Isoniazid

Context: American Thoracic Society guidelines recommend a 9-month course of therapy with isoniazid for treatment of persons with latent tuberculosis infection who are at high risk for reactivation of disease. Major liver injury has been reported with the alternative regimen, a 2-month course of pyrazinamide and rifampin.

Objective: To evaluate the rate of completion and incidence of hepatotoxicity of a short regimen of pyrazinamide and rifampin for latent tuberculosis as compared with standard isoniazid therapy before and after instituting an intensive monitoring program.

Design, setting, and participants: Prospective cohort study of 224 patients in a community setting between 1999 and 2001.

Interventions: Daffy pyrazinamide and rifampin for 2 months or daily isoniazid for 6 months.

Main outcome measures: Treatment completion, hepatotoxicity (fourfold increase of alanine transaminase [ALT]), severe hepatotoxicity (40-fold increase in ALT).

Results: Treatment was completed by 71% (78 of 110 patients) in the pyrazinamide/rifampin group and by 59% (67 of 114 patients) in the isoniazid group (p = 0.07). Hepatotoxicity (ALT > 160 U/L) was documented in 13% (14 of 110 patients) in the pyrazinamide/rifampin group and in 4% (5 of 114 patients) in the isoniazid group (p = 0.03). Severe hepatotoxicity (ALT > 1,600 U/L) occurred in 2 of 43 patients (5%) receiving pyrazinamide/rifampin prior to instituting intensive monitoring. Once more intensive monitoring of liver enzymes was implemented, severe hepatotoxicity occurred in none of 67 patients.

Conclusion: The risk of hepatitis in patients receiving pyrazinamide/rifampin for prevention of latent tuberculosis is increased threefold as compared to patients receiving isoniazid. When patients were monitored more intensively, severe hepatotoxicity did not develop, but the difference did not reach statistical significance (p = 0.15).

Key words: antitubercular agents; hepatitis; patient compliance; pulmonary; tuberculin test; tuberculosis

Abbreviations: ALT = alanine transaminase; AST = aspartate transaminase; CDC = Centers for Disease Control and Prevention

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Prevention of active tuberculosis infection in patients with or without HIV is a priority. Current American Thoracic Society guidelines recommend isoniazid daily for 9 months in patients with latent tuberculosis who are at high risk for reactivation of disease. (1) Risk factors for reactivation tuberculosis include a skin test conversion within the past year, HIV infection or immunosuppression, silicosis, and chronic medical conditions such as diabetes and renal dysfunction. (1) Hepatotoxicity and decreased compliance are a concern with the daily use of isoniazid for 9 months. In research settings, 2 months of daily or twice-weekly pyrazinamide/ rifampin treatment is as effective and has similar hepatotoxicity when compared to 6 to 12 months of daily or twice-weekly isoniazid treatment in patients with HIV-1 infection. (2,3) The Centers for Disease Control and Prevention (CDC) recommended the shortened pyrazinamide/rifampin regimen as an alternative therapy in October 1998. (4) The American Thoracic Society adopted this recommendation the following year. (1) Recent cases of severe hepatotoxicity with the pyrazinamide/rifampin regimen have raised questions concerning its safety in patients without HIV infection in usual practice settings. (5,6) We sought to evaluate the completion rate and hepatotoxicity of a 2-month regimen of daily pyrazinamide/rifampin in the treatment of latent tuberculosis compared with a 6-month regimen of daily isoniazid in a community setting. After severe hepatotoxicity developed in two patients receiving pyrazinamide/rifampin, we implemented more intensive monitoring of liver function. The intensive monitoring allowed the comparison of rates of hepatotoxicity and severe hepatotoxicity in the pyrazinamide/rifampin group. Our findings suggest that although the risk of hepatotoxicity is higher with the pyrazinamide/rifampin regimen, the risk of severe hepatotoxicity may be minimized when patients are monitored as is currently recommended by the CDC.

MATERIALS AND METHODS

Patients were enrolled at the Pitt County Health Department between March 1999 and December 2001. Candidates were required to have a positive purified protein derivative result as defined by current American Thoracic Society criteria. (1) We excluded patients with clinical or radiographic evidence of active tuberculosis infection. Children < 14 years of age were not enrolled in the pyrazinamide/rifampin regimen. Patients were offered the pyrazinamide/rifampin unless they had contraindications (active hepatitis or on medications metabolized through cytochrome P450), or if isoniazid was preferred (contact lens users, jail inmates, oral contraceptive users unwilling to switch contraceptive methods, children < 14 years of age). Patients receiving any medications known to be inducers or inhibitors of the cytochrome P450 system were not enrolled in the pyrazinamide/rifampin treatment regimen, as they would have achieved ineffectively low or dangerously high levels of rifampin. Rifampin is an inducer of the cytochrome P450 system; when administered concurrently with oral contraceptives, inadequate hormone levels could be achieved, resulting in unwanted pregnancy. Rifampin is distributed in the tears and may permanently stain contact lenses. Written informed consent was not required since both regimens were acceptable by the State of North Carolina. The patient was given the right to choose isoniazid even if the individual met our criteria for treatment with pyrazinamide/rifampin. Compliance was assessed by patient interview at follow-up visits. The tuberculosis nurse was responsible for the patient interviews.

Patients received pyrazinamide, 15 mg/kg/d (maximum, 2 g/d), and rifampin, 10 mg/kg/d (maximum, 600 mg/d) for 2 months, or isoniazid, 300 mg/d, and pyridoxine, 50 mg/d, for 6 months. North Carolina currently accepts 6 months of isoniazid as an alternative to the 9-month regimen since compliance is higher with the shorter regimen. Medications were self-administered. Both treatment groups were seen at monthly intervals. Liver function was measured at baseline, 1 month, and at the conclusion of treatment in the pyrazinamide/rifampin group. Hepatotoxicity was defined as transaminase levels more than four times normal (alanine transaminase [ALT] > 160 U/L). Patients in the pyrazinamide/rifampin group who acquired hepatotoxicity had their medications discontinued. They were not rechallenged with pyrazinamide/rifampin or started on isoniazid. Patients with hepatotoxicity in whom alcohol was believed to be a contributing factor were not rechallenged with pyrazinamide/rifampin.

Severe hepatotoxicity was defined as transaminases > 40 times normal (ALT > 1,600 U/L). After the development of severe hepatotoxicity in two individuals receiving pyrazinamide/ rifampin, the follow-up was changed to include clinical evaluation and liver enzyme testing at baseline, 2 weeks, 4 weeks, and 8 weeks in the pyrazinamide/rifampin group. In the isoniazid group, patients underwent liver function testing at baseline, 1 month, and with clinical evidence of hepatitis. Patients with ALT levels three to five times normal who were asymptomatic were seen weekly until completion of therapy. Patients were screened for evidence of HIV infection; they were not screened for viral hepatitis. We used the Fisher exact test, [chi square], or Student t test as appropriate, and report odds ratios and 95% confidence intervals. We used SPSS software to analyze the data (SPSS, Version 9.0; SPSS; Chicago, IL).

RESULTS

Patients were enrolled from March 1999 through December 2001. One hundred ten patients received pyrazinamide/rifampin, and 114 patients received isoniazid. Baseline characteristics of the study groups are shown in Table 1. Patients in the pyrazinamide/ rifampin group were older. Both groups had similar distribution of gender, race, and reported alcohol use. One patient in the isoniazid group and two patients in the pyrazinamide/rifampin group were found to have HIV infection; one patient in each group was known to have a history of chronic hepatitis C. Treatment was completed by 71% of patients in the pyrazinamide/rifampin group and by 59% of patients in the isoniazid group (p = 0.07) [Table 1]. Hepatotoxicity was documented in 13% of patients in the pyrazinamide/rifampin group and in 4% of patients in the isoniazid group (p = 0.03) [Table 1]. Onset of hepatotoxicity occurred in the first 4 weeks of therapy in 13 of 14 patients (Tables 2, 3); all but 1 of the patients were symptomatic with the abnormal transaminase levels. The asymptomatic patient completed the 2-month regimen of pyrazinamide/rifampin despite having elevated transaminase levels (Table 3, case 12). None of the patients who acquired hepatotoxicity died, and none required a liver transplant. ALT levels returned to normal in all patients when the medications were discontinued. Male gender and alcohol use were not associated with development of hepatotoxicity in the pyrazinamide/rifampin or isoniazid groups. Interestingly, the incidence of hepatotoxicity was considerably lower in blacks compared with nonblacks (whites, Hispanics, and Asians) [6% compared with 21%, p = 0.02].

Between March 1999 and July 2000, severe hepatotoxicity developed in two patients in the pyrazinamide/rifampin group (Table 2, cases 4 and 7). Up to that time, 43 patients had been treated with this regimen, 8 of whom acquired hepatotoxicity. As a result of these two cases of severe hepatotoxicity, we changed our policy beginning in August 2000, such that liver function measures were obtained at baseline, and at 2, 4, and 8 weeks. Since implementing this more intensive monitoring, we have treated 67 additional patients with pyrazinamide/rifampin. Hepatotoxicity developed in six patients (9%), but none of these persons had severe hepatotoxicity (Tables 3, 4). Onset of hepatotoxicity tended to occur between week 2 and week 4 of therapy (Table 3).

DISCUSSION

In a community setting, we found a threefold increase in the risk of hepatotoxicity among patients receiving pyrazinamide/rifampin (13%) as compared to isoniazid (4%). The risk of severe hepatotoxicity requiring hospitalization was 5% (2 of 43 patients) in the pyrazinamide/rifampin group prior to the more intensive monitoring. We have seen no cases of severe hepatotoxicity since we began more intensive monitoring that we implemented 12 months prior to the revised recommendations of the CDC. Hepatotoxicity in our setting was higher than previously reported. The risk for hepatotoxicity appeared to be higher in nonblacks, although the number of patients is too low to make a general statement. Alcohol use was more prevalent among patients receiving pyrazinamide/rifampin, although not statistically significant.

In our study, patients who acquired hepatotoxicity while receiving pyrazinamide/rifampin were not rechallenged with these medications. Alcohol was felt to be a contributing factor in 2 of 14 patients who acquired hepatotoxicity. Isoniazid was not offered to patients who acquired hepatotoxicity on the pyrazinamide/rifampin regimen. Due to the cases of severe hepatotoxicity documented with pyrazinamide/ rifampin regimen, we do not recommend rechallenging after the ALT level has normalized.

Twenty-three case reports of severe liver toxicity with the pyrazinamide/rifampin regimen have been reported to the CDC. (5,6) A case was defined as liver injury leading to hospital admission or death. Five of the patients reported by the CDC acquired hepatotoxicity during the second month of therapy, but the true onset of hepatotoxicity is unknown since liver function testing was not routinely performed. In our study, hepatotoxicity tended to occur within the first month of therapy, usually between week 2 and week 4. We contend that more frequent monitoring in the first month would detect patients with hepatotoxicity earlier, thus allowing discontinuation of medications and prevention of severe hepatotoxicity.

Previous trials involving the short course pyrazinamide/rifampin regimen in HIV-seronegative adults have shown a higher incidence of hepatotoxicity as compared with isoniazid. (7-9) In a randomized trial, patients treated with pyrazinamide/rifampin for 2 months had a higher incidence of aspartate transaminase (AST) elevation > 100 IU (17 patients) compared with a 4-month course of rifampin (1 patient) and a 6-month course of isoniazid (5 patients). (8) In a prospective cohort study in HIV-negative inmates receiving pyrazinamide/rifampin for the treatment of latent tuberculosis, 3% (5 of 166 inmates) had an AST level more than three times the normal range. (9) The highest documented AST level was 533 U/L. Baseline AST values were normal, and the mean age of those who acquired hepatotoxicity was not significantly different from the population as a whole. (9)

Given the relatively low incidence of hepatotoxicity in persons receiving a regimen of isoniazid, rifampin, and pyrazinamide for treatment of active tuberculosis, (10) there would appear to be a paradox. One possible explanation is that persons with active disease receive the majority of their treatment two times per week by directly observed therapy. It is possible that intermittent dosing of these medications is associated with less hepatotoxicity. Future studies should be done to investigate the utility and safety of directly observed therapy using this regimen two to three times per week as is given for treatment of active disease. This form of therapy would have the additional benefit of improving patient compliance.

Previous reports on the use of pyrazinamide/ rifampin for treatment of latent tuberculosis infection in patients with HIV infection demonstrated a much lower incidence of hepatotoxicity than we reported. (2,3) It may be that an intact host immune system is an important risk factor for developing liver damage.

It may be argued that hepatotoxicity was documented more often in the pyrazinamide/rifampin group because those individuals were monitored more closely and had more determinations of liver enzymes than the individuals who received isoniazid. It is well known that many patients receiving isoniazid can have asymptomatic elevations of liver enzymes. We believe that it is unlikely that asymptomatic patients would have had significant elevations of liver enzymes (more than four times normal) while receiving isoniazid. Furthermore, we followed standard-of-care practice regarding monitoring of patients who received isoniazid. As a result, those individuals received less monitoring of liver functions, which may have partially affected the results that we report.

This study was a prospective but not randomized trial for several reasons. First, female subjects receiving oral contraceptives were not treated with the short-course regimen because of concerns regarding drug interactions with rifampin. Second, many individuals had been started on isoniazid at outside institutions, ie, jails and alcohol rehabilitation facilities. Finally, children < 14 years old were treated with isoniazid because of limited clinical data to support the short-course regimen in children. It should be noted that a clinical trial utilizing the short-course pyrazinamide/rifampin regimen in German children did not show any evidence of hepatotoxicity. (11)

In conclusion, we found that the risk of hepatotoxicity in patients receiving pyrazinamide/rifampin for prevention of latent tuberculosis is increased threefold as compared to patients receiving isoniazid. Since we have instituted intensive monitoring of these subjects, we have seen no cases of severe hepatotoxicity. Not surprisingly, the completion rate was higher with the short-course regimen. The difference in completion rates may have been even more dramatic had we chosen a 9-month regimen of isoniazid, which is the current recommendation from the CDC. This higher completion rate may justify the use of this short course therapy in patients who may have difficulty with adherence to therapy as long as vigilant monitoring of liver enzymes is performed.

REFERENCES

(1) Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000; 161:S221-S247

(2) Halsey NA, Coberly JS, Desormeaux J, et al. Randomised trial of isoniazid vs rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1 infection. Lancet 1998; 351:786-792

(3) Gordin F, Chaisson RE, Matts JP, et al. Rifampin, and pyrazinamide vs isoniazid for prevention of tuberculosis in HIV-infected persons. JAMA 2000; 283:1445-1450

(4) Centers for Disease Control and Prevention. Use of short-course tuberculosis preventative therapy regimens in HIV-seronegative persons. MMWR Morb Mortal Wkly Rep 1998; 47:911-912

(5) Centers for Disease Control. Fatal and severe hepatitis associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection: New York and Georgia, 2000. MMWR Morb Mortal Wkly Rep 2001; 50:289-291

(6) Centers for Disease Control update. Fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revision in American Thoracic Society/CDC recommendations: United States, 2001. MMWR Morb Mortal Wkly Rep 2001; 50:733-735

(7) Geiter LJ, O'Brien RJ, Kopanoff DE. Short-course preventive therapy for tuberculosis [abstract]. Am J Respir Crit Care Med 1990; 141(Pt 2):A437

(8) Geiter LJ. Results of a randomized, controlled trial to assess the toxicity and patient adherence with two short-course regimens for the prevention of tuberculosis, a two-month regimen of rifampin and pyrazinamide or a four-month regimen of rifampin only, in comparison with a control regimen of six months-isoniazide [thesis]. Baltimore, MD: Johns Hopkins University, School of Hygiene and Public Health,

(9) Bock NN, Rogers T, Tapia JR, et al. Acceptability of short-course rifampin and pyrazinamide treatment of latent tuberculosis infection among jail inmates. Chest 2001; 119:833-835

(10) Combs DL, O'Brien RJ, Geiter LJ. USPHS tuberculosis short-course chemotherapy trial 21: effectiveness, toxicity, and acceptability. Ann Intern Med 1990; 112:397-406

(11) Magdorf K, Arizzi-Ruche AF, Geiter LJ, et al. Compliance and tolerance of new antituberculotic short-term chemoprevention regimes in childhood: a pilot study. Pneumologie 1994; 48:761-764

* From the Brody School of Medicine at East Carolina University, Greenville, NC.

The Brody School of Medicine at East Carolina University supported this work.

Manuscript received January 11, 2002; revision accepted July 23, 2002.

Correspondence to: Lee McNeill, MD, The Brody School of Medicine at East Carolina University, 600 Moye Blvd, Pitt County Memorial Hospital, Teaching Annex Room 389, Greenville, NC 27858; e-mail: mcneillel@mail.ecu.edu.

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