Published ahead of print on November 21, 2002, doi:10.1164/rccm.200209-998OC
American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 824-827, (2003)
© 2003 American Thoracic Society
Safety of 2 Months of Rifampin and Pyrazinamide for Treatment of Latent Tuberculosis
Jason E. Stout,
John J. Engemann,
Allen C. Cheng,
Ellen R. Fortenberry and
Carol D. Hamilton
Division of Infectious Diseases, Duke University Medical Center, Durham, and Wake County Human Services, Raleigh, North Carolina
Correspondence and requests for reprints should be addressed to Jason E. Stout, Box 3306, Duke University Medical Center, Durham, NC 27710. E-mail: stout002{at}mc.duke.edu
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ABSTRACT
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An alternative regimen for the treatment of latent tuberculosis infection is 2 months of rifampin and pyrazinamide, but some patients have died of hepatitis associated with this therapy. One hundred fourteen patients received rifampin/pyrazinamide in Wake County, North Carolina, between December 1999 and May 2002; 60.5% of these patients were homeless, and at least 17% drank alcohol to excess. Seventy-seven patients (67.5%) completed a full 2-month course. Nine patients had a history of viral hepatitis or chronic liver disease. Four of 114 (3.5%; 95% confidence interval, 1.0–8.7%) patients developed hepatitis on therapy, and another two had symptoms consistent with hepatitis but did not report for laboratory testing (total confirmed plus suspected hepatitis rate 5.3%; 95% confidence interval, 2.0–11.1%). No patient who developed hepatitis had a history of viral hepatitis or liver disease, and none had been previously treated with isoniazid. No patients died or were hospitalized due to drug side effects. Rifampin/pyrazinamide was associated with a significantly higher rate of hepatitis than previously described with isoniazid therapy for latent tuberculosis but resulted in a high completion rate. The rifampin/pyrazinamide regimen for latent tuberculosis infection may be useful for high-risk, traditionally nonadherent patient groups, but careful monitoring for toxicity is required.
Key Words: tuberculosis • hepatitis • side effects
Treatment of latent tuberculosis infection (LTBI) is an important priority for tuberculosis elimination in the United States (1, 2). Unfortunately, regimens with demonstrated efficacy require 6–9 months of therapy, are associated with hepatotoxicity, and often have poor completion rates in high-risk populations (3–5). Recent studies evaluated a 2-month regimen of rifampin plus pyrazinamide (RIF/PZA) in human immunodeficiency virus (HIV)-infected individuals, whose risk for developing tuberculosis is markedly increased. The regimen seemed promising because of a relatively short duration of therapy, leading to better completion rates and a low rate of significant side effects (6, 7). Although this regimen was studied in persons who were infected with HIV, the risks and benefits were presumed to apply to the population of patients who did not have HIV. On this basis, the 2000 American Thoracic Society/Centers for Disease Control and Prevention guidelines for treatment of LTBI included the 2-month regimen as an acceptable regimen for people with and without HIV infection (8). Since then, reports of severe and fatal hepatitis have raised concerns about the safety of this regimen (9–11).
The 2-month RIF/PZA regimen was adopted at Wake County Human Services for selected patients in December 1999 and continues to be used in a modified protocol for patient management. We report here the safety and tolerability of this regimen for LTBI in a cohort of patients in Wake County, North Carolina. This cohort was diverse and likely representative of patients who receive the RIF/PZA regimen in health departments across the United States. Some of the results of this study have been previously reported in the form of an abstract (12).
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METHODS
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We examined a cohort of patients who took at least one dose of the combination of RIF/PZA for LTBI at Wake County Human Services in Raleigh, North Carolina, between December 30, 1999, and April 22, 2002. All patients had positive Mantoux skin tests (as defined by the Centers for Disease Control and Prevention [1]), did not have active tuberculosis by clinical and radiographic evaluation, and had not received prior adequate treatment for latent or active tuberculosis. Patients were either treated with 60 doses of daily rifampin (10 mg/kg, maximum daily dose of 600 mg) plus pyrazinamide (20 mg/kg, maximum daily dose of 2,000 mg) or 16 doses of twice-weekly rifampin (10 mg/kg, maximum dose of 600 mg) plus pyrazinamide (50 mg/kg, maximum dose of 4,000 mg). Patients taking daily, self-administered RIF/PZA were asked about baseline signs and symptoms and were then queried monthly about potential medication side effects by public health nurses. Patients taking twice-weekly RIF/PZA received directly observed therapy and were assessed for side effects at the time of each dose. Patients were asked about symptoms of hepatitis (specifically, fever, anorexia, nausea, vomiting, fatigue, dark urine, and jaundice), as well as about any other new symptoms that they experienced while receiving RIF/PZA.
Completion of therapy was defined as having received either 60 daily or 16 twice-weekly doses of RIF/PZA; patients who did not complete the requisite number of doses within 3 months were instructed to start over and take another course. Compliance with therapy was assessed by self-report and pharmacy records for patients who self-administered medications and by direct observation for all other patients. The time to complete therapy was defined as the time from the first dose of RIF/PZA until the last dose was taken; this included time when patients stopped and restarted taking the medication. Demographics, substance use, and comorbidities were all collected from patients' self-reports.
Confirmed hepatitis was defined as elevation of one or both transaminases (aspartate aminotransferase and alanine aminotransferase) to greater than five times the upper limit of normal (normal range = 0–40 for both aspartate aminotransferase and alanine aminotransferase) with one or more accompanying clinical symptoms/signs (nausea, vomiting, abdominal pain, or jaundice). In addition, transaminases had to return to baseline after RIF/PZA therapy was stopped. These criteria are similar to those used by Nolan and colleagues (13). Asymptomatic transaminase elevation to greater than 10 times the upper limit of normal, with continued rise on therapy and resolution after RIF/PZA discontinuation, was also classified as confirmed hepatitis. Suspected hepatitis was defined as two or more symptoms or signs of hepatitis in the absence of laboratory testing.
Continuous variables were expressed as medians and ranges; categorical variables were expressed as numbers and percentages. Confidence intervals were generated using the binomial approximation for proportions. Relationships among categorical variables were assessed with the chi-squared or Fisher's exact test, as appropriate. Differences between continuous variables were tested using the Wilcoxon rank-sum test. A p value of less than 0.05 was considered to be statistically significant (15).
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RESULTS
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We treated 114 patients with RIF/PZA for latent tuberculosis at Wake County Human Services between December 30, 1999, and April 22, 2002. The eligibility criteria for treatment of LTBI with RIF/PZA and subsequent laboratory monitoring evolved as new data and new recommendations became available. From December 1999 to July 2000, patients were selected for RIF/PZA therapy because either they were intolerant of isoniazid or they had been exposed to a patient with isoniazid-resistant tuberculosis. A baseline liver function panel and complete blood count were obtained only for patients with underlying liver disease or HIV infection. Therapy was self-administered or directly observed. In April of 2000, an outbreak of tuberculosis in a local homeless shelter was recognized. Because of an expected poor compliance with 9 months of isoniazid therapy in homeless persons, patients with positive Mantoux tests were prescribed directly observed, twice-weekly RIF/PZA starting July 2000. All patients were monitored with baseline liver function testing and a complete blood count, consistent with national and state TB control recommendations. Further laboratory testing was only performed in patients complaining of new symptoms and in patients with abnormal baseline laboratory values. The policy for provision of RIF/PZA and associated laboratory monitoring was revised in September 2001 after the Centers for Disease Control and Prevention reported 21 cases of severe hepatitis associated with RIF/PZA, including five deaths (16). Symptom screening, liver function testing, and complete blood counts were performed at baseline and after 2, 4, and 6 weeks of therapy. Patients who were taking daily therapy were allowed to complete their course, but all patients thereafter were provided twice weekly, directly observed therapy to allow closer monitoring.
Table 1
describes the demographics of patients who took RIF/PZA. Most (61%) were homeless, and a significant minority (17%) reported a history of heavy alcohol use (more than three alcoholic drinks daily) or binge drinking (more than five alcoholic drinks in 1 day). Routine serologic testing for hepatitis B and hepatitis C was not performed; however, one patient (0.9%) was known to have hepatitis B, and seven (6.1%) tested positive for antibodies to hepatitis C before initiation of RIF/PZA. Five (4.4%) patients who started treatment before August 2001 had a history of hepatitis associated with isoniazid therapy. Sixteen of 87 patients tested (18%) had abnormal baseline liver function studies (aspartate aminotransferase or alanine aminotransferase). Abnormal values were less than twice the upper limit of normal in 12 cases, and twofold to fourfold the upper limit of normal in four cases. Two of these four patients had known hepatitis C and had completed RIF/PZA successfully. The other two patients had a history of heavy alcohol use but no other documented liver disease. One of these patients had confirmed hepatitis, and the other had suspected hepatitis while taking RIF/PZA.
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TABLE 1. Characteristics of 114 patients who took at least one dose of rifampin/pyrazinamide for treatment of latent tuberculosis
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A total of 35 patients (30.1%) self-administered RIF/PZA; 78 (68.4%) received twice weekly, directly observed therapy, and 1 patient took 35 self-administered daily doses plus 7 directly observed, twice-weekly doses. All patients received 600 mg of rifampin (5–13 mg/kg, median of 8 mg/kg). They received 1,250–1,500 mg (median of 1,375 mg) of pyrazinamide daily (13–27 mg/kg, median of 20 mg/kg). Twice-weekly pyrazinamide doses were 2,500–4,000 mg (median of 4,000 mg) or 31–63 mg/kg (median of 48 mg/kg). Of the 114 patients who took at least 1 dose of RIF/PZA, 77 (67%) completed 2 months of therapy. Patients who did not complete therapy took a median 30 daily (range 2–46) or seven twice-weekly (range 1–13) doses of RIF/PZA. Patients who completed therapy did so in a median of 59 days (range 51–177 days); patients on directly observed therapy required less time to complete therapy than patients who self-administered medication (median 55 versus 74.5 days, p < 0.0001). Seventy-one percent of homeless patients completed therapy compared with 65% of other patients taking RIF/PZA (p = 0.51).
Forty patients (35%) who did not get hepatitis complained of at least one new symptom during RIF/PZA therapy. The most common complaints were gastrointestinal disturbance (14 patients) and a rash (9 patients). Seventeen (15%) patients stopped RIF/PZA because of a side effect, but 9 of these 17 patients were able to resume therapy.
Four patients (3.5%) developed confirmed hepatitis while taking RIF/PZA, and another two patients had suspected hepatitis but did not return for laboratory testing. The characteristics of these patients are summarized in Table 2
. None of these patients were known to be infected with HIV. The rate of confirmed plus suspected hepatitis was 5.3% (95% confidence interval, 2.0–11.1%). The doses of RIF/PZA did not differ between patients who developed hepatitis and those who did not (all p > 0.10). No patient required hospitalization or died of hepatitis to our knowledge. The two patients who were lost to follow-up were not admitted to any area hospitals during the time period of the study. The abnormal transaminases of the others returned to normal within 4–7 weeks. None of the 14 patients previously treated with isoniazid, including 5 patients with previous isoniazid-induced hepatitis, developed RIF/PZA-related hepatotoxicity nor did any of the 9 patients with known underlying liver disease. One hundred percent of patients with suspected or confirmed hepatitis consumed alcohol compared with 59% of patients without RIF/PZA associated hepatitis (p = 0.08). Five of the patients with confirmed or suspected hepatitis were diagnosed before routine laboratory monitoring was implemented (of 89 treated; rate in this group, 5.6%) compared with one patient diagnosed after routine laboratory monitoring was implemented (of 29 treated, rate 3.4%, p = 0.54 for comparison with period before monitoring). The one patient with RIF/PZA-associated hepatitis diagnosed after routine laboratory monitoring was implemented was asymptomatic but had an alanine aminotransferase of 20 times and an aspartate aminotransferase of 9 times the upper limit of normal.
During therapy, 18 patients developed abnormal transaminases. Twelve of these patients had values less than twice the upper limit of normal, had no symptoms, and had no pattern of rising transaminases. Four patients had transaminases that were two to five times the upper limit of normal. One of these patients had documented hepatitis C; the etiology of the abnormal transaminases was unclear in the others but was suspected to be alcohol related. None of these four patients had any complaints related to these laboratory abnormalities. Three patients had transaminases that were elevated from 5–10 times the upper limit of normal. Two of these patients had documented hepatitis C with abnormal baseline transaminases; the other patient had a history of heavy alcohol use. None of these three patients had any symptoms, and their transaminases decreased to baseline while continuing therapy.
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DISCUSSION
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Two months of RIF/PZA was reasonably well tolerated in our heterogeneous cohort of patients. Although minor side effects were common, no patients were hospitalized or died because of RIF/PZA. The most common side effects associated with therapy were skin rash and gastrointestinal disturbances. Most patients who experienced these symptoms were able to continue therapy. Importantly, the 67% completion rate for the RIF/PZA regimen in this high-risk population compares favorably with completion rates of 22–49% (4, 5,17) described for 6 months of isoniazid therapy in other cohorts of homeless persons undergoing treatment of LTBI.
The rate of hepatitis (5.3% confirmed plus suspected) was higher than that noted in the two randomized, controlled trials of this regimen in patients with HIV (0% of 380 patients in Haiti [7] and 1.4% of 791 patients in an international study conducted in the United States, Brazil, Haiti, and Mexico [6]). Two more recent observational studies of predominantly HIV-negative jail inmates in Georgia and Maryland noted hepatitis in 0.6% (n = 168) and 1.7% (n = 589) of patients, respectively (18, 19). However, three other recent health-department based studies describe rates of hepatitis from RIF/PZA ranging from 12–20% (20–22). The reasons for the discrepancies among these studies are unclear but may include differences in monitoring, drug dosing, definitions of hepatitis, and patient populations. For example, if all patients with transaminases over five times the upper limit of normal in this study were counted as drug-associated hepatitis, the rate would be increased to 7.9%. We did not include these patients in calculating our rate of hepatitis because (1) many of them had alternative explanations for their abnormal transaminases and (2) these laboratory abnormalities were not associated with any clinical sequelae. Both of the studies of incarcerated, primarily HIV-negative patients showed low rates of hepatitis, whereas this study and other community-based studies found significantly higher rates of hepatitis. Access to and consumption of alcohol may be key factors that explain this difference, as all of the patients with hepatitis in this study consumed alcohol, which is less widely available to incarcerated patients. It is also possible that the immunosuppression caused by HIV infection protects against liver inflammation in response to rifampin or pyrazinamide or the combination. HIV testing was not required before treatment of LTBI, and thus, it was difficult in this study to assess fully the impact of HIV infection on the rate of RIF/PZA-associated hepatitis. Rifampin and pyrazinamide are standard in treatment regimens for active tuberculosis and have not been noted to cause undue toxicity. Whether closer follow-up of cases of tuberculosis leads to earlier detection of incipient toxicity or other factors are at work is unclear. We found no association between the dose of either rifampin or pyrazinamide and the risk of hepatitis, although our statistical power to detect such an association was limited.
There are several limitations of this study. First, patients presenting with abnormal liver function tests were not routinely tested for other causes of acute hepatitis (e.g., viral hepatitis). All patients with hepatitis had a history of alcohol consumption, which may have been responsible for their illness. Second, two of the six patients did not have liver function testing performed and may have had an alternative explanation for their symptoms. Both of these issues could potentially bias this study toward reporting an increased rate of RIF/PZA-associated hepatitis. Excluding the two patients with probable hepatitis had only a small effect on the reported rate of hepatitis in this cohort (from 5.3% to 3.5%). In addition, all of the patients for whom follow-up was obtained had significant relief of their symptoms within a week of stopping RIF/PZA and subsequent resolution of elevated transaminases. The temporal association strongly suggests that RIF/PZA played a role in causing hepatitis in these patients but is not conclusive. Another limitation is the relatively small number of patients with hepatitis, which prevented formal analysis to understand risk factors for hepatitis associated with RIF/PZA.
In an effort to improve completion rates for treatment of LTBI, the 2-month RIF/PZA regimen was recommended for a population that had not been studied in randomized trials. This led to unexpected liver toxicity and reports of severe clinical consequences, including death. The situation underscores the need for clinical trials to form the basis for evidence-based public health recommendations (23). Our data suggest that RIF/PZA, although associated with a significant rate of hepatitis, may be safely used with appropriate monitoring, as outlined in the American Thoracic Society/Centers for Disease Control and Prevention guidelines (11). The RIF/PZA regimen should be considered in populations such as ours where compliance and access to healthcare render alternatives impractical. Twice-weekly therapy with direct observation permits close monitoring for side effects and probably improves the safety profile of the regimen, particularly among patients with poor access to healthcare such as the homeless. Additional studies to identify risk factors for severe hepatitis associated with RIF/PZA may further improve the safety profile of this regimen.
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Acknowledgments
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These data were presented in part as a poster at the 2002 American Thoracic Society Meeting in Atlanta, GA. The authors thank the staff of Clinic E at Wake County Human Services for their assistance with this project and also Michelle Ricci at Wake County Human Services for her assistance in preparation of the poster presentation at the American Thoracic Society.
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FOOTNOTES
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Supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases grants AI07392 and IU01-AI-39156-01, the Agency for Healthcare Research and Quality, the National Institutes of Health/National Heart, Lung, and Blood Institute K07, and the Tuberculosis Academic Award HL-96-022.
Received in original form September 5, 2002;
accepted in final form November 20, 2002
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ABSTRACT
METHODS