The Role of Four Months of Rifampicin in the Treatment of Latent Tuberculosis Infection
To the Editor.
The way that the United States chooses to prevent tuberculosis has always been a subject of interest to the rest of the world. Its decision in the 1950s not to use Bacille Calmette-Gurin (BCG) in the light of conflicting trial evidence was a brave one. It must have been particularly hard on the Chicago infants or the North American Indians for whom BCG had been shown to have a protective effect (1, 2). The decision not to use BCG has also been shown to be questionable in the light of protection against infection with MDR- TB (3).
Credit, however, must be given to the United States for inventing the concept of preventive therapy for latent tuberculosis infection; the initial trials of up to a year of isoniazid alone were appropriate when therapy lasted for 2 years and cost limitation was all important. With the reduction of treatment for active disease to six months, giving treatment for latent infection for longer is no longer appropriate. Meta-analysis has shown there is no additional benefit of giving isoniazid for any longer than 6 months (4), only increased toxicity, and these data have the highest category of evidence level (SIGN 1 ++) (5). The enormous reduction in costs of rifampicin has made a rifampicincontaining preventive regimen very attractive. However, the United States’ venture into 2 months rifampicin and pyrazinamide has proved a disaster owing to serious adverse effects. Men and indeed women are not mice (6).
The advocacy of the 4-month regimen of rifampicin only by Reichman and coworkers must be seriously questioned (7). First, there is the danger of creating rifampicin resistance, which is much harder to treat than isoniazid resistance. The lack of evidence for isoniazid prophylaxis leading to isoniazid resistance as a reason for using rifampicin alone, as suggested by Reichman and coworkers, may be dangerous. Absence of proof (of a single drug prophylaxis resulting in resistance to that drug) is not proof of absence. What has been demonstrated, or rather not demonstrated, in a well conducted trial may not pertain in the hustle and bustle of the service setting where active disease could be missed and a single drug given in error. Second, there has only been one trial of the use of rifampicin alone for latent TB infection, and that with a 3- month regimen (8). “Inferential reasoning” to suggest that 4 months of rifampicin be used is not good enough (SIGN level 4), when absolutely no randomized controlled clinical trial evidence is available. We have enough problems managing patients with rifampicin- resistant disease, created by the medical services, without artificially and unnecessarily providing another potential avenue for its increase. Why is the United States so reluctant to consider the combination of rifampicin and isoniazid for 3 months, which was shown to be as effective as rifampicin alone in the same trial (8), has SIGN level 1+ evidence from trials and 2+ from clinical studies, and has been used extensively in the UK for nearly 20 years, with no reports of serious adverse outcomes (9)?
Conflict of Interest Statement: P.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; P.O. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
PETER DAVIES
Cardiothoracic Centre
Liverpool, United Kingdom
PETER ORMEROD
Blackburn Royal Infirmary
Blackburn Lanes, United Kingdom
References
1. Rosenthal SR, Loewinsohn E, Graham ML, Liverwright D, Thorne MG, Johnson V. BCG vaccination against tuberculosis in Chicago: a twenty year study statistically analysed. Pediatrics 1961;28:622- 641.
2. Stein SC, Aronson JD. The occurrence of pulmonary lesions in BCG vaccinated and unvaccinaled persons. Am Rev Tuberc 1958;68:695- 712.
3. Marcus AM, Rose DN, Henry HS, Scheeler CB. BCG vaccination to prevent tuberculosis in health care workers: a decision analysis. Prev Med 1997;26:201-207.
4. Smieja MJ, Marchetti CA, Cook DJ, Smaill FM. Isoniazid for preventing tuberculosis in non-HIV infected persons (Cochrane Review). The Cochrane Library, Issue 2. Chichester, UK: John Wiley & Sons; 2004.
5. SIGN. 50: A Guideline developers handbook. Scottish Intercollegiate Guidelines Network, February 2001. http:// www.sign.ac.uk/guidelines/ fulltext/50/index.html.
6. Grosset J. The sterilizing value of rifampicin and pyrazinamide in experimental short course chemotherapy. Bull Int Union Tuberc 1978;53:5-12.
7. Reichman LB, Lardizabal A, Hayden CH. Considering the role of four months of rifampicin in the treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2004;170:832-835.
8. Hong Kong Chest Service, Tuberculosis Research Centre Madras and British Medical Research Council. A double blind placebo- controlled clinical trial of three anti-tuberculosis chemoprophylaxis regimens in patients with silicosis in Hong Kong. Am Rev Respir Dis 1992;145:36-41.
9. Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the UK: recommendations 1998. Thorax 1998;53:536-548.
From the Authors:
The commentary of Drs. Davis and Ormerod on our pulmonary perspective (1) considering 4 months rifampin for treatment of latent TB infection (LTBI) presents several problems. We focused entirely on treatment for LTBI, so their advocacy for Bacille Calmette-Gurin (BCG) is not germane.
Concern about selection of resistant mutants with monotherapy suggests that Drs. Davis and Ormerod don’t appreciate the role of bacterial burden (2). LTBI treatment destroys the small number of infecting organisms to prevent full-fledged disease. There is no evidence that LTBI treatment with isoniazid or rifampin monotherapy leads to the development of isoniazid or rifampin resistance.
Since treating heavy bacterial burden disease with monotherapy leads to drug resistance, we emphasized the importance of ruling out disease prior to LTBI treatment. And since HIV-related TB disease may present atypically, and may be overlooked, we specifically recommended against using 4R in LTBI treatment among HIV-infected persons (1). If Drs. Davies and Ormerod worry about patient mistreatment because of “hustle and bustle” in the clinic, they might consider addressing this through tighter protocols and training.
The only randomized clinical trail that evaluated the efficacy of rifampin alone (using 3R) is the same study on which the United Kingdom bases its recommendation for the 3HR regimen (3). While there is no proof that 4R is better, it is surely at least as efficacious as 6H or 3HR. The UK’s programmatic success with the 3HR regimen has been primarily among children (4). Since the United States has adopted a much more aggressive LTBI testing and treatment strategy (including targeting all persons at increased risk, regardless of age), adding isoniazid to rifampin would likely diminish its use due to its perceived toxicity.
TB in the United States (2003) is at an historical low (as is drug resistance) (5), without any use of BCG; but with enhanced LTBI treatment. Unfortunately, this is not the case in the United Kingdom. Despite its use of BCG and limited use of LTBI treatment, the United Kingdom has experienced an alarming increase in TB over the past 10 years. This has led the government to publish an action plan which cites the United States’ committed response to its own TB resurgence as a model for emulation (6).
Our perspective is that 4R is an effective, relatively nontoxic, patient-acceptable, and affordable regimen which, if used appropriately in selected populations and settings, would further accelerate the decline of TB in the United States (1). Perhaps our colleagues in the United Kingdom might seek to achieve similar successes by reconsidering some of their own biases.
Conflict of Interest Statement: L.B.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.H.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
LEE B. REICHMAN
CHRISTOPHER H. HAYDEN
New Jersey Medical School National
Tuberculosis Center
Newark, New Jersey
References
1. Reichman LB, Lardizahal A, Hayden CH. Considering the role of four months of rifampin in the treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2004;170:832-835.
2. American Thoracic Society, Centers for Disease Control and Prevention, Infectious Diseases Society of America. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Cure Med 2000;161:S221-S247.
3. Hong Kong Chest Service, Tuberculosis Research Centre Madras, and British Medical Research Council. A double-blind placebo- controlled clinical trial of three antituberculosis chemoprophylaxis regimens in patients with silicosis in Hong Kong. Am Rev Respir Dis 1992;145:36-41.
4. Ormerod LP. Rifampin and isoniazid prophylactic chemotherapy for tuberculosis. Arch Dis Child 1998;78:169-171.
5. Centers for Disease Control. Reported Tuberculosis in the United States, 2003. Atlanta, GA: US Department of Health and Human Services, CDC: September 2004.
6. UK Department of Health. Stopping tuberculosis in England: an action plan from the \chief Medical Officer. COI Communications for the Department of Health: October 2004. Gateway ref: 1176.
Copyright American Thoracic Society Aug 15, 2005