The Role of Rifampin for the Treatment of Latent TB Infection March 26, 2008 Alfred A. Lardizabal, MD Associate Professor of Medicine New Jersey Medical School Global Tuberculosis institute Treatment of LTBI is a major priority in the quest for TB elimination in the US A major activity of TB control programs is to identify persons with LTBI and treat those with increased risk for developing active TB Treatment can provide individual and public health benefits Current recommended standard therapy is 270 doses of INH (at least 9 mos.) Mainstay for almost 4 decades Known efficacy of more than 90% However, only about 65% or fewer complete therapy under routine program conditions 1
Contacts to Smear Positive TB Cases - 2003 Contact count Contacts per case Contacts evaluated for TB Contacts with TB disease Contacts with LTBI Started treatment for LTBI Completed treatment for LTBI National Objectives 73,319 14.0 80% 95% 1% 26% 73% 59% 85% K. Castro Dear Colleague letter, April 6, 2006 A very serious limiting factor is the occasional occurrence of drug-induced hepatitis and INH s well known reputation for such despite the decrease in the incidence of such complications through the years Approach to TLTBI must be improved if it is to have an impact on the problem of TB Interest in finding shorter, well tolerated regimen for TLTBI In the 2000 ATS/CDC/IDSA statement, 2 alternative regimens are recommended: 2 months RIF/PZA; and 4 months RIF 2RZ associated with serious hepatotoxicity and deaths, causing CDC to subsequently advise against its use 2
4R is now the only ATS/CDC/IDSA recommended alternative to 9H for HIV (-) persons Limited published information on safety, tolerability, and efficacy Considering the Role of 4 Months Rifampin in the Treatment of LTBI Reichman LB, Lardizabal A, Hayden CH. Am J Respir Crit Care Med 2004; 170:832-835 Efficacy Bactericidal for M. tuberculosis Acts well against mycobacterial sub-populations with short bursts of metabolic activity Main reason for today s short-course chemotherapy for TB 3
Efficacy Animal studies with mice: sub-clinical infection after BCG vaccination and challenging with MTB Received 4 treatment regimens: 6H, 3R, 2RZ, 2HRZ Bacilli cultured from spleen significantly lower with 4R and 2RZ compared to 6H Lecoeur HF, et al.experimental short-course preventive chemotherapy with rifampin and pyrazinamide. Am Rev Respir Dis 1989; 140:1189-1193 Efficacy The only randomized clinical trial that evaluated rifampin alone revealed 3R given to persons with silicosis had an efficacy rate of 63% compared to 48% for 6H» Hong Kong Chest Service, Tuberculosis Research Center, 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 Efficacy Several studies have shown that rifampin was efficacious in treatment of LTBI among contacts of INH-resistant cases Villarino M, et al.rifampin preventive therapy for tuberculosis infection with 157 adolescents. Am J Respir Crit Care Med. 1997;155:1735-1738 Polesky A, et al.rifampin preventive therapy for TB in Boston s homeless. Am J Respir Crit Care Med 1996;154:1473 4
Hepatotoxicity The Hong Kong study showed that 3R was least toxic regimen vs. 6H and 3HR Patients treated for active TB developed fewer serious side effects and no hepatitis from rifampin compared to H or Z Yee D, et al. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active TB. Am Rev Respir Crit Care Med 2003;167:1472-1477 INH Resistance 57% of TB cases in the US are in foreign born (CDC, 2006) Higher levels of INH resistant TB among foreign born Vietnam 21%, So. Korea 17%, Haiti 16%, Philippines 16%, China 16%, India 11%, Mexico 9% (CDC) Adherence Shorter rifampin-based regimens have been shown to increase adherence rates» Gordin F, et al. Rifampin and pyrazinamide vs isoniazid for prevention of TB among HIV infected persons. JAMA 2000;283:1445-1450» Halsey NA, et al. Rifampin and pyrazinamide vs isoniazid for the prevention of TB in HIV infected persons. Lancet 1998;351:786-792 5
Adherence San Diego reported from a cohort of about 4000 patients on 6H only 64% completed the regimen» Lo Bue PA, Moser KS, et al. Use of isoniazid for LTBI in a public health clinic. Am Rev Respir Crit Care Med 2003;168:443-447 Rifampin in Treatment of Latent Tuberculosis Infection 1 We argue that 4R is an effective, relatively nontoxic, affordable strategy that clinicians and program managers should consider for more widespread use in selected populations and settings to effectively and efficiently treat LTBI, thereby accelerating the decline of TB in their communities. AJRCCM 2004;170:832-835 Rifampin in Treatment of Latent Tuberculosis Infection 2 Our own experience in Middlesex Co., NJ has shown that when we shifted to 4R for a majority of patients starting late 2002, completion rates have increased to 85%, compared to 66% from January 1999 to June 2000 6
Rifampin in Treatment of Latent Tuberculosis Infection 3 Study in County Chest Clinic 474 Patients 2000 Predominantly 9 months Isoniazid (9H) 2003 Predominantly 4 months Rifampin (4R) Treatment completion 9H 53% 4R 80.5% } P < 0.0001 Treatment completion predicted by regimen (OR 5.1; 95% CI 3.3, 8.1) Lardizabal, A. et al. Chest 2006;130: 1712-1717 Rifampin in Treatment of Latent Tuberculosis Infection 4 Comparison of Regimen Features: 9H and 4R Regimen Feature 9H 4R High efficacy * Lower hepatotoxicity Lower overall cost Higher adherence More effective against INH-resistant strains (e.g., among foreign-born persons) Shorter duration Fewer drug-drug interactions * Good evidence that 3R is at least as efficacious as 6H. Inferential reasoning from other evidence suggests that efficacy of 4R may approach that of 9H. AJRCCM 170; 832-835, 2004 Rifampin in Treatment of Latent Tuberculosis Infection 5 Confirms patient acceptance and compliance with treatment significantly improved with 4R Large scale study to assess safety and efficacy of rifamycins in TLTBI is ongoing 7
Recommendations Advocate broader use of rifampin for TLTBI for specific patient populations Strong caution against use among individuals known to be HIV (+) or have risk factors for HIV coinfection Many drugs that a patient may be on can have interactions with rifampin making its use problematic 8