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Page 1: TB and MDR-TB

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TB and MDR-TB: what is newin 2012?

Educational aims[ To understand the need for new diagnostics for tuberculosis (TB) and describe the

role of GeneXpert[ To describe to what extent drug resistance affects clinical management of multi/

extensively drug resistant-TB, and the importance of having new drugs to managethese difficult-to-treat cases

[ To describe the current evidence on TB/HIV collaborative activities

[ To discuss the importance of providing a public-health response to reach TB elimina-tion through a new post-2015 strategy and to protect new drugs through rational useof treatment regimens

SummaryIn 2007, the 125th anniversary of the discovery of Mycobacterium tuberculosis byRobert Koch followed a particularly significant year in the history of tuberculosis(TB) as, in the same year, the World Health Organization and other internationalorganisations published a series of pillar documents and guidelines that set thepathway to improve the control of TB at the global level. Among these, we canmention the Stop TB Strategy, the guidelines on drug-resistant TB management,the Global Plan to Stop TB 2006–2015 and the International Standard of TBCare. Despite the positive results obtained with the implementation of the newrecommendations, some crucial gaps remained urgent, such as the need forinnovative diagnostic tools for the prompt diagnosis of TB, the rapid identification ofdrug-resistant strains and the development of new drugs to combat the increasingnumber of drug-resistant forms of TB.This year, 130 years after Robert Koch’s discovery, we can recognise that some ofthese requests have been met. This article will describe the progresses made indifferent fields including: laboratory diagnosis and the experience with Xpert1MTB/RIF assay; multi/extensively drug resistant-TB management and develop-ment of new promising drugs; implementation of TB/HIV collaborative activities.

HERMES syllabus link:Module A.1.5, A.1.7,A.1.8, A.1.9;Module B.4;Module I1,I2,I3,I7,I8,I9

Statement of InterestNone declared.

Breathe | December 2012 | Volume 9 | No 2 101DOI: 10.1183/20734735.025312

Marina Tadolini1,Rosella Centis2,Lia D’Ambrosio2,Giovanni BattistaMigliori2

1World Health Organization

Consultant, Global Fund

Technical Review Panel member,2World Health Organization

Collaborating Centre for

Tuberculosis and Lung Disease,

Fondazione S. Maugeri, Care and

Research Institute, Tradate, Italy

G.B. Migliori: World HealthOrganization CollaboratingCentre for Tuberculosis andLung Diseases, FondazioneS. Maugeri, Care and ResearchInstitute, Via Roncaccio 16,21049, Tradate, Italy

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In addition, it will briefly describe the message of the European Union Standardsfor TB Care, recently developed by the European Respiratory Society and theEuropean Centre for Disease Prevention and Control.A strong public-health response is now needed to translate the latestrecommendations into practice, make good use of the new diagnostic toolsand drugs, improve the quality of TB and TB/HIV service worldwide andminimize the development of new cases of MDR-TB, through the correct clinicalmanagement of newly diagnosed, drug susceptible TB cases.


On March 24th, 1882, Robert Koch discoveredthe tuberculosis (TB) bacillus (figs 1 and 2). In2007, the 125th anniversary of the discovery ofMycobacterium tuberculosis was celebrated indifferent ways in different countries as anevent that was perceived as one of the majorachievements for the international medicalcommunity. The European Respiratory Society(ERS) celebrated the anniversary with aneditorial, which is still the most cited in theEuropean Respiratory Journal [1].

The reasons why this editorial has been sowidely read is that, on top of the historicalcelebration, it highlighted several core mes-sages, which are still of relevance.

The first message is clinical

By emphasising the continuing importance ofKoch’s direct smear microscopy (a techniquewhich is over 130 years old), the critical needfor new diagnostics becomes more obvious.Of course, we do not have direct smear only,as culture (on solid and liquid media) anddrug susceptibility testing have also beendeveloped in the meantime [2]. But, unfortu-nately, in 2007, TB diagnosis was based onlyon dated techniques.

The recent availability of a new diagnostictool, able to allow diagnosis of TB and resistanceto rifampicin in one hour and 45 minutes, theXpert1 MTB/RIF assay (GeneXpert; Cepheid,Sunnyvale, CA, USA), is opening a new era in TBdiagnostics [2–6]. We will describe the Xpert1MTB/RIF assay later.

Furthermore, the editorial presented therecently described extensively drug-resistant(XDR) TB to the general public [1], underliningthe limited evidence available and the urgentneed for further surveillance, research andcontrol [7]. We will describe below the coreinformation on this severe form of disease, aswell as the key publications which informedthe recently published guidelines on multi-drug resistant (MDR)-TB management [8].

The second message is one of publichealth

In 2006, almost 125 years after the RobertKoch’s discovery, the new Stop TB Strategy waslaunched by the World Health Organization(WHO). This followed intensive exploration anddiscussion with TB control programme man-agers in high-burden countries, and partnerorganizations, including technical agencies anddonors [9, 10]. The Stop TB Strategy built onthe directly observed treatment, short-course(DOTS) strategy, launched by WHO in 1995.The DOTS strategy (consisting of five core

Figure 1Robert Koch.


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elements: government commitment; diagnosisthrough microscopy; standardised and super-vised treatment; uninterrupted drug supply;and regular programme monitoring) made amajor contribution to improving global TBcontrol [11], with more than 22 million patientstreated under DOTS-based services [12, 13].11 years after its launch, the DOTS strategywas revisited to tackle the new challenges andmake explicit five additional components tobe implemented in order to reach the 2015Millennium Development Goals (MDGs) rele-vant to TB control. Therefore, the Stop TBStrategy consisted of the following elements:1) pursuing high-quality DOTS expansion andenhancement; 2) addressing TB/HIV, MDR-TBand other challenges; 3) contributing to healthsystem strengthening; 4) engaging all careproviders; 5) empowering people with TB andcommunities; and 6) enabling and promotingresearch [13].

It is useful, for educational purposes, todescribe briefly the global targets for TB control.(fig. 3).

The MDG relevant to TB is MDG 6: it isaimed at combating HIV, malaria and otherdiseases. Goal 6, Target 8 is to have haltedand begun to reverse incidence of the diseaseby 2015. The interpretation of Target 8 is thatthe incidence of all forms of TB should befalling by 2015, and two indicators have beendefined for this target: TB prevalence anddeaths (Indicator 23), and the proportion ofcases detected and successfully treated underthe DOTS strategy (Indicator 24) [13].

The Stop TB Partnership targeted: a)reducing the prevalence and death rate by50% compared with their level in 1990 by 2015;and b) eliminating TB by 2050 (fig. 3) [11].

In 2006, the new Global Plan to Stop TB,2006–2015 was launched, describing strate-gies, financial requirements and existing gapsto reach the MDGs in all regions of the world.

Those who are not TB experts will askwhether these targets and indicators havebeen reached already or whether they will bereached by 2015.

According to the latest Global TB Report(2011) published by WHO, the world and mostregions, except Africa, are on track to achievethe MDG target of decreasing tuberculosisincidence by 2015 [9, 10]. As far as the TBmortality is concerned, deaths from tubercu-losis have fallen by 40% globally since 1990,and achievement of the 50% reduction targetby 2015 is likely. Despite the fact that TB

prevalence rates are also falling, the target ofhalving 1990 rates by 2015 is unlikely to beachieved, except in the Americas and theWestern Pacific region [9]. In contrast, elim-ination of TB by 2050 is not achievable with thecurrent trend, although substantial progressesmight be made in the next few decades.

Strategy, objectives, targets and indicatorshad all been targeted toward 2015. That iswhy WHO and partners have already starteddiscussing the steps to be undertaken after2015. This article will go on to describe thelines of the ongoing discussion, as developedby Strategic and Technical Advisory Group forTuberculosis (STAG-TB), the core advisorybody convened once a year by WHO.

Figure 2Direct sputum smear examination.

Figure 3Global TB control targets.


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The third message is educational

In 2006, the International Standards of TBCare (ISTC) were published and widely dis-tributed, to guide both public and privatehealthcare providers to offer quality DOTSservices [14]. In the same year, the WHOguidelines on drug-resistant TB managementwere also published, stressing the importanceof proper use of second-line drugs required totreat drug-resistant and MDR-TB cases [15].

Although the year 2006 witnessed so manyimportant TB events, several TB studies,documents and guidelines were published inthe last two years. In particular, this article willsummarise the core content of three docu-ments, the ERS–European Centre for DiseasePrevention and Control (ECDC) jointly devel-oped European Standards for TB Care (repre-senting the European Union adaptation of theISTC) [16, 17], the 2011 WHO MDR-TB guide-lines (representing an update of previousedition of WHO guidelines) [18] and theupdated policy on TB/HIV collaborative activ-ities, published by WHO in 2012 [14, 19, 20].

Clinical diagnosis of TB andthe role of GeneXpert

The diagnosis of TB is based on microbiolo-gical confirmation of the clinical picture. Inother words, all TB suspects should be testedfor TB by quality-assured bacteriology, asstated by the Stop TB strategy. Worldwide,the most accessible test for pulmonary TBdiagnosis is sputum smear microscopy, fol-lowed by culture, now available both on solidand in liquid media. This constitutes the goldstandard for TB diagnosis. Beside smearmicroscopy and culture, drug susceptibilitytesting (DST) has become more and moreimportant to detect the bacilli resistancepattern to first- and second-line drugs [10].

Conventional methods for M. tuberculosisculture and DST are slow and cumbersome,requiring sequential procedures for the diag-nosis. During this time, patients may beinappropriately treated, drug resistant strainsmay continue to spread, and amplification ofresistance may occur. Therefore, the develop-ment, piloting and rolling-out of novel technol-ogies providing rapid TB identification anddetection of drug resistant strains are thecurrent focus of TB research [6]. In particular,research on the Xpert1 MTB/RIF assay has

proliferated subsequent to WHO endorsementat the end of December 2010 [2–6]. By July2012, .65 peer-reviewed publications hadcome out, testifying the global interest for thenew test.

The Xpert system looks like a coffeemachine, but it is able to tell us in 1 hour and45 minutes whether M. tuberculosis is present,as well as whether resistance to rifampicincan be detected (fig. 4). The self-contained,cartridge-based test does not require muchtraining, or advanced laboratory facilities orbiosafety measures. The GeneXpert platform,launched in 2004, was designed to simplifymolecular testing by integrating and automat-ing the three key processes (sample prepara-tion, amplification and detection) required forreal-time PCR-based molecular testing [2–6].Core components of the system include theinstrument, a personal computer, a barcodescanner and the software (fig. 4). Single-usedisposable cartridges containing lyophilisedreagents, buffers and washes are used forspecific diseases. Target detection and char-acterisation is performed in real time using asix-colour laser detection device.

The Xpert1 MTB/RIF assay employs fiveunique nucleic acid hybridisation probes (mole-cular beacon), each labelled with a differentlycoloured fluorophore responding to a specifictarget sequence within the rpoB gene ofMycobacterium tuberculosis. 95% of mutationsassociated with rifampicin resistance occur inan 81-base pair core region of the rpoB (abacterial RNA polymerase) gene and, together,these five molecular beacons encompass the

Figure 4GeneXpert. ! Cepheid


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entire core region. The generation of all fivefluorescent colours during PCR amplificationindicates the presence of rifampicin-susceptibleM. tuberculosis, while any mutation in the coreregion prevents the binding of the respectivemolecular beacon, resulting in the absence ofcolour and indicating rifampicin resistance.

The main advantage of the GeneXpertsystem is to provide a rapid, simultaneousdiagnosis of both TB and rifampicin resistance.BOHEME and colleagues [3, 4] and others [2, 5, 6]have shown that GeneXpert is highly specific,diagnosing 98.2% of sputum smear positivepatients and 72.5% of smear negative, culture-positive patients (which increased to 90.2% ifthree tests were used), and correctly identifying97.6% of the rifampicin-resistant bacilli.

GeneXpert has the potential to become‘‘the’’ diagnostic test for TB, it is used atpresent for pulmonary (sputum smear posi-tive and negative) TB disease. Initial resultsindicate that the main problem to clarify is howto interpret positive results in different epide-miological settings, as the positive predictivevalue (PPV) of the assay in low-TB incidencesettings is relatively low in detecting rifampicinresistance. In addition, studies are accumulat-ing to evaluate its performance in extrapul-monary and paediatric TB.

One of the distinct advantages of Xpert1MTB/RIF is its suitability for use at district andsub-district level and the technology shouldtherefore not be restricted to central/referencelaboratory level only.

On top of further studies providing evi-dence of the feasibility, efficacy and cost-effectiveness, the new priority is to determinehow to locate GeneXpert within existing na-tional diagnostic algorithm.

The European Standards of TB Care (ESTC)[16] clearly considers the use of rapid diagnos-tic methods and GeneXpert as a must in EUcountries, as this significantly reduces the timeto diagnosis and the time to treatment. Inother words, it contributes to reduce signifi-cantly the infectiousness period of the casesand, therefore, the potentiality for transmissionof TB bacilli within the community.

In addition, the early detection of rifampi-cin resistance, which is a reliable proxy ofmultidrug resistance (pending the limitationsdescribed above), allows the referral of the‘‘potential’’ MDR-TB patient to a specialisedcentre, so that proper management can berapidly implemented [22–24].

Clinical management ofM/XDR-TB, with theavailability of new drugs

The prevalence of drug-resistant TB is alar-mingly high, particularly in the countriesbelonging to the former Soviet Union, assummarised in figures 5 and 6. The new ‘‘globalrecord’’ of MDR-TB prevalence was recentlynotified in Belarus [25] with 35.3% MDR-TBamong new cases and 76.5% MDR-TB amongpreviously treated cases. It clearly demonstratedhow far case mismanagement can affect thechances to control (and eventually eliminate)the disease [23].

As a consequence, additional levels of drugresistance beyond XDR-TB (XDR-TB is definedas resistance to at least rifampicin andisoniazid (the definition of MDR-TB), in addi-tion to resistance to any fluoroquinolone, andto at least one of the three following injectabledrugs used in anti-TB treatment: capreomycin,kanamycin and amikacin) have been describedin Italy, Iran and India [26–28] and, provision-ally, named ‘‘total drug resistance’’ (e.g. casesharbouring Mycobacterium tuberculosis strainswith resistance to all known drugs).

Although WHO has not endorsed thisdefinition, due to the difficulties to agreeingon the panel of drugs which should define it[29], these super-resistant strains are circulat-ing, projecting affected patients back to thepre-antibiotic era when effective drug againstthe bacilli were not available.

In order to effectively tackle the MDR-TBchallenge, ESTC [16] still emphasises theimportance of ensuring rapid diagnosis andappropriate treatment of MDR-TB cases.

Figure 5Proportion of MDR among new TB cases. Latest available data, 1994–2010.Reproduced from [21] with permission from the publisher.


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What are the standards?

They have been defined as ‘‘a living documentthat will be revised as technology, resourcesand circumstances change’’, being designedto complement existing national or interna-tional guidelines.

There are specific characteristics of thecountries of the EU justifying the need for aEuropean-specific adaptation of the ISTCdescribed above into ESTC.

Europe is a heterogeneous setting, withlow-, intermediate- and high-level TB countriesrepresented, and varying levels of MDR-TB andTB/HIV co-infection. TB services are usuallyintegrated and merged within the healthsystem, although vertical programmes are stillin place in some countries. European countriesare committed to pursuing elimination, sharinga common platform (based on the Wolfhezedocuments and the EU Framework action plan)and the ECDC-driven surveillance system.

The core messages included in the ESTCare summarized in table 1.

In 2011, WHO published a revision of theprevious guidelines on MDR-TB management,taking advantage of a recent study on a largeMDR-TB cohort of about 10,000 cases [18, 30],summarised in table 2.

At the same time, the search for newdrugs has become more and more urgent.

One direction followed by researchers wasto evaluate the possible role of drugs in TBtreatment although little was known on theirefficacy, safety and tolerability. Among thesedrugs, linezolid (effective but unfortunatelytoxic [31]) and meropenem’s activity seems tobe promising [32].

The main directions followed developmentof the three most promising compounds in thedevelopment pipeline (delamanid, bedaquilineand PA-824) [33–37].

Delamanid, in combination with a back-ground regimen developed according to theWHO guidelines [33], is associated with anincrease in sputum-culture conversion at 2months in patients with MDR-TB. Furthermore,it is able to increase treatment success anddramatically reduce mortality in these difficult-to-treat cases [34].

In a recent multiple-agent combinationstudy published in the Lancet [35, 37] the14-day early bactericidal activity of Pa-824+mox-ifloxacin+pyrazinamide was found to be sig-nificantly higher than that of bedaquiline,bedaquiline+pyrazinamide, Pa-824+pyrazina-mide and bedaquiline+Pa-824 and comparableto that of the standard treatment regimen of

Figure 6Proportion of MDR among previously treated TB cases. Latest available data, 1994–2010.Reproduced from [21] with permission from the publisher.

Table 1. Rationale for the four key components of the ESTC; adapted from [17]

Diagnosis The ESTC are based on TB suspects identified not only through sputum smear microscopy, but adapted to theEU/EEA setting including culture, DST (drug susceptibility testing) and rapid testing including rapididentification for rifampicin resistance. This is consistent with the culture-based definition used in the EU/EEA.

Treatment Given the availability of rapid diagnostic for TB and rifampicin resistance, the need to start MDR treatmentfrom the beginning, under high-quality management conditions.To ensure quality treatment monitoring based on culture.

HIV/TB andco-morbidities

Universal access to anti-retroviral treatment is available to all HIV infected as well as the capacity to detectall cases. This impacts on the management of provision of isoniazid preventive therapy (IPT).Not only HIV infected but also individuals with a range of immunosuppressive conditions (such as TNF-aantagonist, corticosteroid, cancer treatment, diabetes, intravenous drug use and alcohol abuse) should beevaluated for IPT and proper follow-up for TB.

Public health andprevention

In absence of vertical TB programmes and with the full integration of services, healthcare providers areassuming an important responsibility for ensuring key public health and infection control functions relatedto detection and prevention of TB.


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isoniazid, rifampicin and pyrazinamde withstreptomycin or ethambutol.

This finding opens the way to a potentialnew vision of treatment, in which a single,universal regimen not built around rifampicinand isoniazid (e.g. the two drugs whoseresistance defined MDR-TB) would (hopefully)be able in the near future to treat both drugsusceptible and drug-resistant TB cases [37].


In 2004, WHO published an interim policy oncollaborative TB/HIV activities for immediateguidance to countries on actions to decreasethe dual burden of TB and HIV [38]. Since then,additional evidence has been generated fromrandomised controlled trials, observationalstudies, operational research and best practicesfrom programmatic implementation of thecollaborative TB/HIV activities recommendedby the policy. In 2012, WHO published theupdated policy on collaborative TB/HIV activ-ities, to summarise the current evidence andexperience in implementing collaborative TB/HIV activities [19] (table 3).

The new policy follows the same frameworkas the 2004 interim policy document, structur-ing the activities under three objectives: estab-lishing and strengthening mechanisms forintegrated delivery of TB and HIV services;reducing the burden of TB among people livingwith HIV and reducing the burden of HIVamong people with presumptive TB (that is,people with signs and symptoms of TB or withsuspected TB) and diagnosed TB.

Under the first objective, the updatedpolicy emphasises the need to establishmechanisms for delivering integrated TB/HIV services, preferably at the same timeand location. Integrated TB/HIV servicesshould be also offered as part of other healthprogrammes, such as maternal and childhealth, harm-reduction services and prisonhealth services. Monitoring and evaluation ofcollaborative TB/HIV activities should bedone within one national system usingstandardised indicators and reporting andrecording formats. TB prevalence surveysshould include HIV testing, and HIV surveil-lance systems should incorporate TB screen-ing as routine practice. National and localtargets for collaborative TB/HIV activitiesshould be jointly set, for example throughthe national TB/HIV coordinating body and

national consultations. Long- and medium-term national TB/HIV strategic plans shouldbe developed to scale up activities nation-wide. National HIV programmes and TB-control programmes should establish linkageand partnerships with a broad platform ofgovernmental, nongovernmental and com-munity organisations for programme devel-opment, implementation and monitoring ofTB/HIV collaborative activities.

The second objective describes the inter-ventions to reduce the burden of TB amongpeople living with HIV, which include the earlyprovision of antiretroviral therapy (ART) forpeople living with HIV and the ‘‘three Is forHIV/TB’’: intensified TB case finding followedby high-quality antituberculosis treatment; iso-niazid preventive therapy (IPT); and infectioncontrol for TB. The policy recommends thatall people living with HIV should be regularlyscreened for TB using a simple clinical symp-tom-based algorithm consisting of: a) currentcough; b) fever; c) weight loss; or d) nightsweats. TB symptom screening should beperformed at the time of initial presentationfor HIV care and at every visit to a health facilityor contact with a healthcare worker [39].Screening for TB is important regardless ofwhether they have received or are receiving IPTor ART. Adults and adolescents living with HIVwho report any one of the mentioned symp-toms may have active TB and should beevaluated for TB.

Smear-negative pulmonary and extrapul-monary TB is common among people livingwith HIV and associated with poor treatmentoutcomes and excessive early mortality. Ifsmear-negative pulmonary TB or extrapulmon-ary TB is suspected, diagnostic processesshould be accelerated using all available andappropriate investigations, including mycobac-terial culture [40]. If available, WHO approvedmolecular tests (e.g. Xpert MTB/RIF) should bethe primary diagnostic test for TB in peopleliving with HIV [41]. In case of negativeinvestigations and no improvement to parent-eral antibiotics among seriously ill patients inHIV-prevalent settings, empirical anti-TB treat-ment should be initiated [40]. New TB patientsliving with HIV should receive a standard TBregimen containing 6 months of rifampicin(2HRZE/4RH) on a daily schedule [42] andshould be started on ART regardless of CD4count as soon as possible within the first 8weeks of anti-TB treatment [43].


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Administrative, environmental and perso-nal protective measures against TB infectionin healthcare facilities and congregate set-tings should be put in place. These measuresinclude surveillance of HIV and TB amonghealthcare workers; relocation of health work-ers living with HIV from areas with high TBexposure; and provision of ART and IPT.

Under the third component, the updatedpolicy recommends offering routine HIVtesting not only to patients with presumptiveor diagnosed TB but also to their partnersand family members, as a means of reducingthe burden of HIV in the general community.All TB patients who are found to be HIV-positive should be provided with co-trimox-azole preventive therapy (CPT), regardlessof CD4 cell-count. Antiretroviral treatmentshould be given to all HIV-positive TB pa-tients as soon as possible within the first 8weeks of anti-TB treatment, regardless oftheir CD4 cell-count. HIV-positive TB patientswith profound immunosuppression (e.g. CD4count ,50 cells?mm-3) should receive ARTimmediately, within the first 2 weeks ofinitiating TB treatment. TB patients, theirfamily and community members should be

provided with comprehensive HIV preventionservices.

Public health response to develop a post-2015strategy

In June this year, WHO and partners begandiscussions to define the new post-2015 strategyof TB control and elimination. The perspectiveof TB elimination (the definitions of control andelimination are reported in table 4) has nowbecome central in WHO policies, somethingseveral countries (including in the EU, as well asUSA, Japan and Canada) had committed to asfar back as 1991 [44–47].

Through TB control, we aim at reducing theincidence of TB infection and, consequently, ofTB disease, based on early diagnosis andtreatment of infectious cases of TB, so that wereduce as much as possible the transmission ofTB bacilli within the community.

TB elimination is an additional strategyaimed at reducing the prevalence of TBinfection, based on preventive treatment oflatently TB infected individuals. By reducing thelarge pool of infected individuals, future casesof TB will be prevented as no TB disease willoccur if we do not have infection first [5].

Table 2. Changes to the recommendations on regimen composition between the 2008 and 2011 updates of WHOMDR-TB guidelines

2008 emergency update 2011 update

Include at least four anti-TB drugs with either certain, oralmost certain, effectiveness during the intensive phase of Tx.

Include at least four second-line anti-TB drugs likely to be effective aswell as Z during the intensive phase of Tx.

Consider adding more drugs in patients with extensivedisease or uncertain effectiveness

No evidence found to support the use of more than four second-lineanti-TB drugs in patients with extensive disease. Increasing thenumber of second-line drugs in a regimen is permissible if theeffectiveness of some of the drugs is uncertain.

The regimen should include Z and/or E, one FQ, oneparenteral agent and second-line oral bacteriostatic anti-TBdrugs (no preference of oral bacteriostatic second-line anti-TBdrug was made).

The regimen should include Z, a FQ, a parenteral agent, ethionamide(or prothionamide), and cycloserine, or else PAS if cycloserinecannot be used.

E may be considered effective and included in the regimen ifDST shows susceptibility

E may be used but is not included among the drugs making up thestandard regimen.

Tx with group-5 drugs is recommended only if additionaldrugs are needed to bring the total to four

Group-5 drugs may be used but are not included among the drugsmaking up the standard regimen

Intensive phase minimum of 6 months (minimum 4 monthsafter C conversion) for a total duration of minimum of 18months after C conversion

Intensive phase minimum of 8 months for a total duration o20months

Z: pyrazinamide; E: ethambutol; FQ: fluoroquinolone; PAS: para-aminosalycilic acid ; C: capreomycin; Tx: treatment.


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Initial agreement was built around threemain pillars, including intensified and inno-vative TB care, development and enforcementof bold health-system and social developmentpolicies, and promotion and intensification ofresearch and innovation [5].

While the first pillar will capture the coretechnical principles described in the DOTSand Stop TB Strategy (rapid diagnosis,screening of populations at risk, treatmentand patient support including MDR-TB andTB/HIV, treatment of latently infected indivi-duals), the second pillar will capture thenecessary policies supporting these princi-ples (integration of health services; universal

access; improved vital statistics, infectioncontrol and rationale use of quality drugs;fight against social determinants). The thirdpillar finally will further stimulate researchand rational use of new diagnostic, drugs andvaccines [5, 47].

A strong public health system is necessaryto minimise development of new cases ofMDR-TB, through the correct clinical manage-ment of newly diagnosed, drug susceptibleTB cases. This comprehensive approach,ensuring rational use of drugs, will alsoprotect the investment in developing thenew drugs, and prevent the development ofnew drug resistances [48].

Table 3. WHO-recommended collaborative TB/HIV activities; reproduced from [19] with permission from the publisher

A. Establish and strengthen the mechanisms for delivering integrated TB and HIV services

A.1. Set up and strengthen a coordinating body for collaborative TB/HIV activities functional at all levelsA.2. Determine HIV prevalence among TB patients and TB prevalence among people living with HIVA.3. Carry out joint TB/HIV planning to integrate the delivery of TB and HIV servicesA.4. Monitor and evaluate collaborative TB/HIV activities

B. Reduce the burden of TB in people living with HIV and initiate early antiretroviral therapy (the Three I’s for HIV/TB)

B.1. Intensify TB case-finding and ensure high quality antituberculosis treatmentB.2. Initiate TB prevention with isoniazid preventive therapy and early antiretroviral therapyB.3. Ensure control of TB Infection in health-care facilities and congregate settings

C. Reduce the burden of HIV in patients with presumptive and diagnosed TB

C.1. Provide HIV testing and counselling to patients with presumptive and diagnosed TBC.2. Provide HIV prevention interventions for patients with presumptive and diagnosed TBC.3. Provide co-trimoxazole preventive therapy for TB patients living with HIVC.4. Ensure HIV prevention interventions, treatment and care for TB patients living with HIVC.5. Provide antiretroviral therapy for TB patients living with HIV

Table 4. TB control and elimination


TB control Strategy aimed at reducing the incidence of TB infection and, consequently, of TB disease, based on earlydiagnosis and treatment of infectious cases of TB. Fewer and fewer people in the community will be newlyexposed to the contact with the bacilli and will develop the disease

Elimination Point at which less than one infectious (sputum smear positive) case per 1,000,000 inhabitants emergesannually in the general population or when the prevalence of TB in general population is below 1% andcontinues to decrease.


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10. Raviglione M, Marais B, Floyd K, et al. Scaling upinterventions to achieve global tuberculosis control:progress and new developments. Lancet 2012; 379:1902–1913.

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13. Raviglione MC, Uplekar MW. WHO’s new Stop TBStrategy. Lancet 2006; 367: 952–955.

14. Tuberculosis Coalition for Technical Assistance.International Standards for Tuberculosis Care (ISTC).The Hague, Tuberculosis Coalition for TechnicalAssistance, 2006.

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16. Migliori GB, Zellweger JP, Abubakar I, et al. EuropeanUnion Standards for Tuberculosis Care. Eur Respir J2012; 39: 807–819.

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Key points

N Tuberculosis control is aimed at reducing the incidence of TB infection (and, con-sequently, of TB disease, based on early diagnosis and treatment of infectious cases ofTB), while TB elimination, is an additional strategy aimed at reducing the prevalence ofTB infection, based on preventive treatment of latent TB. TB elimination is challengingdue to the high prevalence of drug resistant TB (particularly in the former Soviet UnionCountries), largely due to case mismanagement and health systems drawbacks. As aresult additional levels of drug resistance beyond XDR-TB are appearing.

N The new Xpert1 MTB/RIF assay (GeneXpert, Cepheid, Sunnyvale, CA, USA), is opening anew era in TB diagnostics allowing a rapid, simultaneous diagnosis of both TB andresistance to rifampicin in 1 hour and 45 minutes.

N New drugs will soon be available in TB treatment, including three promising compounds:delamanid, bedaquiline and PA-824. New strategies have been developed by WHO torespond to the core challenges (2012 updated Policy on collaborative TB/HIV activities,draft post-2015 Strategy towards elimination); the new EU Standards for TB Care havebeen developed jointly by ERS and ECDC.


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21. Zignol M, van Gemert W, Falzon D, et al. Surveillanceof anti-tuberculosis drug resistance in the world: anupdated analysis, 2007–2010. Bull World Health Org2012; 90: 111–119.

22. Dheda K, Migliori GB. The global rise of extensivelydrug-resistant tuberculosis: is the time to bring backsanatoria now overdue? Lancet 2012; 379: 773–775.

23. Migliori GB, Sotgiu G, D’Ambrosio L, et al. TB andMDR/XDR-TB in European Union and EuropeanEconomic Area countries: managed or mismanaged?Eur Respir J 2012; 39: 619–625.

24. Sotgiu G, D’Ambrosio L, Centis R, et al. TB and M/XDR-TB infection control in European TB referencecentres: the Achilles’ heel? Eur Respir J 2011; 38:1221–1223.

25. Skrahina A, Hurevich H, Zalutskaya A, et al. Alarminglevels of drug-resistant tuberculosis in Belarus:results of a survey in Minsk. Eur Respir J 2012; 39:1425–1431.

26. Migliori GB, De Iaco G, Besozzi G, et al. Firsttuberculosis cases in Italy resistant to all testeddrugs. Euro Surveill 2007; 12: E070517.1.

27. Velayati AA, Masjedi MR, Farnia P, et al. Emergenceof new forms of totally drug-resistant tuberculosisbacilli: super extensively drug-resistant tuberculosisor totally drug-resistant strains in Iran. Chest 2009;136: 420–425.

28. Udwadia ZF, Amale RA, Ajbani KK, et al. Totally drug-resistant tuberculosis in India. Clin Infect Dis 2012;54: 579–581.

29. Migliori GB, Centis R, D’Ambrosio L, et al. Totallydrug-resistant and extremely drug-resistant tubercu-losis: the same disease? Clin Infect Dis 2012; 54:1379–1380.

30. Ahuja SD, Ashkin D, Avendano M, et al. Collaborativegroup for meta-analysis of individual patient data inMDR-TB. Multidrug resistant pulmonary tuberculosistreatment regimens and patient outcomes: anindividual patient data meta-analysis of 9,153patients. PLoS Med 2012; 9: e1001300.

31. Sotgiu G, Centis R, D’Ambrosio L, et al. Efficacy,safety and tolerability of linezolid containing regi-mens in treating MDR-TB and XDR-TB: systematicreview and meta-analysis. Eur Respir J 2012 [Epubahead of print DOI: 10.1183/09031936.00022912].

32. De Lorenzo S, Alffenaar JW, Sotgiu G, et al. Efficacyand safety of meropenem/ clavulanate added tolinezolid containing regimens in the treatment of M/XDR-TB. Eur Respir J 2012 [Epub ahead of print DOI:10.1183/09031936.00124312].

33. Gler MT, Skripconoka V, Sanchez-Garavito E, et al.Delamanid for multidrug-resistant pulmonary tuber-culosis. N Engl J Med 2012; 366: 2151–2160.

34. Skripconoka V, Danilovits M, Pehme L, et al.Delamanid improves outcomes and reduces mortal-ity for multidrug-resistant tuberculosis. Eur Respir J2012 [Epub ahead of print doi: 10.1183/09031936.00125812].

35. Diacon AH, Dawson R, von Groote-Bidlingmaier F,et al. 14-day bactericidal activity of PA-824, bedaqui-line, pyrazinamide, and moxifloxacin combinations: a

randomised trial. Lancet 2012 [Epub ahead of print10.1016/S0140-6736(12)61080-0].

36. D’Ambrosio L, Centis R, Migliori GB. Rational use ofTB drugs, present action to preserve future options.N Engl J Med 2012; In press.

37. Migliori GB, Sotgiu G. Treatment of tuberculosis:had we turned the corner? Lancet 2012; 380: 955–957.

38. World Health Organization. Interim policy oncollaborative TB/HIV activities. World HealthOrganization, Geneva, Switzerland, 2004. DocumentWHO/HTM/TB/2004.330.

39. Getahun H, Kittikraisak W, Heilig CM, et al.Development of a standardized screening rule fortuberculosis in people living with HIV in resource-constrained settings: individual participant datameta-analysis of observational studies. PLoSMedicine 2011; 8: 1, e1000391.

40. World Health Organization. Improving the diagnosisand treatment of smear-negative pulmonary andextrapulmonary tuberculosis among adults andadolescents: recommendations for HIV-prevalentand resource-constrained settings. World HealthOrganization, Geneva, Switzerland, 2007. DocumentWHO/HTM/TB/2007.379.

41. World Health Organization. Roadmap for rolling outXpert MTB/RIF for rapid diagnosis of TB and MDR-TB. Geneva, WHO, 2010.

42. World Health Organization. Treatment of tubercu-losis: guidelines; 4th edn. Geneva, Switzerland:World Health Organization, Geneva, Switzerland,2009. Document WHO/HTM/TB/2009.420.

43. World Health Organization. Antiretroviral therapy forHIV infection in adults and adolescents: recom-mendations for a public health approach, 2010revision. Geneva, World Health Organization, 2010.

44. Clancy L, Rieder HL, Enarson DA, et al. Tuberculosiselimination in the countries of Europe and otherindustrialized countries. Eur Respir J 1991; 4:1288–1295.

45. Broekmans JF, Migliori GB, Rieder HL, et al. WorldHealth Organization, International Union AgainstTuberculosis and Lung Disease, and RoyalNetherlands Tuberculosis Association WorkingGroup. European framework for tuberculosis controland elimination in countries with a low incidence.Recommendations of the World Health Organization(WHO), International Union Against Tuberculosisand Lung Disease (IUATLD) and Royal NetherlandsTuberculosis Association (KNCV) Working Group.Eur Respir J 2002; 19: 765–775.

46. Veen J, Migliori GB, Raviglione M, et al.Harmonisation of TB control in the WHO Europeanregion: the history of the Wolfheze Workshops. EurRespir J 2011; 37: 950–959.

47. Tadolini M, Migliori GB. Tuberculosis control andelimination. Eur Respir Mogr 2012; 58: 243–253.

48. Migliori GB, Langendam MW, D’Ambrosio L, et al.Protecting the TB drug pipeline. Stating the case forthe rational use of Fluoroquinolones. Eur Respir J2012 [Epub ahead of print DOI: 10.1183/09031936.00036812].


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