Thank you for viewing this document. We would like to remind you that this material is the property of the author. It is provided to you by the ERS for your personal use only, as submitted by the author. © 2012 by the author ERS Annual Congress Vienna 1–5 September 2012 Postgraduate Course 7 TB and MDR-/XDR-TB: what is new in diagnosis, treatment and follow-up Saturday, 1 September 2012 09:30–13:00 Room: C6 Evidence provided by recent meta-analyses on treatment: what is new? Prof. Giovanni Battista Migliori WHO Collaborating Centre for Tuberculosis and Lung Diseases, Fondazione S. Maugeri Care and Research Institute Tradate Italy [email protected] Aims To describe and discuss: Existing guidelines and definitions Epidemiology of TB and MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation) The new information on MDR-TB diagnosis The new information on MDR-TB treatment, as derived from recent large individual data meta-analyses The principles of MDR-TB control, with prevention and public health aspects Summary The key intervention to achieve TB control is represented by rapid identification and effective treatment of infectious (e.g. sputum smear positive) cases. The golden rule in TB control is to prevent the emergence of drug resistant strains, as their management is difficult and expensive. Drug resistance is a man-made phenomenon, its causes depending on inadequate treatment, transmission and underlying social determinants. Several new guidelines have been published in late 2011 and early 2012, informed by exhaustive meta-analyses. The new information available is summarised in this Unit. The Unit is composed of 5 sections: 1. Surveillance and M&E 2. Diagnosis 3. Treatment 4. Prevention and public health aspects Several pictures were included to allow further discussion of the topic presented. There are several new pieces of information appearing in the literature in late 2011/early 2012. They cover different aspects of MDR-TB management, ranging from surveillance and Monitoring and Evaluation (M&E) to diagnosis, treatment and prevention/ public health aspects. Existing guidelines and definitions They are clearly discussed in the presentation. In particular, the role and contribution of the 2011 update of the WHO MDR-TB guidelines are discussed into details together with the findings of a large individual patient metanalysis involving over 9,000 cases from 32 cohorts globally. Surveillance and M&E Surveillance and M&E are key programmatic components of TB and MDR-TB control and management. Based quality data public health action can be planned, and tuned when necessary. Surveillance In 2010, we cannot say on a scientific ground that MDR-TB is really increasing at the global level. Nearly half a million people are still estimated to develop MDR-TB every year (WHO has not updated the estimates of MDR-TB incidence) and the estimated prevalence of MDR-TB was more recently estimated at 650,000 cases. The highest proportions of MDR-TB ever reported in a survey have 33 recently been found in Minsk, the capital city of Belarus, where MDR-TB was found in 35.3% (95%CI: 27.7-42.8) of new patients and 76.5% (95%CI: 66.1-86.8) of those previously treated, and initial reports are that results from a nationwide survey in Belarus are consistent with the urban findings. From January 2010 to October 2011 the number of countries reporting at least one case of XDR-TB has risen from 58 to 77. The WHO and partners will need to decide whether to carry on with the current approach to drug resistance surveillance, or, whether to expand it and introduce new technologies in order to answer the key questions, such as whether current interventions are “helping or hurting”. Monitoring and evaluation Globally, the numbers of cases of MDR-TB notified to WHO (and therefore presumed to have started treatment) have continued to rise. Notified cases have increased from 29,000 in 2008, to 53,000 in 2010, which represented 18% of the 290,000 (range, 210,000 – 380,000) cases of MDR-TB estimated to occur among patients with pulmonary TB who were notified in the same year. However, it is generally recognised that these increases in notifications are rising too slowly, falling well short of the targets of the Global Plan to Stop TB, 2011-2015, and only 25% are treated according to WHO standards (see below for news on clinical management). Presently surveillance-based information (particularly, data on drug/regimens selection based on drug susceptibility results, duration of treatment and adverse events) is not sufficiently accurate to inform guidelines. As of today, WHO and other major Scientific Societies’ guidelines are largely based on expert opinion, in absence of better evidence. In order to collect the best possible evidence, WHO has supported a large study, whose details are reported below. Furthermore, ERS and ECDC have produced the EU Standards for TB care summarising the standard actions necessary to diagnose TB, treat TB, manage HIV co-infection and other morbidities and prevent/control the disease. This document has been published on April 1, 2012 in the Eur Respir J. Methodology of the metanalyses on MDR- and XDR-TB Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB cases. Study senior Authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. All the necessary additional information necessary to produce a quality data-set were provided, and a rigorous data-quality evaluation was performed prior to the analysis. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Diagnosis of MDR-TB Treatment requires diagnosis first, but unfortunately less than 2% of new cases and 6% or re-treatment cases globally were tested for MDR-TB in 2010, although in the European region the figures were 30% and 51% respectively. In the diagnosis of MDR-TB, sensitive and specific results have been obtained for rifampicin susceptibility in the MTB/RIF test, which is considered a reliable proxy for MDR-TB in high burden settings (see laboratory presentation). Reports are emerging, however, of discordant results between MTB/RIF and conventional drug susceptibility tests (DST) and, perhaps as a result, reports from countries show that health workers are reluctant to start patients on treatment for MDR-TB following a single result of rifampicin resistance from a MTB/RIF test. Recent guidance from WHO is that any person at high risk of MDR-TB should be started on appropriate treatment immediately, while an additional sputum specimen undergoes conventional culture and DST. Previous work has shown the crucial importance of this advice for those patients with HIV infection. Future research should show whether another rapid test (using MTB/RIF with a different specimen, or using another technology) would suffice, in order not to obviate the clear advantage of MTB/RIF, namely its speed of diagnosis. 34 Treatment of MDR-TB Recently, inappropriate use of TB treatment regimens has been shown to be the main cause of development of MDR-TB in the European Union, suggesting that physicians shoulder much of the responsibility. Too many countries are still insisting that patients need to fail the old “Category II” (which adds streptomycin to the isoniazid, rifampicin, ethambutol and pyrazinamide that are used in first line treatment) before being considered for MDR-TB treatment. This effectively ensures that the majority of patients starting second-line treatment are resistant to all these drugs. The widespread inappropriate use of fluoroquinolones (FQ) merely adds to the risk of developing extensively drug resistant (XDR) TB. A metanalysis showed that TB patients had a 3-fold higher risk of developing XDR-TB when prescribed FQ before TB diagnosis, compared to TB patients who were not exposed to FQ. Among the measures for promoting a rational use of drugs the following have been recently suggested: 1. promoting and enforcing internationally recognized treatment, care standards and guidelines; 2. enforcing prescription-only use of anti-TB drugs; 3. promoting education on the correct use of anti-TB drugs and 4. reducing any financial incentive potentially able to encourage irrational use of medicines. While these are essential measures, careful attention needs also to be paid to national treatment policies that can unwittingly lead to amplification of resistance, especially if drug resistance surveillance information is ignored. Since 2010, new evidence-based guidelines from WHO have confirmed the need to prescribe at least 4 drugs to which the strain is susceptible for at least 20 months Recommendations were to design regimens including at least pyrazinamide, a fluoroquinolone, a parenteral agent, ethionamide (or prothionamide), and either cycloserine or PAS (p-aminosalicylic acid) if cycloserine cannot be used. The core results of the metanalysis from the large cohort including 9135 cases are described below. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted Odds Ratio (aOR): 2.5 [95% confidence interval: 1.1, 6.0]), ofloxacin (aOR: 2.5 [1.6, 3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3, 2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3, 3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7, 4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7, 4.3]), ofloxacin (aOR: 2.3 [1.3, 3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4, 2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9, 3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4, 6.0]). In summary this study suggests to use at least four drugs likely to be effective in the initial intensive phase and at least three in the continuation phase. However, being the analysis restricted to cohorts of patients in whom drug susceptibility testing was routinely performed, the study results cannot be applied when standardized regimens are used without routine drug susceptibility testing. Given the well-known limitations of drug susceptibility testing for several second-line drugs, these results should be interpreted with caution and applied in experienced, reference centres. In terms of treatment duration, the highest odds of success were associated with 7-8.5 months duration of the initial intensive phase and with a total duration of 18-20 months. As more evidence was urgently needed to indicate the best treatment for XDR-TB cases, a subanalysis was performed on 405 XDR-TB cases from 26 cohorts. In addition for 6,724 MDR-TB patients results of susceptibility testing for fluoroquinolones and at least one second-line injectable were available. Compared to treatment failure, relapse and death, treatment success was lower in the 405 patients affected by XDR-TB (adjusted OR: 0.2 [95%CL: 0.2, 0.3]), and next lower in 426 patients with MDR-TB+ resistance to fluoroquinolones (aOR: 0.3 [0.2, 0.4]). The 1,130 patients with MDR-TB+resistance to injectables also reported lower success rates (aOR: 0.6 [0.5, 0.7]) compared to the 4,763 patients with MDR-TB but no additional resistance. No single drug was significantly associated with treatment success in MDR-TB+ resistance to fluoroquinolones and in XDR-TB patients. In XDR-TB patients, success was highest if at least 6 drugs were used in the intensive phase (4.9 [1.4-16.6]) and 4 in the continuation phase (6.1 [1.4-26.3]). The odds of success in XDR-TB patients were highest when the intensive phase of treatment reached 6.6-9.0 months and total treatment duration 20.1-25.0 months. 35 In the population of patients with MDR-TB studied, those with additional resistance to a second line injectable or to fluoroquinolones had worse treatment outcomes, particularly if they were both meeting the XDR-TB definition. In patients with XDR-TB, regimens containing more drugs than those recommended in MDR-TB but lasting for a similar duration of time were associated with best results. As all data in the analysis were from observational studies, bias may be substantial and better quality evidence will be needed to guide the optimization of regimens. The exact role of the drugs presently prescribed off-label (e.g. linezolid) and which are potentially effective, but expensive and toxic, needs to be clarified. A recent metanalysis including the vast majority of published cases treated with linezolid (based on individual data) provided additional evidence that 58.9% of cases experienced adverse events, of which 68.4% were major. The proportion of adverse events was significantly higher when the linezolid daily dosage exceeds 600 mg. New drugs are being developed and tested in the treatment of MDR-TB, but since they are being tested one by one in clinical trials where they are simply added to the optimized background regimen, and compared to the optimized regimen alone, they will add little to possible policy guidance once Phase IIb, and then Phase III studies are completed in 2017 or 2018. What promises more are trials of multiple regimens such as those conducted by the Global Alliance of TB Drug Development with Pa-824, moxifloxacin and pyranzinamide. However, even here, useful conclusions will not be available for some time, and even then, they are likely to be restricted to patients with proven susceptibility to these three drugs. There are increasing calls for these experimental drugs to be used for compassionate treatment in XDR-TB patients with limited treatment options. Guidance is available. Many countries, especially in Eastern Europe, continue to use surgery, but not in any standardised way. It is difficult to develop evidence based policy, but well-designed studies are possible, and necessary. Prevention and public health aspects Another big challenge where countries are already feeling pressure, is that increasing numbers of patients are already being diagnosed with MDR-TB especially through introduction of new rapid tests, while treatment is only available for a relatively small proportion. Where national policy has MDR-TB cases being treated only in specialised health facilities, this further emphasizes the need for rapid increases in the pool of qualified human resources, the availability of adequate infrastructures, and policies for treatment in the community. Improved infrastructure will also be necessary to ensure endof-life and palliative care for untreatable XDR-TB cases under adequate infection control conditions. Prisoners, the HIV infected, and drug users, are all groups with increased risk of TB, and in certain circumstances, of MDR-TB, but they are often neglected by researchers and policy makers. Emphasizing this neglect is the fact that there are very few recent papers addressing MDR-TB in these populations. There is however, growing interest in non-communicable diseases and diabetes mellitus has been known for decades to be associated with TB, and, more recently, with MDR-TB. This presents challenges particularly to those providing care for diabetes, as well as for the community responsible for TB care. In conclusion, countries are little better prepared for the MDR-TB epidemic than they were 2 years ago. Although science is increasingly offering better technology that might be useful for TB control, funds for public health programmes are threatened from the global to the national level, while many hospitals in Africa and the former Soviet Union remain “dirty, dark and sad, with almost no infection control measures”, and providing little more than lodging for incurably drug resistant patients. Governments will be judged by their responses to these situations. The core interventions to prevent and control XDR –TB, include: 1. Preventing XDR-TB through basic strengthening TB and HIV control. The new Stop TB strategy and the Global Plan to Stop TB are the key reference documents to guide these priority interventions. 2. Improving management of individuals suspected to be affected by XDR-TB through accelerated access to laboratory facilities with rapid DST test for rifampicin and isoniazid resistance and DST for MDR-TB cases and improved detection of cases suspecting of harbouring MDR strains both in high and low HIV prevalence settings. 36 3. Strengthening management of XDR-TB and treatment design in both HIV-negative and positive individuals, through adequate use of second-line drugs and patient-centred approaches to ensure support and supervision. 4. Standardising the definition of XDR-TB. 5. Increasing health care worker infection control and protection mainly (but not exclusively) in high HIV prevalence settings. 6. Implementing immediate XDR-TB surveillance activities through the existing network of SRLs and NRLs. 7. Initiating advocacy, communication and social mobilization activities to inform and raise awareness about TB and XDR-TB. Within the framework of these recommendations, USAID in collaboration with WHO and other partners has developed a tool (the MDR/XDR-TB Assessment and Monitoring Tool) to be used for preparing national or sub-national plans for MDR/XDR-TB prevention and control; providing baseline information and monitoring progress; providing data and analysis to prepare Green Light Committee (GLC) and Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) applications; providing information to guide requests for external technical assistance; providing information to guide donor investment in MDR/XDR-TB interventions, as mentioned in the previous section. Conclusions The publication of new MDR-TB management guidelines deriving from a large individual data-based metanalysis is a major step towards improved management of M/XDR-TB cases. Evidence from existing trials will shed further light on how better to manage MDR-TB in the next future. EU standards are also available to guide the day-to-day activity of physicians and nurses who are called to manage TB cases. References 1. Nathanson E, Nunn P, Uplekar M, Floyd K, Jaramillo E, et al. MDR Tuberculosis – Critical steps for prevention and control. N Engl J Med 2010; 363:1050-8. This article summarises the key priorities needing to be implemented to control MDR-TB. A key article summarising the status-of-the-art on the public health aspects related to MDR-TB 2. Gandhi N, Nunn P, Dheda K, Schaaf HS, Zignol M, van Soolingen D, Jensen P, Bayona J. Multidrug- resistant and extensively drug resistant tuberculosis: a threat to global control of tuberculosis. Lancet. 2010;375:1830-43. A summary on all new aspects related to M/XDR-TB. 3. World Health Organization. Global tuberculosis control. Geneva, Switzerland: WHO, 2011 (WHO/HTM/TB/2011.16). The annual TB report from WHO. All figures are there! 4. Skrahina A, Zalutskaya A, Sahalchyk E, Astrauko A, van Gemert W, Hoffner S, Rusovich V, Zignol M. Alarming levels of drug-resistant tuberculosis in Belarus: results of a survey in Minsk. Eur Respir J 2012;39:1425-31. The article reports on the new world record: the highest ever reported prevalence of MDR-TB is presently in Minsk, Belarus. 5. Boehme CC, Nicol MP, Nabeta P, Michael JS, Gotuzzo E, Tahirli R, Gler MT, Blakemore R, Worodria W, Gray C, Huang L, Caceres T, Mehdiyev R, Raymond L, Whitelaw A, Sagadevan K, Alexander H, Albert H, Cobelens F, Cox H, Alland D, Perkins MD. Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study. Lancet. 2011 Apr 30;377(9776):1495-505. A must. The paper summarizes the first large scale GeneXpert implementation project results. 6. Salvo F, Sadutshang TD, Migliori GB, Zumla A, Cirillo DM. Xpert MTB/RIF test for tuberculosis. Lancet. 2011 Aug 6;378(9790):481-482. An interesting field experience on the use of GeneXpert. Not everything works perfectly, and room for improvement exists. 7. Trébucq A, Enarson DA, Chiang CY, Van Deun A, Harries AD, et al. Xpert MTB/RIF for national tuberculosis programmes in low-income countries: when, where and how? Int J Tuberc Lung Dis, 2011; 15(12):1567-72. Interesting perspective on how best to use GeneXpert in countries. 8. Langendam MW, van der Werf MJ, Huitric E, Manissero D. Prevalence of inappropriate tuberculosis treatment regimens: A systematic review. Eur Respir J 2012;39:1012-20. 37 9. Van der Werf MJ, Langendam MW, Huitric E, Manissero D. Knowledge of tuberculosis treatment prescription of health workers: A systematic review. Eur Respir J 2012; in press; 10. van der Werf MJ, Langendam MW, Huitric E, Manissero D. Multidrug resistance after inappropriate tuberculosis treatment: A meta-analysis. Eur Respir J 2012;39:1511-9 References 8–10. Three papers belonging to a special ERJ TB Series focused on the risk that non-rationale use of drugs for diseases other than TB (and FQ in particular) creates drug resistance. Major new evidence available in the series. 11. Raviglione MC, Lange C, Migliori GB. Preventing and managing antimicrobial resistance: imperative for chest physicians. Eur Respir J. 2011;37:978-81. A summary of the WHOrecommended action to limit development of drug resistance through rationale use of antibiotics. 12. WHO. Guidelines for the Programmatic Management of Drug-resistant tuberculosis: Emergency Update 2008. Annex 5, p 208. WHO/HTM/TB/2008.402. The 2008 WHO guidelines: still very useful to read. 13. Falzon D, Jaramillo E, Schünemann H.J, et al. WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. Eur Respir J 2011; 38:516-528. The new WHO guidelines on MDR-TB management. 14. Migliori GB, Eker B, Richardson MD, Sotgiu G, Zellweger JP, et al. A retrospective TBNET assessment of linezolid safety, tolerability and efficacy in multidrug-resistant tuberculosis. Eur Respir J 2009; 34: 387–393. Linezolid: the best study available showing how effective and toxic the drug is. 15. Sotgiu G, Ferrara G, Matteelli A, Richardson MD, Centis R, Ruesch-Gerdes S, Toungoussova O, Zellweger JP, Spanevello A, Cirillo D, Lange C, Migliori GB. Epidemiology and clinical management of XDR-TB: a systematic review by TBNET. Eur Respir J 2009;33:871–881. The first and best systematic review available on XDR-TB management. 16. Dheda K, Migliori GB. The global rise of extensively drug-resistant tuiberculosis: is the time to bring back sanatoria now overdue? Lancet 2012; 379:773-5. The need for improving hospital management of non-curable XDR-TB cases (including better infection control and palliative care) is discussed in this interesting viewpoint focusing on South Africa and Eastern Europe. 17. Raviglione M, Marais B, Floyd K, Lönnroth K, et al. Scaling up interventions to achieve global tuberculosis control: progress and new developments. Lancet 2012;379:1902-13. A comprehensive review of the TB control priorities to meet the Global Plan and Millennium Development Goals (MDG). 18. Menzies D, The Collaborative Group for Meta-Analysis of Individual Patient Data in MDRTB. Specific treatment parameters and treatment outcomes of multidrug-resistant tuberculosis: an Individual Patient Data (IPD) Meta-Analysis. PloS Med 2012; in press. The article includes the results of an individual patient meta-analysis on 9,153 cases of MDR-TB from 32 cohorts worldwide, including important new information on number of drugs necessary and duration of treatment. 19. Migliori GB, Ahuja S, Ashkin D, et al. Outcomes for multidrug-resistant tuberculosis patients with and without resistance to fluoroquinolones and second-line injectable drugs: a metaanalysis of individual patient data. Eur Respir J 2012; in press. The Abstract, that will be presented in an oral presentation during the ERS Conference in Vienna summarizes the key findings on the individual patient meta-analysis performed on over 400 XDR-TB cases. This study represents a sub-analysis of the main study (18). 20. Migliori GB, Zellweger JP, Abubakar I, et al. European Union Standards for Tuberculosis Care. Eur Respir J 2012;39:807-19. The EU Standards for TB Care is a key documents coproduced by ERS and ECDC. It summarises the 21 “Standards” which allow a physician to manage correctly a TB patient. A Standard is a simple set of actions which, based on evidence, needs to be undertaken by each health staff when dealing with a TB case or an individual harbouring risk factors for TB infection and disease. The EU Standards represent an adaptation of the International Standards performed by an international group of experts coordinated by ERS for its “clinical component and by ECDC for the “public health” component. 38 21. Sotgiu G, Centis R, D'Ambrosio L, et al. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J. 2012 Apr 10. [Epub ahead of print]. This study represents the best possible evidence on efficacy, safety and tolerability of linezolid. This metanalysis is performed according to high quality standards on individual data from the vast majority of the linezolidtreated cases published (121 cases of 12 cohorts from 11 Countries) with final outcomes. Evaluation 1. What is the definition of XDR-TB? And that of MDR-TB? 2. Is XDR-TB a real problem in Europe? 3. What are the countries mostly affected by M/XDR-TB? What are the main risk factors for TB and MDR-TB in Europe? 4. What are the public health consequences of managing incorrectly a new pan-susceptible TB case? 5. What is the news on diagnosis of MDR-TB? 6. And its challenges? 7. What is the news on treatment of MDR-TB according to the recent evidence coming from large individual data meta-analyses? 8. What are the recommended interventions to control MDR-TB? 39 Evidence provided by recent metanalyses on treatment: what is new? GB Migliori WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Tradate Italy Aims To describe and discuss: • Existing guidelines and definitions • Epidemiology of MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation) • The new information on MDR-TB diagnosis • The new information on MDR-TB treatment deriving from recent meta-analyses • The principles of MDR-TB control, with prevention and public health aspects Aims To describe and discuss: • Existing guidelines and definitions • Epidemiology of MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation) • The new information on MDR-TB diagnosis • The new information on MDR-TB treatment deriving from recent meta-analyses • The principles of MDR-TB control, with prevention and public health aspects 40 Guidelines for the programmatic management of drug-resistant tuberculosis (1) 1 Background information on DR-TB 2 Framework for effective control of DR-TB 3 Political commitment and coordination 4 Definitions: case registration, bacteriology and treatment outcomes 5 Case-finding strategies 6 Laboratory aspects 7 Treatment strategies for MDR-TB and XDR-TB 8 Mono- and poly-resistant strains 9 Treatment of DR-TB in special conditions and situations 10 DR-TB and HIV infection 11 Initial evaluation, monitoring of treatment and management of adverse effects 41 Guidelines for the programmatic management of drug-resistant tuberculosis (2) 12 Treatment delivery and community-based DR-TB support 13 Management of patients with MDR-TB treatment failure 14 Management of contacts of MDR-TB patients 15 Drug resistance and infection control 16 Human resources: training and staffing 17 Management of second-line antituberculosis drugs 18 Category IV recording and reporting system 19 Managing DR-TN through patient-centered care ANNEX 1 Drug information sheets ANNEX 2 Weight-based dosing of drugs for adults ANNEX 3 Suggestions for further reading ANNEX 4 Legislation, human rights, and patient’s right in TB care prevention and control ANNEX 5 Use of experimental drugs outside of clinical trials ANNEX 5 Methodology Causes of DR Causes of MDR Patient mismanagement 42 DOTS MDR-TB FUNDING: Government Commitment (10$/ case) DIAGNOSIS: SS microscopy, QA and safety measures > money Up to 20,000 $/ case +C, DST, SRL, QA, infection control TREATMENT: SCC,DOT, 6-8 months, no hospitalization 24 months, mandatory DOT & hospitalization in reference facilities TB drugs only, no AE relevant toxicity, need special drugs + expertise TREATMENT MONITORING: SS, standard outcome definitions C, DST, special outcome definitons Definitions • • • • Mono-R Poly-R MDR XDR • SS+, C+ • Cure, failure • Treatment monitoring Definitions MDR-TB = Strains resistant to at least INH and RIF (most important 1st-line drugs) XDR-TB = MDR TB strains with additional resistance to any fluoroquinolone and any of the 3 injectable second-line drugs (amikacin, kanamycin, capreomycin) TDR, XXDR = Resistance to all drugs (not standardised defin) TB with any MDR TB drug resistance TDR/XXDR TB XDR TB 43 XDR= HR + 1 FQ + 1 Injectable (KM or AMK or CM) 1st-line oral •INH Injectables •RIF •SM Fluoroquinolones •PZA •KM •Cipro •EMB •AMK •Oflox •Levo •CM •(Rfb) •Moxi Oral bacteriostatic 2nd line •ETA/PTA •PASA •CYS •(Gati) Unclear efficacy Not routinely recommended, efficacy unknown, e.g., amoxacillin/clavulanic acid, clarithromycin, clofazamine, linezolid, inmipenem/cilastatin, high dose isonizid Aims To describe and discuss: • Existing guidelines and definitions • Epidemiology of MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation) • The new information on MDR-TB diagnosis • The new information on MDR-TB treatment deriving from recent meta-analyses • The principles of MDR-TB control, with prevention and public health aspects Estimated absolute numbers of reported cases with MDR-TB* <100 100–999 1000–9999 >10,000 *among reported pulmonary TB patients 44 Distribution of MDR-TB among new TB cases, 1994-2010. Distribution of MDR-TB among previously treated TB cases, 1994-2010. 13 top settings with highest % of MDR-TB among new cases, 2001-2010 Minsk, Belarus (2010) Preliminary results ERJ 2012 35.3 45 Notifications of MDR-TB increasing BUT only ~ 1 in 6 (16%) of estimated cases of MDR-TB among reported TB patients diagnosed and treated in 2010 Notified cases of MDR-TB Global Plan target ~270,000 in 2015 MDR-TB cases treated and estimated numbers not treated for MDR-TB, among notified TB patients, 2010 290,000 53,000 19,000 Proportion of TB patients tested for MDR-TB remains low New cases Previously treated Global plan target for 2015 = 20% Global plan target for 2015 = 100% Trend of MDR-TB among new cases, Estonia, Latvia and…Tomsk Oblast, RF Estonia Latvia Tomsk oblast, RF TB notification rate % MDR among new 46 Countries that had reported at least one XDR-TB case by Oct 2011 Aims To describe and discuss: • Existing guidelines and definitions • Epidemiology of MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation) • The new information on MDR-TB diagnosis • The new information on MDR-TB treatment deriving from recent meta-analyses • The principles of MDR-TB control, with prevention and public health aspects 20/36 HBCs* have insufficient capacity to diagnose MDR-TB ≥1 Culture and DST <1 laboratories per 5M, 2010 *HBC= high-burden country Countries = Afghanistan, Armenia, Azerbaijan, Bangladesh, Belarus, Brazil, Bulgaria, Cambodia, China, DR Congo, Estonia, Ethiopia, Georgia, India, Indonesia, Kazakhstan, Kenya, Kyrgyzstan, Latvia, Lithuania, Mozambique, Myanmar, Nigeria, Pakistan, Philippines, Republic of Moldova, Russian Federation, South Africa, Tajikistan, Tanzania, Thailand, Uganda, Ukraine, Uzbekistan, Viet Nam, Zimbabwe 47 The “magic” Gene Xpert The message Any person at high risk of MDR-TB should • undergo rapid testing • to start an appropriate treatment immediately • while an additional sputum specimen undergoes conventional culture and DST Aims To describe and discuss: • Existing guidelines and definitions • Epidemiology of MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation) • The new information on MDR-TB diagnosis • The new information on MDR-TB treatment deriving from recent meta-analyses • The principles of MDR-TB control, with prevention and public health aspects 48 The challenge of MDR Expensive and toxic drugs are necessary Grouping drugs Group 1 1st-line oral •INH •RIF Group 2 Injectables •SM Group 3 Fluoroquinolones •Cipro •PZA •KM •EMB •AMK •Oflox •Levo •CM •(Rfb) •Moxi •(Gati) Group 4 Oral bacteriostatic 2nd line •ETA/PTA •PASA •CYS Group 5 Unclear efficacy Not routinely recommended, efficacy unknown, e.g., amoxacillin/clavulanic acid, clarithromycin, clofazamine, linezolid, inmipenem/cilastatin, high dose isonizid 49 How to design a MDR-TB regimen Metanalysis of 9,153 cases from 32 Countries • Treatment success vs. to failure/relapse, was associated with use of: • later generation quinolones, ofloxacin, ethionamide or prothionamide • use of 4 or more likely effective drugs in the initial intensive phase, and 3 or more likely effective drugs in the continuation phase. • Maximum odds of success: initial intensive phase of 7.1-8.5 months and total treatment duration of 18.6-21.5 months Changes to the recommendations on regimen composition between the 2008 and 2011 updates of WHO MDR-TB guidelines 2008 emergency update 2011 update Include at least four anti-TB drugs with either certain, or almost certain, effectiveness during the intensive phase of Tx Consider adding more drugs in patients with extensive disease or uncertain effectiveness Include at least 4 2nd -line anti-TB drugs likely to be effective as well as Z during the intensive phase of Tx The regimen should include Z and/or E one FQ, one parenteral agent and 2nd -line oral bacteriostatic anti-TB drugs (no preference of oral bacteriostatic 2nd -line anti-TB drug was made). The regimen should include Z a FQ, a parenteral agent, ethionamide (or prothionamide), and cycloserine, or else PAS if cycloserine cannot be used. No evidence found to support the use of > 4 2nd-line anti-TB drugs in patients with extensive disease. Increasing the number of 2nd -line drugs in a regimen is permissible if the effectiveness of some of the drugs is uncertain. E may be considered effective and included in the regimen E may be used but is not included among the drugs making if DST shows susceptibility up the standard regimen. Tx with Group 5 drugs is recommended only if additional drugs are needed to bring the total to 4 Group 5 drugs may be used but are not included among the drugs making up the standard regimen Intensive phase min 6 months (min 4 months after C conversion) for a total duration of min 18 months after C conversion Intensive phase min 8 months for a total duration>=20 months 50 Treatment monitoring • Treatment failure was detected best with monthly culture in MDR-TB cases. • Thus the available evidence does not support replacing monthly culture (or quarterly culture) with monthly smear 51 Consilium for MDR-TB case and programme management 52 4,853 C+, 361 MDR, 64 XDR MDR-TB, suscep to at least one FLD MDR-TB, resistant to all FLD XDR-TB TDR-TB (MDR+FQ+ Gr IV) Eur Respir J 2007 Author Avendano Burgos Chan Chiang Cox DeRiemer Escudero Geerligs Granich/Banerjee Holts Kim(Shim) Kim(Yim) Kwon Leimane/Riekstina Lockman Masjedi Migliori Mitnick Munsiff/Li Narita ORiordan Palmero Park Perez-Guzman Quy Schaaf Shin Shiraishi Tupasi Uffredi Van Deun Yew N° Success 64 30 134 72 54 5 14 40 74 1073 432 118 85 679 128 16 17 417 127 39 19 70 60 15 79 20 353 54 97 23 440 84 N° Treated Treatment Success vs Fail and Relapse and Death and Default 72 45 194 125 77 47 18 43 100 2174 1288 182 129 945 218 27 83 654 671 66 28 112 131 33 157 36 535 61 159 41 603 99 Pooled Success = 0.54 (0.48 to 0.60) Inconsistency (I-square) = 97.4% Treatment outcomes by MDR-TB patient group XDR TB (n=405) MDR-TB +FQr MDR-TB +INJr (n = 426) (n=1130) MDR-TB, susceptto FQ & Inj Total (n=4763) Pooled Outcomes (From study level meta-analysis) Success 40% (27, 53) 48% (36, 60) 56% (45, 66) 64% (57, 72) Failed/Relapse 22% (15, 28) 18% (14, 21) 12% (9, 15) Died 15% (8, 23) 11% (3, 19) 8% (3, 14) 8% (5, 11) 9% (5, 12) Defaulted 16% (8, 24) 12% (1,23) 16% (7, 24) 18% (12,24) 17% (11, 22) 4% (2, 6) 62% (54,69) 7% (4, 9) 53 Association between clinical characteristics and treatment success vs. failure/relapse/death in the different MDR-TB sub-groups Odds of success vs failure/relapse/death Characteristics Male sex (vs female)* Older age (per 10 years older)* HIV positive (vs HIV neg.)* Extensive disease (vs not)* Prior TB treatment* None FLD only FLD and SLD MDR sub-groups: † Not resistant to a FQN nor a 2nd line injectable Resistant to a second-line injectable, but not a FQN Resistant to a fluoroquinolone, but not a 2nd line injectable Resistant to both a fluoroquinolone and at least one 2nd line injectable (XDR) Pulmonary resection surgery performed (vs not) † Experienced a serious adverse event (vs not) † INTENS PHASE XDR N° drugs N 0-2 24 3 47 4 46 5 36 6+ 20 CONT PHASE aOR 1.0 0.8 0.3 0.5 (95%CI) (0.9, 1.1) (0.8, 0.9) (0.2, 0.4) (0.4, 0.6) 1275 4410 618 1.0 0.6 0.2 (Reference) (0.5, 0.8) 0.15, 0.3) 4763 1130 1.0 0.6 (Reference) (0.5, 0.7) 426 0.3 (0.2, 0.40 405 373 1511 0.2 1.5 1.0 0.2, 0.3) (0.9, 2.6) (0.8, 1.2) MDR–TB+FQr aOR (95%CI) N MDR–TB+INJr aOR (95%CI) N 10 1.0 (reference) 29 1.0 (reference) 32 1.9 (0.8, 4.3) 1.8 (0.5, 6.6) 4.9 (1.4, 16.6) XDR 49 35 27 N aOR (95%CI) N 0-2 27 1.0 (ref) 35 3 32 3.3 (1.3, 8.5) 27 4 28 6.1 (1.4, 26.3) 17 2.3 (0.7, 7.6) prev TX > 30 days 27 1.6 (0.7, 3.8) 1.4 (0.3, 6.4) 1.1 (0.4, 2.9) 83 137 1.0 (reference) 1.7 (0.5, 5.2) 1.3 (0.5, 3.1) 1.2 (0.4, 3.4) 1.3 (0.5, 3.3) MDR-TB, susceptible to FQ & Inj N 45 62 165 296 380 aOR (95%CI) 1.0 (reference) 1.1 (0.5, 2.3) 1.9 (1.0, 3.7) 1.7 (0.8, 3.8) 1.0 (0.5, 1.8) MDR, susceptible to FQ & Inj MDR–TB+INJr N aOR (95%CI) N aOR (95%CI) 46 1.0 (ref) 77 1.0 (ref) 2.5 (0.8, 7.4) 33 12.2 (3.4, 44) 133 5.9 (3.1, 11.0) 27 3.1 (0.5, 21.1) 101 3.7 (1.7, 8.2) 239 6.0 (2.8, 13.1) 20 2.3 (0.7, 7.2) 100 3.1 (1.7, 6.0) 233 4.7 (2.7, 8.1) Drug received during previous TX periods Age/ sex Country of birth 43/F IT 3 SRHEZ; FQ,Eth,AK,PAS,C,K,C yc,Rb,Clof,Dap,Cl,Th 49/F IT 3 SRHEZ; FQ,Eth,AK,PAS,C,K,C yc,Rb,Clof, Dap,Cl,Th aOR (95%CI) aOR (95%CI) 120 MDR–TB+FQr N° drugs 5+ N 4653 6724 615 4792 1.0 (ref) TX dur (mo Hospit Admis (days) SS conv (days) C conv (days) SRHEZ; FQ,Eth,AK,PAS,C,K, Cyc,Rb,Clof 422 No No Died 94 SRHEZ; FQ,Eth,AK,PAS,C,K,C yc,Rb,Clof,Dap,Cl,Th 625 No No Died 60 Drug resistance at XDR diagnosis Out come First tuberculosis cases in Italy resistant to all tested drugs GB Migliori ([email protected]), G De Iaco, G Besozzi, R Centis, DM Cirillo WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Care and Research Institute, Tradate Eurosurveillance 2007 54 XDR alone XDR+2sli XDR+sliG4† n = 301 n = 68 n = 48 n =42 Cured 43 (27, 58) 30 (17, 43) 34 (-, -) 19 (0, 48)* XDR+sliG4EZ Treatment outcome Failed 20 (15, 25) 29 (8, 50) 33 (-, -) 26 (14, 38) Died 13 (6, 20) 18 (7, 29) 30 (18, 41)* 35 (21, 50)* Failed or died 35 (26, 45) 54 (40, 69)* 48 (-, -) 49 (37, 61) Defaulted 15 (5, 24) 15 (3, 27) 18 (-, -) 19 (6, 32) XDR+sliG4EZ XDR-alone XDR+2sli XDR+sliG4 n = 301 n = 68 n = 48 n =42 Cured 1.0 (reference) 0.4 (0.2, 0.8) 0.6 (0.2, 1.6) 0.5 (0.2, 1.7) Failed 1.0 (reference) 2.1 (1.0, 4.5) 1.8 (0.7, 4.7) 1.9 (0.7, 5.3) Died 1.0 (reference) 1.6 (0.6, 4.4) 1.7 (0.6, 4.9) 1.8 (0.6, 5.3) Failed or Died 1.0 (reference) 2.6 (1.2, 4.4) 2.6 (1.1, 6.7) 2.8 (1.0, 7.9) Defaulted 1.0 (reference) 1.0 (0.3, 2.6) 0.5 (0.2, 1.8) 0.5 (0.1, 2.0) Treatment outcome 55 Building a regimen for XDR-TB 56 AE in Linezolid- containing regimens. Sotgiu et al, ERJ 2012 Aims To describe and discuss: • Existing guidelines and definitions • The epidemiology of TB and MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation) • The new information on MDR-TB diagnosis • The new information on MDR-TB treatment • The principles of MDR-TB control, with prevention and public health aspects 57 TB patients with inappropriate regimen have a 27fold higher risk of developing MDR-TB Multidrug resistance after inappropriate tuberculosis treatment: A meta-analysis Marieke J. van der Werf, Miranda W. Langenda, Emma Huitric, Davide Manissero ERJ 2012 in press Global Policy: MDR-TB and XDR-TB 1. 2. 3. 4. 5. 6. 7. 8. Strengthen basic TB control, to prevent M/XDR-TB Scale-up programmatic management and care of MDR-TB and XDR-TB Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB Ensure availability of quality drugs and their rational use Expand MDR-TB and XDR-TB surveillance Introduce infection control, especially in high HIV prevalence settings Mobilize urgently resources domestically and internationally Promote research and development into new diagnostics, drugs and vaccines Global Policy: MDR-TB and XDR-TB 1. 2. Strengthen basic TB control, to prevent M/XDR-TB Scale-up programmatic management and care of MDR-TB and XDR-TB 3. Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB 4. Ensure availability of quality drugs and their rational use Expand MDR-TB and XDR-TB surveillance Introduce infection control, especially in high HIV prevalence settings Mobilize urgently resources domestically and internationally Promote research and development into new diagnostics, drugs and vaccines 5. 6. 7. 8. 58 Global Policy: MDR-TB and XDR-TB 1. 2. 3. 4. 5. 6. 7. 8. Strengthen basic TB control, to prevent M/XDR-TB Scale-up programmatic management and care of MDR-TB and XDR-TB Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB Ensure availability of quality drugs and their rational use Expand MDR-TB and XDR-TB surveillance Introduce infection control, especially in high HIV prevalence settings Mobilize urgently resources domestically and internationally Promote research and development into new diagnostics, drugs and vaccines Global Policy: MDR-TB and XDR-TB 1. 2. 3. 4. 5. 6. 7. 8. Strengthen basic TB control, to prevent M/XDR-TB Scale-up programmatic management and care of MDR-TB and XDR-TB Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB Ensure availability of quality drugs and their rational use Expand MDR-TB and XDR-TB surveillance Introduce infection control, especially in high HIV prevalence settings Mobilize urgently resources domestically and internationally Promote research and development into new diagnostics, drugs and vaccines Global Policy: MDR-TB and XDR-TB 1. 2. 3. 4. 5. 6. 7. Strengthen basic TB control, to prevent M/XDR-TB Scale-up programmatic management and care of MDR-TB and XDR-TB Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB Ensure availability of quality drugs and their rational use Expand MDR-TB and XDR-TB surveillance Introduce infection control, especially in high HIV prevalence settings Mobilize urgently resources domestically and internationally 8. Promote research and development into new diagnostics, drugs and vaccines 59 1966, the last anti-TB drug was discovered Bedaquiline Delamanid Carlo Forlanini, first notes on Pneumothorax January 7th, 1907 60 Interventions over time: old weapons might be useful again to manage XDR First sanatorium Germany, 1857 First Dispensary, Scotland, 1897 BCG vaccination Pneumotorax, Italy, 1907 Drugs, 1945-1962 Koch, Mtb, 1882 MMR,1950-1980 Fox:Ambulatory treatment, 1968 Styblo model, 1978 DOTS, 1991 Outbreak Management, sanatoria Risk Group Management screening drug therapy Socio-economic improvement 61 Pneumothorax “Nobody wants me around..” Lancet. 2012 Feb 25;379(9817):773-5 The global rise of extensively drug-resistant tuberculosis: is the time to bring back sanatoria now overdue? Dheda K, Migliori GB. 62 XDR and TB control: which future ? 63 64
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