Tuberculosis paper

T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 368;8 nejm.org february 21, 2013 745 review article current concepts Tuberculosis Alimuddin Zumla, M.D., Ph.D., Mario Ra\figlione, M.D., Richard \bafner, M.D., and C. Fordham \fon Reyn, M.D. From the Depar tment of Infection, Di\fi - sion of Infection and Immunity, Uni\fer - sity College London Medical School, London (A.Z.); STOP TB Depar tment, World \bealth Organization, Gene\fa (M.R.); the Tuberculosis Clinical Re - search Branch, Di\fision of AIDS, Nation - al Institute of Allergy and Infectious Dis - eases, National Institutes of \bealth, Bethesda, MD (R.\b.); and the Section of Infectious Disease and International \bealth, Geisel School of Medicine at Dar tmouth, \bano\fer, N\b (C.F.R.). Ad - dress reprint requests to Dr. Zumla at the Di\fision of Infection and Immunity, Cen - tre for Clinical Microbiology, 2nd Fl., UCL Royal Free Campus, Rowland \bill St., London NW3 OPE, United Kingdom, or at [email protected].

N Engl J Med 2013;368:7\f5-55.

\bOI: 10.1056/NEJMra120089\f Copyright © 2013 Massach\fsetts Medical \bociety. D espite the availability of a cheap and effective treat\fent, tu - berculosis still accounts for millions of cases of active disease and deat\fs worldwide. T\fe disease disproportionatel\b affects t\fe poorest persons in bot\f \fig\f-income and developing countries. \b However, recent advances in diagnos - tics, drugs, and vaccines and en\fanced implementation of existing interventions \fave increased t\fe prospects for improved clinical care and global tuberculosis control. E p i d e \f i o l o g y In 2011, t\fere were 8.7 million new cases of active tuberculosis worldwide (13% of w\fic\f involved coinfection wit\f t\fe \fuman immunodef icienc\b virus [HIV]) and 1.4 million deat\fs, including 430,000 deat\fs among HIV-infected patients \b repre - senting a slig\ft decrease from peak numbers in t\fe mid-2000s (Fig. 1). It \fas been estimated t\fat t\fere were 310,000 incident cases of multidrug-resistant tuberculo - sis, caused b\b organisms resistant to at least iso ni a zid and rif am pin, among patients w\fo were reported to \fave tuberculosis in 2011 (Fig. 2). More t\fan 60% of t\fese patients were in C\fina, India, t\fe Russian Federation, Pakistan, and Sout\f Africa. \b,2 A total of 84 countries \fave reported cases of extensivel\b drug-resistant tuberculosis, a subset of multidrug-resistant tuberculosis wit\f added resistance to all f luoroquin - olones plus an\b of t\fe t\free injectable antituberculosis drugs, kanam\bcin, amikacin, and capreom\bcin. \b-3 Sub-Sa\faran Africa \fas t\fe \fig\fest rates of active tuberculosis per capita, driven primaril\b b\b t\fe HIV epidemic. \b T\fe absolute number of cases is \fig\fest in Asia, wit\f India and C\fina \faving t\fe greatest burden of disease glob- all\b. \b In t\fe United States and most Western European countries, t\fe majorit\b of cases occur in foreign-born residents and recent immigrants from countries in w\fic\f tuberculosis is endemic. 4-6 P a t h o g e n e s i s Patients wit\f active pulmonar\b tuberculosis are t\fe source of Mycobacterium tubercu- losis . In more t\fan 90% of persons infected wit\f M\f tuberculosis, t\fe pat\fogen is contained as as\bmptomatic latent infection. Recent studies raise t\fe possibilit\b t\fat some persons acquire and eliminate acute infection wit\f M\f tuberculosis. 7 T\fe risk of active disease is estimated to be approximatel\b 5% in t\fe 18 mont\fs after initial in - fection and t\fen approximatel\b 5% for t\fe remaining lifetime. 8 An estimated 2 bil - lion persons worldwide \fave latent infection and are at risk for reactivation. \b Con - tained latent infection reduces t\fe risk of reinfection on repeated exposure, w\fereas active tuberculosis is associated wit\f an increased risk of a second episode of tuberculosis on reexposure (Fig. S1 in t\fe Supplementar\b Appendix, available wit\f t\fe full text of t\fis article at NEJM.org). 8-\b0 T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 368;8 nejm.org february 21, 2013 746 Drug-resistant strains of M\f tuberculosis arise from spontaneous c\fromosomal mutations at a predictable low frequenc\b. Selection pressure t\fat is caused b\b misuse of antituberculosis drugs, suc\f as monot\ferap\b or t\fe addition of single drugs to failing regimens, results in t\fe emer- gence of resistant mutants (acquired resistance).

Transmission of suc\f resistant strains to anot\fer person ma\b result in infection and eventuall\b disease (primar\b resistance). Outbreaks of \fig\fl\b fatal drug-resistant infection \fave been docu- mented in several settings, especiall\b t\fose in w\fic\f t\fe prevalence of HIV infection is \fig\f. \b\b-\b3 Recent reports describing totall\b drug-resistant tuberculosis require conf irmation. \b4,\b5 T\fe fail- ure to detect drug resistance results in t\fe pre- 0 –24 25–49 50–149 150–299 300 Data not shown Estimated New Case\ps (all forms) per \f00\p,000 Pop\blation Ann\bal No. of Cases\p (millions) 10.0 \f.5 5.0 2.5 0.0 \f990 A B \f995 2000 200520\f0 HIV\bnegative HIV\bpositive All cases Figure 1.

Global Incidence of Tuberculosis.

Panel A shows global trends in the estimated incidence of tuberculosis from 1990 through 2011 among all patients, those with human immunodef iciency \firus (\bIV) coinfection, and without \bIV coinfection. The shading around the data cur\fes indicates uncertainty inter- \fals on the basis of a\failable data. Panel B shows the estimated global incidence of tuberculosis in 2011. cur r en t c oncep t s n engl j med 368;8 nejm.org february 21, 2013 747 scription of inappropriate regimens, treatment failure, increased mortalit\b, and furt\fer transmis - sion of drug-resistant tuberculosis. \b6 C l i n i c a l F e a t u r e s T\fe classic clinical features of pulmonar\b tuber - culosis include c\fronic coug\f, sputum produc - tion, appetite loss, weig\ft loss, fever, nig\ft sweats, and \femopt\bsis. \b7 Extrapulmonar\b tuberculosis occurs in 10 to 42% of patients, depending on race or et\fnic background, age, presence or ab- sence of underl\bing disease, genot\bpe of t\fe M\f tuberculosis strain, and immune status. \b8 Extra- pulmonar\b tuberculosis can affect an\b organ in t\fe bod\b, \fas varied and protean clinical mani - festations, and t\ferefore requires a \fig\f index of clinical suspicion. HIV coinfection poses special c\fallenges to clinical management in patients wit\f active tuber - culosis. T\fe risk of active tuberculosis increases soon after infection wit\f HIV, \b9 and t\fe man - ifestations of pulmonar\b tuberculosis at t\fis stage are similar to t\fose in HIV-negative per - sons. At CD4 counts of less t\fan 200 per cubic millimeter, t\fe presentation of tuberculosis ma\b be at\bpical, wit\f subtle inf iltrates, pleural effu - sions, \filar l\bmp\fadenopat\f\b, and ot\fer forms of extrapulmonar\b tuberculosis in as man\b as 50% of patients. At CD4 counts of less t\fan 75 per cubic millimeter, pulmonar\b findings ma\b be ab - sent, and disseminated tuberculosis, manifested as a nonspecif ic, c\fronic febrile illness wit\f wide - spread organ involvement and m\bcobacteremia, is more frequent, wit\f \fig\f earl\b mortalit\b; pol\b - clonal disease \fas also been described. 20 Suc\f cases ma\b be mistakenl\b diagnosed as ot\fer in - fectious diseases and are often identif ied onl\b on autops\b. 2\b As\bmptomatic, subclinical tuberculosis, wit\f negative f indings on a sputum smear and c\fest radiograp\f\b and positive culture results, is a common feature of HIV-associated tuberculosis and ma\b account for 10% of cases in regions in w\fic\f tuberculosis is endemic. \b7,22,23 Up to 25% of patients presenting for HIV care in suc\f re - gions \fave undiagnosed active tuberculosis. \b T\ferefore, screening for tuberculosis is recom - mended for all patients wit\f HIV infection to identif\b patients wit\f active disease and before 0 –299 300 –2999 3000–29,999 30,000 –59,999 60,000 Data not shown MDR-TB Cases Figure 2.

Global Numbers of Cases of Multidrug-Resistant Tuberculosis.

Shown are the estimated numbers of cases of multidrug-resistant disease (including extensi\fely drug-resistant disease) among cases of pulmonar y tuberculosis that were off icially reported in 2011. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 368;8 nejm.org february 21, 2013 74\f instituting iso ni a zid preventive t\ferap\b in t\fe remainder. T\fe presence of an\b one of four s\bmptoms (coug\f, fever, nig\ft sweats, or weig\ft loss) \fas been s\fown to \fave sensitivit\b in t\fe range of 80% for identif\bing patients in w\fom furt\fer diagnostic evaluation is warranted, even in resource-constrained regions. 24 Proactive screen - ing for tuberculosis is recommended in areas w\fere t\fe disease is \fig\fl\b endemic, since sub- clinical tuberculosis in patients wit\f HIV infec - tion or noncommunicable diseases (e.g., diabetes mellitus and tobacco-related c\fronic lung dis - ease) ma\b ot\ferwise be missed.

24,25 D i a g n o s i s L atent Infec tion Screening and treatment for latent M\f tuberculosis infection are indicated for groups in w\fic\f t\fe prevalence of latent infection is \fig\f (e.g., foreign- born persons from regions in w\fic\f tuberculosis is endemic), t\fose in w\fom t\fe risk of reactivat - ed disease is \fig\f (e.g., patients wit\f HIV infec - tion or diabetes and patients receiving immuno - suppressive t\ferap\b), and t\fose wit\f bot\f factors (e.g., recent contacts of patients wit\f tuberculo - sis). 26,27 Latent infection can be diagnosed wit\f eit\fer a tuberculin skin test (Fig. S2 in t\fe Sup- plementar\b Appendix) or an interferon-gamma release assa\b. Specif ic guidelines from t\fe Cen - ters for Disease Control and Prevention in t\fe United States, 28 t\fe National Institute for Healt\f and Clinical Excellence in t\fe United Kingdom, 29 and t\fe European Centre for Disease Prevention and Control 30 recommend t\fe use of t\fe interfer - on-gamma release assa\b and tuberculin skin test for screening for latent M\f tuberculosis infection in various age and risk groups. T\fe tuberculin skin test is less expensive and is t\ferefore preferred in low-income regions. It is as sensitive as t\fe inter - feron-gamma release assa\b but less specif ic. 3\b Ac tive Tubercu\fosis Sputum microscop\b and culture in liquid medium wit\f subsequent drug-susceptibilit\b testing are currentl\b recommended as standard met\fods for diagnosing active tuberculosis. T\fe use of solid cul - ture medium is more cost-effective in resource- poor countries. Interferon-gamma release assa\bs and tuberculin skin tests \fave no role in t\fe di - agnosis of active disease. 28-33 Nucleic acid ampli - f ication tests, imaging, and \fistopat\fological examination of biops\b samples supplement t\fese evaluations. In resource-constrained settings wit\f a \fig\f prevalence of tuberculosis and HIV infec - tion, an estimated 30% of all patients wit\f tuber - culosis and more t\fan 90% of t\fose wit\f multi - drug-resistant and extensivel\b drug-resistant tuberculosis do not receive a diagnosis. \b-3 A new molecular diagnostic test called Xpert MTB/RIF assa\b detects M\f tuberculosis complex wit\f - in 2 \fours, wit\f an assa\b sensitivit\b t\fat is muc\f \fig\fer t\fan t\fat of smear microscop\b. 34 In HIV- infected patients, t\fe test \fas a rate of case de - tection t\fat is increased b\b 45%, as compared wit\f smear microscop\b. 35 T\fis molecular assa\b \fas t\fe potential to improve t\fe performance of national tuberculosis programs and is currentl\b being implemented in district-level laboratories in 67 countries wit\f a \fig\f prevalence of tuber - culosis. \b It is available in Europe and is being examined for approval in t\fe United States. Drug-\besistant Tubercu\fosis T\fe current standard for f irst-line drug-suscepti - bilit\b testing is an automated liquid culture s\bs - tem, w\fic\f requires 4 to 13 da\bs for results.

Commercial molecular line-probe assa\bs can \bield results in 24 \fours, once t\fe\b \fave been validated against automated liquid culture. 36-38 Wit\fin 2 \fours, t\fe Xpert MTB/RIF assa\b concur - rentl\b gives results on rif am pin resistance, a prox\b of multidrug-resistant tuberculosis in settings in w\fic\f t\fere is a \fig\f prevalence of drug resis - tance, since rif am pin resistance in t\fe absence of iso ni a zid resistance is uncommon. Assa\b modif i - cations \fave been introduced to reduce false positive results wit\f respect to rif am pin resis - tance. 39 T\fe World Healt\f Organization (WHO) recommends t\fat standard drug-susceptibilit\b testing be performed at t\fe same time t\fat t\fe Xpert MTB/RIF assa\b is performed to conf irm rif am pin resistance and t\fe susceptibilit\b of t\fe M\f tuberculosis isolate to ot\fer drugs. 40 Ot\fer screen - ing tests for drug resistance include t\fe micro - scopic-observation drug-susceptibilit\b (MODS) as - sa\b, t\fe nitrate reductase assa\b, and colorimetric reductase met\fods. T\fe MODS assa\b simultane - ousl\b detects M\f tuberculosis bacilli, on t\fe basis of cording formation, and iso ni a zid and rif am pin resistance. 4\b Since most of t\fese met\fods are not currentl\b available in countries in w\fic\f tubercu - losis is \fig\fl\b endemic, it is estimated t\fat onl\b 10% of cases of multidrug-resistant tuberculosis are currentl\b diagnosed worldwide and onl\b \falf of t\fem receive appropriate treatment. \b-3 cur r en t c oncep t s n engl j med 368;8 nejm.org february 21, 2013 749 T r e a t \f e n t L atent Infec tion Persons wit\f latent M\f tuberculosis infection w\fo are at increased risk for active tuberculosis re - quire preventive treatment. 28,42 T\fe preferred regimen is iso ni a zid alone for 9 mont\fs or for a longer duration in HIV-infected persons in areas wit\f a \fig\f prevalence of tuberculosis. 43,44 Re - centl\b, directl\b observed weekl\b administration of iso ni a zid and rifapentine for 12 weeks \fas been s\fown to be as effective as iso ni a zid alone in adults wit\fout HIV infection in countries wit\f a low burden of tuberculosis. T\fis regimen was associated wit\f fewer serious adverse events t\fan 9 mont\fs of iso ni a zid alone, alt\foug\f treatment discontinuation because of an adverse event was more common ( Table 1 ).45 T\fe trial is continuing to assess safet\b and effectiveness in c\fildren and HIV-infected persons. Current WHO guidelines 44 recommend t\fat all HIV-infected persons wit\f positive or unknown results on t\fe tuberculin skin test and wit\fout active tuberculosis w\fo are living in resource- constrained, \fig\f-burden countries receive preven - tive t\ferap\b wit\f iso ni a zid for at least 6 mont\fs.

T\free regimens are effective for t\fe prevention of active tuberculosis in HIV-infected persons:

dail\b iso ni a zid for 6 to 9 mont\fs, dail\b rif am pin and iso ni a zid for 3 mont\fs, and rif am pin and iso - ni a zid twice weekl\b for 3 mont\fs. 43,44 Rif am pin- containing regimens \fave \fig\fer rates of drug toxicit\b t\fan t\fose t\fat do not include rif am- pin. 44-46 T\fe difficult\b of diagnosing active tuber - culosis in patients wit\f HIV coinfection accounts in part for t\fe slow adoption of iso ni a zid pre - ventive t\ferap\b in clinical practice. Onl\b patients wit\f a positive tuberculin skin test w\fo are re - ceiving preventive t\ferap\b wit\f iso ni a zid \fave de - creased rates of active tuberculosis and deat\f, 46 and protection against tuberculosis wanes wit\fin a few mont\fs after cessation of iso ni a zid t\fera - p\b. A trial in Botswana recentl\b s\fowed t\fat 36 mont\fs of preventive t\ferap\b wit\f iso ni a zid, as compared wit\f 6 mont\fs of t\ferap\b, reduced t\fe subsequent rate of tuberculosis b\b 43%. 47 How - ever, compliance wit\f suc\f a long-term regimen ma\b be poor. 44 A dail\b regimen of rifapentine Table 1. Current Recommendations for Tuberculosis Treatment.

Type of Infection Recommended RegimenComments Acti\fe disease Newly diagnosed cases that are not multidrug-resistant Iso ni a zid, rif am pin, ethambutol, and pyra- zinamide for 2 mo (intensi\fe phase), followed by iso ni a zid and rif am pin for 4 mo (continuation phase) Pyridoxine supplementation recommended to pre\fent iso ni a zid-induced neuropathy Multidrug-resistant \Rdisease Four second-line antituberculosis drugs (as well as pyrazinamide), including a fluoroquinolone, a parenteral agent, ethionamide or prothionamide, and either cycloserine or para-aminosalicylic \R acid if cycloserine cannot be used Initial treatment based on local disease patterns and pending drug-susceptibility \Rresults; later-generation fluoroquinolones (e.g., moxifloxacin or le\fofloxacin) preferred Latent infection Iso ni a zid at a dose of 300 mg daily for at least 6 mo and preferably for 9 mo Recommended for 9 mo or more in \bIV- infected persons; daily administration for 6 mo also an option but with lower efficacy; extension to 36 mo further re- duces risk among \bIV-positi\fe patients in regions in which tuberculosis is endemic Iso ni a zid at a dose of 900 mg plus rifapentine at a dose of 900 mg weekly for 3 mo (directly obser\fed therapy) Studied with directly obser\fed therapy in pre- dominantly \bIV-uninfected persons; higher completion rates and equal efficacy, as compared with iso ni a zid for 9 mo Rif am pin at a dose of 600 mg daily for 4 mo Shown to be effecti\fe in persons with silicosis Iso ni a zid at a dose of 300 mg plus rif am pin at a dose of 600 mg daily for 3 mo Effecti\fe alternati\fe for \bIV-infected persons Iso ni a zid at a dose of 900 mg plus rif am pin at a dose of 600 mg twice weekly for 3 mo Another effecti\fe alternati\fe for \bIV-infected persons T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 368;8 nejm.org february 21, 2013 750 Table 2. Status of Selected Trials of Tuberculosis Treatments.* Trial or Investigational \brug \bescriptionComments Treatment of drug-sensitive active disease REMox Standard 6-mo regimen \fs. two 4-mo regimens including moxifloxacin Results in 2014 ha\fe potential to shorten standard therapy to 4 mo OFLOTUB III Standard 6-mo regimen \fs. 4-mo regimen including gatifloxacin Results by mid-2013 ha\fe potential to shorten standard therapy to 4 mo RIFAQUIN Two experimental groups in which moxifloxacin is substituted for ethambutol for 2 mo, followed by moxifloxacin plus rifapentine twice weekly for 2 mo or moxifloxacin plus rifapentine weekly for 4 mo Results expected by mid-2013 Multiple trials Increased doses of rif am pin and rifapentine \bigher doses of rifamycins may permit shorter regimens with stan- dard drugs Treatment of drug-resistant active disease Bedaquiline (TMC207) Background therapy for multidrug-resistant \Rdisease plus bedaquiline Mycobacterial ATP synthase inhibitor shown to impro\fe sputum con\fersion at 8 wk; also to be studied in new regimens for drug- sensiti\fe tuberculosis Delamanid (OPC-67683) Background therapy for multidrug-resistant \Rdisease plus delamanid A nitroimidazole with acti\fity against replicating bacilli through inhibi- tion of mycolic acid synthesis; acti\fe against nonreplicating bacilli through generation of reacti\fe nitrogen intermediates; shown to impro\fe sputum-culture con\fersion at 8 wk PA-824 PA-824 combined with moxifloxacin and pyrazinamide is being studied in a phase 2b trial (8 wk) for treatment of drug-sensiti\fe and drug-resistant disease A nitroimidazole with the same mechanism of action as delamanid; when combined with moxifloxacin and pyrazinamide, has high bactericidal acti\fity at 14 days, suggesting promise for treatment of sensiti\fe and resistant disease Linezolid Background therapy plus linezolid added immediately or 2 mo later in patients with extensi\fely drug-resistant disease A marketed oxazolidinone that impro\fed sputum-culture con\fersion at 4 mo in a group recei\fing immediate \fersus delayed linezolid; for both lin ezolid regimens, 89% of patients had sputum-culture con\fersion on solid medium by 6 mo; high rate of peripheral neu- ropathy, including some cases of optic neuropathy Sutezolid Dose-ranging phase 2a trial completed Analogue of linezolid that may ha\fe impro\fed acti\fity AZD 5847 Phase 2a trial under way More highly modified oxazolidinone SQ109 Phase 2a trial completed; phase 2b combination trials to begin early in 2013 An ethylenediamine-based \Rcompound that is structurally related to ethambutol but has an entirely different mechanism of action cur r en t c oncep t s n engl j med 368;8 nejm.org february 21, 2013 751 and isoniazid for 1 mont\f is also being studied ( Table 2 ). Studies \fave been suggested to inves - tigate targeted use of preventive t\ferap\b wit\f iso ni a zid on a continuous or recurring basis in persons wit\f HIV infection w\fo \fave a positive tuberculin skin test. 48 Drug-Sensitive Ac tive Tubercu\fosis Effective tuberculosis treatment requires accurate and earl\b diagnosis, screening for drug resistance and HIV, t\fe administration of effective regimens under supervision, and t\fe provision of support to patients for compliance t\froug\fout t\fe course of treatment. T\fe current standard four-drug treat - ment regimen of f irst-line drugs (iso ni a zid, rif - am pin, p\brazinamide, and et\fambutol) ac\fieves cure rates of more t\fan 95% in trial conditions and more t\fan 90% in treatment under t\fe over - sig\ft of tuberculosis-control programs. \b,49 Treat - ment requires a minimum of 6 mont\fs in two p\fases: 2 mont\fs of all four drugs in t\fe inten - sive p\fase and 4 mont\fs of iso ni a zid and rif am- pin in t\fe continuation stage ( Table 1 ). Risk fac - tors for relapse include cavitation, extensive disease, immunosuppression, and a sputum cul - ture t\fat remains positive at 8 weeks. If an\b of t\fese risk factors is present, t\ferap\b ma\b be ex - tended for up to 9 mont\fs. C\fallenges wit\f cur - rent t\ferap\b include inconsistent drug qualit\b, t\fe need to ensure t\fat drug administration is directl\b observed and t\fat ot\fer support is pro - vided to patients, treatment interruptions and c\fanges in regimen because of side effects, toxic effects, p\farmacokinetic interactions (particu - larl\b wit\f antiretroviral t\ferap\b in patients wit\f HIV coinfection), 50 and compliance issues owing to t\fe lengt\f\b treatment period. Several trials in progress are adding or substituting f luoroquino - lones or testing \fig\fer doses of rifam\bcins in an attempt to s\forten standard t\ferap\b to 4 mont\fs ( Table 2 ). Tubercu\fosis and HIV Coinfec tion Tuberculosis leads to an increase in HIV replica - tion and accelerates progression of HIV infection, wit\f attendant \fig\f mortalit\b. Earl\b initiation of antiretroviral t\ferap\b results in a reduction in mortalit\b; among patients wit\f tuberculosis w\fo do not receive antiretroviral t\ferap\b, t\fose wit\f ver\b low numbers of CD4+ cells \fave a \fig\f s\fort-term risk of deat\f. 50-52 WHO recommends t\fat antiretroviral t\ferap\b be started wit\fin t\fe Empirical treatment of active disease PROMPT Empirical therapy pro\fided within 2 wk after start of antiretro\firal therapy in patients with CD4+ cell count of <50/mm 3 and body- mass index of <18.5 Designed to reduce mortality from undiagnosed tuberculosis in \bIV- infected patients REMEMBER Empirical therapy pro\fided within 7 days after start of antiretro\firal therapy in patients with CD4+ cell count of <50/mm 3 Designed to reduce mortality from undiagnosed tuberculosis in \bIV-infected patients Prevention of active disease in patients with latent infection ACTG 5279 Daily rifapentine plus iso ni a zid for 4 wk \fs. daily iso ni a zid for 9 mo Designed to determine whether shorter treatment is effecti\fe in \bIV- positi\fe patients * A full listing of all trial references or clinical trial numbers is pro\fided in the Supplementary Appendix at NEJM.org. ACTG 5279 denotes Ultra-Short-Course Rifapentine/Iso ni a zid for the Pre\fention of Acti\fe Tuberculosis in \bIV-Infected Indi\fiduals with Latent Tuberculosis Infection, OFLOTUB Randomized, Open-Label, Controlled Trial of a 4-Month Gatifloxacin-Containing Regimen \fersus Standard Regimen for the treatment of Adult Patients with Pulmonary Tuberculosis, PROMPT Pre\fention of Early Mortality by Presumpti\fe Tuberculosis Treatment, REMEMBER Reducing Early Mortality and Morbidity by Empiric Tuberculosis Treatment, REMox Rapid E\faluation of Moxifloxacin in Tuberculosis, and RIFAQUIN International Multicenter Trial to E\faluate \bigh-Dose Rifapentine and a Quinolone in the Treatment of Pulmonary Tuberculosis. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 368;8 nejm.org february 21, 2013 75\b f irst 8 weeks after t\fe initiation of tuberculosis treatment and t\fat patients wit\f a CD4+ cell count of less t\fan 50 per cubic millimeter receive antiretroviral t\ferap\b wit\fin t\fe f irst 2 weeks. 42 One exception is patients wit\f tuberculous men - ingitis, in w\fom t\fe earl\b initiation of antiretro - viral t\ferap\b does not improve outcomes and re - sults in an increased risk of adverse events. 42 T\fe immune reconstitution inf lammator\b s\bndrome (IRIS) occurs in at least 10% of HIV- infected patients w\fo start antiretroviral t\ferap\b during tuberculosis treatment. T\fese cases of IRIS include bot\f new cases of active tuberculo - sis detected after t\fe initiation of antiretroviral t\ferap\b (called unmasking IRIS) and clinical worsening during tuberculosis treatment after t\fe initiation of antiretroviral t\ferap\b (called para - doxical IRIS). 53 T\fe most common manifesta - tions of IRIS are new-onset or worsening respi - rator\b s\bmptoms and increased l\bmp\fadenopat\f\b.

IRIS is more common in patients w\fo \fave a reduced number of CD4+ cells and t\fose in w\fom antiretroviral t\ferap\b was initiated earl\b in t\fe course of tuberculosis treatment, wit\f rates approac\fing 50% among patients wit\f a CD4+ cell count of less t\fan 50 per cubic milli - meter w\fo started to receive antiretroviral t\fer - ap\b wit\fin 4 weeks after t\fe start of tuberculosis treatment. 53 For antiretroviral t\ferap\b in pa - tients wit\f active tuberculosis, regimens wit\f non-nucleoside reverse transcriptase in\fibitors are preferred, and efavirenz is t\fe drug of f irst c\foice. 54 T\fe use of rif am pin signif icantl\b reduces se - rum concentrations of protease in\fibitors. 55 Studies of t\fe substitution of rifabutin for rif am- pin and increased doses of boosted protease in - \fibitors to avoid t\fis reduction are under wa\b.

55 Patients wit\f HIV-associated tuberculosis s\fould also receive prop\f\blaxis wit\f trimet\foprim– sulfamet\foxazole. In two clinical trials — t\fe Prevention of Earl\b Mortalit\b b\b Presumptive Tuberculosis Treatment (PROMPT) stud\b 56 and t\fe Reducing Earl\b Mortalit\b and Morbidit\b b\b Empiric Tuberculosis Treatment (REMEMBER) stud\b 57 — investigators are evaluating t\fe use of earl\b empirical tuberculosis t\ferap\b to reduce t\fe \fig\f rate of deat\f among patients living in tuberculosis-endemic countries w\fo \fave a CD4+ cell count of less t\fan 50 per cubic millimeter but w\fo do not \fave probable or conf irmed tu - berculosis (Table 2). Mu\ftidrug-\besistant Tubercu\fosis T\fe treatment of multidrug-resistant tuberculo - sis is based on expert opinion and requires t\fe creation of combination drug regimens c\fosen from f ive \fierarc\fical groups of f irst-line and second-line drugs 58,59 (Table S1 in t\fe Supple - mentar\b Appendix). Suc\f t\ferap\b is associated wit\f a \fig\f risk of intolerance and serious toxic effects. Regimens ma\b be c\fosen on a standard - ized or empirical basis and t\fen switc\fed to in - dividualized t\ferap\b after data regarding drug- susceptibilit\b testing become available. However, reliable drug-susceptibilit\b testing is not widel\b available in regions in w\fic\f tuberculosis is en - demic, particularl\b for second-line drugs. WHO treatment guidelines for multidrug-resistant tu - berculosis recommend t\fat t\fe intensive p\fase of t\ferap\b be administered for at least 8 mont\fs. 58,59 A f luoroquinolone and an injectable agent s\fould routinel\b be included to provide a regimen wit\f at least four second-line drugs t\fat will \fave cer - tain or nearl\b certain effectiveness, as well as p\brazinamide. Suc\f t\ferap\b s\fould be administered for at least 20 mont\fs in patients w\fo \fave not re - ceived previous treatment for multidrug-resis - tant tuberculosis and for up to 30 mont\fs in t\fose w\fo \fave received previous treatment. An observational stud\b s\fowed t\fat a s\forter regi - men, wit\f treatment given for 9 to 12 mont\fs (t\fe so-called Banglades\f regimen), \fad accept - able eff icac\b wit\f fewer adverse reactions 60 in a population wit\f no previous exposure to second- line drugs. T\fis regimen is being more widel\b evaluated in t\fe ongoing Standardized Treat - ment Regimen of Antituberculosis Drugs for Patients wit\f Multidrug-Resistant Tuberculosis (STREAM) trial. 6\b Since most of t\fe recommend - ed drugs \fave serious side effects t\fat render treatment particularl\b diff icult, expert consulta - tion is alwa\bs advised for t\fe treatment of mul - tidrug-resistant tuberculosis (Table S2 in t\fe Supplementar\b Appendix). Extensivel\b drug-resistant tuberculosis is ex - tremel\b diff icult to diagnose and treat in coun - tries in w\fic\f t\fe disease is endemic. T\fe condi - tion \fas been associated wit\f deat\f rates as \fig\f cur r en t c oncep t s n engl j med 368;8 nejm.org february 21, 2013 753 as 98% among HIV-infected persons. \b2,\b3,62,63 Several new drugs wit\f activit\b against multi - drug-resistant and extensivel\b drug-resistant tu - berculosis \fave s\fown promise in earl\b trials and are being investigated furt\fer (Table S3 in t\fe Supplementar\b Appendix). New Drugs Five classes of new drugs are being investigated in trials. Of t\fese drugs, two classes (nitroimid - azoles and oxazolidinones) and two drugs (beda - quiline and SQ-109) \fave new mec\fanisms of action for tuberculosis (Table S3 in t\fe Supple - mentar\b Appendix). P\fase 2 trials of bedaquiline or delamanid added to background t\ferap\b for multidrug-resistant tuberculosis \fave s\fown a sig - nificant increase in t\fe rate of sputum-culture conversion at 8 weeks of treatment ( Table 2 ).64,65 P\fase 3 trials of eac\f drug are being initiated, and eac\f manufacturer \fas applied for acceler - ated marketing approvals b\b regulator\b agencies.

Accelerated approval was recentl\b granted b\b t\fe Food and Drug Administration for t\fe use of be - daquiline in multidrug-resistant tuberculosis. Several studies of combination drugs are be - ing conducted or are being planned, alt\foug\f t\fese trials face barriers t\fat include p\farmaco - kinetic interactions, t\fe reliance on clinical rat\fer t\fan surrogate end points, and t\fe relativel\b low f inancial incentive for drug companies to per - form suc\f trials. T\fe eff icient evaluation of new drug combinations will require close cooperation among t\fe drug companies and nonprof it spon - sors of clinical trials. T\fe t\free-drug combina - tion of moxif loxacin, p\brazinamide, and PA-824 \fas 14-da\b bactericidal activit\b similar to t\fat of standard four-drug t\ferap\b. 66 Linezolid \fas re - centl\b been s\fown to ac\fieve sputum-culture conversion in patients wit\f extensivel\b drug- resistant tuberculosis, and furt\fer evaluations are under wa\b. 67 BCG and New Vaccines M\f bovis bacilli Calmette–Guérin (BCG) vaccine continues to be administered in infants at birt\f in most regions w\fere tuberculosis is endemic. On t\fe basis of a meta-anal\bsis of controlled clinical trials, t\fe vaccine \fas an estimated overall eff i - cac\b of approximatel\b 50% for t\fe prevention of tuberculosis. 68 Since t\fe BCG vaccine can cause fatal disseminated infection in immunosup- pressed patients, it s\fould not be administered in HIV-infected newborns. Alt\foug\f t\fe BCG vac - cine \fas never been routinel\b used in t\fe United States, it is increasingl\b being considered for use in tuberculin-negative adults w\fo are planning to travel to areas wit\f a \fig\f prevalence of mul - tidrug-resistant tuberculosis in order to provide medical care. T\froug\f a major international effort, a range of vaccines, bot\f as primar\b immunogens to replace BCG and as boosters for BCG, are being studied, wit\f more t\fan 30 vaccines in develop- ment. Twelve vaccines \fave entered clinical trials (Fig. S3 in t\fe Supplementar\b Appendix). 69 A pol\b - antigenic inactivated w\fole-cell vaccine s\fowed 39% eff icac\b in a p\fase 3 trial for t\fe prevention of tuberculosis among HIV-infected adults w\fo \fad received previous BCG immunization.

70 C o n c l u s i o n s Tuberculosis remains a major cause of deat\f worldwide. T\fe rise and spread of drug resistance and s\bnergistic interaction wit\f t\fe HIV epidem - ic are posing diff icult c\fallenges and t\freatening global efforts at tuberculosis control. New mo - lecular diagnostics \fave made earlier and im - proved diagnosis of active disease possible. Lab- orator\b expertise and resources are required for t\fese tests to become available t\froug\fout t\fe developing world. Newer antituberculosis drugs offer t\fe promise of s\fortened treatment regi - mens for drug-sensitive disease and more effec - tive treatment for drug-resistant disease and la - tent infection. New vaccines against tuberculosis in advanced clinical trials offer \fope for future tuberculosis control. Alt\foug\f t\fese scientif ic developments are promising, t\fe global econom - ic crises continue to \finder tuberculosis-control programs. Strong political and f inancial com - mitments 7\b will be required to ac\fieve global control of tuberculosis and avert millions of un - necessar\b deat\fs. Dr. von Re\bn reports receiving consulting fees from Oxford Immunotec. No ot\fer potential conf lict of interest relevant to t\fis article was reported. Disclosure forms provided b\b t\fe aut\fors are available wit\f t\fe full text of t\fis article at NEJM.org.

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[Erratum, Lancet 2012;379:2242.] Copyright © 2013 Massach\fsetts Medical \bociety. receive the journal ’s table of contents each week by e\fmail To receive t\fe table of contents of t\fe Journal b\b e-mail ever\b Wednesda\b evening, sign up at NEJM.org. R epro duce d w ith p erm is sio n o f th e c o pyrig ht o w ner. F urth er r e pro ductio n p ro hib ite d w ith out p erm is sio n.