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  PULMONARYPERSPECTIVE GettingPersonalPerspectivesonIndividualizedTreatmentDurationinMultidrug-Resistant and Extensively Drug-Resistant Tuberculosis Jan Heyckendorf  1,2 , Ioana D. Olaru 1,2 , Morten Ruhwald 3 , and Christoph Lange 1,2,4,5 1 Division of Clinical Infectious Diseases, and  2 German Center for Infection Research (DZIF), Research Center Borstel, Borstel,Germany;  3 Department of Infectious Disease Immunology, Section for Human Immunology, Statens Serum Institute, Copenhagen,Denmark;  4 International Health/Infectious Diseases, University of L¨ ubeck, L¨ ubeck, Germany; and  5 Department of Medicine, University of Namibia School of Medicine, Windhoek, Namibia  Abstract Tuberculosis (TB) differs from most other bacterial infectiousdiseases by a very long duration of combination antibiotic therapy required to achieve relapse-free cure. Although the standardrecommended  “ short-course ”  treatment length for TB is 6 months,the World Health Organization recommends a duration of 20months for the treatment of patients with multidrug-resistant andextensively drug-resistant TB (M/XDR-TB). Apart from the long duration of anti-TB therapy, treatment of M/XDR-TB is very expensive and often associated with adverse drug events. Theoptimal duration for treatment of TB likely differs betweenindividuals and depends on a variety of variables, such as the extentof the disease, the immune status of the host, and the virulenceand the drug resistance of the causative strain of   Mycobacteriumtuberculosis. SomepatientswithM/XDR-TBmayhavetobetreatedwith currently available antituberculosis drug regimens for morethan 20 months, whereas much shorter treatment durationsmay be possible to achieve cure for the majority of patients withM/XDR-TB. Personalization of the duration of treatment forTB, especially for patients with M/XDR-TB, would be highly desired. Until recently there has been little interest in theidenti 󿬁 cation of biosignatures that could eventually lead toindividual recommendations for the duration of anti-TB therapy.This pulmonary perspective reviews the knowledge on clinical andradiological scores, host- and pathogen disease – related pro 󿬁 les,molecules,andsignaturesthatarecurrentlyexploredasbiomarkersto personalize the duration of therapy in TB. Keywords:  biomarkers; multidrug-resistant tuberculosis;personalized medicine; treatment duration; extensively drug-resistant tuberculosisTuberculosis (TB) is a leading causeof morbidity and mortality worldwide.Although the overall burden of TB has beendeclining at an annual average of 2.2%, inthe past years the number of patients withmultidrug-resistant (MDR)-TB, de 󿬁 nedby   in vitro  drug resistance of   Mycobacteriumtuberculosis  to the two most effective drugsfor TB treatment, rifampicin and isoniazid,and extensively drug-resistant (XDR)-TB,de 󿬁 ned as MDR-TB plus  in vitro  drug resistance of   M. tuberculosis  to amikacin,capreomycin, or kanamycin plus any  󿬂 uoroquinolone, is dramatically increasing.According to the latest reports by the WorldHealth Organization (WHO), numbers of patients identi 󿬁 ed with M/XDR-TB in theyears 2010 to 2012 were 54,887, 61,907, and83,715, respectively. However, the estimatednumbers of patients with M/XDR-TBare much higher at 450,000 cases, withcorresponding 300,000 patients withpulmonary MDR-TB in 2012. Moreover,XDR-TB has been reported in 92 countries,and 9.6% of all MDR-TB cases meet theXDR-TB de 󿬁 nition (1).Treatment against M/XDR-TB isrecommended witha combinationof atleastfour drugs shown to be effective by   in vitro drug susceptibility testing over a periodof 20 months (2). This is an exceptionaltreatment duration compared with otherinfectious diseases (3). Evidence for this (Received in srcinal form February 25, 2014; accepted in final form June 18, 2014)Funded by a grant from the German Ministry of Education and Research (Bundesministerium f¨ ur Bildung und Wissenschaft, BMBF) for the German Center of Infection Research (DZIF) Clinical Tuberculosis Unit (C.L.). Author Contributions: J.H. contributed to the idea, concept, and design of the manuscript; the acquisition, analysis, and interpretation of the data; drafting andrevising of the article; and approved the final version of the draft for publication. I.D.O. contributed to the acquisition and interpretation of the data, drafting andrevising of the article, and approved the final version of the draft for publication. M.R. contributed to the acquisition and interpretation of the data, draftingand revising of the article, and approved the final version of the draft for publication. C.L. contributed to the idea, concept, and design of the manuscript; theacquisition, analysis, and interpretation of the data; drafting and revising of the article; and approved the final version of the draft for publication.Correspondence and requests for reprints should be addressed to Christoph Lange, M.D., Division of Clinical Infectious Diseases, German Center for InfectionResearch (DZIF) Clinical Tuberculosis Unit, Research Center Borstel, Parkallee 35, 23845 Borstel, Germany. E-mail:  Am J Respir Crit Care Med Vol 190, Iss 4, pp 374–383, Aug 15, 2014Copyright  ©  2014 by the American Thoracic SocietyOriginally Published in Press as DOI: 10.1164/rccm.201402-0363PP on June 18, 2014Internet address: 374  American Journal of Respiratory and Critical Care Medicine Volume 190 Number 4 |  August 15 2014  recommendation comes from an individualpatient data metaanalysis of observationaldata from 9,153 patients (4). However,related to the extent of the disease, theimmune status of the host, the drug-resistance pattern, and virulence of thebacteria, the duration of anti-TB treatmentnecessary to achieve relapse-free cure ishighly variable (Figure 1). This leaves the20-month treatment recommendation forpatients with M/XDR-TB as an averageestimate, which is likely incorrect for thegreat majority of individual patients. Theextent of the variation has recently beendemonstrated, when a 9-month  “ short-course ”  drug regimen for the treatment of MDR-TB was shown to be highly effectiveto achieve successful treatment outcomein a study from Bangladesh, a country with low levels of   󿬂 uoroquinolone drug resistance of   M. tuberculosis  (5). TheSTREAM trial aims to further validate thispromising approach in Ethiopia, Republicof South Africa, and Vietnam (6).A shorter duration of treatment mightalso be used in children with limited MDR-TB disease, where 12 to 15 months of therapy might be suf  󿬁 cient to attain cure,whereas in children with extensive diseasea treatment duration of 18 months afterculture conversion would be necessary (7).A recently published study showed thatmore than 90% of children with MDR-TBreceiving a median duration of therapy of 13 months had a favorable outcome (8).This would support individualizing MDR-TB therapy according to disease severity.Although the current WHO treatmentguidelines suggest the adaption of treatmentduration based on a patient ’ s bacteriologicalstatus or  “ other markers for treatmentprogress, ”  there is no guidance concerning the consequences of these markers, and themeaning of   “ other markers for treatmentprogress ”  is not explained. Due to theimportant in 󿬂 uence of host and pathogen variables to achieve relapse-free cure withcurrently available medications and theoverall long duration of anti-TB treatmentof M/XDR-TB, individualization of the duration of M/XDR-TB treatmentwould be highly desirable. In additionto improvements in cost-effectiveness,individualized treatment regimens achievehigher success rates than standardizedtreatment regimens (9) and may possibly lead to better quality of life. However, theonly biomarker validated to guide clinicianson decisions for the duration of therapy in any bacterial infection to date is theprocalcitonin level in community-acquiredpneumonia (10).The development of clinical andradiological scores and identi 󿬁 cation of host- and pathogen disease – related pro 󿬁 les,molecules, and signatures to monitor theeffect of anti-TB therapy is rapidly evolving.The discovery of biomarkers to guideclinicians for the duration of M/XDR-TBtreatment will have far-reaching clinicaland economic consequences.This perspective elucidates theexpanding   󿬁 eld of TB biomarker researchfor therapy response and introducespotential future approaches for individually tailored TB treatment durations, especially needed for the management of M/XDR-TB. Pathogen-related Markers Microscopy and Culture In the early course of anti-TB treatment, themost frequently used method to evaluatea patient ’ s state of infectiousness is theidenti 󿬁 cation of acid-fast bacilli by sputumsmear microscopy (11). As a measure fortreatment outcome, culture conversion(CC) is part of WHO outcome criteria,which have been revised for M/XDR-TBrecently (12). The time to CC (TCC)has also been evaluated as a marker fortreatment outcome (13 – 16) (Table 1).In four different studies with patientswith MDR-TB under second-line drug treatment, the median TCCs were reportedbetween 62 and 152 days (13 – 17) comparedwith representative 78 days in patients withdrug-susceptible TB (17). The median timeto smear conversion (SC) was 83 days inpatients with MDR-TB (16) and 23 daysin drug-susceptible TB (18), with similardisease characteristics affecting TCC and treatment start0thresholdpan drug-susceptible TB BIOMARKERLEVEL FACTORS INFLUENCING DURATION OF TB THERAPY disease severity, host’s immune status & genetic background,bacterial virulence & drug-resistance, availability & quality of therapy TREATMENT REGIMEN DURATION OF TREATMENT (MONTHS) 6 12 18 20TB meningitisM/XDR-TBrifampicin-resistantTB TREATMENT PHASE INTENSIVECONTINUATION BIOMARKER-GUIDEDTREATMENT DURATION INCREASINGDURATION OFTHERAPYTREATMENT FAILURE Figure 1.  Hypothetical model of biosignatures to individualize the duration of antituberculosis(anti-TB) therapy. The individual duration of anti-TB therapy to achieve relapse-free cure variessubstantially among patients with tuberculosis (TB). Factors that influence the duration of therapyin TB are the severity of the disease, the immune status and genetic background of the host, thevirulence and drug resistance of the bacteria, and the availability and quality of anti-TB therapy.Biomarkers related to bacterial load, clinical symptoms, and immune activation change with differentkinetics in individual patients during the course of anti-TB therapy. Currently, fixed treatment durations(  lower panel  ) with an intensive treatment phase ( dark gray  ) and a continuation treatment phase(  light gray  ) are recommended for different manifestations of TB and different levels of   Mycobacteriumtuberculosis  drug resistance. Biosignatures indicating cure (  green lines ) or treatment failure (  blue line )could provide information to guide physicians on the decisions for anti-TB treatment duration inthe future. M/XDR = multidrug-resistant/extensively drug-resistant. (Illustration with support of KarenSmith Korsholm/SCILL, Copenhagen, Denmark.) PULMONARY PERSPECTIVE Pulmonary Perspective  375  Table 1.  Candidate Biomarkers to Monitor Treatment Responses during Antituberculosis Therapy Marker Classi 󿬁 cation MaterialEvaluated inM/XDR-TB Remarks Reference Pathogen-related markersTCC Time until a patient is consideredculture negativeSputum Yes Evaluated for survival prediction,treatment response, and failure13, 16, 17Whole blood bactericidal activity Bactericidal activity against Mycobacterium tuberculosis in whole blood culture duringTB treatmentWhole blood No Marker for treatment response 91TTD Time until a culture is positivein daysSputum Yes MDR-TB with delayed TTD, treatmentresponse20 – 23TB-RNA Quanti 󿬁 cation of mycobacterialRNA Sputum No Treatment response 31, 37TB-DNA Quanti 󿬁 cation of mycobacterialDNA Sputum, urine Not speci 󿬁 ed Treatment response 32, 35, 36, 38TB-antigens Quanti 󿬁 cation of mycobacterialantigensSputum, urine,serumNot speci 󿬁 ed Treatment response 24 – 30Host-related markersClinical itemsClinical score Changes of patientcharacteristics in thecourse of treatmentClinical scoreitemsNot speci 󿬁 ed Treatment response 39, 40Radiological parametersChest radiograph score Change of TB correlateswith treatmentChest X-rays Yes Outcome prediction and treatmentresponse41 – 43Chest CT scan TB correlates with TTD CT scans Single drug-resistant, noM/XDR-TBLonger TTD in patients withcavitary disease42 18 F-FDG PET Decline of SUVmax  18 F-FDG PET Not speci 󿬁 ed Treatment response 44 – 47Chemokines, cytokines, proteins, and peptides Acute-phase proteins/peptides PCT, CRP, sTREM-1, hemeoxygenase-1, sICAM-1,suPAR, sLAG-3,granzyme B, sTNFR I,and sTNFR IISerum/plasma No Therapy response and therapyoutcome prediction55, 92, 93Cytokines andchemokines Among others IFN- g , TNF- a ,IL-8, IL-6, IP-10, VEGF,IL-10, MIP-1a, IL-13 andsCD40L, MCP-1Sputum, serum,plasmaNo or notspeci 󿬁 edTherapy response and therapyoutcome prediction, correlationwith bacterial markers51, 54, 94, 95Nutritional markers Adiponectin, leptin, fetuin-A,and retinol-binding proteinPlasma Not speci 󿬁 ed Severity of disease and treatmentresponse96Release assays and speci 󿬁 c cellular responsesImmunophenotype of speci 󿬁 ccellsDifferent cytokine responsesof antigen-speci 󿬁 c T cellsand frequency changesof these cellsWhole bloodand PBMCSome studies Therapy response, correlation withpathogen-related markers andoutcome63, 68, 71, 97Cell populationsImmune cells without speci 󿬁 cstimulationExpression of characterizingsurface markers (i.e., CD25and CD127 for Treg)Whole bloodand PBMCSome studies Disease severity and treatmentresponse71, 73, 98 AntibodiesCirculating antibodies againstTB antigensHigh throughput proof of TBantigens (i.e., antibodiesagainst ESAT-6, CFP-10)Serum No Treatment response 99Proteomics and transcriptomics and gene expressionGene-expression patterns Different signatures for distinct disease statusTotal RNA No Treatment response 83, 84, 86, 87Single or small number geneexpression changesCandidate gene-expressionchangesRNA No Treatment response 100Protein patterns Treatment response signatures SerumproteinsNo Treatment response 80, 81Mass spectrometry VOC Proof of mycobacterialsubstancesBreath No Treatment response 76 – 78Metabolomic patterns Changes of metabolicpatternsUrine No Treatment response 75Drug levels and drug activityTB drug activity or plasma concentrationIndividual drug activity Plasma No Different concentrations/activity predictsoutcome101 Definition of abbreviations : CFP-10 = 10-kDa-culture-filtrate-antigen; CRP = C-reactive protein; ESAT-6 = early secretory antigenic target-6;IP-10 = IFN- g –inducible protein 10; MCP-1 = monocyte chemotactic protein-1; MDR = multidrug-resistant; MIP-1a = macrophage inflammatory proteins1alpha; PCT = procalcitonin; PBMC = peripheral blood mononuclear cells; sCD40L = suluble cluster of differentiation 40 ligand; sLAG-3 = solublelymphocyte activation gene-3 protein; sICAM-1 = soluble intercellular adhesion molecule-1; sTNFR = soluble tumor-necrosis factor receptor; sTREM-1 =solubletriggering receptorexpressed onmyeloid cells-1; suPAR = soluble urokinase-typeplasminogenactivator receptor; SUVmax= maximumstandardizeduptakevalue;TB= tuberculosis;TCC= timetoculture conversion;TNF= tumor-necrosisfactor;TTD = time to detection; VEGF= vascular endothelialgrowthfactor; VOC = volatile organic compounds; XDR = extensively drug-resistant;  18 F-FDG PET = fluorodeoxyglucose positron emission tomography. PULMONARY PERSPECTIVE 376  American Journal of Respiratory and Critical Care Medicine Volume 190 Number 4 |  August 15 2014  SC. However, culture- and smear-basedmarkers cannot serve as indicators forpositive therapy response after CC, and thesensitivities for both 2-month smear (24%)and culture (40%) results to predict relapsewere shown to be low (19). In the above-mentioned studies, CC ranged from 62 to152 days, representing a relatively shortduration of time in contrast to the entirelength of therapy and leading to a gapof about 15 months between the lastpositive culture and treatment end, asrecommended by the WHO. The declineof colony-forming units on solid mediacultures or the time to culture positivity inliquid media in the early phase of treatmenthas been developed to assess the  “ early bactericidal activity  ”  of a single drug ora combination of drugs (20, 21). Timeto culture positivity has already beendescribed as marker for treatmentresponse in patients with drug-susceptibleTB (22, 23). Possibly, analysis of serialmeasurements of the time to culturepositivity during the early phase of treatment in patients with M/XDR-TBmight help predict the total time needed forindividual relapse-free cure; however, atthis point in time this remains hypothetical.Importantly, patients with MDR-TB notachieving CC are more likely to fail therapy (13), and reverting of cultures to positiveafter CC or failure to achieve CC may bea strong predictor for treatment failure. Monitoring Antigens of   M. tuberculosis  during Treatment During infection,  M. tuberculosis – derivedantigens are released from the site of infection. These are available for directidenti 󿬁 cation in sputum, blood, urine, orexhaled breath and have been evaluatedfor diagnostic purposes (24, 25) and couldpotentially be used also for monitoring of TB treatment responses (26 – 28) (Table1). Limitations to this approach are low levels of antigens available, necessitating highly sensitive assays. At present,mycobacterial lipoarabinomannan (LAM)remains the only explored  M. tuberculosis antigen with suf  󿬁 cient speci 󿬁 city forclinical use (24, 25). Concentrations of LAM in urine specimens of patients withactive TB correlate with sputum bacillary load (29). However, the sensitivity of theLAM urine assays in patients with activeTB is too low to suggest that this target isa promising marker to monitor treatment(24), especially in HIV-uninfectedpatients (30).To avoid delays that occur whentherapy response assessments dependon  M. tuberculosis  growth in cultures,quanti 󿬁 cation of   M. tuberculosis – speci 󿬁 cnucleic acids by ampli 󿬁 cation methods area more rapid alternative for treatmentmonitoring. Results can be available withinhours. Whereas  M. tuberculosis – speci 󿬁 cDNA can remain detectable also long after sterile cure, the identi 󿬁 cation of   M. tuberculosis – speci 󿬁 c RNA products,which are shorter lived, is a promising method to identify viable bacteria (31).Another interesting approach includestreating samples with propidium monoazide,which can bind the DNA from nonviablebacteria and prevent it from being ampli 󿬁 edby polymerase chain reaction; thus only  viable organisms are detected (32). Monitoring Nucleic Acids of   M. tuberculosis  during Treatment In principle,  M. tuberculosis – speci 󿬁 cnucleic acids can be isolated from differentcompartments, such as sputum and urine(33, 34). However, in a recent directcomparison quanti 󿬁 cation of sputum  M. tuberculosis , DNA was inferior comparedwith culture-guided methods to assess TBtreatment responses (35). The reduction of detectable  M. tuberculosis  DNA measuredby the Xpert MTB/RIF was too poor inspeci 󿬁 city to serve as reliable marker fortreatment response monitoring (36). Incontrast, RNA is a marker for viablebacteria, and the decline of quanti 󿬁 ablemycobacterial RNA in sputum specimenof patients with TB under treatment hasrecently been introduced as promising marker to monitor early treatmentresponses in an early bactericidal activity study (37) (Table 1). Monitoring theexcretion of   M. tuberculosis – speci 󿬁 c nucleicacids in the urine of patients with TB aftertreatment initiation could serve as a markerfor bacterial killing (38) and may haveadvantages over sputum analyses fortreatment monitoring.With currently available technologies,all pathogen-related markers for TB therapy responses have a short detection phase inrelation to the total recommended durationof anti-TB treatment. Pathogen-relatedmarkers might be better suitable to identify treatment failures and relapses (31, 37)rather than to serve as markers of successfultreatment outcome or the time fortreatment duration. As the risk for relapseis substantially increased when treatmentis discontinued at the time when bacteriaare not directly or indirectly identi 󿬁 ed by currently available methods, host-relatedmarkers could be more appropriate toidentify the individual duration of anti-TBtherapy. Host Markers Clinical Scores A simple way to evaluate patient response totreatment is the observation of changes ingeneral clinical characteristics of patientswith TB. Low-cost clinical scoring systemshave been developed to predict mortality and treatment failure and to monitortreatment response (39, 40). The valueof such scores depends on baselinecharacteristics of the patients with TB,the clinical setting, and the training,commitment, and accuracy of the medicalstaff recording the data. In contrast topatients with minimal disease, people withadvanced stages of the disease should havethe highest probability for changes inthe clinical score on positive treatmentresponses. Although studies are ongoing tocompare clinical scores in patients withdifferent levels of drug-resistant TB, it isspeculative at this moment whether slowerbacterial clearance in M/XDR-TB is alsorelated to the kinetic of clinical scoresbefore and after culture conversion,especially in the continuation phaseof the treatment.Clinical scores, although appealing duetotheirsimplicityandlowcost,arelikelynotsensitive enough to indicate the end of treatment and are subject to a high degreeof inter- and intraobserver variability.However, it should be explored whethera combination of a clinical score withbacterial/host-derived markers or resultsof imaging studies may be able to serveas instruments for therapy monitoring. Imaging Conventional chest X-rays and computedtomography (CT) scans are used to assessthe extent of disease before treatmentinitiation and at intervals in the course of treatment (41, 42) (Table 1). A simplenumerical score describing the extent of pathological changes on conventional chestradiographs has been suggested by Ralph andcolleagues (41). However, radiological PULMONARY PERSPECTIVE Pulmonary Perspective  377
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