Rifapentine

Rifapentine (also known as cyclopentyl rifampicin and Priftin) is a medication recommended by the World Health Organization as a first-line treatment for TB. It was first synthesized in 1965 by the Italian company that developed rifampicin and approved by the U.S. Food and Drug Administration (FDA) as a treatment for pulmonary TB in 1998. Rifapentine is a long-acting derivative of rifampicin, and therefore is similar in structure to rifampicin. The primary benefit of rifapentine is that it simplifies TB treatment; its long-acting nature means that the drug is taken only once or twice weekly by patients. In addition, clinical studies have also demonstrated that rifapentine could potentially shorten the current six-month treatment regimen for latent TB. Rifapentine is not available for commercial use in South Africa. **Rifapentine (RPT)** Dosage ------ _Adults_ - Initial intensive phase dose: 600 mg orally two times a week with at least 72 hours between doses for 2 months - Continuation phase dose: Following the 2 month intensive phase, 600 mg orally once a week for at least 4 months _Children_ 15 years or older: - Initial intensive phase dose: 600 mg orally two times a week with at least 72 hours between doses for 2 months - Continuation phase dose: Following the 2 month intensive phase, 600 mg orally once a week for at least 4 months 12 years to less than 15 years weighing less than 45 kg: - Initial intensive phase dose: 450 mg orally two times a week with at least 72 hours between doses for 2 months. - Continuation phase dose: 450 mg orally once a week for at least 4 months following the initial phase 12 years to less than 15 years weighing 45 kg or more: - Initial intensive phase dose: 600 mg orally two times a week with at least 72 hours between doses for 2 months - Continuation phase dose: 600 mg orally once a week for at least 4 months following the initial phase _Notes on dosing_ - To be eligible for rifapentine therapy, patients must be more than 12 years of age; have culture- positive, noncavitary pulmonary tuberculosis; be infected with TB strains that are susceptible to rifampicin, isoniazid, and pyrazinamide; and be HIV negatve. Only HIV-negative patients should receive rifapentine - During the intensive phase, rifapentine should be administered in combination with daily companion drugs (such as ethambutol, pyrazinamide, and streptomycin). - The continuous phase of treatment may consist of rifapentine with isoniazid or an appropriate anti-TB medication. - Patients with resistance to rifampicin should not be given rifapentine, due to cross resistance between these drugs. How it works ------------ Rifapentine is similar in structure to rifampicin and uses a similar mechanism against TB bacteria. It kills TB bacteria by inhibiting bacterial RNA polymerase, which is the enzyme responsible for transcribing DNA into RNA (RNA is subsequently used to make bacterial proteins). By disrupting the bacterial RNA polymerase only, rifapentine eliminates TB bacteria while leaving human RNA polymerase unaffected. Rifapentine has a long half-life in serum and is therefore administered less frequently. Its half-life is 5 times that of rifampicin. Side effects ------------ Mild side effects include red, orange, or brown discoloration of skin, tears, sweat, saliva, urine, or tools, which is a harmless but potentially alarming side effect if the patient is not forewarned; nausea and loss of appetite; stomach pain; mild skin rash or itching; headache; and joint pain. Less common side effects include vomiting; diarrhea; blood in stools; and, in rare cases, liver problems. Pricing ------- Rifapentine (Brand: Priftin) 150 mg, 100 tablets: $363.48 / R2988 Price per tablet: $3.63 / R30 (exchange rate 21/09/2011) (Rifapentine is not available in South Africa) Clinical trials and approval ---------------------------- Rifapentine is recommended by the WHO as a first-line drug for the treatment of TB. It demonstrates excellent activity against TB bacteria in vitro , animal studies, and clinical trials. Rifapentine is as effective as rifampicin at eliminating TB bacteria. Clinical trials have demonstrated rifapentine to be safe and effective for the treatment of TB. Several studies, however, have suggested that patients treated with rifapentine have a slightly higher risk of relapse following the completion of treatment. A 2002 study in the USA and Canada administered rifapentine to a group of HIV positive patients with non drug-resistant TB who had completed a 2 month intensive phase of treatment. These patients received either 600 mg rifapentine plus 900 mg isoniazid once a week or 600 mg rifampicin plus 900 mg isoniazid twice a week. Rifapentine was shown to be safe and effective in HIV negative patients, which was the basis for the current CDC recommendation for using rifapentine and isoniazid in selected patients during the continuation phase of therapy. However, rates of relapse among rifapentine-receiving patients were slightly higher; crude rates of failure/relapse were 46/502 (9.2%) in patients administered rifapentine-isoniazid, and 28/502 (5.6%) in those given rifampicin-isoniazid[^Benator] Early on, this study had included a group of HIV-positive patients. However, recruitment in the HIV-positive study arm was stopped in 1997 after 4 of 36 patients in the rifapentine-isoniazid group experienced relapse with acquired rifampicin-monoresistant TB. Researchers have subsequently advised against administering rifapentine to patients co-infected with HIV and TB.[^Munsiff] A study in 2007 used the mouse model to compare the effectiveness of rifapentine- and moxiflocacin-containing regiments with that of the standard daily short course regimen with rifampicin, isoniazid, and pyrazinamide. Researchers found that replacing rifampicin with rifapentine and isoniazid with moxifloxacin dramatically increased the activity of the standard daily regimen and led to negativity in mice after only 2 months. They concluded that their results warrant urgent clinical investigation, and suggested that rifapentine should no longer be viewed solely as a long-acting substitute for rifampicin. According to the study’s authors, “our results suggest that treatment regimens based on daily and thrice-weekly administration of rifapentine and moxifloxacin may permit shortening the current 6 month duration of treatment to 3 months or less."[^Rosenthal] Rifapentine has also showed considerable promise as an effective treatment for latent TB. A study in 2005 demonstrated that a three-month, once-weekly regimen of rifapentine combined with either isoniazid or moxifloxacin were as active as the current treatment of daily isoniazid for 6–9 months.[^Nuermberger] In addition, a 10 year trial concluded in 2011 and sponsored by the international Centers for Disease Control and Prevention (CDC) recently demonstrated that a once-weekly regimen of rifapentine and isoniazid for just 3 months is as effective as a standard self-administered 9-month daily regimen of isoniazid alone, and has a significantly higher completion rate. The study was one of the largest ever conducted on latent TB preventative therapy, and consisted of 8053 participants in South Africa who were randomized to receive either 3 months of once-weekly rifapentine 900 mg plus isoniazid 900 mg (administered with directly observed supervision), or the current standard treatment regimen (9 months of self-administered daily isoniazid 300 mg). Of the study volunteers, 7 cases of TB occurred in the group assigned rifapentine, while 15 occurred in the standard treatment group. The rate of permanent drug discontinuation due to adverse side effects was slightly higher with the rifapentine/isoniazid regimen (4.7% vs 3.6%). Despite this, the rate of participants who completed treatment was substantially higher with the rifapentine regimen than with the standard regimen (82% vs 69%). This demonstrates that reducing the required treatment regimen from 270 doses to just 12 doses through rifapentine therapy could potentially lead to better rates of completion and patient compliance. Due to these encouraging results, the CDC has launched an effort to develop new guidelines on the use of the treatment regimen. In addition, current clinical trials are investigating the tolerability of the rifapentine-containing regimen amongst children and HIV positive patients.[^March] Advocacy issues --------------- - More clinical information is needed on the effectiveness, safety, and tolerability of rifapentine-containing regimens as a treatment for both active and latent TB in children and patients co-infected with HIV and TB. - The long-acting nature of rifapentine therapy simplifies TB treatment and has been shown to potentially lead to increased patient compliance. - It is recommended that the price of rifapentine therapy be reduced to increase access. [^Benator]: D Benator et al. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet. 2002 Aug 17; 360(9332): 528-534 [^Munsiff]: SS Munsiff et al. Rifapentine for the Treatment of Pulmonary Tuberculosis. Clin Infect Dis. (2006) 43(11): 1468-1475 [^Rosenthal]: IM Rosenthal et al. Daily Dosing of Rifapentine Cures Tuberculosis in Three Months or Less in the Murine Model. PLoS Med. 2007 Dec; 4(12): e344 [^Nuermberger]: E Nuermberger et al. Rifapentine, Moxifloxacin, or DNA Vaccine Improves Treatment of Latent Tuberculosis in a Mouse Model. Am J Respir Crit Care Med. 2005 Dec 1; 172(11): 1452-1456 [^March]: March, David. Simpler Combination Therapy as Good as Old Regimen to Prevent Full-Blown TB in People with and Without HIV. Johns Hopkins Medicine. 7 July 2011.