Postgraduate Course 7 TB and MDR-/XDR-TB: what is new in diagnosis, treatment and follow-up
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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: C6Evidence 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
giovannibattista.migliori@fsm.it
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
33recently 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.
34Treatment 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 sub-
analysis 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.
35In 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 end-
of-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.
363. 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.
379. 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 WHO-
recommended 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 MDR-
TB. 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 meta-
analysis 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 co-
produced 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.
3821. 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 linezolid-
treated 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?
39Evidence 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
40Guidelines 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
41Guidelines 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
42DOTS MDR-TB
FUNDING: Government > money
Commitment (10$/ case)
Up to 20,000 $/ case
DIAGNOSIS: SS microscopy, +C, DST, SRL, QA,
QA and safety measures infection control
TREATMENT: SCC,DOT, 6-8 24 months, mandatory DOT
months, no hospitalization & hospitalization in
reference facilities
TB drugs only, no AE relevant toxicity, need
special drugs + expertise
TREATMENT MONITORING: C, DST, special outcome
SS, standard outcome definitons
definitions
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)
TDR/XXDR TB
TB with any
drug MDR TB XDR TB
resistance
43XDR= HR + 1 FQ + 1 Injectable (KM or AMK or CM)
1st-line
oral
•INH Injectables
•RIF •SM Fluoroquinolones
•Cipro Oral bacteriostatic 2nd line
•PZA •KM
•ETA/PTA Unclear efficacy
•EMB •AMK •Oflox Not routinely recommended,
•(Rfb) •CM •Levo •PASA efficacy unknown, e.g.,
amoxacillin/clavulanic acid,
•Moxi •CYS clarithromycin, clofazamine,
linezolid, inmipenem/cilastatin,
•(Gati) 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*
10,000
*among reported pulmonary TB patients
44Distribution 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
45Notifications 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
MDR-TB cases treated and
Notified cases of MDR-TB
estimated numbers not treated
Global Plan target ~270,000 in 2015 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 Global plan target
for 2015 = 20% 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
46Countries 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 DSTThe “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
48The challenge of MDR
Expensive and
toxic drugs are
necessary
Grouping drugs
Group 1
1st-line
Group 2
oral
•INH Injectables Group 3
•RIF •SM Fluoroquinolones Group 4
•Cipro Oral bacteriostatic 2nd line Group 5
•PZA •KM
•ETA/PTA Unclear efficacy
•EMB •AMK •Oflox Not routinely recommended,
•(Rfb) •CM •Levo •PASA efficacy unknown, e.g.,
amoxacillin/clavulanic acid,
•Moxi •CYS clarithromycin, clofazamine,
linezolid, inmipenem/cilastatin,
•(Gati) high dose isonizid
49How 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 Include at least 4 2nd -line anti-TB drugs likely to be effective
almost certain, effectiveness during the intensive phase of as well as Z during the intensive phase of Tx
Tx
Consider adding more drugs in patients with extensive No evidence found to support the use of > 4 2nd-line anti-TB
disease or uncertain effectiveness 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.
The regimen should include Z and/or E one FQ, one The regimen should include Z a FQ, a parenteral agent,
parenteral agent and 2nd -line oral bacteriostatic anti-TB ethionamide (or prothionamide), and cycloserine, or else
drugs (no preference of oral bacteriostatic 2nd -line anti-TB PAS if cycloserine cannot be used.
drug was made).
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 Group 5 drugs may be used but are not included among the
drugs are needed to bring the total to 4 drugs making up the standard regimen
Intensive phase min 6 months (min 4 months after C Intensive phase min 8 months for a total duration>=20
conversion) for a total duration of min 18 months after C months
conversion
50Treatment 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
51Consilium for MDR-TB case and
programme management
524,853 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
N°
N° Treatment Success vs Fail and
Author Success
Treated
Relapse and Death and Default
Avendano 64 72
Burgos 30 45
Chan 134 194
Chiang 72 125
Cox 54 77
DeRiemer 5 47
Escudero 14 18
Geerligs 40 43
Granich/Banerjee 74 100
Holts 1073 2174
Kim(Shim) 432 1288
Kim(Yim) 118 182
Kwon 85 129
Leimane/Riekstina 679 945
Lockman 128 218
Masjedi 16 27
Migliori 17 83
Mitnick 417 654
Munsiff/Li 127 671
Narita 39 66
ORiordan 19 28
Palmero 70 112 Pooled Success = 0.54 (0.48
Park 60 131
Perez-Guzman 15 33 to 0.60)
Quy
Schaaf
79
20
157
36
Inconsistency (I-square) =
Shin 353 535 97.4%
Shiraishi 54 61
Tupasi 97 159
Uffredi 23 41
Van Deun 440 603
Yew 84 99
Treatment outcomes by MDR-TB patient group
XDR TB MDR-TB MDR-TB MDR-TB, Total
(n=405) +FQr +INJr suscept-
(n = 426) (n=1130) to FQ &
Inj
(n=4763)
Pooled Outcomes
(From study level
meta-analysis)
Success 40% (27, 53) 48% (36, 60) 56% (45, 66) 64% (57, 72) 62% (54,69)
Failed/Relapse 22% (15, 28) 18% (14, 21) 12% (9, 15) 4% (2, 6) 7% (4, 9)
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)
53Association between clinical characteristics and treatment
success vs. failure/relapse/death in the different MDR-TB
sub-groups
Odds of success vs
Characteristics failure/relapse/death
N aOR (95%CI)
Male sex (vs female)* 4653 1.0 (0.9, 1.1)
Older age (per 10 years older)* 6724 0.8 (0.8, 0.9)
HIV positive (vs HIV neg.)* 615 0.3 (0.2, 0.4)
Extensive disease (vs not)* 4792 0.5 (0.4, 0.6)
Prior TB treatment*
None 1275 1.0 (Reference)
FLD only 4410 0.6 (0.5, 0.8)
FLD and SLD 618 0.2 0.15, 0.3)
MDR sub-groups: †
Not resistant to a FQN nor a 2nd line injectable 4763 1.0 (Reference)
Resistant to a second-line injectable, but not a FQN 1130 0.6 (0.5, 0.7)
Resistant to a fluoroquinolone, but not a 2nd line
injectable 426 0.3 (0.2, 0.40
Resistant to both a fluoroquinolone and at least one
2nd line injectable (XDR) 405 0.2 0.2, 0.3)
Pulmonary resection surgery performed (vs not) † 373 1.5 (0.9, 2.6)
Experienced a serious adverse event (vs not) † 1511 1.0 (0.8, 1.2)
INTENS MDR-TB, susceptible
XDR MDR–TB+FQr MDR–TB+INJr
PHASE to FQ & Inj
N° drugs N aOR (95%CI) N aOR (95%CI) N aOR (95%CI) N aOR (95%CI)
0-2 24 1.0 1.0
10 29 45
(reference) (reference)
1.0 (reference) 1.0 (reference)
3 47 1.7 1.1
32 27 62
(0.5, 5.2) (0.5, 2.3)
1.9 1.6 1.3 1.9
4 46 49 83 165
(0.8, 4.3) (0.7, 3.8) (0.5, 3.1) (1.0, 3.7)
1.8 1.4 1.2 1.7
5 36 35 137 296
(0.5, 6.6) (0.3, 6.4) (0.4, 3.4) (0.8, 3.8)
4.9 1.1 1.3 1.0
6+ 20 27 120 380
(1.4, 16.6) (0.4, 2.9) (0.5, 3.3) (0.5, 1.8)
CONT MDR, susceptible to
PHASE XDR MDR–TB+FQr MDR–TB+INJr
FQ & Inj
N° drugs N aOR (95%CI) N aOR (95%CI) N aOR (95%CI) N aOR (95%CI)
1.0 (ref)
0-2 27 1.0 (ref) 35 46 1.0 (ref) 77 1.0 (ref)
3.3 2.5 12.2 5.9
3 32 27 33 133
(1.3, 8.5) (0.8, 7.4) (3.4, 44) (3.1, 11.0)
6.1 3.1 3.7 6.0
4 28 27 101 239
(1.4, 26.3) (0.5, 21.1) (1.7, 8.2) (2.8, 13.1)
2.3 2.3 3.1 4.7
5+ 17 20 100 233
(0.7, 7.6) (0.7, 7.2) (1.7, 6.0) (2.7, 8.1)
prev
Drug received Hospit SS TX
Age/ Country TX > Drug resistance at C conv Out
during previous Admis conv dur
sex of birth 30 XDR diagnosis (days) come
TX periods (days) (days) (mo
days
43/F IT SRHEZ; SRHEZ; 422 No No Died
3 FQ,Eth,AK,PAS,C,K,C FQ,Eth,AK,PAS,C,K,
94
yc,Rb,Clof,Dap,Cl,Th Cyc,Rb,Clof
49/F IT SRHEZ; SRHEZ; 625 No No Died
3 FQ,Eth,AK,PAS,C,K,C FQ,Eth,AK,PAS,C,K,C
60
yc,Rb,Clof, Dap,Cl,Th yc,Rb,Clof,Dap,Cl,Th
First tuberculosis cases in Italy resistant to all tested drugs
GB Migliori (gbmigliori@fsm.it), 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
54XDR alone XDR+2sli XDR+sliG4† XDR+sliG4EZ
Treatment outcome
n = 301 n = 68 n = 48 n =42
Cured 43 (27, 58) 30 (17, 43) 34 (-, -) 19 (0, 48)*
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-alone XDR+2sli XDR+sliG4 XDR+sliG4EZ
Treatment outcome
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)
55Building a regimen for XDR-TB
56AE 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
57TB patients with inappropriate regimen have a 27-
fold 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. Strengthen basic TB control, to prevent
M/XDR-TB
2. 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
5. Expand MDR-TB and XDR-TB surveillance
6. Introduce infection control, especially in high HIV
prevalence settings
7. Mobilize urgently resources domestically and
internationally
8. Promote research and development into new
diagnostics, drugs and vaccines
Global Policy: MDR-TB and XDR-TB
1. Strengthen basic TB control, to prevent M/XDR-TB
2. 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
5. Expand MDR-TB and XDR-TB surveillance
6. Introduce infection control, especially in high HIV
prevalence settings
7. Mobilize urgently resources domestically and
internationally
8. Promote research and development into new
diagnostics, drugs and vaccines
58Global Policy: MDR-TB and XDR-TB
1. Strengthen basic TB control, to prevent M/XDR-TB
2. 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
5. Expand MDR-TB and XDR-TB surveillance
6. Introduce infection control, especially in high HIV
prevalence settings
7. Mobilize urgently resources domestically and
internationally
8. Promote research and development into new
diagnostics, drugs and vaccines
Global Policy: MDR-TB and XDR-TB
1. Strengthen basic TB control, to prevent M/XDR-TB
2. 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
5. Expand MDR-TB and XDR-TB surveillance
6. Introduce infection control, especially in
high HIV prevalence settings
7. Mobilize urgently resources domestically
and internationally
8. Promote research and development into new
diagnostics, drugs and vaccines
Global Policy: MDR-TB and XDR-TB
1. Strengthen basic TB control, to prevent M/XDR-TB
2. 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
5. Expand MDR-TB and XDR-TB surveillance
6. Introduce infection control, especially in high HIV
prevalence settings
7. Mobilize urgently resources domestically and
internationally
8. Promote research and development
into new diagnostics, drugs and
vaccines
591966, the last anti-TB drug was discovered
Bedaquiline
Delamanid
Carlo Forlanini,
first notes on Pneumothorax
January 7th, 1907
60Interventions 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, MMR,1950-1980
1882 Fox:Ambulatory treatment, 1968
Styblo model, 1978
DOTS, 1991
sanatoria Outbreak Management,
Risk Group Management
screening
drug therapy
Socio-economic improvement
61Pneumothorax
“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.
62XDR and TB control: which future ?
6364
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