To the Editors:
Isoniazid (INH) for 9 months (9H) is the best-studied regimen for preventing reactivation tuberculosis (TB) when latent tuberculosis infection (LTBI) is diagnosed.1,2 Shorter LTBI regimens based on other antituberculosis medications are of growing interest given concerns about INH-related hepatotoxicity,3 poor adherence attributed to long duration of INH regimens,4,5 and the growing proportion of foreign-born TB cases with INH-resistance.6 For pediatric LTBI patients, either INH-intolerant or contacts of INH-resistant TB cases, the American Academy of Pediatrics recommends 6 months of rifampin (6R).2
The Philadelphia Tuberculosis Control program (Phila-TBC) follows the American Academy of Pediatrics recommendation for 6R in <12-year-old patients, and the Center for Disease Control and Prevention recommendation for 4 months rifampin (4R) in ≥12-year-old patients.1 The dose of 10 to 20 mg/kg was given once daily (maximum 600 mg); Phila-TBC provides all medication; younger patients use capsule content mixed with palatable food. On business days, patients <5 years of age receive home-based directly observed preventive therapy by a disease surveillance investigation worker (DSI-worker); patients aged 6 to 18 years preferably receive school-based directly observed preventive therapy, with medication provided by the DSI worker monthly and administered by the school nurse daily. For nonbusiness days, the DSI worker provides appropriate amount of medication and monitors compliance the next business day. Patients are also monitored monthly or bimonthly in the clinic by the pediatric specialist. For selected patients, self-administered therapy is allowed with medication picked up by the parents during clinic visits; compliance is monitored with pill counts in the clinic. Baseline and follow-up serum hepatic enzymes are not performed routinely unless there are preexisting liver disease or hepatotoxicity signs. Testing for human immunodeficiency virus is advised for patients >13 years of age; documentation of maternal human immunodeficiency virus testing during pregnancy is sought for younger patients.
The Pennsylvania Department of Health National Electronic Disease Surveillance System was used to identify Philadelphia residents <18 years of age, diagnosed with LTBI and reported to Phila-TBC between January 1, 2004 and December 31, 2009. Charts were reviewed for patients treated with rifampin. If the regimen was changed from 9H to rifampin, the length of 4R or 6R was reduced by the percentage of the 9H course already completed.
Hepatotoxicity was considered elevation of serum hepatic enzyme values >3× the upper limit of normal (ULN).3 Data were analyzed using Microsoft Excel (2003 version, Microsoft Corporation, Redmond, WA).
Of 872 LTBI cases reported as <18 years old, 58 were treated with rifampin. Patient and treatment characteristics are shown in Table, Supplemental Digital Content 1, https://links.lww.com/INF/A945. No subjects were known to be infected with human immunodeficiency virus; test results were documented for 50. Of 6 known source cases infecting 9 study subjects, 4 were foreign-born and 2 were US-born. Mycobacteria isolated in sputum cultures from the 4 foreign-born source cases were proven to be INH-resistant but rifampin-sensitive; both US-born source cases were mycobacteria sensitive to all anti-TB drugs.
Baseline laboratory tests, measuring serum hepatic enzymes, were performed in 16 patients (27%) due to chronic hepatitis B infection in 1, INH intolerance in 4, or physician's preference; all were normal.
The majority of patients (88%) completed the regimen within the expected time frame and 1 later; 3 patients did not complete the regimen due to nonadherence, pregnancy, rifampin intolerance, for 1 case each; 3 were lost to follow-up.
Only 3 patients (5%) experienced new symptoms during rifampin treatment, without any hepatotoxicity. The first patient was 10 years old, foreign-born, with unknown hepatitis B and C serology, reporting anorexia 50 days after starting 6R. Transaminases and total bilirubin were normal. The anorexia resolved within 30 days, and 6R was completed. The second patient was 15 years old, on 4R due to INH-intolerance, with negative hepatitis tests and normal baseline transaminases. After 68 doses of rifampin, abdominal pain and vomiting developed and the patient, who was not using contraception, was found to be pregnant. She elected to discontinue therapy after being counseled on the risks of congenital and reactivation TB. The third patient was 11 years old, on 4R due to INH-intolerance, with negative hepatitis serology and normal baseline and follow-up transaminases. However, follow-up total bilirubin rose to 2.2× ULN, from a baseline of 0.2× ULN. Rifampin was discontinued on day 40 after counseling on the risks of reactivation TB.
Several studies comparing different regimens have shown less hepatotoxicity with rifampin monotherapy,4,5,7,8 even when only the first 4 months of 9H were considered.8 Data from studies in adults demonstrate comparable efficacy of 4R with INH regimens,4,7 better adherence, less treatment interruptions in schools/prisons, and improved cost-effectiveness.5 However, drug interactions could limit rifampin use in some patients. Larger trials with longer follow-up are needed to establish efficacy, to monitor for the emergence of rifampin-resistant mycobacteria, and to determine the optimum duration of treatment for children with LTBI in this era where drug resistance may undermine our efforts to control or eliminate tuberculosis.
Irini Daskalaki, MD
Tuberculosis Control Program Division of Disease Control Philadelphia Department of Public Health Drexel University College of Medicine St. Christopher's Hospital for Children Philadelphia, PA [email protected]
Jaehyun Byun, MD
University of Pennsylvania School of Medicine Philadelphia, PA
M. Christina Dogbey, MPH
Tuberculosis Control Program Division of Disease Control Philadelphia Department of Public Health
Cymara Tolbert-Warren, BS
Drexel University School of Public HealthPhiladelphia, PA
Barbara M. Watson, MB ChB, FRCP
Tuberculosis Control Program Division of Disease Control Philadelphia Department of Public Health Philadelphia, PA
1.Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Recomm Rep.
2.Pediatric Tuberculosis Collaborative Group. Targeted tuberculin skin testing and treatment of latent tuberculosis infection in children and adolescents. Pediatrics
3.Saukkonen JJ, Cohn DL, Jasmer RM, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med
4.Hong Kong Chest Service/Tuberculosis Research Centre MBMRC. A double-blind placebo-controlled clinical trial of three antituberculosis chemoprophylaxis regimens in patients with silicosis in Hong Kong. Am Rev Respir Dis.
5.Reichman LB, Lardizabal A, Hayden CH. Considering the role of four months of rifampin in the treatment of latent tuberculosis infection. Am J Respir Crit Care Med
6.Menzies HJ, Winston CA, Holtz TH, et al. Epidemiology of tuberculosis among US- and foreign-born children and adolescents in the United States, 1994–2007. Am J Public Health
7.Polesky A, Farber HW, Gottlieb DJ, et al. Rifampin preventive therapy for tuberculosis in Boston's homeless. Am J Respir Crit Care Med
8.Page KR, Sifakis F, Montes de Oca R, et al. Improved adherence and less toxicity with rifampin vs isoniazid for treatment of latent tuberculosis: a retrospective study. Arch Intern Med