We are living in a time of great change and excitement in TB drug development. The last year has witnessed a number of epochal changes, including the approval and rollout of the most rapid test for TB ever discovered, the GeneXpert; the combination TB drug studies in the relapse mouse model of Eric Nuermberger and Jacques Grosset at Johns Hopkins with support from the TB Alliance; the progression of TMC207 into late phase II and of OPC67683 into phase III; and the first new regimen EBA study, NC-001 also from the Alliance.

Five renowned AIDS and TB activists and public health experts have written an editorial in *The Lancet* welcoming the leadership of Lucica Ditiu of Stop TB. They also call for more vocal leadership from all organisations working to end the TB epidemic. They also say that we need an aspirational goal to galvanise the struggle against TB: TB is treatable and therefore we should aim to have no deaths from the disease. Time for zero deaths from tuberculosis -------------------------------------- Source: [The Lancet, Volume 378, Issue 9801, Pages 1449 - 1450, 22 October 2011](http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61521-3) Salmaan Keshavjee (a), Mark Harrington (b), Gregg Gonsalves (a), Lucy Chesire (c), Paul E Farmer (a) When Robert Koch presented his discovery of the tuberculosis bacillus in March, 1882, he hoped it would lead to the eradication of “this terrible plague of mankind”.[1] More than a century later, tuberculosis remains a leading killer of adults: of about 9.4 million people newly infected with tuberculosis each year, 3.5 million are undiagnosed and continue to transmit the disease and more than 1.7 million die. Tuberculosis is the main killer of people with HIV infection; drug-resistant strains continue to spread; and paediatric tuberculosis remains an area of neglect. [2, 3] In the past decade, the number of new cases of tuberculosis worldwide has barely declined, and the number of deaths remains catastrophic: more than 4,500 per day for this largely treatable disease. As aLancet editorial pointed out, “A status quo in tuberculosis control is unacceptable.”[4] This status quo is not inevitable. A logical place to look for fresh leadership and vision is the Stop TB Partnership. Created in 2001 as a network of international organisations, countries, technical agencies, and donors, the Partnership was tasked with ensuring that every patient with tuberculosis has access to effective diagnosis and treatment. In its first decade, however, the Stop TB Partnership—housed at WHO headquarters in Geneva—seems to have operated essentially as a subsidiary of WHO's Tuberculosis Department with the majority of funds going to WHO's Tuberculosis Department, rather than external partners. [5, 6] But this situation may yet change. The newly appointed Executive Secretary of the Partnership, Lucica Ditiu, has initiated steps to address potential financial and administrative conflicts of interest in the Stop TB Partnership's relation with WHO. More importantly, Ditiu has called for a bold new vision in the struggle against tuberculosis. She and her team have started a campaign to prevent a million deaths among patients co-infected with HIV and tuberculosis. [7] She should be congratulated for these steps and supported in her efforts by her Board, the WHO Director-General, governments of countries with a high-burden of tuberculosis, and the tuberculosis community. Transforming the Partnership into an effective, independent, and transparent body capable of acting as a locus for innovative thinking is a crucial step in recasting the global struggle against tuberculosis. Changing the tenor of advocacy around tuberculosis is another important step. Without the networks of grassroots health activists and civil society institutions that define the HIV/AIDS movement, the global tuberculosis community has been unable to successfully scale-up patient-centred approaches to care, or hold governments and key international bodies (including funders) to account with regard to their commitments to tackle this disease. The health-activist community must take urgent steps to remedy this. Investment in tuberculosis-specific efforts of existing HIV/AIDS and civil society organisations—building on such efforts in Brazil, Kenya, India, South Africa, Uganda, and Zambia—or groups working on related social issues would be a start. Much would be achieved if leaders of global health initiatives—the Global Fund to Fight AIDS, Tuberculosis and Malaria, the US President's Emergency Plan For AIDS Relief, the US Global Health Initiative, and UNICEF—became more vocal in their demand for better tuberculosis outcomes and innovative approaches to stemming the disease. These organisations have the capacity to bring key stakeholders to the table: the diagnostic and pharmaceutical industries; partners addressing social antecedents to tuberculosis (for example poverty, discrimination, and detention); those who provide treatment of tuberculosis comorbidities (HIV and diabetes); and, in many settings, private providers of tuberculosis diagnosis and care. Most vitally, an aspirational goal must define the struggle ahead. [8] Effective treatment for tuberculosis has been available since the 1940s, and there is little reason for large numbers of people to be dying from this disease. [9] New diagnostics and treatment approaches are needed—especially for children, patients co-infected with HIV, those with extra-pulmonary disease, and patients with multidrug-resistant and extensively drug-resistant tuberculosis. But even today, when appropriate and tailored programmes have been put in place, a clear movement towards zero deaths has been observed in places as daunting as the prisons of Tomsk, Russia—where previously as many as a quarter of all patients had died. [10] Therefore, as UNAIDS and UNICEF embark on their own campaigns for zero deaths, [11, 12] it is critical that the tuberculosis community as a whole aspires to the same demonstrably achievable goal, and works in solidarity to accomplish it. *SK has chaired and participated in the Green Light committee at the Stop TB Partnership and WHO, is a member of the MDR-TB working group at the Stop TB Partnership, and has received research funding from the Eli Lilly Foundation. MH is director of Treatment Action Group, has been a member of WHO's Strategic Advisory Group for Tuberculosis, and has been involved in working groups with the Stop TB Partnership. LC is director of the TB ACTION group in Kenya, has participated in working groups at the Stop TB Partnership, is a member of WHO's Strategic Advisory Group for Tuberculosis, and an alternate member of the communities delegation to the board of the Global Fund to Fight AIDS, Tuberculosis and Malaria. GG and PF declare that they have no conflicts of interest.* References ---------- 1 Koch R. Die aetiologie der tuberculose, a translation by Berna Pinner and Max Pinner with an introduction by Allen K Krause. Am Rev Tuberc 1932; 25: 285-323. 2 Lönnroth K, Castro KG, Chakayah JM, et al. Tuberculosis control and elimination 2010—50: cure, care, and social development.Lancet 2010; 375: 1814-1829. 3 Keshavjee S, Farmer PE. Picking up the pace—scale-up of MDR tuberculosis treatment programs. N Engl J Med 2010; 369: 1781-1784. 4 The Lancet. A new era for global tuberculosis control?. Lancet 2011; 378: 2. 5 Treatment Action Group (TAG). Steps being taken by the Coordinating Board to reduce conflict of interest and improve transparency in the Stop TB Partnership. http://www.treatmentactiongroup.org/base.aspx?id=4462. (accessed Sept 10, 2011). 6 Stop TB Partnership Secretariat Financial Management Report Summary Statement of Income and Expenditure for the year ending 31 December 2010. Expenditures. March, 2011. Washington DC, p 6.http://www.stoptb.org/assets/documents/about/cb/meetings/20/1.11-07%20The%20Stop%20TB%20Partnership%20Financial%20Report%202010/1.11%20-%207.2%20Financial%20Report.pdf. (accessed Sept 29, 2011). 7 Stop TB Partnership/World Health Organization. Time to act: save a million lives by 2015. Prevent and treat tuberculosis among people living with HIV. Geneva: World Health Organization, 2011.http://www.stoptb.org/assets/documents/resources/publications/acsm/TB_HIV_Brochure_Singles.pdf. (accessed Sept 26, 2011). 8 Castro KG, LoBue P. Bridging implementation, knowledge, and ambition gaps to eliminate tuberculosis in the United States and globally. Emerg Infect Dis 2011; 17: 337-342. 9 Dye C, Williams BG. Eliminating human tuberculosis in the twenty-first century. J R Soc Interface 2008; 5: 653-662. 10 Keshavjee S, Gelmanova I, Pasechnikov A, et al. Treating multi-drug resistant tuberculosis in Tomsk, Russia: developing programs that address the linkage between poverty and disease. Ann N Y Acad Sci 2008; 1136: 1-11. 11 UNICEF. Believe in zero—achieving zero. http://www.unicef.ie/Content.aspx?PageDetailId=84&AspxAutoDetectCookieSupport=1. (accessed Sept 26, 2011). 12 UNAIDS. UNAIDS: 2011—2015 Strategy. Getting to zero. Geneva: UNAIDS, 2010.http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2010/JC2034_UNAIDS_Strategy_en.pdf.(accessed Sept 26, 2011).

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a Program in Infectious Disease and Social Change, Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA 02115, USA b Treatment Action Group, New York, NY, USA c TB ACTION Group, Nairobi, Kenya

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.

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.