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New hope for the treatment of multi-drug-resistant tuberculosis?
RESPIRATORY MEDICINE (2001) 95, 435–436 doi:10.1053/rmed.2001.1081, available online at http://www.idealibrary.com on
Editorial
New hope for the treatment of multi-drugresistant tuberculosis? P. D. O. DAVIES Tuberculosis Research Unit, Cardiothoracic Centre, Thomas Drive, Liverpool L14 3PE, UK It is nearly 20 years since the world realized that tuberculosis was increasing and 10 years since the WHO declared tuberculosis to be a global emergency (1). Yet so far only one completely new therapeutic option for tuberculosis has been undergoing trials: Mycobacterium vaccae (2). At approximately the same time as tuberculosis was increasing the relatively new threat of multi-drug-resistant tuberculosis (tuberculosis resistant to at least isoniazid and rifampicin: MDRTB) began to appear (3). Five years earlier a virtually new disease emerged: AIDS. Now the combination of AIDS and MDRTB threatens the world with its most serious disease combination since tuberculosis began its modern pandemic in industrial Europe some 200 years ago. In the past two decades the contrast between the development of new drugs against HIV and tuberculosis has been striking. For the former we have at least 20 new compounds, with more being produced every year; for the latter, precisely none. To add insult to injury the media supported by politicians and pop idols are bellowing for pharmaceutical companies to reduce the cost of HAARTs. But where were these voices in the 1970s campaigning for cheaper rifampicin so that tuberculosis could be brought under control in Africa and poorer parts of Asia before the advent of AIDS came to break apart the existing fragile healthcare structures? The hypocrisy is easily explained by the perception that AIDS is a rich man’s disease, and therefore forms a ready market for pharmaceutical products, while TB is the poor man’s. But in this respect public perception lead by an illinformed media machine is wrong. AIDS is undoubtedly a poor man’s disease, as the orphans of central and Southern Africa testify, while tuberculosis is increasing in many developed countries. In the U.K. cases increased by 10% in the year 2000 and more than half of TB cases are now born in the developing world (4). Interestingly, some of those individuals who have made the most out of our current world economic system are belatedly funding some aspects of tuberculosis control (5,6). In the meantime investment by pharmaceutical companies into anti-tuberculosis drugs remains derisory. With this background it is encouraging to find that Professor Stanford and others have not given up hope in the one new therapeutic option we have on trial: M. vaccae. The theory behind the possible therapeutic benefit to the human immune response to M. vaccae seems sound. The switch from a Th2 to a Th1 response by the use of M. vaccae as an adjuvent to standard treatment has been well demonstrated (7). Early non-randomized trials of the 0954-6111/01/060435+02 $35?00/0
vaccine appeared to be encouraging (8). The first small controlled trials gave some cause for optimism (9,10), but the results of a larger randomized control trial with over 170 patients in each arm, showed no benefit when M. vaccae immunotherapy was added to standard antituberculosis chemotherapy in patients with fully drug susceptible bacteria (11). So, M. vaccae could not improve on optimal chemotherapy in full drug-susceptible disease. It is unfortunately not going to provide us with the means to shorten the standard regimens to less than 6 months, a factor which would have been so important in improving compliance and lowering the cost of treatment. But there are other important areas for investigation into the possible efficacy of M. vaccae in the therapy of mycobacterial disease, specifically against MDRTB and environmental mycobacteria. In this issue of Respiratory Medicine preliminary results of studies of the efficacy of M. vaccae on MDRTB are published (12). As the authors rightly say this series of pilot studies have weaknesses, not least the fact that there were no placebo controls. Although is shows that M. vaccae may be effective and is certainly not harmful, no true claim for its efficacy can be made from this publication. Nevertheless, the journal is right to publish these findings as a preliminary publication. There are good precedents for so doing, especially where TB is concerned (13). It is hoped that it may stimulate suitable funding for further randomized trials, although the difficulties of carrying out such trials in MDRTB patients are many and varied. In the absence of realistic levels of investment into research for new drugs for tuberculosis, M. vaccae seems to be the only hope on the horizon. M. vaccae may offer new hope for MDRTB but the question mark must remain for the time being.
References 1. Centres for Disease Control. Tuberculosis—United States, first 39 weeks, 1985. MMWR 1985; 34: 625–627. 2. Stanford JL, Stanford CA, Rook GAW, Grange JM. Immunotherapy for tuberculosis. Investigative and practical aspects. Clin Immunother 1994; 1: 430–440. 3. Pabloz Mendez A, Laszlo A, Bustreo F, et al. Antituberculosis drug resistance in the world: the WHO/ IUATLD global project on anti-tuberculosis drug resistance surveillance 1994–1997. WHO/TB/97.229. # 2001 HARCOURT PUBLISHERS LTD
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4. Rose AMC, Watson JM, Graham C, et al. Tuberculosis at the end of the 20th century in England and Wales: results of a national survey in 1998. Thorax 2001; 56: 173–179. 5. Soros G. The Crisis of Global Capitalism. London: Little Brown and Co., 1998. 6. Gates B. Business @ the Speed of Light. New York: Warner Books, 1999. 7. Grange J. Immunotherapy: a new strategy for tuberculosis control? Respir Med 1997; 91: 1–4. 8. Stanford JL, Stanford CA. Immunotherapy for tuberculosis with M. vaccae. J. Med Microbiol 1996; 44: 24–34. 9. Corlan E, Marcia C, Macacei C, Stanford JL, Stanford CA. Immunotherapy with Mycobacterium vaccae in the treatment of tuberculosis in Romania 1. Newly-diagnosed pulmonary disease. Respir Med 1997; 91: 13–19.
10. Corlan E, Marcia C, Macacei C, Stanford JL, Stanford CA. Immunotherapy with Mycobacterium vaccae in the treatment of tuberculosis in Romania 2. Chronic or relapsed disease 2. Respir Med 1997; 9: 121–119. 11. Durban Immunotherapy Trial Group. Immunotherapy with Mycobacterium vaccae in patients with newly diagnosed pulmonary tuberculosis: randomized controlled trial. Lancet 1999; 354: 116–119. 12. Stanford JL, Stanford CA, Grange JM, Lan NN, Etemadi A. Does immunotherapy with heat-killed Mycobacterium vaccae offer hope for the treatment of multi-drug resistant pulmonary tuberculosis. Respir Med 2001; 95: 444–447. 13. Condos R, Rom WN, Schluger NW. Treatment of multidrugresistant pulmonary tuberculosis with interferon-g via aerosol. Lancet 1997; 349: 1513–1515.
Editorial
New hope for the treatment of multi-drugresistant tuberculosis? P. D. O. DAVIES Tuberculosis Research Unit, Cardiothoracic Centre, Thomas Drive, Liverpool L14 3PE, UK It is nearly 20 years since the world realized that tuberculosis was increasing and 10 years since the WHO declared tuberculosis to be a global emergency (1). Yet so far only one completely new therapeutic option for tuberculosis has been undergoing trials: Mycobacterium vaccae (2). At approximately the same time as tuberculosis was increasing the relatively new threat of multi-drug-resistant tuberculosis (tuberculosis resistant to at least isoniazid and rifampicin: MDRTB) began to appear (3). Five years earlier a virtually new disease emerged: AIDS. Now the combination of AIDS and MDRTB threatens the world with its most serious disease combination since tuberculosis began its modern pandemic in industrial Europe some 200 years ago. In the past two decades the contrast between the development of new drugs against HIV and tuberculosis has been striking. For the former we have at least 20 new compounds, with more being produced every year; for the latter, precisely none. To add insult to injury the media supported by politicians and pop idols are bellowing for pharmaceutical companies to reduce the cost of HAARTs. But where were these voices in the 1970s campaigning for cheaper rifampicin so that tuberculosis could be brought under control in Africa and poorer parts of Asia before the advent of AIDS came to break apart the existing fragile healthcare structures? The hypocrisy is easily explained by the perception that AIDS is a rich man’s disease, and therefore forms a ready market for pharmaceutical products, while TB is the poor man’s. But in this respect public perception lead by an illinformed media machine is wrong. AIDS is undoubtedly a poor man’s disease, as the orphans of central and Southern Africa testify, while tuberculosis is increasing in many developed countries. In the U.K. cases increased by 10% in the year 2000 and more than half of TB cases are now born in the developing world (4). Interestingly, some of those individuals who have made the most out of our current world economic system are belatedly funding some aspects of tuberculosis control (5,6). In the meantime investment by pharmaceutical companies into anti-tuberculosis drugs remains derisory. With this background it is encouraging to find that Professor Stanford and others have not given up hope in the one new therapeutic option we have on trial: M. vaccae. The theory behind the possible therapeutic benefit to the human immune response to M. vaccae seems sound. The switch from a Th2 to a Th1 response by the use of M. vaccae as an adjuvent to standard treatment has been well demonstrated (7). Early non-randomized trials of the 0954-6111/01/060435+02 $35?00/0
vaccine appeared to be encouraging (8). The first small controlled trials gave some cause for optimism (9,10), but the results of a larger randomized control trial with over 170 patients in each arm, showed no benefit when M. vaccae immunotherapy was added to standard antituberculosis chemotherapy in patients with fully drug susceptible bacteria (11). So, M. vaccae could not improve on optimal chemotherapy in full drug-susceptible disease. It is unfortunately not going to provide us with the means to shorten the standard regimens to less than 6 months, a factor which would have been so important in improving compliance and lowering the cost of treatment. But there are other important areas for investigation into the possible efficacy of M. vaccae in the therapy of mycobacterial disease, specifically against MDRTB and environmental mycobacteria. In this issue of Respiratory Medicine preliminary results of studies of the efficacy of M. vaccae on MDRTB are published (12). As the authors rightly say this series of pilot studies have weaknesses, not least the fact that there were no placebo controls. Although is shows that M. vaccae may be effective and is certainly not harmful, no true claim for its efficacy can be made from this publication. Nevertheless, the journal is right to publish these findings as a preliminary publication. There are good precedents for so doing, especially where TB is concerned (13). It is hoped that it may stimulate suitable funding for further randomized trials, although the difficulties of carrying out such trials in MDRTB patients are many and varied. In the absence of realistic levels of investment into research for new drugs for tuberculosis, M. vaccae seems to be the only hope on the horizon. M. vaccae may offer new hope for MDRTB but the question mark must remain for the time being.
References 1. Centres for Disease Control. Tuberculosis—United States, first 39 weeks, 1985. MMWR 1985; 34: 625–627. 2. Stanford JL, Stanford CA, Rook GAW, Grange JM. Immunotherapy for tuberculosis. Investigative and practical aspects. Clin Immunother 1994; 1: 430–440. 3. Pabloz Mendez A, Laszlo A, Bustreo F, et al. Antituberculosis drug resistance in the world: the WHO/ IUATLD global project on anti-tuberculosis drug resistance surveillance 1994–1997. WHO/TB/97.229. # 2001 HARCOURT PUBLISHERS LTD
436
EDITORIAL
4. Rose AMC, Watson JM, Graham C, et al. Tuberculosis at the end of the 20th century in England and Wales: results of a national survey in 1998. Thorax 2001; 56: 173–179. 5. Soros G. The Crisis of Global Capitalism. London: Little Brown and Co., 1998. 6. Gates B. Business @ the Speed of Light. New York: Warner Books, 1999. 7. Grange J. Immunotherapy: a new strategy for tuberculosis control? Respir Med 1997; 91: 1–4. 8. Stanford JL, Stanford CA. Immunotherapy for tuberculosis with M. vaccae. J. Med Microbiol 1996; 44: 24–34. 9. Corlan E, Marcia C, Macacei C, Stanford JL, Stanford CA. Immunotherapy with Mycobacterium vaccae in the treatment of tuberculosis in Romania 1. Newly-diagnosed pulmonary disease. Respir Med 1997; 91: 13–19.
10. Corlan E, Marcia C, Macacei C, Stanford JL, Stanford CA. Immunotherapy with Mycobacterium vaccae in the treatment of tuberculosis in Romania 2. Chronic or relapsed disease 2. Respir Med 1997; 9: 121–119. 11. Durban Immunotherapy Trial Group. Immunotherapy with Mycobacterium vaccae in patients with newly diagnosed pulmonary tuberculosis: randomized controlled trial. Lancet 1999; 354: 116–119. 12. Stanford JL, Stanford CA, Grange JM, Lan NN, Etemadi A. Does immunotherapy with heat-killed Mycobacterium vaccae offer hope for the treatment of multi-drug resistant pulmonary tuberculosis. Respir Med 2001; 95: 444–447. 13. Condos R, Rom WN, Schluger NW. Treatment of multidrugresistant pulmonary tuberculosis with interferon-g via aerosol. Lancet 1997; 349: 1513–1515.