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: 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
                            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

                                                  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 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.

                                                    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 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.

                                                  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 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.

                                               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 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?

                                                 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              > 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

                                                                   43
XDR= 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

                                                                                   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
                                                  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

                                                                                           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
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
             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

                                                                                 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     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

                                                                                                                                    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

                               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)

                                                                                                            53
Association 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

                                                                                                                                               54
XDR 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)

                                                                                             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 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

                                                                           58
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

      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

                                                                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,                         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

                                                                                                                    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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