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Tuberculosis Overview & Update June 2010 Stephan L. Kamholz, MD.

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Presentation on theme: "Tuberculosis Overview & Update June 2010 Stephan L. Kamholz, MD."— Presentation transcript:

1 Tuberculosis Overview & Update June 2010 Stephan L. Kamholz, MD

2 Objectives Understand epidemiology, clinical presentation & immunopathogenesis of TB Gain familiarity with standard and newer diagnostic modalities for TB Review therapies and approaches to TB control

3 Disclosure No stocks, bonds, salaried board positions No direct industry research grant funds No personal financial interest in any product, device or drug

4 Case Presentation

5 56 year old woman with rheumatoid arthritis…new cough 56 yo woman h/o RA, GERD p/w three wks of weakness, night sweats, & chills. Patient had a flu shot 5 weeks ago at medicine clinic (went for routine check up) and had flu-like symptoms (chills, body aches, cough with little sputum) since then. No sick contacts, no recent travel within two years. Seen by rheumatologist 3 weeks ago c/o flu symptoms but told that she didn't have an infections. Weakness gradually worsened over the 3 weeks respiratory symptoms (cough/yellow sputum) persisted, developed appetite loss & fatigue ED.

6 56 year old woman with rheumatoid arthritis …new cough Past History: PPD 2 years ago, non reactive (? RA rx at that time?); Came to USA from Bolivia 30 years ago RA (Rheumatoid Arthritis) (ICD9 714.0) GERD (Gastroesophageal Reflux Disease) (ICD9 530.81): Surgical History: CS (Cesarean Section) (ICD9 669.70) Meds: Leflunomide [Arava ]; Adalimumab [Humira ].

7 56 year old woman with rheumatoid arthritis …new cough

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11 Guerra RL et al. Use of the amplified mycobacterium tuberculosis direct test in a public health laboratory: test performance and impact on clinical care. Chest. 2007 Sep;132(3):946-51 The Amplified Mycobacterium tuberculosis Direct Test (MTD; Gen-Probe; San Diego, CA) is a nucleic-acid amplification test for rapid pulmonary tuberculosis (PTB) diagnosis. RESULTS: A total of 1,151 respiratory specimens from 638 PTB suspects were analyzed. MTD sensitivity, specificity, positive predictive value, and negative predictive value were 91.7%, 98.7%, 96.7%, and 96.5% overall, respectively; and 98.7%, 97.8%, 98.7%, and 97.8% for smear-positive patients; and 62.2%, 98.9%, 85.2%, and 96.1% for smear-negative patients. In the MTD group, concordance between definitive and clinician presumptive diagnoses was 78% (95% confidence interval [CI], 64 to 88%), similar to that for the non-MTD group (79%; 95% CI, 68.4 to 89.6%). Concordance between definitive diagnosis and the MTD test was 98% (95% CI, 94.1 to 100%). CONCLUSION: For smear-positive PTB suspects, MTD had excellent concordance with definitive diagnosis,

12 Dixon WG et al. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: Results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2009 Oct 22. [Epub ahead of print] Risk of TB in patients with RA is felt to be increased following anti-TNF rx. Proposed differential risk between the anti-TNF drugs etanercept (ETA), infliximab (INF) and adalimumab (ADA). Compare directly the risk between drugs, to explore time to event, site of infection and the role of ethnicity, using data from the British Society for Rheumatology Biologics Register compared TB rates in 10712 anti-TNF treated patients (3913 ETA, 3295 INF, 3504 ADA) and 3232 patients with active RA treated with traditional DMARDs. RESULTS: As of 04/08, 40 cases of TB were reported, all in the anti-TNF cohort. The rate of TB was higher for the monoclonal antibodies ADA (144 events/ 100,000 person years (pyrs)) and INF (136/100,000 pyrs) than ETA (39/ 100,000 pyrs). After adjustment, the incidence rate ratio compared to ETA-treated patients was 3.1 (95% CI 1.0, 9.5) for INF and 4.2 (1.4, 12.4) for ADA. 13/40 cases occurred after stopping therapy. 25/40 (62%) cases were extra-pulmonary, of which 11 were disseminated. Patients of non-white ethnicity had a six-fold increased risk of TB compared to white patients treated with anti-TNF therapy. CONCLUSION: The rate of TB in patients with RA treated with anti-TNF therapy was 3-4 fold higher in patients receiving INF and ADA compared to ETA.

13 TB Epidemiology

14 W.H.O. 2009 TB Report

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16 2009 - 13th annual report on global control of tuberculosis (TB) - World Health Organization Globally, estimated 9.27 million incident cases of TB in 2007. Increase from 9.24 million cases in 2006, 8.3 million cases in 2000 and 6.6 million cases in 1990. Most of the cases in 2007 were in Asia (55%) and Africa (31%), with small proportions of cases in the Eastern Mediterranean Region (6%), the European Region (5%) and the Americas (3%). The five countries that rank first to fifth in terms of total numbers of cases in 2007 are India (2.0 million), China (1.3 million), Indonesia (0.53million), Nigeria (0.46 million) and South Africa (0.46 mill). Of the 9.27 million incident TB cases in 2007,an estimated 1.37 million (15%) were HIV-positive; 79% of these HIV- positive cases were in the African Region and 11% were in the South-East Asia Region.

17 2009 - 13th annual report on global control of tuberculosis (TB) - World Health Organization Although incident cases of TB increased in absolute terms as a result of population growth, the number of cases per capita is falling. The rate of decline is slow, at less than 1% per year. Globally, rates peaked at 142 cases per 100 000 population in 2004. In 2007, there were an estimated 139 incident cases per 100 000 population. Incidence rates are falling in five of the six WHO regions (the exception is the European Region, where rates are approximately stable).

18 2009 - 13th annual report on global control of tuberculosis (TB) - World Health Organization Estimated 13.7 million prevalent cases of TB in 2007 (206 per 10 5 population), a decrease from 13.9 million cases (210 per 10 5 population) in 2006. Estimated 1.3 million deaths occurred among HIV negative incident cases of TB (20 per 10 5 population) in 2007. There were an additional 456 000 deaths among incident TB cases who were HIV-positive; these deaths are classified as HIV deaths in the International Statistical Classification of Diseases (ICD-10).

19 2009 - 13th annual report on global control of tuberculosis (TB) - World Health Organization Estimated 0.5 million cases of multi drug resistant TB (MDR -TB) in 2007. 27 countries (of which 15 are in the European Region) that account for 85% of all such cases. The countries ranking 1 to 5 in terms of MDR - TB cases are India (131 000), China (112 000), the Russian Federation (43 000), South Africa (16 000) and Bangladesh (15 000). By the end of 2008, 55 countries and territories had reported at least one case of extensively drug resistant TB (XDR -TB).

20 TB – USA – 2008 www.cdc.gov/.../dsTB2008Data

21 TB – New York State – 2008 NYSDOH Report - March 24, 2009 TB cases were reported in all regions of the state and in all age groups. In NYS there were 1,200 cases of TB in 2008, a 2% increase over 2007. 76% of cases were among persons born outside the United States, reflecting the high burden of TB in Latin America, East Asia, Africa, and the Indian subcontinent. In New York City there were 895 cases, for a rate of 11.2 cases per 100,000, a 2% decrease from 2007 and a 21.3% decrease over 5 years. In the 57 counties outside New York City, 305 cases (2.8 cases per 100,000 population) were reported, a 17% increase from 2007. But overall there has been a 10% decrease in cases over the last five years. More than half (56 percent) of the cases outside New York City were reported in three counties: Nassau, Westchester, and Suffolk. In 2008 12 cases of multi-drug resistant TB were reported, compared with 20 to 30 cases of multi-drug resistant TB annually in recent years. Patients with drug-resistant TB must be treated for longer periods with less effective drugs.

22 Tuberculosis The pathway from transmission to infection to disease

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24 Transmission of TB Patient with active pulmonary tuberculosis coughs, releasing AFB into atmosphere Each organism is surrounded by a sphere of hydration known as the droplet nucleus Mass median diameter of droplet nuclei is 1 - 2 microns Host inhales droplet nuclei which evade the mucociliary clearance mechanism and impact in peripheral alveoli of the mid and lower lung zones

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26 Macrophage phagocytosis of tubercle bacilli

27 Intra-cytoplasmic events Inhaled mycobacteria phagocytosed by alveolar macrophage...phagosomal vacuole also contains components of class II MHC Anticipated fusion of lysosome with phagosome is inhibited, perhaps by sulfolipids, leading to unimpeded proliferation of M. tb. in macrophage Evidence of specific inhibition of fusion of vesicular proton-ATPase which results in less than adequate acidification of vacuole Sturgill-Koszycki et al. Science 1994;263:678-681.

28 Antigen presentation Cell-cell interactions post-phagocytosis

29 Immunopathogenetic Steps Ultimately, mycobacterial antigens processed for presentation [with MHC] to CD4+ T-helper cells which have been primed by macrophage release of Il-1 Lymphocyte secretes lymphokines leading to clonal expansion of antigen specific CD4+ cells and stimulation of macrophages...a subset of cytotoxic T cells may lyse infected macrophages permitting M. tb. to be phagocytosed by activated macrophages [IFN-gamma, etc] Positive tuberculin skin test develops in immunocompetent individuals {Delayed hypersensitivity}

30 Symptomatology Constitutional illness is attributable to the immune response Cytokines [TNF, interferon-gamma, Il-1] can evoke many of the classic symptoms of tuberculosis, e.g., fever, sweats, weight loss, anorexia Localizing symptoms [e.g., cough] related to impingement of lesions on airways or stimulation of interstitial stretch receptors Dyspnea occurs only with very extensive lung involvement

31 Possible outcomes post infection

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33 Progressive Primary TB Initial parenchymal focus progresses Characteristic of tuberculosis in the pediatric age group and occurs with increased frequency in immunocompromised hosts Tuberculous pneumonia, often accompanied by hilar and/or mediastinal lymph node enlargement

34 Progressive Primary Case Vignette 27 year old woman from West Indies with one month fever, achy left chest pain, muco- purulent cough, night sweats and 7 lb. weight loss; HIV risks ???? WBC 19.K, Na + 133; sputum C/S = N.O.F.; Sputum AFB smears X 3 (-) CXR

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37 Initial Hematogenous Dissemination May occur with primary or reactivation disease Tubercle bacilli gain access to lung lymphatics, reach hilar nodes and undergo lympho-hematogenous dissemination Lung apices, meninges, epiphyses of bones, kidneys, adrenals, liver are seeded Primary lung lesion and peripheral foci heal in the immunocompetent host Disseminated [miliary] disease develops in some individuals [children, HIV, etc]

38 Miliary TB Diffuse tiny pulmonary nodules 1 - 2 mm in diameter [resembling millet seeds] representing hematogenous dissemination to lung Multiple other organs affected Patients extremely ill with spiking fevers, sweats, weight loss, hematologic abnormalities …can have respiratory failure, shock

39 Miliary TB Case Vignette 27 yr. old woman, known HIV, S/P intrathecal chemorx. for B-cell lymphoma [pre-antiretroviral era] Fevers, night sweats, anorexia, weight loss, mild DOE Lymphopenia & hyponatremia CXR

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42 Post FA, Wood R, Pillay GP. Pulmonary tuberculosis in HIV infection: radiographic appearance is related to CD4+ T-lymphocyte count Tuber Lung Dis. 1995 Dec;76(6):518-21 CD4+ T-lymphocyte count was used as a marker of HIV disease progression. Upper zone infiltrate typical of Pulmonary TB reactivation was present in 18 patients. This pattern was associated with early HIV infection (mean CD4+ T-cell count 389) and had 78% positive predictive value for identifying patients with > 200 CD4+ T- lymphocytes/microL. Pleural effusion was present in 32 patients and occurred over a wide intermediate range of CD4+ T-cell counts (mean 185). Lower or midzone infiltrates, adenopathy, interstitial pattern or normal radiograph occurred in 136 patients and were associated with advanced HIV disease (mean CD4+ T-cell count 105). These patterns had 84%, 89%, 89% and 100% positive predictive value, respectively, for identifying patients with < 200 CD4+ T- cell/microL. CONCLUSION: Pulmonary tuberculosis in HIV-positive patients presents with a spectrum of radiographic abnormalities predictive of stage of HIV disease progression.

43 Pleural TB Often develops 3 to 6 up to 24 months after initial infection, however, can accompany parenchymal reactivation Lymphocytic exudative pleural effusion is a common manifestation Probably represents rupture of sub-pleural [parenchymal] focus of viable mycobacteria into pleural space followed by exuberant lymphocytic inflammatory response

44 Pleural TB Case Vignette 40 year old woman with acute severe right chest pain and T 38.5 o C Known tuberculin skin test conversion 11 months ago, refused isoniazid chemoprophylaxis CXR

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46 Diagnosis of Tuberculous Pleurisy Lymphocytic exudative effusion: CD 4 cells as high as 65%, CD 8 cells up to 19% High protein, normal or low glucose Elevated adenosine deaminase {> 53 U/ml} with pleural/serum ADA ratio > 1.5 Elevated interferon- and interferon- Demonstration of caseating granulomata on biopsy; growth of AFB from fluid or biopsy Positive direct AFB smear of fluid unusual except in HIV-associated TB pleural effusion

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48 Reactivation TB {a.k.a. Post-Primary TB} Characteristically upper lobe disease with cavitation Occurs in previously infected individuals due to some diminution in immune surveillance, usually older patients May have extra-pulmonary involvement Represents the most common type of tuberculosis encountered in the U.S., probably 2/3 to ¾ cases

49 Reactivation TB - Case Vignette (Mr. XDR of the 1990s) 44 year old street person admitted with cough, fatigue, night sweats, dyspnea Past history of admissions for inpatient TB treatment X 7 over 4 year period Known resistant isolate CXR

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52 Confirmed the etiology Robert Koch, MD

53 Acid Fast Stain Cell wall lipids make cell surface hydrophobic, conferring resistance to staining with basic aniline dyes Ziehl Nielsen acid fast stain often applied with heat; once stained, AFB resist decolorization; acid/alcohol decolorizer used, however organisms remain reddish Fluorescent staining possible using fluorochrome methodology

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55 Fluorochrome Stain

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57 Invasive sampling techniques Bronchoscopic sampling Pleural Disease [already discussed re: case] Other extra-pulmonary sites…site specific sampling

58 Tuberculosis Newer diagnostic modalities –Identification & sensitivity testing of clinical specimens –Immunodiagnostic testing pf patients

59 Luciferase Reporter Assay

60 Hazbón MHHazbón MH, Guarín N, Ferro BE, Rodríguez AL, Labrada LA, Tovar R, Riska PF, Jacobs WR Jr. J Clin Microbiol. 2003 Oct;41(10):4865-9.Guarín NFerro BERodríguez ALLabrada LATovar RRiska PF Jacobs WR Jr Photographic and luminometric detection of luciferase reporter phages for drug susceptibility testing of clinical Mycobacterium tuberculosis isolates. Luminometric detection of LRP activity offers higher sensitivity and quantitative results, while a Polaroid film detection method offers a "low-tech" inexpensive alternative that is called the Bronx box. In this work we evaluated, improved, and compared the performance of the luminometer and the Bronx box formats for drug susceptibility testing with LRPs by using 51 clinical isolates of M. tuberculosis, with the agar proportion method (PM) serving as reference. The sensitivity in detecting resistance to isoniazid and rifampin, antibiotics that define multidrug resistance (MDR), was 100% for both methods. The turnaround time for results was reduced from 3 weeks for PM to 54 or 94 h for luminometry or the Bronx box,

61 Luciferase Reporter Assay (A) Bronx box. The Polaroid film cassette is placed over the microtiter plate containing the LRP-infected mycobacterial cultures. The door is closed, and the overnight film exposure begins. (B) Drug susceptibility test result gained from the Bronx box [turnaround time = 94 hours] [Ref: Hazbon MH et al. J Clin Microbiol. 2003 October; 41(10): 4865–4869]

62 Dusthackeer A et al. Construction and evaluation of luciferase reporter phages [LRP] for the detection of active and non- replicating tubercle bacilli. J Microbiol Methods. 2008 Apr;73(1):18-25 Improved sensitivity and specificity with new LRP…Che12, the first true temperate phage infecting M. tuberculosis LRP constructs exhibited detectable luciferase activity in dormant as well as in actively growing M. tuberculosis. TB cases among the HIV infected population often result from the reactivation of latent bacilli, it would be useful to develop LRP that can detect dormant bacteria

63 Polymerase Chain Reaction Tests for TB 1,090 tissue and body fluid specimens from 1,032 patients with suspected TB were subjected to acid-fast bacillus (AFB) smear, culture, and the AMPLICOR MTB PCR test. The PCR was negative for all eight specimens that yielded MAC only The sensitivity, specificity, positive predictive value, and negative predictive value for the AMPLICOR MTB PCR test were 76.4%, 99.8%, 92.8%, and 99.2%, respectively. PCR results were available within 6.5 hours, compared with an average of 3 weeks for culture of M tuberculosis. Conclusions: These data establish the utility of the AMPLICOR MTB PCR test for the rapid detection of M tuberculosis in tissue and body fluid specimens other than respiratory secretions. (CHEST 1998; 113:1190-94)

64 Quantiferon Test Interferon Gamma Release Assays take advantage of this natural process in infected immunocompetent individuals. When antigens specific for a given infecting agent (often in the form of purified protein derivatives) are applied to whole-blood samples from infected individuals, T cells sensitized to the antigens will be present in the blood, and will bind to the antigen. The T cells will then release Interferon-Gamma; the presence of sensitized T-cells in infected individuals will result in far higher levels of IFN-G release than among uninfected individuals. The presence of IFN-G can then be quantified using a single step enzyme-linked immunosorbent assay (ELISA) using anti-IFN-G antibodies.

65 Quantiferon Test (NY City DOH offers QFTB-Gold) Studies assessing QFT-G suggest a specificity of 98.1% and a sensitivity of 89.0% was reported in 118 patients with culture- confirmed TB. QFT-G was compared with TST by using two tuberculin units of RT-23. In a group of 99 healthy, BCG-vaccinated medical students in Korea, the specificity of QFT-G was 96%, compared with 49% for the TST. Among 54 patients with pulmonary TB disease, the sensitivity of the QFT-G was 81%, compared with 78% for the TST. QFT-G and the TST were compared in an unselected population of 318 hospitalized patients. QFT-G had greater sensitivity for TB disease (67%) than did TST (33%), but indeterminate QFT-G responses were common (21%) among patients with negative TST results, the majority of whom were thought to be immunocompromised or immunosuppressed.

66 Use of Quantiferon Test FDA approved QFT-G as an in vitro diagnostic aid using peptide mixtures simulating ESAT-6 and CFP-10 proteins to stimulate cells in heparinized whole blood. Detection of IFN-g by ELISA is used to identify in vitro responses to ESAT-6 and CFP-10 that are associated with M. tuberculosis infection QFT-G can be used in all circumstances in which the TST is used, including contact investigations, evaluation of recent immigrants who have had BCG vaccination, and TB screening of health-care workers and others undergoing serial evaluation for M. tuberculosis infection. QFT-G usually can be used in place of (and not in addition to) the TST. A positive QFT-G result should prompt the same public health and medical interventions as a positive TST result. No reason exists to follow a positive QFT-G result with a TST. Persons who have a positive QFT-G result, regardless of symptoms or signs, should be evaluated for TB disease before LTBI is diagnosed. At a minimum, a chest radiograph should be examined for abnormalities consistent with TB disease.

67 Tuberculosis Approaches to treatment & prevention –Historical –Current –Future [prevention]

68 Edward L. Trudeau, MD

69 Trudeau Sanatorium–Saranac NY

70 Why sanatoria might have been beneficial … Ustianowski A et al. Prevalence and associations of vitamin D deficiency in foreign-born persons with tuberculosis in London. J Infect. 2005 Jun;50(5):432-7 Incidence of tuberculosis is high amongst foreign-born persons resident in developed countries. Vitamin D is important in the host defense against TB in vitro and deficiency may be an acquired risk factor for this disease. Study to determine the incidence and associations of vitamin D deficiency in TB patients diagnosed in London, UK. METHODS: Case-note analysis of 210 unselected patients diagnosed with TB who had plasma vitamin D (25(OH)D3) levels routinely measured. Prevalence of 25(OH)D3 deficiency and its relationship to ethnic origin, religion, site of TB, sex, age, duration in the UK, month of 25(OH)D3 estimation and TB diagnosis were determined. RESULTS: Of 210 patients 76% were 25(OH)D3 deficient and 56% had undetectable levels. 70/82 Indian, 24/28 East African Asian, 29/34 Somali, 14/19 Pakistani and Afghani, 16/22 Sri Lankan and 2/6 other African patients were deficient (with 58, 17, 23, 9, 6 and 1 having undetectable levels, respectively). Only 0/6 white Europeans and 1/8 Chinese/South East Asians had low plasma 25(OH)D3 levels. Muslims, Hindus and Sikhs all had equivalent rates of deficiency though Hindus were more likely to have undetectable levels (odds ratio 1.87, 95% CI 1.27-2.76). CONCLUSIONS: 25(OH)D3 deficiency commonly associates with TB among all ethnic groups apart from white Europeans, and Chinese/South East Asians. Our data support a lack of sunlight exposure and potentially a vegetarian diet as contributors to this deficiency.

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74 TB Treatment Latent TB Infection (LTBI) Active, drug sensitive disease Drug Resistant Disease

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77 TB Rx Regimens www.uspharmacist.com/content/c14112

78 TB TREATMENT Start a Four drug regimen: INH, RIF, EMB, PZA begin for suspected/confirmed case [unless MDR- TB suspected or re-treatment case] Notify public health authorities within 24 hours Initiate contact screening Armamentarium - First line agents: Isoniazid, rifampin, ethambutol, pyrazinamide (in the past: streptomycin) Traditional second line drugs: ethionamide, cycloserine, para- aminosalicylic acid, viomycin, kanamycin, capreomycin Newer agents in use: quinolones, substituted macrolides, rifabutin, rifapentine, amoxicillin-clavulanate, clofazimine Need for expanded therapeutic arsenal because of prevalence of resistant

79 Fixed Dose Combination Tablets IUATLD & WHO recommendation to ensure proper treatment Requires high quality FDCs which have high rifampin bioavailability Problems have been attributed to poor drug quality rather than low absorption Blomberg B et al. Bull World Health Organ 2001:79(1):61-68

80 Fixed combination drugs Strategy: increase compliance and reduce risk of resistance Rifater® = INH + RIF + PZA Rifamate® = INH + RIF Patients cannot take single drugs

81 Issues in Therapy Drug Resistance

82 XDR TB – Treatment Issues

83 Probability of Resistance to anti-TB Drugs High probability [10 -3 ]: Ethionamide, cycloserine, viomycin, capreomycin, thiacetazone Intermediate probability [10 -6 ]: Isoniazid, streptomycin, kanamycin ethambutol, p-aminosalicylic acid Low probability [10 -8 ]: Rifampin

84 Mechanisms of Resistance Isoniazid Rifampin Ethambutol Pyrazinamide Streptomycin Fluoroquinolones katG inhA mutations rpoB EmbCAB sequence Amidase [pncA] rpsL rrs Single amino acid substitutions

85 Principles of MDR-TB Rx. A regimen with at least two [preferably 3] drugs to which the isolate is sensitive Supervised treatment until cure Compliance with treatment is often difficult to achieve, due to the presence of multiple co-morbidities, psychiatric disorders, substance abuse, and social disorganization in some patients…

86 Surgical Management of MDR-TB Indications: 1-Medical rx. failed failure highly likely 2-predominantly localized disease 3-adequate cardiopulmonary status 4-rx. regimen contains 2 effective drugs 27 MDR-TB patients [42 mos. mean follow- up]: 1 peri-op death; 11% complications; 92% sputum conversion +/or (-) post-op Chiang CY et al. Int J Tuberc Lung Dis 2001;5(3):272-77. Chiang CY et al. Int J Tuberc Lung Dis 2001;5(3):272-77.

87 Emerg Infect Dis. 2007 Mar;13(3):380-7. Links Worldwide emergence of extensively drug-resistant tuberculosis. Shah NSShah NS, Wright A, Bai GH, Barrera L, Boulahbal F, Martín-Casabona N, Drobniewski F, Gilpin C, Havelková M, Lepe R, Lumb R, Metchock B, Portaels F, Rodrigues MF, Rüsch-Gerdes S, Van Deun A, Vincent V, Laserson K, Wells C, Cegielski JP.Centers for Disease Control and Prevention, Atlanta, Georgia, USA. sshah@montefiore.orgWright ABai GHBarrera LBoulahbal FMartín-Casabona N Drobniewski FGilpin CHavelková MLepe RLumb RMetchock BPortaels FRodrigues MFRüsch-Gerdes SVan Deun AVincent VLaserson KWells CCegielski JP Mycobacterium tuberculosis strains that are resistant to an increasing number of second-line drugs used to treat multidrug-resistant tuberculosis (MDR TB) are becoming a threat to public health worldwide. We surveyed the Network of Supranational Reference Laboratories for M. tuberculosis isolates that were resistant to second-line anti-TB drugs during 2000-2004. We defined extensively drug-resistant TB (XDR TB) as MDR TB with further resistance to > or = 3 of the 6 classes of second-line drugs. Of 23 eligible laboratories, 14 (61%) contributed data on 17,690 isolates, which reflected drug susceptibility results from 48 countries. Of 3,520 (19.9%) MDR TB isolates, 347 (9.9%) met criteria for XDR TB. Further investigation of population-based trends and expanded efforts to prevent drug resistance and effectively treat patients with MDR TB are crucial for protection of public health and control of TB

88 XDR TB Cases – WHO – June 2008

89 The TB Alliance The TB Alliance is a not-for-profit, product development partnership accelerating the discovery and development of new TB drugs that will shorten treatment, be effective against susceptible and resistant strains, be compatible with antiretroviral therapies for those HIV-TB patients currently on such therapies, and improve treatment of latent infection. The TB Alliance is committed to ensuring that approved new drug regimens are affordable, widely adopted and available to those who need them.

90 Support of the TB Alliance

91 TB Drugs in Development

92 Tuberculosis Vaccine Past, Present & Future TB Vaccine Timeline

93 Candidate TB Vaccines Recombinant BCG vaccines – expressing immunodominant antigens and/or cytokines. Live, attenuated strains of M. tuberculosis – including singly and doubly auxotrophic mutants. Nonpathogenic mycobacteria – including M. vaccae (a soil mycobacterium, which has been tested as an adjunctive immunotherapeutic in adult pulmonary TB patients. M. microti (the vole bacillus; tested in humans by the British MRC), M. smegmatis (a rapidly-growing, non-pathogen) and M. habana (a slow-growing photochromogen originally isolated from monkeys). Non-mycobacterial microbial vectors – including attenuated Salmonella and Vaccinia virus, expressing immunodominant mycobacterial antigens. Subunit vaccines – protein-, lipid, and carbohydrate-based, but mostly protein/peptide antigens have been the focus to date. DNA vaccines - with various adjuvants; independently and in prime- BCG boost paradigms.

94 TB Control – The Funding Gap Extensively drug-resistant TB (XDR-TB). The spread of XDR-TB poses a serious threat to progress and could even reverse recent gains. It will take an additional US$ 650 million globally to implement control of both XDR-TB and multi-drug-resistant TB (MDR-TB) in 2007 alone, (Dr Mario Raviglione, Director of the WHO Stop TB Department) "Beyond that, because of the threat of XDR-TB, research to identify new diagnostics, drugs and vaccines is more vital than ever." Overall funding gap. Although funds for TB control have risen substantially since 2002, reaching US$ 2 billion, an additional US$ 1.1 billion will be needed to meet the 2007 funding requirements set by the Global Plan to Stop TB (2006-2015). A total of US$ 56 billion- -half of which should be funded by endemic countries and the other half by donors--is needed for the 10-year plan, but current funding commitments indicate a gap of at least US$ 31 billion.

95 Summary Mankinds most important infectious disease Concerted efforts by WHO and local/national health authorities provide greatest hope of control New diagnostic modalities are available New drugs and promising vaccines in the pipeline


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