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.

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Open letter to the Stop TB Partnership on the need to strengthen its role in the struggle against TB

Activists from across the world have written an open letter to Professor Rifat Atun, chairman of the co-ordinating board of the Stop TB Partnership expressing concerns about the current and future governance of the organisation and its relationship with the World Health Organisation.

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Gene Xpert

The Gene Xpert is a new test for tuberculosis. It can find out if a person is infected with TB, and also if the TB bacterium of the person has resistance to one of the common TB drugs, rifampicin.

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TMC207

TMC207 (also known as bedaquiline, R207910 or the ‘J’ compound) is an experimental anti-TB drug. Discovered by Johnson & Johnson, TMC207 is the first compound in a new class of potent anti-TB drugs, the first new class in 60 years. Studies have shown that it is effective against both drug-resistant and susceptible TB. A recently completed phase II trial found that it reduces the time it takes for sputum to become negative in patients, meaning that it has the potential to shorten the duration of TB treatment. Clinical phase II trials are currently being carried out to evaluate the effectiveness of TMC207 for TB treatment. How it works ------------ TMC207 is categorized as a diarylquinoline. This is an entirely new class of TB drug that works by inhibiting an enzyme that is vital for the production of energy, or ATP, in TB bacteria. This enzyme is called ATPase. TMC207 binds to ATPase and prevents it from supplying energy for the bacterial cell, which kills the bacterium. Pre-clinical trials ------------------- Researchers at Johnson & Johnson published their first report on TMC207 in 2005. They found that TMC207 was effective against both drug-sensitive (i.e. non-resistant) and drug-resistant TB bacteria in vitro. In mice, the drug was found to exceed the effectiveness of isoniazid and rifampicin when taken alone. When substituted for first-line drugs in the standard treatment programme, the activity of each new combination with TMC207 was improved.[^Andries] A study published in 2006 examined TMC207 as a treatment for MDR TB using the mouse model. Mice were treated with various combinations of TMC207 with the standard regimen of second-line drugs (amikacin, pyrazinamide, moxifloxacin, and ethionamide). Combinations that included TMC207 were found to be more effective against MDR TB than the current regimen in nearly every case.[^Lounis] A study in 2008 examined the activity of TMC207 against TB bacteria in mice lungs. Most notably, the study found that using a triple combination of TMC207 with rifapentine and pyrazinamide achieved outstanding bactericidal activity, with lung culture negativity in 9 of 10 mice.[^Veziris] These early studies revealed some potentially important attributes of TMC207. Firstly, the mouse model suggested a synergistic interaction between TMC207 and pyrazinamide, meaning that these drugs may be more powerful when given in combination than either drug alone. More studies are needed to investigate this. Secondly, the drug showed activity against both drug-resistant and non drug-susceptible strains of TB, meaning that it could work as a treatment for MDR / XDR TB. Additionally, in-vitro studies of TMC207 showed that the drug is a potent sterilizing agent, meaning that it is able to effectively eliminate TB bacteria. If the behavior of TB bacteria has this same property in-vivo (in human patients), then TMC207 could shorten the duration of TB treatment. This would be a much-needed change to what is currently a very lengthy and cumbersome treatment programme. The sterilizing ability of TMC207 also might make it a powerful drug in the struggle to eradicate TB.[^Matteelli] Phase I trials -------------- A phase I trial, the first stage of testing in human patients, was completed in South Africa. Results were published in 2008. The study examined the Early Bactericidal Activity (EBA), meaning its activity against TB early on, in 75 different TB-infected patients who had not had prior TB treatment. Of these patients, 31% were HIV positive. For seven days, these patients took either 600mg rifampicin, 300mg isoniazid, or a particular dose of TMC207. Researchers found that the bactericidal activity (i.e. ability to eliminate TB bacteria) of TMC207 at a dose of 7400 mg daily was similar to that of the other two first-line drugs, rifampicin and isoniazid. They found that TMC207 took slightly longer to start eliminating TB bacteria, with bactericidal effects beginning on day 4. In addition, the drug was well tolerated in patients, with no serious side effects.[^Rustomjee] Another phase I trial is currently being carried out at University Hospitals (UH) Case Medical Center in the U.S. This trial will give TMC207 to 32 healthy individuals to test for the drug’s safety and tolerability. The study will also examine whether TMC207 has any drug interactions with other TB medications, such as rifabutin and rifampicin.[^TB Online] Researchers believe that there may be a drug-drug interaction between TMC207 and rifampicin, which is of major concern given that rifampicin is a first-line TB drug. An enzyme (called CYP3A4) that metabolizes - and thereby activates - TMC207 is inhibited by rifampicin. This means that when both drugs are used together, rifampicin may prevent TMC207 from working properly. A study among 16 volunteers indicates that rifampicin might indeed make TMC207 less powerful.[^Lounis] More studies are needed to investigate this interaction. Phase II trials --------------- In a phase II trial, experimental drugs are given to a larger group of patients than in phase I. A phase II trial for TMC207 is currently being carried out in South Africa. The study is coordinated by teams of researchers at the Univ. of Stellenbosch, Univ. of Witwatersrand, Aurum Health, Medical Research Council, and Tibotec. This trial has two stages. The first stage has already been completed, and results were published in 2009. The purpose was to determine whether TMC207 was effective in reducing the time it took for patients to convert to sputum-negative. A group of 47 patients, all of whom were HIV negative and had been newly diagnosed with MDR TB, were randomly assigned to two groups. The first group received TMC207 at a dose of 400 mg daily for 2 weeks, followed by 200 mg three times a week for 6 weeks. The second group received the standard five-drug, second-line regimen for treating MDR TB, and a placebo was used instead of TMC207. Researchers found that TMC207 reduced the time it took for sputum to convert to negative in patients. At the end of the trial, 9% of patients who took the placebo were sputum-negative, as compared to 48% of those who received TMC27. TMC207 eliminated TB bacteria more quickly, and it was shown to be safe and well tolerated in patients. The only side effect that was significantly more common in the group that took TMC207 was nausea (26% vs. 4%). Researchers concluded that “the clinical activity of TMC207 validates ATPsynthase as a viable target for the treatment of tuberculosis.”[^Diacon] The second stage of this two-part trial will be a multinational study of patients in South Africa, Peru, Latvia, India, Brazil, Thailand, The Philippines and Russia. Because the first part of the study showed that TMC207 is highly effective against TB, the study’s second stage will be open label and non-randomised. Future developments ------------------- Johnson & Johnson’s research subsidiary, Tibotec, is managing the clinical development of TMC207 to determine whether the drug can be used in the treatment of MDR / XDR TB. Tibotec will elaborate a program whereby developing countries can gain access to TMC207. In addition, Tibotec has given the TB Alliance a royalty-free license to develop TMC207 for drug-sensitive TB. Current and future clinical trials of TMC207 will examine the potential use of TMC207 in the treatment of children with MDR TB; for the treatment of latent TB infection; for use in combination with antiretrovirals; and as a shortened treatment regimen for drug-sensitive TB.[^Matteelli] Advocacy Issues --------------- - More clinical information is needed on the use of TMC207 in TB patients with HIV co-infection. - Organizations in South Africa have called for TMC207 to be made immediately available for compassionate use. They recommend that clinicians in South Africa apply to the Medicines Control Council (MCC) for Section 21 authorizations to use bedaquiline. These authorizations are already being used to procure access to PAS, a less effective and harder to tolerate medication than TMC207.[^TAC] [^Andries]: K Andries et al. A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis. Science. 2005 Jan 14; 307(5707): 223-7 [^Lounis]: N Lounis et al. Combinations of R207910 with Drugs Used To Treat Multidrug-Resistant Tuberculosis Have the Potential to Shorten Treatment Duration. Antimicrobial Agents and Chemotherapy. 2006 Nov; 50(11): 3543-3547. [^Veziris]: N Veziris et al. A Once-Weekly R207910-Containing Regimen Exceeds Activity of the Standard Daily Regimen in Murine Tuberculosis. Am J Respir Crit Care Med. 2009 Jan 1; 179(1): 75-9 [^Matteelli]: A Matteelli et al. TMC207: the First Compound of a New Class of Potent Anti-Tuberculosis Drugs. Future Microbiol. 2010 June; 5(6): 849-858. [^Rustomjee]: R Rustomjee et al. Early Bactericidal Activity and Pharmokinetics Of the Diarylquinoline TMC207 in Treatment of Pulmonary Tuberculosis. Antimicrob Agents Chemother. 2008 Aug; 52(8): 2831-5. [^TB Online]: The Medical News. [TMC207 represents first new class of anti-TB drugs in the past 60 years](http://www.tbonline.info/posts/2011/8/1/uh-case-medical-center-commence-phase-1-clinical-t/ "UH Med Centre"). [^Lounis]: N Lounis. Impact of the interaction of R207910 with rifampin on the treatment of tuberculosis studied in the mouse model. Antimicrob Agents Chemother. 2008 Oct; 52(10):3568-72 [^Diacon]: AH Diacon et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med. 2009 Jun 4;360(23):2397-405 [^Matteelli]: A Matteelli et al. TMC207: the First Compound of a New Class of Potent Anti-Tuberculosis Drugs. Future Microbiol. 2010 June; 5(6): 849-858 [^TAC]: [Mobilize Against TB](http://www.tbonline.info/posts/2011/8/30/addressing-tb-crisis-south-africa/ "TAC").

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How TB is treated

The standard TB regimen is a six month course of antibiotics but the duration and drugs used may vary according to a patient’s age, type of TB infection, and whether they have been treated before.  Treating TB takes longer than treating other types of bacterial infections because the bacteria that cause TB grow slowly, and die slowly.  The standard six month course of treatment consists of two phases.  The first phase lasts two months and is called the intensive phase.  The second phase lasts four months and is called the continuous phase.

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A quick reference to drugs commonly used in the management of TB

This is a very useful quick reference guide to first and second-line TB drugs from the WRHI.

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Mobilise against TB

Statement by the Treatment Action Campaign, the HIV Clinicians Society of Southern Africa, Médecins Sans Frontières, SECTION27 (incorporating the AIDS Law Project), HIV i-Base, Wits Reproductive Health and HIV Institute (WRHI), Jhpiego and the Centre for the AIDS Programme of Research in South Africa (CAPRISA)

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My experience with the health system and TB

Lihle Dlamini is the Deputy General Secretary of the Treatment Action Campaign. Her HIV activism started in 2002 when she was diagnosed with TB and experienced the horrors of the South African public health system.

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Diagnostic tests for active tuberculosis

This article descibes the tests that are used to diagnose active TB.

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How TB drugs work

Use this slideshow to see the different TB drugs and how they work.

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