences between continuous variables were assessed using the Mann-Whitney U test. Differences in categorical variables were assessed using Pearson's χ2 test or Fisher's exact test. Age was evaluated as a continuous variable and as a categorical variable, with the age of 35 years used as the cutoff value for clinical significance. Two-sided P values of >.05 were considered to be significant. The institutional review boards of the State of Tennessee Department of Health (Nashville) and Vanderbilt University (Nashville) approved the study.

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Results

Characteristics at baseline. The 423 patients in the overall cohort were predominantly male, and only 30 patients were >35 years of age (table 1). All patients were white; most were Hispanic and identified Spanish as their primary language. Almost two-thirds (n = 188) of the patients with a known duration of residence in the United States had immigrated within 5 years of the start of the study. Guatemala and Mexico were the most common countries of origin, and 86 patients claimed US origin.

Table 1.
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Table 1.

Baseline characteristics of 423 patients with latent tuberculosis infection who received treatment with rifampin and pyrazinamide.

Risk factors for tuberculosis were reported by 387 patients, with foreign birth and foreign travel to areas where tuberculosis is endemic being the most common risk factors reported (table 1). Few patients had known contact with an individual with tuberculosis, and none reported recent incarceration or homelessness. Of 23 patients with >1 risk factor, 19 patients reported both foreign birth and foreign travel, and 4 patients reported both foreign birth and known contact with an individual with tuberculosis. There were 9 patients who had previously received a diagnosis of LTBI, including 2 patients who had not completed a previous course of treatment with INH and 7 patients who had received no prior treatment for LTBI.

All 423 patients were healthy at baseline, and none reported having liver disease, HIV infection, or viral hepatitis. One patient reported having type 2 non-insulin-dependent diabetes mellitus. In total, 27 patients took other medications during the study, the most common of which were medroxyprogesterone acetate (n = 12), oral contraceptives (n = 6), and medications for gastroesophageal reflux disease (n = 4). Approximately one-third of patients reported alcohol use, and few reported binge drinking or consumed >1 drink/day. None reported illicit drug use. At baseline, 14 patients (3.3%) had elevated ALT levels, but all of these patients had aspartate aminotransferase levels of <2 times the ULN.

Completion of therapy and clinical outcomes. Study outcomes are listed in table 2. The treatment completion rate was 83.2%, with most patients (94.3%) completing RZ treatment within 10 weeks of initiation of treatment. Of the 71 patients who did not complete RZ treatment, there were 28 patients who subsequently completed treatment with either INH (self-administered therapy or DOPT of 6 or 9 months' duration) or rifampin (self-administered therapy of 4 months' duration), and none developed hepatotoxocity. Another 8 patients began treatment with INH after discontinuing RZ therapy but were lost to follow-up before completion of treatment. There were 25 patients who did not complete treatment who developed hepatotoxicity (including 12 patients with asymptomatic hepatotoxocity and elevation of ALT levels), 22 patients who developed other clinical symptoms, 23 patients who were lost to follow-up, and 1 patient who chose to stop receiving treatment because the regimen contained “too many pills.”

Table 2.
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Table 2.

Clinical outcomes for outcomes for 423 patients with latent tuberculosis infection who received treatment with rifampin and pyrazinamide.

Clnical symptoms developed in 68 patients and occurred both early in therapy and late in therapy. There were 57 patients (13.5% of the total cohort) with elevated ALT levels during RZ therapy, and 18 (31.6%) of these patients had ALT levels that were >10 times the ULN. During treatment, 4 patients received negative results of tests for hepatitis A virus (HAV), 8 received negative results of tests for HBV, 8 received negative results of tests for HCV, and 37 received negative results of tests for HIV.

Risk factors for failure to complete RZ therapy. Risk factors for noncompletion of RZ therapy included older age, development of clinical symptoms, female sex, longer duration of residence in the United States, lower rifampin dose, and higher body weight at baseline (table 3). In multivariate analysis, the development of clinical symptoms and older age remained independent predictors of noncompletion of RZ therapy. Duration of residence in the United States was highly correlated with age (€ = 0.443, by Spearman's coefficent test; P < .001), and, thus, was not included in the model.

Table 3.
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Table 3.

Risk factors for failure to complete treatment with rifampin and pyrazinamide.

Outcomes for the cases of hepatotoxicity. Among patients in the overall cohort, the incidence of hepatotoxicity during RZ treatment was 69 cases/1000 persons treated (table 4). In total, 15 patients developed hepatotoxicity with symptoms, and 14 patients developed asymptomatic hepatotoxocity diagnosed by elevation of ALT levels. No patients in the overall cohort who had received prior treatment for LTBI or who had elevation of ALT levels at baseline developed hepatotoxicity. Only 13 case patients reported alcohol use, including 1 patient who consumed ∼12 beers/week and 1 who was a weekend binge drinker. The use of other medications, including acetaminophen/propoxyphene, esomeprazole magnesium, amlodipine besylate, and/or atorvastatin calcium, was reported by 3 case patients. The few case patients who were tested for viral hepatitis or HIV infection had negative results (4 patients received negative results of tests for HAV, 6 received negative results of tests for HBV, 6 received negative results of tests for HCV, and 7 received negative results of tests for HIV).

Table 4.
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Table 4.

Characteristics of 29 patients with hepatotoxicity.

Hepatotoxicity developed after receipt of only 7 doses of RZ in 1 patient, and 17 patients (58.6%) developed hepatotoxocity after the patient had received 12 doses of RZ (9 patients had symptoms, and 8 patients did not). There were 4 case patients who completed therapy, including 2 with symptoms and 2 without symptoms. Of these, 1 asymptomatic case patient had a peak ALT level of 313 U/L eleven days prior to completion of treatment, and 1 had a peak ALT level of 584 U/L twenty-eight days after completion of treatment. One patient with symptomatic hepatotoxicity reported experiencing mild nausea and abdominal pain during therapy and had an ALT level of 109 U/L. His ALT level rose to 581 U/L thirty-eight days after completion of treatment, although the severity of his symptoms did not change. The other patient with symptomatic hepatotoxicity developed nausea, vomiting, and abdominal pain and had an ALT level of 1120 U/L twenty-four days after completion of treatment. Each of these patients recovered fully.

Two patients were hospitalized for severe hepatotoxicity during treatment with RZ. One patient was a healthy 20-year-old Hispanic man who was born in Texas and whose risks for tuberculosis included travel to Mexico. He was taking acetaminophen/propoxyphene at baseline; he denied using alcohol or illicit drugs and had unknown HIV infection status. The patient developed anorexia, abdominal pain, and jaundice after receipt of the 15th dose of RZ. He was hospitalized for 3 days with a peak ALT level of 2800 U/L, and he had negative results of serologic tests for HAV, HBV, and HCV. A normal ALT value was recorded 6 months after RZ treatment was stopped. The second hospitalized patient was a healthy, 35-year-old, HIV-negative Hispanic man who had immigrated from Mexico 18 years prior to the initiation of RZ treatment. He reported using alcohol an average of less than once per day and denied taking other medications. He developed nausea and abdominal pain after receipt of the 14th dose of RZ and was hospitalized for 2 days with a peak ALT level of 2399 U/L. In the hospital, the patient received negative results of serologic tests for HAV, HBV, and HCV, but the results of drug screening tests were positive for methamphetamines and barbiturates. His ALT levels returned to normal within 35 days after receipt of his last dose.

Risk factors for hepatotoxicity. Risk factors for the development of hepatotoxicity during RZ therapy included older age, longer duration of residence in the United States, lower dose of rifampin, and higher body weight at baseline (table 5). In multivariate analysis, older age remained independently associated with hepatotoxicity. Duration of residence in the United States was not included in the model because of the strong correlation with age.

Table 5.
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Table 5.

Variables associated with hepatotoxicity.

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Discussion

The present study demonstrates that targeted tuberculin testing and treatment are an effective strategy for tuberculosis surveillance and prevention in high-risk populations [2, 21]. The plant described herein is an example of a high-yield site, in that most employees were foreign born, 6 employees had previously developed tuberculosis, and more than one-quarter of employees had LTBI. However, the success of a targeted tuberculin testing program is largely dependent on the provision and completion of a safe and effective treatment regimen, ideally within a short time frame.

Our findings confirm that the risk of development of hepatotoxicity during RZ treatment is unacceptably high, even when a regimen of intermittent dosing and biweekly clinical monitoring are used. The incidence of hepatotoxicity among our study cohort (69 cases/1000 persons treated) is consistent with rates reported in other studies that involved daily self-administration of RZ by HIV-seronegative patients (range, 18–94/1000) [7, 13–15]. A number of the cases that we report occurred late in therapy, and more than half of the cases were asymptomatic and were detected through routine laboratory screening. This suggests that the hepatotoxocity rate may have been higher if all patients had received frequent laboratory monitoring. Although the clinical significance of asymptomatic transaminitis that occurs during RZ therapy is unclear, a patient involved in one asymptomatic case developed ALT levels of >10 times the ULN after the completion of therapy. Of further concern, Kunimoto et al. [22] described a patient with no underlying hepatotoxocity risk who developed fulminant hepatic failure that required liver transplantation, despite adherence to revised ATS/CDC monitoring guidelines. In addition, at least 11 RZ-associated deaths have occurred since the regimen was widely incorporated into practice [20]. Thus, our findings, combined with the findings of these reports, provide ample evidence that RZ does not meet the safety standard required for treatment for LTBI.

In the present study, older age was a strong predictor of RZ-associated hepatotoxicity, and the associated risk for persons who were >35 years of age was >3 times that of younger persons. In a similar study, Jasmer et al. [14] demonstrated that, among persons who were >35 years of age, the risk of developing hepatotoxocity due to RZ was significantly greater than the risk of developing hepatotoxocity due to INH. Unfortunately, our ability to obtain adequate data on other potential risk factors, such as acetaminophen use, viral hepatitis, HIV infection, and excessive alcohol use, was limited by the retrospective design of the study. These exposures increase the risk for hepatic injury during tuberculosis treatment and may have contributed to the occurrence of RZ-associated liver injury in the present study [23–25]. Clearly the benefit of any regimen for the treatment of LTBI must be carefully weighed against the margin of safety, and patients should be carefully evaluated for the presence of underlying liver disease and the concomitant use of hepatotoxic agents prior to treatment.

The etiology of hepatic injury that occurs during RZ treatment is unclear, but pyrazinamide is likely the offending drug [14, 26]. Of note, the incidence of hepatotoxicity may be higher when rifampin and pyrazinamide are used together than when both drugs are combined with isoniazid for the treatment of tuberculosis [27]. This difference may be because of antagonism between isoniazid and either pyrazinamide or rifampin, as suggested in both in vitro studies and murine models [28, 29]. Because most of our patients received similar doses of pyrazinamide, we cannot determine whether the risk for hepatic injury was dose related. The cumulative pyrazinamide dose used for daily regimens is higher than that used for twice-weekly regimens, yet the hepatotoxicity incidence associated with each regimen appears to be similar. This suggests that mechanisms of hepatic injury other than direct toxic effects may be present. First, lower rates of hepatotoxicity during treatment with RZ have been reported in HIV-positive cohorts compared with HIV-negative cohorts, which suggests that intact host immunity may contribute to RZ-associated liver injury [30]. Second, a role for genetic predisposition has been demonstrated by Sharma et al. [31], who showed that patients with specific HLA alleles (the absence of HLA-DQA1*0102 or the presence of HLA-DQB1*0201) were at increased risk of developing drug-induced hepatotoxicity due to antituberculosis medications. Last, at least 1 case report of idiosyncratic liver injury that was likely caused by drug hypersensitivity has been attributed to RZ therapy [18].

Despite expectations for superior treatment-completion rates in association with use of a shorter regimen, completion rates in previous studies that used daily self-administration of RZ have been generally disappointing, ranging from 57% to 80% [7, 9, 12–15]. In contrast, 83% of patients in the present study completed RZ therapy through the use of DOPT. Chaisson et al. [16] also demonstrated higher rates of completion of RZ therapy through the use of intermittent treatment and DOPT. Thus, the advantage of shorter rifampin-based regimens may be primarily associated with the provision of DOPT rather than with the shorter treatment duration. When the additional 28 patients who completed a subsequent course of treatment with either INH or rifampin were included in analysis, almost 90% of the cohort in the present study completed therapy for LTBI. This suggests that the use of interpreters, intensive education and counseling, and the onsite provision of medication and monitoring may also enhance completion of LTBI therapy.

The development of clinical symptoms was a strong predictor for discontinuation of treatment with RZ. Most patients had only minor complaints, such as rash, nausea, or other nonhepatotoxic symptoms, a finding consistent with other reports of low tolerability of RZ, compared with INH [14, 15]. Perhaps by providing better education with regard to the benefits of therapy for LTBI, by evaluating and treating nonsignificant complaints, and by giving frequent reassurance during therapy, individuals who are receiving any regimen may be encouraged to complete therapy despite mild medication intolerance. The finding that older persons were more likely to discontinue treatment may be attributed to the association between older age and hepatotoxicity.

Despite early enthusiasm for treatment with RZ, current data provide substantial evidence that the risk of toxicity is unacceptably high, even with the use of careful screening, frequent clinical and laboratory monitoring, DOPT, and close communication with patients. A high margin of safety is needed for treatment of LTBI, because the risk of progression to tuberculosis is relatively low for persons with LTBI [32]. The expected advantage of higher completion rates with use of the shorter RZ regimen has not been proven outside of settings in which DOPT is used. These findings support current ATS/CDC guidelines that indicate that RZ generally should not be used for treatment of LTBI [20].

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Acknowledgments

We thank the Tennessee Department of Health staff for their dedication to the clinical management of patients and to the elimination of tuberculosis in Tennessee. We also thank Dr. Timothy Sterling, for scientific input and critical review of the manuscript, and Dr. Marion Kainer, for statistical consultation.

Potential conflicts of interest. All authors: no conflicts.

  • Received April 20, 2004.
  • Accepted July 23, 2004.
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  1. Clin Infect Dis. (2004) 39 (12): 1764-1771. doi: 10.1086/425610
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