Isoniazid and Rifapentine for Treatment of Latent Tuberculosis
By Mary-Louise Scully M.D.
Dr. Scully is Director, Travel and Tropical Medicine Center Sansum Clinic, Santa Barbara, CA.
Dr. Scully reports no financial relationships to this field of study
Synopsis: A three-month regimen of isoniazid and rifapentine has been shown to be noninferior to a nine-month regimen of daily isoniazid in healthy patients aged ≥ 12 years.
Source: CDC. Recommendations for Use of an Isoniazid-Rifapentine Regimen with Direct Observation to Treat Latent Mycobacterium tuberculosis Infection. MMWR 2011; 60(48):1650-1653.
In this report, the new CDC recommendations for the concomitant use of isoniazid (INH) and rifapentine (RPT) administered weekly for 12 weeks as directly observed therapy (DOT) are detailed. Three randomized controlled trials have shown that this new combination regimen is as effective for preventing tuberculosis (TB) as the standard regimen of INH daily for 9 months without DOT.
The largest and most recent of these trials included 7,731 predominantly HIV seronegative patients with latent TB who were felt to be at high risk for progression to active TB infection. The study was an open-label, randomized, noninferiority trial conducted in four low incidence countries – Brazil, Canada, Spain, and the United States. Subjects received either 12 oral doses of directly observed once weekly INH - 900mg plus RPT - 900mg (combination group) or 9 months of self-administered daily INH - 300mg (INH-only group) and were followed for 33 months.1
In the modified intention-to-treat analysis, TB developed in 7 of 3,986 patients in the combination group (cumulative rate, 0.19%) compared to 15 of 3,745 in the INH-only group (cumulative rate 0.43%) yielding a difference of 0.24 percentage points. The completion rate was 82.1% for the combination group and 69.0% in the INH-only group (p<0.001). Permanent drug discontinuations for any reason were more common with INH-only than INH-RPT (31.0% versus 17.9%) but permanent drug discontinuations attributed to an adverse event were more common in the INH-RPT group than INH-only (4.9% versus 3.7%, p =0.009).
The proportions of patients with any adverse event or any serious adverse event were less in the combination group than the INH-only group but the rates of grade 3, 4, and 5 toxic effects did not differ according to study group. Discontinuation because of hepatotoxicity was more common in the INH-only group (2.7% versus 0.4%, p<0.001) but permanent discontinuations of study drugs attributed to a possible hypersensitivity reaction were higher in the INH-RPT group than the INH-only group (2.9% versus 0.4%, p<0.001). Six of the 152 possible INH-RPT hypersensitivity reactions included hypotension.
The combination regimen of INH-RPT given as 12 weekly DOT doses is an acceptable alternative to 9 months of daily INH for latent TB treatment in healthy patients aged >12 years of age. Other acceptable regimens as options for treatment of latent tuberculosis remain in place and include Rifampin (RIF) for four months, or INH plus RIF for three months. Rifampin plus pyrazinamide (PZA) should not be used because of the potential risk of severe hepatotoxicity. The preferred regimen for children aged 2-11 years remains 9 months of daily INH. The combination regimen of INH-RPT is not recommended for children <2 years, HIV-infected patients receiving antiretroviral treatment (since drug interactions have not been studied), pregnant women, or women expecting to become pregnant during therapy.
It is recommended that baseline hepatic chemistry tests be performed in patients with HIV, liver disease, regular alcohol use, and in the immediate post-partum period (≤ 3 months after delivery), and be considered for older patients, or patients taking multiple medications for chronic medical conditions.
Commentary
Rifapentine (RPT) is a rifamycin derivative with a long half-life and greater potency against Mycobacterium tuberculosis. Similar to rifampin, rifapentine can cause red/orange discoloration of urine, tears, saliva, sweat, skin, teeth, and cerebrospinal fluid and can permanently stain contact lenses and dentures. Rifapentine, like all rifamycins, induces activity of the cytochrome P-450 oxidative enzymes and the P-glycoprotein transport system, causing drug interactions with warfarin, HIV-1 protease inhibitor drugs, hormonal contraceptives, and methadone, to name just a few.
The dosage for the combination regimen is INH 15 mg/kg rounded up to the nearest 50 or 100 mg with a maximum dose of 900mg weekly. Rifapentine is given at a maximum dose of 900 mg weekly for weights above 50 kg, with dose adjustments made for lower weights (see chart in box 1). At the present time, rifapentine is formulated as 150 mg tablets packaged in blister packs that should be kept sealed until usage. INH is formulated as 100 mg and 300 mg. Therefore a 60 kg patient would take a total of 9 pills weekly (3 of the 300mg INH pills and 6 of the 150 mg RPT pills). The cost of RPT is estimated at about $3.95 per pill and INH is about $0.46 per pill, so the cost of the 12-week INH-RPT program would be about $427.00 versus $124.00 for INH alone. New formulations of larger dosage per tablet of RPT would reduce the pill burden and a fixed dose INH-RPT combination is reportedly in development.
Many of us recall only too well the evolution and subsequent demise of the RIF- PZA regimen recommendation. Initial studies done primarily in HIV-infected patients did not demonstrate significant hepatotoxicity, which only became obvious once the regimen was used more broadly in the population.2 RIF-PZA is now clearly contra-indicated because of the risk of fatal hepatotoxicity. Therefore, it will be very important to monitor for all adverse events in the new INH-RPT regimen, especially with regard to the hypersensitivity reactions that were noted. As an editorialist points out, we will need to monitor for the possible development of rifamycin resistance in M. tuberculosis and determine the duration of protection against active tuberculosis the new regimen will provide.3
But for many of us who regularly face the challenge of convincing a healthy patient with latent TB to take INH daily for 9 months, this regimen, should it continue to prove effective and safe, is a welcome option.
References
- Sterling TR, et al. Three months of Rifapentine and Isoniazid for Latent Tuberculosis Infection. N Engl J Med 2011; 365:2155-2166.
- CDC. Severe isoniazid-associated liver injuries among persons being treated for latent tuberculosis-United States, 2004-2008. MMWR 2010;59:224-229.
- Dye C. Practical Preventative Therapy for Tuberculosis? N Engl J Med 2011; 365:2230-2231.
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