Comment
been available in the USA and Europe for the treatment of HIV-1 infection since 2012. Cobicistat is the first pharmacokinetic drug without antiretroviral activity to be used in an antiretroviral therapy regimen. However, because the dose cannot be adjusted, the single-tablet coformulated regimen should be used with caution in elderly patients and those with underlying nephropathy. The future expansion of multiple-drug, oncedaily regimens is likely to increase the development of fixed-dose combinations. The combination of dolutegravir, lamivudine, and abacavir that is in development is of particular interest to clinicians for several reasons. Dolutegravir is a more potent integrase inhibitor than elvitegravir and does not require pharmacokinetic boosting. Dolutegravir has been approved by the FDA, and regimens containing the drug have outperformed several existing first-line treatments in clinical trials.9–13 This new combination does not contain tenofovir and emtricitabine, which are present in the existing fix-dose combinations, representing a potential benefit for patients in view of resistance and long-term toxicity associated with these components.
1
Joshua R Sawyer, Qing Ma, *Chiu-Bin Hsiao
11
School of Pharmacy and Pharmaceutical Sciences (JRS, QM), and Infectious Disease Division, School of Medicine and Biomedical Sciences (C-BH), University at Buffalo, State University of New York, Buffalo, NY, USA; and Positive Health Clinic, Allegheny General Hospital, Pittsburgh, PA 15212, USA (C-BH) [email protected] We declare that we have no competing interests.
2
3
4
5
6
7
8
9 10
12
13
Sax PE, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet 2012; 379: 2439–48. DeJesus E, Rockstroh JK, Henry K, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet 2012; 379: 2429–38. Cohen CJ, Molina JM, Cahn P, et al. Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE Trials. J Acquir Immune Defic Syndr 2012; 60: 33–42. Crauwels H, van Heeswijk RPG, Stevens M, et al. Clinical perspective on drug–drug interactions with the non-nucleoside reverse transcriptase inhibitor rilpivirine. AIDS Rev 2013; 15: 87–101. Vikram A, Florian J, Marcus KA, Reynolds KS, Lewis LL, Sherwat AI. Does an increase in serum creatinine always reflect renal injury? The case of Stribild. J Clin Pharmacol 2013; 54: 279–81. Frentz D, Boucher CA, van de Vijver DA. Temporal changes in the epidemiology of transmission of drug-resistant HIV-1 across the world. AIDS Rev 2012; 14: 17–27. Elion R, Cohen C, Gathe J, et al. Phase 2 study of cobicistat versus ritonavir each with once-daily atazanavir and fixed-dose emtricitabine/ tenofovir df in the initial treatment of HIV infection. AIDS 2011; 25: 1881–86. Gallant JE, Koenig E, Andrade-Villanueva J, et al. Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/ tenofovir disoproxil fumarate in treatment-naive HIV type 1-infected patients: week 48 results. J Infect Dis 2013; 208: 32–39. Boyd MA, Cooper DA. SPRING-2 the future of antiretroviral therapy. Lancet Infect Dis 2013; 13: 908–09. Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis 2013; 13: 927–35. Walmsley S, Antela A, Clumeck N, et al, for the SINGLE investigators. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med 2013; 369: 1807–18. Clotet B, Khuong MS, Antinori A, et al. Once-daily dolutegravir versus darunavir/ritonavir in antiretroviral naive subjects: 48 week subgroup analyses from FLAMINGO. 14th European AIDS Conference; 2013; Brussels, Belgium; Oct 16–19, 2013. PS4/6. Patel DA, Snedecor SJ, Tang WY, et al. 48-week efficacy of dolutegravir relative to commonly used 3rd agents in treatment-naive HIV-1-infected patients: a systematic review and network meta-analysis. 14th European AIDS Conference; Oct 16–19, 2013; Brussels, Belgium; 2013. PE7/7.
Advancing the portfolio of tuberculosis diagnostics, drugs, biomarkers, and vaccines Despite effective drug treatment and the widespread use of the BCG vaccine, tuberculosis causes about 1·3 million deaths every year.1 About 3 million cases of tuberculosis remain undiagnosed and continue to spread the disease. Nearly half a million cases of multidrugresistant tuberculosis are diagnosed worldwide every year and a third of patients with this disease will die because of failure of diagnosis or unavailability of appropriate www.thelancet.com/infection Vol 14 April 2014
treatment.1 Drug resistance beyond extensively drugresistant tuberculosis is increasingly being reported.1,2 These appalling data are a cause for grave concern because more than two decades have elapsed since WHO declared tuberculosis a global emergency.3 In South Africa, a substantial proportion of patients who are treated in hospital for extensively drug-resistant tuberculosis die, and many others are discharged back
Published Online March 24, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70028-3
267
Comment
into the community, continuing to spread the disease.4 Calls for introduction of sanatoria4,5 and the ensuing debate6 from these pleas have generated a new wave of unwarranted pessimism that needs to be replaced with optimism.7 Increases in funder, political, and scientific investments over the past 5 years have led to advances in development of an expanded portfolio of new tuberculosis vaccines,8 diagnostics,9 and drugs.10,11 Although several tuberculosis vaccines are in phase 2 and 2b trials, vaccine evaluation is a lengthy high-risk process as shown by the failure of the Oxford modified vaccinia Ankara virus expressing antigen 85A (MVA85A) tuberculosis vaccine.12 It will take at least a decade before the true effect of this new vaccine portfolio is known. To achieve global tuberculosis control, it is crucial to find and treat all patients with active pulmonary tuberculosis,1 rendering them non-infectious. The introduction of newer diagnostics will no doubt facilitate this proactive search. The development of a range of new diagnostic tests for tuberculosis1,9 is encouraging and every new diagnostic test that comes to market should be assessed rigorously for diagnostic accuracy, robustness under operational field conditions, cost-effectiveness, and practical usefulness, and should be tailored to the environment of local services to ensure continuum of care. A few developers have rushed their diagnostic products into the market without adequate evaluation but only two diagnostics are in advanced stages of assessment and implementation: Xpert MTB/RIF assay nucleic acid amplification test for simultaneous detection of Mycobacterium tuberculosis DNA and rifampicin resistance in sputum13; and detection of mycobacterial cell-wall lipoarabinomannan (LAM) in urine to diagnose tuberculosis in patients with advanced HIV disease.14 Xpert MTB/RIF assay is being extensively rolled-out worldwide for use in adults and children in several settings. Trial data show that this roll-out might not have a major effect on treatment outcomes when compared with empirical treatment started on clinical suspicion or use of traditional sputum microscopy when used under decentralised programmatic conditions.15,16 Phenotypical culture-based assays remain the cornerstone for resistance testing, although colorimetric methods and phage-based assays are being developed to identify rifampicin, isoniazid, and fluoroquinolone resistance. Microarray-based multiplexing and nucleic acid-based deep-sequencing methods for the 268
simultaneous detection of M tuberculosis DNA and drug resistance to several first-line and second-line drugs now provide further hope for rapid point-of-care diagnostics for multidrug-resistant tuberculosis. Development of tuberculosis-centric diagnostic tests is important, but it is prudent to realise that it might not fit into the longer-term goals of optimum alignment of health care for non-communicable and other communicable diseases, which is moving away from disease-focused silos. When a patient presents with a respiratory-tract infection at any point in care, the diagnostic test needs to be able to differentiate tuberculosis from other bacterial and viral causes of respiratory-tract infections to give the best treatment outcomes. Technological advances present a unique opportunity to address this unmet need, and should use a sputum sample from the patient at point of care.17 Hope that the lengthy course of treatment can be shortened is provided by the many new or repurposed antituberculosis drugs that are in late phases of clinical development,10,11 but drug development also needs to focus on the estimated 2 billion people with latent tuberculosis infection who might go on to develop active disease in the presence of HIV or immunosuppression. For these patients, two parallel approaches are needed— short, effective, and well tolerated treatments for tuberculosis, and an effective postexposure vaccine to prevent tuberculosis. Tuberculosis-biomarker development has lagged behind other advances in management of the disease. Hostgenetic transcriptomic signatures to define biomarkers of tuberculosis disease activity, cure, and relapse for drug and vaccine field evaluation have not yet materialised.18 For valid comparisons to be made between drug, diagnostic, biomarker, and vaccine trials, research groups must cross-fertilise their work and standardise sample procurement, processing, storage, and analysis. The focus on research for new tuberculosis instruments should not divert stakeholders from tackling the socioeconomic causes and drivers of the tuberculosis epidemic.19 Inequalities in wealth, drug stock-outs, and poor access to quality health services remain key factors that sustain the tuberculosis epidemic. With inadequate or poorly functioning, ill-equipped, health services to diagnose or treat patients, a longer delay occurs between diagnosis of active tuberculosis and an effective cure, perpetuating the spread of tuberculosis in the www.thelancet.com/infection Vol 14 April 2014
Comment
community. Parallel focus and investment into provision of basic health services, and the tackling of poverty, less than optimum nutrition, crowded poorly ventilated living or working conditions, inadequate housing, social stigma, and other comorbidities, are essential. Political will, poverty alleviation, and good governance are essential components of the global control strategy for tuberculosis.
6 7
8
9
10
Alimuddin I Zumla, Marco Schito, *Markus Maeurer Division of Infection and Immunity, University College London, London, UK (AIZ); Department of Medical Microbiology, University College London Hospitals NHS Trust, London, UK (AIZ); Henry M Jackson Foundation—Division of AIDS, TB Clinical Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA (MS); Therapeutic Immunology Division, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden (MM); and CAST, Karolinska University Hospital, Stockholm SE-14186, Sweden (MM) [email protected] We declare that we have no conflicting interests. 1 2
3 4
5
WHO. World Health Organisation Global Tuberculosis report 2013. http:// www.who.int/tb/publications/global_report/en/ (accessed Nov 12, 2013). Migliori GB, Sotgiu G, Gandhi NR, et al. Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis. Eur Respir J 2013; 42: 169–79. WHO. TB–a global emergency. WHO Press Release. Geneva: World Health Organization, 1993. Pietersen E, Ignatius E, Streicher EM, et al. Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study. Lancet 2014; published online Jan 16. http://dx.doi.org/10.1016/S01406736(13)62675-6. Dheda K, Migliori GB. The global rise of extensively drug-resistant tuberculosis: is the time to bring back sanatoria now overdue? Lancet 2012; 379: 773–75.
11
12
13
14
15
16
17
18
19
Hughes J, Cox H. Sanatoria for drug-resistant tuberculosis: an outdated response. Lancet 2012; 379: 2148. Zumla A, George A, Sharma V, Herbert N, Baroness Masham of Ilton. WHO’s 2013 global report on tuberculosis: successes, threats, and opportunities. Lancet 2013; 382: 1765–57. Kaufmann SHE, Lange C, Rao M, et al. Progress in tuberculosis vaccine development and host-directed therapies—a state of the art review. Lancet Respir Med 2014; published online March 24. http://dx.doi. org/10.1016/S2213-2600(14)70033-5. Lawn SD, Mwaba P, Bates M, et al. Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test. Lancet Infect Dis 2013; 13: 349–61. Zumla A, Nahid P, Cole ST. Advances in the development of new tuberculosis drugs and treatment regimens. Nat Rev Drug Discov 2013; 12: 388–404. Zumla A, Gillespie SH, Hoelscher M, et al. New antituberculosis drugs, regimens, and adjunct therapies: needs, advances, and future prospects. Lancet Infect Dis 2014; published online March 24. http://dx.doi.org/ 10.1016/S1473-3099(13)70328-1. Tameris MD, Hatherill M, Landry BS, et al, for the MVA85A 020 Trial Study Team. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet 2013; 381: 1021–28. Steingart KR, Schiller I, Horne DJ, Pai M, Boehme CC, Dendukuri N. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev 2014; 1: CD009593. Lawn SD, Dheda K, Kerkhoff AD, et al. Determine TB-LAM lateral flow urine antigen assay for HIV-associated tuberculosis: recommendations on the design and reporting of clinical studies. BMC Infect Dis 2013; 13: 407. Theron G, Zijenah L, Chanda D, et al. Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial. Lancet 2013; 382: 424–35. Theron G, Peter J, Dowdy D, Langley I, Squire SB, Dheda K. Do high rates of empirical treatment undermine the potential effect of new diagnostic tests for tuberculosis in high-burden settings? Lancet Infect Dis 2014; published online Jan 14. http://dx.doi.org/10.1016/S1473-3099(13)70360-8. Zumla A, Gant V, Bates M, Mwaba P, Maeurer M, Memish ZA. Rapid diagnostics urgently needed for killer infections. Lancet Respir Med 2013; 1: 284–85. Joosten SA, Fletcher HA, Ottenhoff TH. A helicopter perspective on TB biomarkers: pathway and process based analysis of gene expression data provides new insight into TB pathogenesis. PLoS One 2013; 8: e73230. Zumla A, Mwaba P, Huggett J, Kapata N, Chanda D, Grange J. Reflections on the white plague. Lancet Infect Dis 2009; 9: 197–202.
Corrections Grinsztejn B, Hosseinipour MC, Ribaudo HJ, et al. Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial. Lancet Infect Dis 2014; 14: 281–90—In the Discussion section of this Article, the text at the end of the first paragraph should have read “similarly, the overall incidence of primary or secondary outcomes was higher in the delayed group, predominantly tuberculosis and WHO stage 2 and 3 events (p=0·025)”. The correction has been made to the online version as of March 24. The print version is correct.
www.thelancet.com/infection Vol 14 April 2014
269
been available in the USA and Europe for the treatment of HIV-1 infection since 2012. Cobicistat is the first pharmacokinetic drug without antiretroviral activity to be used in an antiretroviral therapy regimen. However, because the dose cannot be adjusted, the single-tablet coformulated regimen should be used with caution in elderly patients and those with underlying nephropathy. The future expansion of multiple-drug, oncedaily regimens is likely to increase the development of fixed-dose combinations. The combination of dolutegravir, lamivudine, and abacavir that is in development is of particular interest to clinicians for several reasons. Dolutegravir is a more potent integrase inhibitor than elvitegravir and does not require pharmacokinetic boosting. Dolutegravir has been approved by the FDA, and regimens containing the drug have outperformed several existing first-line treatments in clinical trials.9–13 This new combination does not contain tenofovir and emtricitabine, which are present in the existing fix-dose combinations, representing a potential benefit for patients in view of resistance and long-term toxicity associated with these components.
1
Joshua R Sawyer, Qing Ma, *Chiu-Bin Hsiao
11
School of Pharmacy and Pharmaceutical Sciences (JRS, QM), and Infectious Disease Division, School of Medicine and Biomedical Sciences (C-BH), University at Buffalo, State University of New York, Buffalo, NY, USA; and Positive Health Clinic, Allegheny General Hospital, Pittsburgh, PA 15212, USA (C-BH) [email protected] We declare that we have no competing interests.
2
3
4
5
6
7
8
9 10
12
13
Sax PE, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet 2012; 379: 2439–48. DeJesus E, Rockstroh JK, Henry K, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet 2012; 379: 2429–38. Cohen CJ, Molina JM, Cahn P, et al. Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE Trials. J Acquir Immune Defic Syndr 2012; 60: 33–42. Crauwels H, van Heeswijk RPG, Stevens M, et al. Clinical perspective on drug–drug interactions with the non-nucleoside reverse transcriptase inhibitor rilpivirine. AIDS Rev 2013; 15: 87–101. Vikram A, Florian J, Marcus KA, Reynolds KS, Lewis LL, Sherwat AI. Does an increase in serum creatinine always reflect renal injury? The case of Stribild. J Clin Pharmacol 2013; 54: 279–81. Frentz D, Boucher CA, van de Vijver DA. Temporal changes in the epidemiology of transmission of drug-resistant HIV-1 across the world. AIDS Rev 2012; 14: 17–27. Elion R, Cohen C, Gathe J, et al. Phase 2 study of cobicistat versus ritonavir each with once-daily atazanavir and fixed-dose emtricitabine/ tenofovir df in the initial treatment of HIV infection. AIDS 2011; 25: 1881–86. Gallant JE, Koenig E, Andrade-Villanueva J, et al. Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/ tenofovir disoproxil fumarate in treatment-naive HIV type 1-infected patients: week 48 results. J Infect Dis 2013; 208: 32–39. Boyd MA, Cooper DA. SPRING-2 the future of antiretroviral therapy. Lancet Infect Dis 2013; 13: 908–09. Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis 2013; 13: 927–35. Walmsley S, Antela A, Clumeck N, et al, for the SINGLE investigators. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med 2013; 369: 1807–18. Clotet B, Khuong MS, Antinori A, et al. Once-daily dolutegravir versus darunavir/ritonavir in antiretroviral naive subjects: 48 week subgroup analyses from FLAMINGO. 14th European AIDS Conference; 2013; Brussels, Belgium; Oct 16–19, 2013. PS4/6. Patel DA, Snedecor SJ, Tang WY, et al. 48-week efficacy of dolutegravir relative to commonly used 3rd agents in treatment-naive HIV-1-infected patients: a systematic review and network meta-analysis. 14th European AIDS Conference; Oct 16–19, 2013; Brussels, Belgium; 2013. PE7/7.
Advancing the portfolio of tuberculosis diagnostics, drugs, biomarkers, and vaccines Despite effective drug treatment and the widespread use of the BCG vaccine, tuberculosis causes about 1·3 million deaths every year.1 About 3 million cases of tuberculosis remain undiagnosed and continue to spread the disease. Nearly half a million cases of multidrugresistant tuberculosis are diagnosed worldwide every year and a third of patients with this disease will die because of failure of diagnosis or unavailability of appropriate www.thelancet.com/infection Vol 14 April 2014
treatment.1 Drug resistance beyond extensively drugresistant tuberculosis is increasingly being reported.1,2 These appalling data are a cause for grave concern because more than two decades have elapsed since WHO declared tuberculosis a global emergency.3 In South Africa, a substantial proportion of patients who are treated in hospital for extensively drug-resistant tuberculosis die, and many others are discharged back
Published Online March 24, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70028-3
267
Comment
into the community, continuing to spread the disease.4 Calls for introduction of sanatoria4,5 and the ensuing debate6 from these pleas have generated a new wave of unwarranted pessimism that needs to be replaced with optimism.7 Increases in funder, political, and scientific investments over the past 5 years have led to advances in development of an expanded portfolio of new tuberculosis vaccines,8 diagnostics,9 and drugs.10,11 Although several tuberculosis vaccines are in phase 2 and 2b trials, vaccine evaluation is a lengthy high-risk process as shown by the failure of the Oxford modified vaccinia Ankara virus expressing antigen 85A (MVA85A) tuberculosis vaccine.12 It will take at least a decade before the true effect of this new vaccine portfolio is known. To achieve global tuberculosis control, it is crucial to find and treat all patients with active pulmonary tuberculosis,1 rendering them non-infectious. The introduction of newer diagnostics will no doubt facilitate this proactive search. The development of a range of new diagnostic tests for tuberculosis1,9 is encouraging and every new diagnostic test that comes to market should be assessed rigorously for diagnostic accuracy, robustness under operational field conditions, cost-effectiveness, and practical usefulness, and should be tailored to the environment of local services to ensure continuum of care. A few developers have rushed their diagnostic products into the market without adequate evaluation but only two diagnostics are in advanced stages of assessment and implementation: Xpert MTB/RIF assay nucleic acid amplification test for simultaneous detection of Mycobacterium tuberculosis DNA and rifampicin resistance in sputum13; and detection of mycobacterial cell-wall lipoarabinomannan (LAM) in urine to diagnose tuberculosis in patients with advanced HIV disease.14 Xpert MTB/RIF assay is being extensively rolled-out worldwide for use in adults and children in several settings. Trial data show that this roll-out might not have a major effect on treatment outcomes when compared with empirical treatment started on clinical suspicion or use of traditional sputum microscopy when used under decentralised programmatic conditions.15,16 Phenotypical culture-based assays remain the cornerstone for resistance testing, although colorimetric methods and phage-based assays are being developed to identify rifampicin, isoniazid, and fluoroquinolone resistance. Microarray-based multiplexing and nucleic acid-based deep-sequencing methods for the 268
simultaneous detection of M tuberculosis DNA and drug resistance to several first-line and second-line drugs now provide further hope for rapid point-of-care diagnostics for multidrug-resistant tuberculosis. Development of tuberculosis-centric diagnostic tests is important, but it is prudent to realise that it might not fit into the longer-term goals of optimum alignment of health care for non-communicable and other communicable diseases, which is moving away from disease-focused silos. When a patient presents with a respiratory-tract infection at any point in care, the diagnostic test needs to be able to differentiate tuberculosis from other bacterial and viral causes of respiratory-tract infections to give the best treatment outcomes. Technological advances present a unique opportunity to address this unmet need, and should use a sputum sample from the patient at point of care.17 Hope that the lengthy course of treatment can be shortened is provided by the many new or repurposed antituberculosis drugs that are in late phases of clinical development,10,11 but drug development also needs to focus on the estimated 2 billion people with latent tuberculosis infection who might go on to develop active disease in the presence of HIV or immunosuppression. For these patients, two parallel approaches are needed— short, effective, and well tolerated treatments for tuberculosis, and an effective postexposure vaccine to prevent tuberculosis. Tuberculosis-biomarker development has lagged behind other advances in management of the disease. Hostgenetic transcriptomic signatures to define biomarkers of tuberculosis disease activity, cure, and relapse for drug and vaccine field evaluation have not yet materialised.18 For valid comparisons to be made between drug, diagnostic, biomarker, and vaccine trials, research groups must cross-fertilise their work and standardise sample procurement, processing, storage, and analysis. The focus on research for new tuberculosis instruments should not divert stakeholders from tackling the socioeconomic causes and drivers of the tuberculosis epidemic.19 Inequalities in wealth, drug stock-outs, and poor access to quality health services remain key factors that sustain the tuberculosis epidemic. With inadequate or poorly functioning, ill-equipped, health services to diagnose or treat patients, a longer delay occurs between diagnosis of active tuberculosis and an effective cure, perpetuating the spread of tuberculosis in the www.thelancet.com/infection Vol 14 April 2014
Comment
community. Parallel focus and investment into provision of basic health services, and the tackling of poverty, less than optimum nutrition, crowded poorly ventilated living or working conditions, inadequate housing, social stigma, and other comorbidities, are essential. Political will, poverty alleviation, and good governance are essential components of the global control strategy for tuberculosis.
6 7
8
9
10
Alimuddin I Zumla, Marco Schito, *Markus Maeurer Division of Infection and Immunity, University College London, London, UK (AIZ); Department of Medical Microbiology, University College London Hospitals NHS Trust, London, UK (AIZ); Henry M Jackson Foundation—Division of AIDS, TB Clinical Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA (MS); Therapeutic Immunology Division, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden (MM); and CAST, Karolinska University Hospital, Stockholm SE-14186, Sweden (MM) [email protected] We declare that we have no conflicting interests. 1 2
3 4
5
WHO. World Health Organisation Global Tuberculosis report 2013. http:// www.who.int/tb/publications/global_report/en/ (accessed Nov 12, 2013). Migliori GB, Sotgiu G, Gandhi NR, et al. Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis. Eur Respir J 2013; 42: 169–79. WHO. TB–a global emergency. WHO Press Release. Geneva: World Health Organization, 1993. Pietersen E, Ignatius E, Streicher EM, et al. Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study. Lancet 2014; published online Jan 16. http://dx.doi.org/10.1016/S01406736(13)62675-6. Dheda K, Migliori GB. The global rise of extensively drug-resistant tuberculosis: is the time to bring back sanatoria now overdue? Lancet 2012; 379: 773–75.
11
12
13
14
15
16
17
18
19
Hughes J, Cox H. Sanatoria for drug-resistant tuberculosis: an outdated response. Lancet 2012; 379: 2148. Zumla A, George A, Sharma V, Herbert N, Baroness Masham of Ilton. WHO’s 2013 global report on tuberculosis: successes, threats, and opportunities. Lancet 2013; 382: 1765–57. Kaufmann SHE, Lange C, Rao M, et al. Progress in tuberculosis vaccine development and host-directed therapies—a state of the art review. Lancet Respir Med 2014; published online March 24. http://dx.doi. org/10.1016/S2213-2600(14)70033-5. Lawn SD, Mwaba P, Bates M, et al. Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test. Lancet Infect Dis 2013; 13: 349–61. Zumla A, Nahid P, Cole ST. Advances in the development of new tuberculosis drugs and treatment regimens. Nat Rev Drug Discov 2013; 12: 388–404. Zumla A, Gillespie SH, Hoelscher M, et al. New antituberculosis drugs, regimens, and adjunct therapies: needs, advances, and future prospects. Lancet Infect Dis 2014; published online March 24. http://dx.doi.org/ 10.1016/S1473-3099(13)70328-1. Tameris MD, Hatherill M, Landry BS, et al, for the MVA85A 020 Trial Study Team. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet 2013; 381: 1021–28. Steingart KR, Schiller I, Horne DJ, Pai M, Boehme CC, Dendukuri N. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev 2014; 1: CD009593. Lawn SD, Dheda K, Kerkhoff AD, et al. Determine TB-LAM lateral flow urine antigen assay for HIV-associated tuberculosis: recommendations on the design and reporting of clinical studies. BMC Infect Dis 2013; 13: 407. Theron G, Zijenah L, Chanda D, et al. Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial. Lancet 2013; 382: 424–35. Theron G, Peter J, Dowdy D, Langley I, Squire SB, Dheda K. Do high rates of empirical treatment undermine the potential effect of new diagnostic tests for tuberculosis in high-burden settings? Lancet Infect Dis 2014; published online Jan 14. http://dx.doi.org/10.1016/S1473-3099(13)70360-8. Zumla A, Gant V, Bates M, Mwaba P, Maeurer M, Memish ZA. Rapid diagnostics urgently needed for killer infections. Lancet Respir Med 2013; 1: 284–85. Joosten SA, Fletcher HA, Ottenhoff TH. A helicopter perspective on TB biomarkers: pathway and process based analysis of gene expression data provides new insight into TB pathogenesis. PLoS One 2013; 8: e73230. Zumla A, Mwaba P, Huggett J, Kapata N, Chanda D, Grange J. Reflections on the white plague. Lancet Infect Dis 2009; 9: 197–202.
Corrections Grinsztejn B, Hosseinipour MC, Ribaudo HJ, et al. Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial. Lancet Infect Dis 2014; 14: 281–90—In the Discussion section of this Article, the text at the end of the first paragraph should have read “similarly, the overall incidence of primary or secondary outcomes was higher in the delayed group, predominantly tuberculosis and WHO stage 2 and 3 events (p=0·025)”. The correction has been made to the online version as of March 24. The print version is correct.
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