- Email: [email protected]
Post DOTS, post genomics: the next century of tuberculosis control
A second issue raised by the Bangladesh experience is the need to demystify tuberculosis treatment. The success of the CHW approach challenges the myth that physicians are essential at all stages of tuberculosis treatment. Trained local women with good supervision can accomplish seeming miracles in the villages of developing countries. The more that tuberculosis treatment is brought outside hospital walls and the control of experts the greater the success of DOTS; the example of oral rehydration therapy in many developing countries including Bangladesh bears testimony to this.6 The third issue of concern is gender. In the BRAC programme, only about a third of tuberculosis patients are women. Although BRAC programmes are womenfocused, the social and cultural factors that prevent a woman with tuberculosis from contacting another woman next door for treatment are a matter of grave concern. These stigmatising factors, which are probably more deep-rooted than previously thought, need to be
identified for eradication.7
future
efforts
towards
tuberculosis
References 1
Chowdhury AMR, Ishikawa N, Alam A, et al. Controlling a forgotten disease: using voluntary health workers for tuberculosis control in rural Bangladesh. IUATLD Newsletter 1991; 1–4. 2 WHO press release. Breakthrough in TB control announced by World Health Organization. Geneva: WHO, 1997. 3 Chowdhury AMR, Chowdhury SA, Islam MN, et al. Control of tuberculosis by community health workers in Bangladesh. Lancet 1997; 350: 169–72. 4 Lovell CH. Breaking the cycle of poverty. Hartford: Kumarian Press, 1992. 5 Chowdhury AMR, Vaughan JP, Chowdhury SA, Abed FH. Demystifying the control of tuberculosis in rural Bangladesh. In: Porter J, Grange J, editors. Tuberculosis—an interdisciplinary perspective. London, Imperial College Press (in press). 6 Chowdhury AMR, Cash RA. A simple solution: teaching mothers to treat diarrhoea at home in Bangladesh. Dhaka: University Press Ltd, 1996. 7 Grange JM, Zumla A. Making DOTS succeed. Lancet 1997; 350:158.
Post DOTS, post genomics: the next century of tuberculosis control
Alexander S Pym, Stewart T Cole. At the end of another decade of our fluctuating relationship with tuberculosis, it is not clear whether we should be optimistic or pessimistic. The raw statistics are bad: an estimated 30 million people have died of tuberculosis in the past 10 years.1 The WHO has rightfully declared this to be a global health emergency. Almost in the same breath, it was announced that a solution to this global disaster had been discovered, the widespread implementation of directly observed therapy short-course (DOTS), a set of measures (essentially 6 months of intermittent supervised therapy) that have existed for over 2 decades.2 Although this renewed commitment to fight tuberculosis is a welcome change after years of neglect, DOTS alone will struggle to control tuberculosis. Despite some notable successes,3 DOTS implementation has been slower than anticipated reaching only 12% of tuberculosis cases worldwide by the end of 1996.4 Recent projections suggest that even if this rate of implementation were substantially increased, tuberculosis mortality will not be halved before 2030.5 Evidence is also emerging that DOTS is unable to control tuberculosis in countries with high levels of HIV infection,6 and in other countries it is failing to achieve adequate cure rates.7 An estimated one third of the world’s population are latently infected with tuberculosis, 10% of whom (in the absence of HIV coinfection) will develop tuberculosis. This vast reservoir of potential cases—an unknown proportion infected with potentially untreatable multidrug-resistant tuberculosis— Lancet 1999; 353: 1004–05 Unité de Génétique Moléculaire Bactérienne, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris Cedex 15, France (A S Pym MRCP, Prof S T Cole PhD); and Wellcome Trust Tropical Centre, University of Liverpool, Liverpool, UK (A S Pym) Correspondence to: Professor Stewart T Cole
1004
Mycobacterium tuberculosis bacillus (colour transmission electron micrograph ✕44 000 The way is now open for assessing the 4000 genes in the organism’s genome for their potential as subunit vaccines
means a DOTS programme would have to be sustained for decades even after full coverage is achieved, a daunting task given the fragility of national tuberculosis programmes and the history of tuberculosis control. With the exception of molecular diagnostics and epidemiology, the basic sciences have contributed little to tuberculosis control since the advent of rifampicin 30 years ago. But, by contrast with therapeutics, mycobacterial research has developed considerably over the last decade. Central to this renaissance has been the development of efficient systems for genetically manipulating mycobacteria8 and the sequencing of the Mycobacterium tuberculosis
THE LANCET • Vol 353 • March 20, 1999
genome.9 These advances have enabled the application of superior systems of analysis such as large scale systematic gene inactivation and global surveys of gene expression and strain diversity with DNA arrays, which have the potential to define the molecular basis of virulence.10 Although aspects of immunity to tuberculosis remain poorly understood, new approaches to vaccine design are now possible. The genetic modification of BCG to secrete cytokines11 or to overexpress specific antigens12 can enhance its immunogenicity. Comparative genomics and techniques for single-gene knockout open the way for new rationally attenuated vaccines derived from M tuberculosis.13 The demonstration that recombinant antigens when administered as a DNA vaccine can be immunoprotective in animal models14,15 means that any of the 4000 genes identified in the M tuberculosis genome could be rapidly assessed for their potential as subunit vaccines (figure). Development of a new generation of antituberculosis drugs is technologically feasible, either by rational design against one of the plethora of drug targets revealed by the genome sequence, or empirically by rapid methods of invitro and in-vivo testing to screen existing or new combinatorial drug libraries for antimycobacterial activity. More potent drugs with minimum inhibitory concentrations in the picogram rather than microgram range could be administered less frequently as welltolerated slow-release preparations, thus improving patient adherence to treatment. A priority would be the development of single-hit or very-short-course chemotherapy,5 as exemplified by the use of single-dose rifampicin, ofloxacin, and minocycline (ROM) to treat certain forms of leprosy.16 Targeting the genomically identified anaerobic enzymes and the iron and oxygenstorage systems that may be metabolically essential for “persisting” organisms (that conventionally require 6 months of therapy to eradicate), is one promising approach. Ultimately, new drug development will require greater commitment from the pharmaceutical industry, perhaps achievable through tax incentives or other sociopolitical interventions. As with a preventative vaccine and shortened therapies, diagnostic techniques of increased sensitivity could act synergistically with a DOTS programme.5 DNA-based diagnostics have already been written off by many as too expensive for widespread use. However, if adapted imaginatively they could be a sensitive and cost-effective way of implementing large-scale active case finding. The completion of other mycobacterial genome sequencing projects will enable the identification of species-specific antigens. These antigens could form the basis of a skin or serological test that reliably distinguishes between latent tuberculosis and exposure to environmental mycobacteria, an accurate method for monitoring the effect of control
THE LANCET • Vol 353 • March 20, 1999
programmes on the size of the latently infected population. It is hard not to be unashamedly optimistic at the scientific prospects for the next decade. It will be a formidable challenge though to reap the full potential of these advances. There are already over 40 potential vaccine candidates, but the cost and complexity of advancing even one of them into phase-three trials is enormous.17 Whereas truly global DOTS coverage remains an important shortterm objective, wider acknowledgement of the limitations of DOTS would help generate the political will needed to swiftly develop a new generation of tuberculosis-control strategies. Apart from eradicating poverty this is our best bet for tuberculosis control before the end of the next century. References 1
2 3
4 5 6
7
8
9
10 11
12
13
14 15 16
17
Dolin PJ, Ravigilione MC, Kochi A. Global tuberculosis incidence and mortality during 1990–2000. Bull World Health Organ 1994; 72: 213–20. Bayer R, Wilkinson D. Directly observed therapy for tuberculosis: history of an idea. Lancet 1995; 345: 1545–48. China Tuberculosis Control Collaboration. Results of directly observed short-course chemotherapy in 112 842 Chinese patients with smearpositive tuberculosis. Lancet 1996; 347: 358–62. WHO Global Tuberculosis Programme. Global tuberculosis control. WHO report 1998. Geneva: WHO, 1998. WHO/TB/98–237. Murray CJL, Salomon JA. Modeling the impact of global tuberculosis control strategies. Proc Natl Acad Sci USA 1998; 95: 13881–86. Kenyon TA, Mwasekaga MJ, Huebner R, et al. Low levels of drug resistance amidst rapidly increasing tuberculosis and human immunodeficiency virus co-epidemics in Botswana. Int J Tuberc Lung Dis 1999; 3: 4–11. Zwarenstein M, Schoeman JH, Vundule C, et al. Randomised controlled trial of self-supervised and directly observed treatment of tuberculosis. Lancet 1998; 352: 1340–43. Pelicic V, Reyrat JM, Gicquel B. Genetic advances for studying Mycobacterium tuberculosis pathogenicity. Mol Microbiol 1998; 28: 413–20. Cole ST, Brosch R, Parkhill J, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998; 393: 537–44. Strauss JE, Falkow S. Microbial pathogenesis: genomics and beyond. Science 1998; 276: 707–12. Murray PJ, Aldovini A, Young RA. Manipulation and potentiation of antimycobacterial immunity using recombinant bacille Calmette-Guérin strains that secrete cytokines. Proc Natl Acad Sci USA 1996; 93: 934–39. Stover CK, Bansal GP, Hanson MS, et al. Protective immunity elicited by recombinant bacille Calmette-Guérin (BCG) expressing outer surface protein A (OspA) lipoprotein: a candidate Lyme disease vaccine. J Exp Med 1993; 178: 197–209. Berthet F-X, Lagranderie M, Gounon P, et al. Attenuation of virulence by disruption of the Mycobacterium tuberculosis erp gene. Science 1998; 282: 759–62. Tascon RE, Colston MJ, Ragno S, et al. Vaccination against tuberculosis by DNA injection. Nat Med 1996; 2: 888–92. Huygen K, Content J, Denis O, et al. Immunogenicity and protective efficacy of a tuberculosis DNA vaccine. Nat Med 1996; 2: 893–98. Single-lesion Multicentre Trial Group. Efficacy of single-dose multidrug therapy for the treatment of single-lesion paucibacillary leprosy. Indian J Lepr 1997; 69: 121–29 (reprinted Lepr Rev 1997; 68: 341–49). Jacobs GG, Johnson JL, Boom WH, et al. Tuberculosis vaccines: how close to human testing? Tuber Lung Dis 1997; 78: 159–69.
1005
identified for eradication.7
future
efforts
towards
tuberculosis
References 1
Chowdhury AMR, Ishikawa N, Alam A, et al. Controlling a forgotten disease: using voluntary health workers for tuberculosis control in rural Bangladesh. IUATLD Newsletter 1991; 1–4. 2 WHO press release. Breakthrough in TB control announced by World Health Organization. Geneva: WHO, 1997. 3 Chowdhury AMR, Chowdhury SA, Islam MN, et al. Control of tuberculosis by community health workers in Bangladesh. Lancet 1997; 350: 169–72. 4 Lovell CH. Breaking the cycle of poverty. Hartford: Kumarian Press, 1992. 5 Chowdhury AMR, Vaughan JP, Chowdhury SA, Abed FH. Demystifying the control of tuberculosis in rural Bangladesh. In: Porter J, Grange J, editors. Tuberculosis—an interdisciplinary perspective. London, Imperial College Press (in press). 6 Chowdhury AMR, Cash RA. A simple solution: teaching mothers to treat diarrhoea at home in Bangladesh. Dhaka: University Press Ltd, 1996. 7 Grange JM, Zumla A. Making DOTS succeed. Lancet 1997; 350:158.
Post DOTS, post genomics: the next century of tuberculosis control
Alexander S Pym, Stewart T Cole. At the end of another decade of our fluctuating relationship with tuberculosis, it is not clear whether we should be optimistic or pessimistic. The raw statistics are bad: an estimated 30 million people have died of tuberculosis in the past 10 years.1 The WHO has rightfully declared this to be a global health emergency. Almost in the same breath, it was announced that a solution to this global disaster had been discovered, the widespread implementation of directly observed therapy short-course (DOTS), a set of measures (essentially 6 months of intermittent supervised therapy) that have existed for over 2 decades.2 Although this renewed commitment to fight tuberculosis is a welcome change after years of neglect, DOTS alone will struggle to control tuberculosis. Despite some notable successes,3 DOTS implementation has been slower than anticipated reaching only 12% of tuberculosis cases worldwide by the end of 1996.4 Recent projections suggest that even if this rate of implementation were substantially increased, tuberculosis mortality will not be halved before 2030.5 Evidence is also emerging that DOTS is unable to control tuberculosis in countries with high levels of HIV infection,6 and in other countries it is failing to achieve adequate cure rates.7 An estimated one third of the world’s population are latently infected with tuberculosis, 10% of whom (in the absence of HIV coinfection) will develop tuberculosis. This vast reservoir of potential cases—an unknown proportion infected with potentially untreatable multidrug-resistant tuberculosis— Lancet 1999; 353: 1004–05 Unité de Génétique Moléculaire Bactérienne, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris Cedex 15, France (A S Pym MRCP, Prof S T Cole PhD); and Wellcome Trust Tropical Centre, University of Liverpool, Liverpool, UK (A S Pym) Correspondence to: Professor Stewart T Cole
1004
Mycobacterium tuberculosis bacillus (colour transmission electron micrograph ✕44 000 The way is now open for assessing the 4000 genes in the organism’s genome for their potential as subunit vaccines
means a DOTS programme would have to be sustained for decades even after full coverage is achieved, a daunting task given the fragility of national tuberculosis programmes and the history of tuberculosis control. With the exception of molecular diagnostics and epidemiology, the basic sciences have contributed little to tuberculosis control since the advent of rifampicin 30 years ago. But, by contrast with therapeutics, mycobacterial research has developed considerably over the last decade. Central to this renaissance has been the development of efficient systems for genetically manipulating mycobacteria8 and the sequencing of the Mycobacterium tuberculosis
THE LANCET • Vol 353 • March 20, 1999
genome.9 These advances have enabled the application of superior systems of analysis such as large scale systematic gene inactivation and global surveys of gene expression and strain diversity with DNA arrays, which have the potential to define the molecular basis of virulence.10 Although aspects of immunity to tuberculosis remain poorly understood, new approaches to vaccine design are now possible. The genetic modification of BCG to secrete cytokines11 or to overexpress specific antigens12 can enhance its immunogenicity. Comparative genomics and techniques for single-gene knockout open the way for new rationally attenuated vaccines derived from M tuberculosis.13 The demonstration that recombinant antigens when administered as a DNA vaccine can be immunoprotective in animal models14,15 means that any of the 4000 genes identified in the M tuberculosis genome could be rapidly assessed for their potential as subunit vaccines (figure). Development of a new generation of antituberculosis drugs is technologically feasible, either by rational design against one of the plethora of drug targets revealed by the genome sequence, or empirically by rapid methods of invitro and in-vivo testing to screen existing or new combinatorial drug libraries for antimycobacterial activity. More potent drugs with minimum inhibitory concentrations in the picogram rather than microgram range could be administered less frequently as welltolerated slow-release preparations, thus improving patient adherence to treatment. A priority would be the development of single-hit or very-short-course chemotherapy,5 as exemplified by the use of single-dose rifampicin, ofloxacin, and minocycline (ROM) to treat certain forms of leprosy.16 Targeting the genomically identified anaerobic enzymes and the iron and oxygenstorage systems that may be metabolically essential for “persisting” organisms (that conventionally require 6 months of therapy to eradicate), is one promising approach. Ultimately, new drug development will require greater commitment from the pharmaceutical industry, perhaps achievable through tax incentives or other sociopolitical interventions. As with a preventative vaccine and shortened therapies, diagnostic techniques of increased sensitivity could act synergistically with a DOTS programme.5 DNA-based diagnostics have already been written off by many as too expensive for widespread use. However, if adapted imaginatively they could be a sensitive and cost-effective way of implementing large-scale active case finding. The completion of other mycobacterial genome sequencing projects will enable the identification of species-specific antigens. These antigens could form the basis of a skin or serological test that reliably distinguishes between latent tuberculosis and exposure to environmental mycobacteria, an accurate method for monitoring the effect of control
THE LANCET • Vol 353 • March 20, 1999
programmes on the size of the latently infected population. It is hard not to be unashamedly optimistic at the scientific prospects for the next decade. It will be a formidable challenge though to reap the full potential of these advances. There are already over 40 potential vaccine candidates, but the cost and complexity of advancing even one of them into phase-three trials is enormous.17 Whereas truly global DOTS coverage remains an important shortterm objective, wider acknowledgement of the limitations of DOTS would help generate the political will needed to swiftly develop a new generation of tuberculosis-control strategies. Apart from eradicating poverty this is our best bet for tuberculosis control before the end of the next century. References 1
2 3
4 5 6
7
8
9
10 11
12
13
14 15 16
17
Dolin PJ, Ravigilione MC, Kochi A. Global tuberculosis incidence and mortality during 1990–2000. Bull World Health Organ 1994; 72: 213–20. Bayer R, Wilkinson D. Directly observed therapy for tuberculosis: history of an idea. Lancet 1995; 345: 1545–48. China Tuberculosis Control Collaboration. Results of directly observed short-course chemotherapy in 112 842 Chinese patients with smearpositive tuberculosis. Lancet 1996; 347: 358–62. WHO Global Tuberculosis Programme. Global tuberculosis control. WHO report 1998. Geneva: WHO, 1998. WHO/TB/98–237. Murray CJL, Salomon JA. Modeling the impact of global tuberculosis control strategies. Proc Natl Acad Sci USA 1998; 95: 13881–86. Kenyon TA, Mwasekaga MJ, Huebner R, et al. Low levels of drug resistance amidst rapidly increasing tuberculosis and human immunodeficiency virus co-epidemics in Botswana. Int J Tuberc Lung Dis 1999; 3: 4–11. Zwarenstein M, Schoeman JH, Vundule C, et al. Randomised controlled trial of self-supervised and directly observed treatment of tuberculosis. Lancet 1998; 352: 1340–43. Pelicic V, Reyrat JM, Gicquel B. Genetic advances for studying Mycobacterium tuberculosis pathogenicity. Mol Microbiol 1998; 28: 413–20. Cole ST, Brosch R, Parkhill J, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998; 393: 537–44. Strauss JE, Falkow S. Microbial pathogenesis: genomics and beyond. Science 1998; 276: 707–12. Murray PJ, Aldovini A, Young RA. Manipulation and potentiation of antimycobacterial immunity using recombinant bacille Calmette-Guérin strains that secrete cytokines. Proc Natl Acad Sci USA 1996; 93: 934–39. Stover CK, Bansal GP, Hanson MS, et al. Protective immunity elicited by recombinant bacille Calmette-Guérin (BCG) expressing outer surface protein A (OspA) lipoprotein: a candidate Lyme disease vaccine. J Exp Med 1993; 178: 197–209. Berthet F-X, Lagranderie M, Gounon P, et al. Attenuation of virulence by disruption of the Mycobacterium tuberculosis erp gene. Science 1998; 282: 759–62. Tascon RE, Colston MJ, Ragno S, et al. Vaccination against tuberculosis by DNA injection. Nat Med 1996; 2: 888–92. Huygen K, Content J, Denis O, et al. Immunogenicity and protective efficacy of a tuberculosis DNA vaccine. Nat Med 1996; 2: 893–98. Single-lesion Multicentre Trial Group. Efficacy of single-dose multidrug therapy for the treatment of single-lesion paucibacillary leprosy. Indian J Lepr 1997; 69: 121–29 (reprinted Lepr Rev 1997; 68: 341–49). Jacobs GG, Johnson JL, Boom WH, et al. Tuberculosis vaccines: how close to human testing? Tuber Lung Dis 1997; 78: 159–69.
1005