Consider Rifampin BUT Be Cautious

Abstract

The majority of cases of active tuberculosis stem from patients with latent tuberculosis infection (LTBI). Treatment of this population is essential in order to achieve the goal of tuberculosis reduction and elimination. Approximately 40 years ago, the United States adopted the treatment of LTBI as a primary strategy to prevent tuberculosis disease and essentially rejected the broad-scale use of the bacille Calmette-Guín vaccine. Ironically, bacille Calmette-Guérin is the most widely used viable vaccine in the world, with > 3 billion doses administered globally. The decision not to use the vaccine in the United States was based on the epidemiologic observation that tuberculosis has a relatively low prevalence in the United States, and the fact that the vaccine is ineffective for the prevention of pulmonary tuberculosis in adults.1Kaufmann ST Mittrûcker HW Vaccination against tuberculosis: current status and future promise.Semin Respir Crit Care Med. 2004; 3: 345-352Crossref Scopus (1) Google ScholarTreatment of LTBI, however, has been challenging on many levels. Those of us who enjoy the role of taking care of these patients can attest to the fact that many eligible patients never initiate therapy and of those who start, only approximately 50 to 60% will complete the regimen.2American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America. Targeted tuberculin testing and treatment of latent tuberculosis infection.Am J Respir Crit Care Med. 2000; 161: S221-S247Crossref PubMed Scopus (1564) Google Scholar Barriers include lack of understanding of the importance of treatment, the absence of symptoms, the risk of toxicity, and the long duration of the therapy.Over the years, isoniazid has become the drug of choice in the treatment of LTBI, and it is the only drug used for LTBI that has been evaluated on a large scale in randomized controlled trials. The effectiveness of the drug, as compared to placebo, in reducing the incidence of tuberculosis is reported in the literature to range from 25 to 92%.3Nuermberger E Bishai WR Grosset JH Latent tuberculosis infection.Semin Respir Crit Care Med. 2004; 3: 317-336Crossref Scopus (38) Google Scholar It is worth pointing out that subgroup analyses have demonstrated a strong relationship between adherence and effectiveness.4International Union Against Tuberculosis. Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial.Bull World Health Organ. 1982; 60: 555-564PubMed Google Scholar As physicians who have the privilege of working in tuberculosis control, we cannot help but ask: At what point in time did such large variabilities in effectiveness become acceptable for developing the standard of care in a disease that is responsible for so much global morbidity and mortality?In this issue of CHEST (see page 1712), Lardizabal et al5Lardizabal A Passannante M Kojakali F et al.Enhancement of treatment completion with four months of rifampin.Chest. 2006; 130: 1712-1717Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar explore the role of 4 months of rifampin (4R) for the treatment of LTBI. This strategy is recommended as an alternative to the 9 months of isoniazid (9H) regimen in the 2000 Centers for Disease Control and Prevention (CDC)/American Thoracic Society guidelines for treatment of LTBI. The study revealed that patients receiving 4R were more likely to complete treatment for LTBI than those receiving standard 9H.5Lardizabal A Passannante M Kojakali F et al.Enhancement of treatment completion with four months of rifampin.Chest. 2006; 130: 1712-1717Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar The findings are in keeping with another study6Menzies RI Dion M Rabinovitch B et al.Treatment completion and costs of a randomized trial of rifampin for 4 months versus isoniazid for 9 months.Am J Respir Crit Care Med. 2004; 170: 445-449Crossref PubMed Scopus (148) Google Scholar that showed that patient adherence with 4R is excellent and also appears to be associated with lower costs and fewer side effects when compared to 9H.The authors5Lardizabal A Passannante M Kojakali F et al.Enhancement of treatment completion with four months of rifampin.Chest. 2006; 130: 1712-1717Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar are correct in their assertion that much of the hesitancy in adopting this regimen stems from the disappointing fact that there is very little published data regarding its efficacy. To date, there is only one randomized clinical trial7Hong Kong Chest Service, Tuberculosis Research Centre, Madras and BMJ Research Council, 1992. 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: 36-41Crossref PubMed Scopus (298) Google Scholar evaluating the efficacy of rifampin against isoniazid, which revealed that tuberculosis rates were reduced by 63% in patients who received a 3-month regimen of rifampin, compared to a 48% risk reduction in subjects who received 9H. The study was confined to a cohort of Chinese men with silicosis, hardly a snapshot of our current at-risk population.7Hong Kong Chest Service, Tuberculosis Research Centre, Madras and BMJ Research Council, 1992. 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: 36-41Crossref PubMed Scopus (298) Google Scholar It is hard to comprehend that in the context of so many discoveries in modern drug therapy, that we are still unable to answer fundamental questions about rifampin, a drug that is celebrating its 40th year.Given that it is unlikely that a novel vaccine will emerge in the near future, our best potential bridge to that day is a short-course regimen that is inexpensive and well tolerated. We concur with Lardizabal et al5Lardizabal A Passannante M Kojakali F et al.Enhancement of treatment completion with four months of rifampin.Chest. 2006; 130: 1712-1717Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar that a short-course rifampin regimen has great appeal. In addition, rifampin also has the added benefit of performing well in the growing number of contacts to isoniazid-resistant cases.Now for the part about the big “BUT.” Rifampin is an exciting alternative, BUT it must be used with caution. We cannot afford to incite further the development of rifampin resistance. It is widely accepted that the small bacillary load in patients with LTBI precludes the development of de novo rifampin resistance. However, it has also been shown that the treatment of patients who are harboring active tuberculosis with rifampin monotherapy would be a potentially devastating blow to our limited armamentarium of effective antituberculosis agents by increasing resistance. It is estimated that as many as 11 million people are coinfected with HIV and tuberculosis, and it must be emphasized that because of the frequent extrapulmonary presentations in patients with HIV disease, excluding active tuberculosis can be very difficult even with unlimited resources.8Corbett EZ Watt CJ Walker N et al.The growing burden of tuberculosis: global trends and interactions with the HIV epidemic.Arch Intern Med. 2003; 163: 1009-1021Crossref PubMed Scopus (2170) Google ScholarThe main weakness of this study is the retrospective design with the use of historical control subjects. Unfortunately, a large component of the tuberculosis literature is confined to small studies with inherently limiting study designs. Extrapolating data is a dangerous game. This lesson we learned all too well from the 2-month regimen of pyrazinamide and rifampin that was originally studied in HIV patients, and when introduced widely into clinical practice for treatment of LTBI was associated with alarming rates of hepatotoxicity and death.9Centers for Disease Control and Prevention. Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection, United States, 2003.MMWR Morb Mortal Wkly Rep. 2003; 52: 735-739PubMed Google Scholar The present study did not address the issue of HIV status of their patient population.Despite these limitations, we believe that 4R should be adopted on a more widespread basis. The dismal adherence rates associated with treatments with 9H require us to promote preventive strategies in our public health tuberculosis programs that will actually work. The success in adherence, clinical tolerance, and reduced costs with the 4R regimen indicate that, at the present time, this represents a solid stepping-stone to the future when we have effective vaccines and short-course therapies that will finally eliminate this disease from humankind.We applaud the authors for continuing to shine the light on this issue. In addition, we are enthusiastic about recent published data10Schechter M Zajdenverg R Falco G et al.Weekly rifapentine/isoniazid or daily rifampin/pyrazinamide for latent tuberculosis in household contacts.Am J Respir Crit Care Med. 2006; 173: 922-926Crossref PubMed Scopus (113) Google Scholar on the safety and effectiveness of isoniazid and rifapentine for 3 months. We also commend the CDC commitment to compare isoniazid and rifapentine vs daily isoniazid in the highly anticipated US Public Health Service Study 26 by the Tuberculosis Trials Consortium of the CDC. This however is not enough. It is time for us as a medical community to engage each other, our governments and the international community to rise to the challenge of developing randomized controlled trials to help us make responsible medical and public health recommendations. We believe that the one third of the world that happens to be infected with this disease deserves this much. The majority of cases of active tuberculosis stem from patients with latent tuberculosis infection (LTBI). Treatment of this population is essential in order to achieve the goal of tuberculosis reduction and elimination. Approximately 40 years ago, the United States adopted the treatment of LTBI as a primary strategy to prevent tuberculosis disease and essentially rejected the broad-scale use of the bacille Calmette-Guín vaccine. Ironically, bacille Calmette-Guérin is the most widely used viable vaccine in the world, with > 3 billion doses administered globally. The decision not to use the vaccine in the United States was based on the epidemiologic observation that tuberculosis has a relatively low prevalence in the United States, and the fact that the vaccine is ineffective for the prevention of pulmonary tuberculosis in adults.1Kaufmann ST Mittrûcker HW Vaccination against tuberculosis: current status and future promise.Semin Respir Crit Care Med. 2004; 3: 345-352Crossref Scopus (1) Google Scholar Treatment of LTBI, however, has been challenging on many levels. Those of us who enjoy the role of taking care of these patients can attest to the fact that many eligible patients never initiate therapy and of those who start, only approximately 50 to 60% will complete the regimen.2American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America. Targeted tuberculin testing and treatment of latent tuberculosis infection.Am J Respir Crit Care Med. 2000; 161: S221-S247Crossref PubMed Scopus (1564) Google Scholar Barriers include lack of understanding of the importance of treatment, the absence of symptoms, the risk of toxicity, and the long duration of the therapy. Over the years, isoniazid has become the drug of choice in the treatment of LTBI, and it is the only drug used for LTBI that has been evaluated on a large scale in randomized controlled trials. The effectiveness of the drug, as compared to placebo, in reducing the incidence of tuberculosis is reported in the literature to range from 25 to 92%.3Nuermberger E Bishai WR Grosset JH Latent tuberculosis infection.Semin Respir Crit Care Med. 2004; 3: 317-336Crossref Scopus (38) Google Scholar It is worth pointing out that subgroup analyses have demonstrated a strong relationship between adherence and effectiveness.4International Union Against Tuberculosis. Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial.Bull World Health Organ. 1982; 60: 555-564PubMed Google Scholar As physicians who have the privilege of working in tuberculosis control, we cannot help but ask: At what point in time did such large variabilities in effectiveness become acceptable for developing the standard of care in a disease that is responsible for so much global morbidity and mortality? In this issue of CHEST (see page 1712), Lardizabal et al5Lardizabal A Passannante M Kojakali F et al.Enhancement of treatment completion with four months of rifampin.Chest. 2006; 130: 1712-1717Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar explore the role of 4 months of rifampin (4R) for the treatment of LTBI. This strategy is recommended as an alternative to the 9 months of isoniazid (9H) regimen in the 2000 Centers for Disease Control and Prevention (CDC)/American Thoracic Society guidelines for treatment of LTBI. The study revealed that patients receiving 4R were more likely to complete treatment for LTBI than those receiving standard 9H.5Lardizabal A Passannante M Kojakali F et al.Enhancement of treatment completion with four months of rifampin.Chest. 2006; 130: 1712-1717Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar The findings are in keeping with another study6Menzies RI Dion M Rabinovitch B et al.Treatment completion and costs of a randomized trial of rifampin for 4 months versus isoniazid for 9 months.Am J Respir Crit Care Med. 2004; 170: 445-449Crossref PubMed Scopus (148) Google Scholar that showed that patient adherence with 4R is excellent and also appears to be associated with lower costs and fewer side effects when compared to 9H. The authors5Lardizabal A Passannante M Kojakali F et al.Enhancement of treatment completion with four months of rifampin.Chest. 2006; 130: 1712-1717Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar are correct in their assertion that much of the hesitancy in adopting this regimen stems from the disappointing fact that there is very little published data regarding its efficacy. To date, there is only one randomized clinical trial7Hong Kong Chest Service, Tuberculosis Research Centre, Madras and BMJ Research Council, 1992. 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: 36-41Crossref PubMed Scopus (298) Google Scholar evaluating the efficacy of rifampin against isoniazid, which revealed that tuberculosis rates were reduced by 63% in patients who received a 3-month regimen of rifampin, compared to a 48% risk reduction in subjects who received 9H. The study was confined to a cohort of Chinese men with silicosis, hardly a snapshot of our current at-risk population.7Hong Kong Chest Service, Tuberculosis Research Centre, Madras and BMJ Research Council, 1992. 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: 36-41Crossref PubMed Scopus (298) Google Scholar It is hard to comprehend that in the context of so many discoveries in modern drug therapy, that we are still unable to answer fundamental questions about rifampin, a drug that is celebrating its 40th year. Given that it is unlikely that a novel vaccine will emerge in the near future, our best potential bridge to that day is a short-course regimen that is inexpensive and well tolerated. We concur with Lardizabal et al5Lardizabal A Passannante M Kojakali F et al.Enhancement of treatment completion with four months of rifampin.Chest. 2006; 130: 1712-1717Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar that a short-course rifampin regimen has great appeal. In addition, rifampin also has the added benefit of performing well in the growing number of contacts to isoniazid-resistant cases. Now for the part about the big “BUT.” Rifampin is an exciting alternative, BUT it must be used with caution. We cannot afford to incite further the development of rifampin resistance. It is widely accepted that the small bacillary load in patients with LTBI precludes the development of de novo rifampin resistance. However, it has also been shown that the treatment of patients who are harboring active tuberculosis with rifampin monotherapy would be a potentially devastating blow to our limited armamentarium of effective antituberculosis agents by increasing resistance. It is estimated that as many as 11 million people are coinfected with HIV and tuberculosis, and it must be emphasized that because of the frequent extrapulmonary presentations in patients with HIV disease, excluding active tuberculosis can be very difficult even with unlimited resources.8Corbett EZ Watt CJ Walker N et al.The growing burden of tuberculosis: global trends and interactions with the HIV epidemic.Arch Intern Med. 2003; 163: 1009-1021Crossref PubMed Scopus (2170) Google Scholar The main weakness of this study is the retrospective design with the use of historical control subjects. Unfortunately, a large component of the tuberculosis literature is confined to small studies with inherently limiting study designs. Extrapolating data is a dangerous game. This lesson we learned all too well from the 2-month regimen of pyrazinamide and rifampin that was originally studied in HIV patients, and when introduced widely into clinical practice for treatment of LTBI was associated with alarming rates of hepatotoxicity and death.9Centers for Disease Control and Prevention. Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection, United States, 2003.MMWR Morb Mortal Wkly Rep. 2003; 52: 735-739PubMed Google Scholar The present study did not address the issue of HIV status of their patient population. Despite these limitations, we believe that 4R should be adopted on a more widespread basis. The dismal adherence rates associated with treatments with 9H require us to promote preventive strategies in our public health tuberculosis programs that will actually work. The success in adherence, clinical tolerance, and reduced costs with the 4R regimen indicate that, at the present time, this represents a solid stepping-stone to the future when we have effective vaccines and short-course therapies that will finally eliminate this disease from humankind. We applaud the authors for continuing to shine the light on this issue. In addition, we are enthusiastic about recent published data10Schechter M Zajdenverg R Falco G et al.Weekly rifapentine/isoniazid or daily rifampin/pyrazinamide for latent tuberculosis in household contacts.Am J Respir Crit Care Med. 2006; 173: 922-926Crossref PubMed Scopus (113) Google Scholar on the safety and effectiveness of isoniazid and rifapentine for 3 months. We also commend the CDC commitment to compare isoniazid and rifapentine vs daily isoniazid in the highly anticipated US Public Health Service Study 26 by the Tuberculosis Trials Consortium of the CDC. This however is not enough. It is time for us as a medical community to engage each other, our governments and the international community to rise to the challenge of developing randomized controlled trials to help us make responsible medical and public health recommendations. We believe that the one third of the world that happens to be infected with this disease deserves this much.