Zumla Et Al 2014 New TB Drugs

www.thelancet.com/infection Vol 14 April 2014 327

Review

New antituberculosis drugs, regimens, and adjunct therapies: needs, advances, and future prospectsAlimuddin I Zumla, Stephen H Gillespie, Michael Hoelscher, Patrick P J Philips, Stewart T Cole, Ibrahim Abubakar, Timothy D McHugh, Marco Schito, Markus Maeurer, Andrew J Nunn

About 13 million people died of tuberculosis in 2012, despite availability of e ective drug treatment. Barriers to improvements in outcomes include long treatment duration (resulting in poor patient adherence and loss of patients to follow-up), complex regimens that involve expensive and toxic drugs, toxic e ects when given with antiretroviral therapy, and multidrug resistance. After 50 years of no antituberculosis drug development, a promising pipeline is emerging through the repurposing of old drugs, re-engineering of existing antibacterial compounds, and discovery of new compounds. A range of novel antituberculosis drugs are in preclinical development, several phase 2 and 3 trials are underway, and use of adjunct therapies is being explored for drug-sensitive and drug-resistant tuberculosis. Historical advances include approval of two new drugs, delamanid and bedaquiline. Combinations of new and existing drugs are being assessed to shorten the duration of therapy and to treat multidrug-resistant tuberculosis. There has also been progress in development of new antituberculosis drugs that are active against dormant or persister populations of Mycobacterium tuberculosis. In this Review, we discuss recent advances in antituberculosis drug discovery and development, clinical trial designs, laboratory methods, and adjunct host-directed therapies, and we provide an update of phase 3 trials of various uoroquinolones (RIFAQUIN, NIRT, OFLOTUB, and REMoxTB). We also emphasise the need to engage the community in design, implementation, and uptake of research, to increase international cooperation between drug developers and health-care providers adopting new regimens.

IntroductionIn 1993, WHO declared tuberculosis a global public health emergency.1 Authors of the 18th WHO Global Tuberculosis Report2 estimated that the number of incident cases of tuberculosis worldwide in 2012 was 86 million, including 29 million cases in women and 530 000 in children. Tuberculosis caused 13 million deaths, including 320 000 deaths in people with HIV. About 170 000 deaths were caused by multidrug-resistant tuberculosis, a relatively high total when compared with the estimated 450 000 global incident cases of multidrug-resistant tuberculosis. Only about a fth of the 450 000 people estimated to have developed multidrug-resistant tuberculosis in 2012 were actually detected, raising major issues about the quality of laboratory and tuberculosis services. Moreover, of the 94 000 people who were detected as eligible for treatment for multidrug-resistant tuberculosis in 2012, only 77 000 patients were actually started on treatment2 because second-line antituberculosis drugs were not available.3,4 In this Review, we assess advances in antituberculosis drug discovery and development, explore the results of continuing and recently completed phase 2 and 3 trials, and present an overview of new clinical trial designs, laboratory methods, and adjunct host-directed therapies.

Historical perspectiveAug 23, 2013, marked the 70th anniversary of experiment 11, Antagonistic Actinomycetes done by Albert Schatz at Rutgers University, part of a series of experiments that led to the discovery of streptomycin, an antibiotic puri ed from Streptomyces griseus and the rst substance with an e ective bactericidal action against M tuberculosis.5 Within 1 year of its discovery, streptomycin

provided the rst hope for tuberculosis drug treatment.6 Results of small observational studies of streptomycin in human tuberculosis infections were promising, but its ability to consistently cure patients and to combat tuberculosis was unknown. The UK Medical Research Council Tuberculosis Unit led the way for the rst investigation of its kind (the randomised controlled trial) for assessment of new antituberculosis drugs7,8 and showed that drug resistance develops rapidly when one drug is used for treatment. Findings showed e cacy of streptomycin at 6 months (27% of patients receiving bedrest died compared with 7% who received streptomycin), although the 5 year follow-up data showed no bene t since death rates (58% death rate in those given streptomycin vs 76% in controls) were e ectively the same and almost all patients acquired streptomycin resistance.7,8 Several other antituberculosis drugs were discovered and developed in the 1950s, including aminosalicylic acid, isoniazid, pyrazinamide, cycloserine, and kanamycin. These discoveries paved the way for combination therapy, which generally lasted 18 months or longer and evolved from the results of a series of clinical trials. A major breakthrough came in the 1960s with the introduction of rifampicin because this allowed treatment duration to be shortened to 9 months. The reintroduction of pyrazinamide at a lower dose than was previously used enabled the creation of the widely used current regimen. Researchers also discovered the weaker drug ethambutol in the 1960s.8

Need for new antituberculosis drugs and regimensAlthough current treatment regimens for drug-sensitive tuberculosis are highly e ective when adherence of

Lancet Infect Dis 2014; 14: 32740

Published OnlineMarch 24, 2014http://dx.doi.org/10.1016/S1473-3099(13)70328-1

Centre for Clinical Microbiology, Division of Infection and Immunity, University College London, London, UK (Prof A I Zumla FRCP, Prof T D McHugh PhD); University College London Hospitals NHS Foundation Trust, London, UK (Prof A I Zumla); School of Medicine, University of St Andrews, St Andrews, UK (Prof S H Gillespie DSc); Department for Infectious Diseases and Tropical Medicine, University of Munich, Munich, Germany (Prof M Hoelscher FRCP); German Centre for Infection Research, Munich, Germany (Prof M Hoelscher); Medical Research Council Clinical Trials Unit at University College London, London, UK (P P J Phillips PhD, Prof I Abubakar FRCP, Prof A J Nunn MSc); Global Health Institute, Ecole Polytechnique Fdrale de Lausanne, EPFLSV/GHI/UPCOL, Lausanne, Switzerland (Prof S T Cole FRS); Henry M Jackson Foundation-Division of AIDS, TB Clinical Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA (M Schito PhD); and Centre for Allogeneic Stem Cell Transplantation, Therapeutic Immunology Division, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden (Prof M Maeurer MD)

Correspondence to:Prof Alimuddin I Zumla, Centre for Clinical Microbiology, Division of Infection and Immunity, Royal Free Campus, University College London, London W1T 4JF, [email protected]

328 www.thelancet.com/infection Vol 14 April 2014

Review

patients is optimum and under trial conditions,911 outcomes are far from ideal when given in the realities of real-life tuberculosis programmatic conditions. WHO-recommended treatment regimens for drug-sensitive12 and drug-resistant tuberculosis13 have several inherent problems, making new antituberculosis drugs and treatment regimens a clinical and public health priority.

The rst problem is that treatment of drug-sensitive disease is longlasting at least 6 months.12 Furthermore, all four of the most e ective rst-line oral drugs (rifampicin, isoniazid, pyrazinamide, and ethambutol) must be taken together during the rst 2 months of treatment, and two (rifampicin and isoniazid) for a subsequent 4 months in the continuation phase, causing issues with patient adherence. When given in suboptimum programmatic conditions, these regimens are associated with high rates of non-adherence and increased mortality, and can create chronic cases of infectious drug-resistant tuberculosis.14 Thus, a priority for drug development has been for new tuberculosis drugs that will shorten regimens. Potent sterilising drugs that can shorten treatment duration to 2 months or less would improve adherence, and reduce programme supervision and distribution costs. Furthermore, drugs that would reduce both total length of treatment and frequency of drug intake would be ideal. Studies of the lifecycle of M tuberculosis have shown that mycobacteria develop a dormancy phenotype under conditions of anaerobiosis and nutrient depletion.1518 Bacterial populations of persisters can last for up to 100 days after the start of antituberculosis treatment16 and need resuscitation promotion factor for replication to trigger rapid multiplication of dormant bacilli.19 These dormant bacteria are tolerant to many antituberculosis drugs, which is one reason why a lengthy duration of antituberculosis treatment is required.20 Thus, new drugs and regimens are needed so that all persisters can be killed, whatever the stage of development M tuberculosis bacilli have reached.20

Second, new drugs are needed to tackle the growing global problem of multidrug-resistant and extensively drug-resistant tuberculosis.21 Multidrug-resistant tuber-culosis, caused by M tuberculosis bacilli resistant to at least isoniazid and rifampicin, is now widespread throughout the world, with about half a million cases reported in 2012.2 Extensively drug-resistant tuberculosis (resistance to rifampicin, isoniazid, plus any uoroquinolone, and at least one of three injectable second-line drugs: amikacin, kanamycin, or capreo mycin) has been reported in 92 countries.2 Patients with multidrug-resistant tuber-culosis need a combination of second-line and third-line antituberculosis drugs,22,23 which are much more expensive, more toxic, and less e ective than are standard treatments. WHO recom mendations for the treatment of multidrug-resistant or extensively drug-resistant tuber-culosis include second-line drugs and a treatment duration of 1824 months or longer.13,14 These guidelines are based

on low-grade evidence, expert opinion, and little observational data, and do not have the rigour of evidence based on data from randomised controlled trials. Implementation of these guidelines results in a wide range of treatment regimens that are dependent on the availability of drug-susceptibility testing, cost, physician preference, and drug availability in developing countries. Thus, new regimens for multidrug-resistant or extensively drug-resistant tuber culosis that are shorter, more tolerable, and more e ective, and have been trialled under programmatic conditions, are urgently needed.21

Third, antituberculosis drugs can interact with antiretroviral therapy (ART), which poses an enormous management problem in sub-Saharan Africa where tuberculosis cases are driven mainly by the HIV epidemic.24 Fourth, new therapies are needed for improved treatment of persons with latent tuberculosis infection from both drug-sensitive and drug-resistant strains of M tuberculosis before it converts into active disease. WHO estimates that about 2 billion people have latent tuberculosis infection,25,26 and more than 100 million people with latent tuberculosis infection will develop active disease during their lifetime. Although the incidence of tuberculosis is relatively low in developed countries, reactivation of latent tuberculosis infection in local and migrant communities account for a large tuberculosis burden.27 New antituberculosis drugs and other intervention strategies2830 to improve treatment of latent tuberculosis infection are seen as the way forward for elimination of tuberculosis.

Therefore, new antituberculosis drugs should have a good safety pro le, be more potent than existing drugs, be able to reduce the duration of therapy, be e ective to treat multidrug-resistant and extensively drug-resistant tuberculosis, be compatible with concomitant ART, and have no antagonistic activity against other tuberculosis drugs in the treatment regimen. For treatment of latent tuberculosis infection, drugs should be e ective against the various replication and physiological states of M tuberculosis.20,26,29

Discovery of new tuberculosis drugsIn February, 2000, representatives from academia, industry, major government agencies, non-govern-mental organisations, and donors met in South Africa to discuss the crises facing antituberculosis treatment; the drug development landscape looked bleak. Nowadays, the landscape is being revitalised with a range of novel drugs in preclinical development and several new compounds being assessed at all stages of clinical trials.22,23,28 After several decades of near inactivity in antituberculosis drug development, the pipeline has increased in the past 5 years ( gure 1). Increases in the tuberculosis drugs portfolio are being achieved through repurposing of old drugs, re-engineering of existing antibacterial compounds, and discovery of new


Review

compounds. The most rapid progress has been made by researchers repurposing or redosing known anti-tuberculosis drugs such as rifamycins (rifampicin, rifapentine), uoroquinolones (moxi oxacin, gati oxacin), and riminophenazines (clofazimine). These drugs have all entered advanced phase 3 studies. Other non-antibiotic drugs such as e ux-pump inhibitors3133 show anti mycobacterial potency in preclinical studies, although proof of concept in human beings needs to be established.

Advances in preclinical developmentThe discovery of entirely new and novel compounds remains challenging. After whole-genome sequencing of M tuberculosis, much e ort was put into genome-derived, targeted approaches, which have yet to realise their potential.28 A major advance in the screening e cacy for novel targets was achieved by researchers shifting from single-enzyme targets to phenotypic screening of the whole bacterial cell.49 In this method, libraries of small molecules are added to replicating and non-replicating cultures of M tuberculosis and tested for growth inhibition. This approach incorporates cell permeability and solubility in the primary screen, but does not lead to knowledge of the addressed target, which needs to be identi ed later. Whole bacteria cell screening identi ed diarylquinolines (bedaquiline),34 benzo thiazines (BTZ-043 and PBTZ-169),35 and imidazopyridine amide (Q-203).36 Although many novel compounds are in the preclinical-hit-to-lead-optimisation phase, the pipe line for the early clinical development phase is very small. To our knowledge, no tuberculosis-speci c drugs are in phase 1 studies. Of the eight compounds that are in the preclinical development stage ( gure 2), only four are scheduled to advance to clinical assessment in the next 24 months.

TBA-354, a second-generation nitroimidazole that was identi ed from more than 1000 analogues, shows similar in-vitro anti-M-tuberculosis activity as did delamanid, but better activity than PA-824, and shows slightly improved

activity at higher doses in a mouse model of tuberculosis (1000-fold reduction in colony forming unit). The major improvement compared with the rst-generation nitroimidazoles is a better bioavailability in animals, suggesting a longer exposure to the drug than with PA-824 or delamanid.37

Riminophenazinesexempli ed by clofazimine, originally a dyeshow potential to shorten treatment of multidrug-resistant tuberculosis, but skin colouration due to accumulation in fatty tissue and organs is a major side-e ect. To reduce discoloration, TBI-166 was selected from 69 riminophenazine derivatives and rst preclinical data suggests that it has retained the same anti mycobacterial properties.50

Q203 is an optimised compound made from imidazopyridines, a new class of drugs36 that inhibit mycobacterial growth by blocking the respiratory cytochrome bc1 complexessential to maintain the proton gradient and ATP synthesis. Although the drug has a similar target as bedaquiline, it inhibits ATP synthesis more potently in both aerobic and hypoxic conditions. It is active against multidrug-resistant and extensively drug-resistant isolates of M tuberculosis from human beings, and data from mice models show a 1001000-fold reduction of colony-forming units and a blocking of granuloma formation.36

Two benzothiazinones, PBTZ-169 and BTZ-043, are in late stage clinical development. Both drugs use a novel mechanism of action that inhibits the enzyme decaprenylphosphoryl--D-ribose 2 epimerase (DprE1) in M tuberculosis.48 Inhibition of this enzyme prevents the formation of decaprenyl phosphoryl arabinose (a key precursor in the biosynthesis of the cell wall arabinans), which results in cell lysis and bacterial death.48 Both compounds show a 1001000-fold reduction of colony-forming units in a chronic mouse model and in-vitro experiments suggest synergy with bedaquiline. By targeting the mycobacterial cell wall, benzothiazinones a ect replicating bacilli more than dormant bacilli.

Figure 1: Global pipeline of new tuberculosis drugs2,2224,3148

Used with permission of the Stop TB Partnership Working Group on New Drugs.

GatifloxacinMoxifloxacinRifapentine

AZD-5847LinezolidSutezolidSQ109Novel regimensBedaquilineDelamanidPA-824

CPZEN-45DC-159aQ203SQ609SQ641TBI-166BTZ-043PBTZ-169TBA-354

PreclinicalDiscovery Clinical

CyclopeptidesDiarylquinolinesDprE inhibitorsInhA inhibitorLeuRS inhibitorMacrolidesMycobacterial gyrase inhibitorsPyrazinamide analoguesRiminophenazinesRuthenium(II) complexesSpectinamidesTranslocase-1 inhibitors

Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone

Lead optimisation Preclinical development Phase 1 Phase 2 Phase 3


Review

Phase 2a early bactericidal studiesThe most successful approach to yield novel drugs has been to re-engineer old antibacterial drug classes and improve their antimycobacterial potencies.23,28 Examples of such redesigned sca olds are the nitroimidazoles (delamanid, PA-824, and TBA-354) and 1,2-ethylenediamine (SQ109). Oxazolidinones such as linezolid were developed for Gram-positive bacterial infections and were later shown to have anti-M-tuberculosis activity. Four modi ed versions of oxazolidinone derivatives (sutezolid, AZD-5847, radezolid, and tedizolid) might have improved activity against M tuberculosis and avoid mye lo -suppressiona problem with linezolid.38,51 These oxazolidinones are being studied in a head-to-head comparison in marmosets to help to select the best candidate for phase 2b studies in people. This study is complemented by studies in the hollow- bre model to determine the degree of inhibition of mitochondrial protein synthesis.52 The development of sutezolid is the most advanced so far.53 In a phase 1, 14 day, early bactericidal study, reductions in bacterial load (measured in decline in colony forming units) were slightly more pronounced in the 600 mg twice a day regimen than in the group given 1200 mg four times a day (009 log per day vs 007 log per day). 14% of patients had transiently increased liver enzyme alanine transaminase and

aspartate aminotransferase.53 A similar phase 2a early bactericidal study in South Africa used di erent doses of AZD-5847 (clinicaltrials.gov identi er: NCT01516203).

Combination of carbapenems with clavulanic acid (a -lactamase inhibitor) has shown promising bactericidal activity against replicating and non-replicating isolates of M tuberculosis.54 Faropenem, an orally active carbapenem, is in a phase 2a early bactericidal study.55 Although the drugs oral bioavailability is better than is that for other carbapenems, its short half-life requires patients to take several doses per day, which makes it impractical for use in individuals with drug-sensitive tuberculosis.

Advances in phase 2b and phase 3 trialsRecent advances in tuberculosis treatment include submissions to regulatory agencies for approval of two new drugs, bedaquiline and delamanid. The US Food and Drug Administration (FDA) used its regulatory path for accelerated approval after review of scarce e cacy data to approve bedaquiline as part of combination treatment for adults with multidrug-resistant tuberculosis when other alternatives are not available.40 European Medicines Agency have recently approved delamanid.41 Combinations between these new drugs with existing antituberculosis therapies could lead to regimens that are better tolerated, shorter, and have fewer drugdrug interactions compared

Figure 2: Mechanisms of action of tuberculosis drugs in preclinical development

DNA

DNA gyrase: quinolones Inhibit DNA synthesis Moxifloxacin Gatifloxacin

RNA polymerase: rifamycins Inhibit transcription Rifampicin Rifapentine Rifabutin

mRNA

Peptide

ADP ATP

H+

2 H+

O2 H2O

ATPsynthase: diarylquinolinesInhibit ATP synthesis Bedaquiline

Cytochrome bc complex:imidazopyridinesEssential for proton gradient and ATP synthesis Q203

Ribosome: oxazolidinones Inhibit protein synthesis Linezolid Sutezolid AZD-5847 Radezolid Tedizolid

Cell wall synthesis: dimethlyamine Inhibit cell wall synthesis (transport and processing) SQ109

Cell wall

DprE1: benzothiazinone Inhibit cell wall synthesis BTZ-043 PBTZ-169

Transpeptidase + -lactamasecarbapenems+ clavulanic acid Inhibit cell wall synthesis Faropenem

InhA: isoniazid Inhibit cell wall synthesis Isoniazid

Arabinosyl transferase: ethambutol Inhibit cell wall synthesis Ethambutol

Respiratory chain

Multiple targets: nitroimidazoles Inhibit cell wall synthesis and cell respiration Delamanid PA-824 TBA-354

Multiple targets: pyrazinamide Including intracellular acidification, disrupts plasma membrane Pyrazinamide

Multiple targets: riminophenazines Targeting the outer membrane and possibly bacterial respiratory chain and ion transporters Clofazimine TBI-166


Review

with existing regimens. Since antituberculosis drugs need to be given in combination to prevent drug resistance, trials are underway with companion drugs to simplify, improve, or shorten treatment regimens for drug-sensitive and multidrug-resistant tuberculosis (table 1, table 2).

Assessment of new drugs and doses in phase 2 trialsPhase 2 trials allow generation of important data for safety, dosing, and e cacy, which guide the planning of phase 3 studies. This approach is being used to test novel drugs, especially those for multidrug-resistant tuberculosis. A phase 2 study of bedaquiline42 added to a background regimen for 2 months signi cantly reduced time to culture conversion in 24 weeks and was well tolerated by patients.56 Moreover, fewer patients developed resistance to the companion drugs in the bedaquiline treatment group than in the control group.43,57 A phase 3 trial is now planned. Since phase 2 data show a signi cantly increased mortality in users, its use in drug-sensitive patients is not indicated until more safety data are available.

Delamanid, developed mainly for multidrug-resistant tuberculosis, has early bactericidal activity and researchers have de ned an optimum dose.44,58 The addition of

delamanid to standard-of-care chemotherapy in patients with multidrug-resistant tuberculosis was associated with a signi cantly higher proportion of sputum culture conversion at 2 monthsie, 454% versus 296%.59,60 In November, 2013, the Committee for Medicinal Products for Human Use of the European Medicines Agency granted a marketing authorisation for delamanid as part of an appropriate combination regimen for multidrug-resistant tuberculosis in adults, which was conditional on the inavailability of an otherwise e ective regimen due to tolerability or resistance issues.41 A phase 3 trial is underway (table 2).

Recognition is increasing that the currently recommended dose of rifampicin (450600 mg) was chosen without investigators doing studies of multiple ascending doses or pharmacokinetics.61,62 Some have called for evaluation and de nition of the e ect of higher doses of rifampicin.61,62 A 2013 study (HIGHRIF2) assessed the safety, tolerability, and pharmacokinetics of 900 mg and 1200 mg doses of rifampicin in combination with the standard regimen components over 2 months. Results of these trials are expected soon. Results from a phase 2a study have shown that use of up to 35 mg/kg of rifampicin over 14 days is safe and well tolerated.62

Trial registration number*

Study groups Phase Status

Rifampicin

HIGHRIF1 NCT01392911 Rifampicin (10 mg/kg vs 20 mg/kg vs 25 mg/kg vs 30 mg/kg vs 35 mg/kg); dose-escalation study

2a Results expected 2014

RIFATOX ISRCTN55670677 2 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (20 mg/kg vs 15 mg/kg vs 10 mg/kg of rifampicin)

2b Results expected 2014

HIGHRIF2 NCT00760149 2 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (1200 mg vs 900 mg vs 600 mg of rifampicin)


HIRIF NCT01408914 2 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (20 mg/kg vs 15 mg/kg vs 10 mg/kg of rifampicin)

2b Recruiting

PanACEA MAMS-TB-01

NCT01785186 Isoniazid, rifampicin (35 mg/kg), pyrazinamide, and ethambutol vs isoniazid, rifampicin (10 mg/kg), pyrazinamide, and SQ109 vs isoniazid, rifampicin (20 mg/kg), pyrazinamide, andSQ109 vs isoniazid, rifampicin (20 mg/kg) pyrazinamide, and moxi oxacin vs isoniazid, rifampicin (10 mg/kg), pyrazinamide, and ethambutol

2b Recruiting

Isoniazid

A5312 NCT01936831 Isoniazid (15 mg/kg vs 10 mg/kg vs 5 mg/kg); includes patients with INHA mutation 2a In development

Rifapentine

TBTC 29X NCT00694629 Isoniazid, rifapentine (20 mg/kg vs 15 mg/kg vs 10 mg/kg of rifapentine), and ethambutol vs isoniazid, rifampicin, pyrazinamide, and ethambutol


RPT study NCT00814671 Isoniazid, rifapentine, pyrazinamide, and ethambutol (600 mg vs 450 mg of rifapentine) vs isoniazid, rifampicin, pyrazinamide, and ethambutol; uses Simons two-stage design


RioMAR NCT00728507 Isoniazid, rifapentine, pyrazinamide, and moxi oxacin (75 mg/kg of rifapentine) vs isoniazid, rifampicin, pyrazinamide, and ethambutol


RIFAQUIN ISRCTN44153044 2 months of moxi oxacin, rifampicin, pyrazinamide, and ethambutol, and then 2 months of moxi oxacin and rifapentine (900 mg) twice a week vs 2 months of moxi oxacin, rifampicin, pyrazinamide, and ethambutol, and then 4 months of moxi oxacin and rifapentine (1200 mg) once a week vs 2 months of isoniazid, rifampicin, pyrazinamide, and ethambutol, and then 4 months of isoniazid and rifampicin

3 Results expected 2014

TBTC S31 4 months of isoniazid and rifapentine supplemented by pyrazinamide and ethambutol in the rst 2 months (1200 mg of rifapentine) vs 6 months of isoniazid and rifampicin supplemented by pyrazinamide and ethambutol in the rst 2 months

3 In development

(Table 1 continues on next page)


Review

Drugs to eradicate persister populations of M tuberculosisInvestigators have described mechanisms and pathways for the formation of persister and dormant M tuberculosis populations,1620 which are being used to guide targeted drug development and treatment regimens for latent tuberculosis infection. Combinations of drugs with adjunct immunotherapy might be needed for more

e ective eradication of persister populations. Up to 90% of M tuberculosis isolates from untreated patients have evidence of lipid bodiesapparent in mycobacterial cells in a dormant state and an important target for drug development,19 in-vitro studies,16,17,63,64 and animal studies.65 A reduced, but still substantial, pool of ATP is maintained during dormancy in persister mycobacteria.66 Targeting of this pool has led to identi cation of 32 clusters of



(Continued from previous page)

Fluoroquinolones

A5307 NCT01589497 Moxi oxacin, rifampicin, pyrazinamide, and ethambutol vs rifampicin, pyrazinamide, and ethambutol vs isoniazid, rifampicin, pyrazinamide, and ethambutol (after 2 days of isoniazid, rifampicin, pyrazinamide, and ethambutol)

2a Recruiting

NIRT 3-weekly46

CTRI/2012 /10/003060

4 months of isoniazid, rifampicin, and gati oxacin supplemented by pyrazinamide in the rst 2 months vs 4 months of isoniazid, rifampicin, and moxi oxacin supplemented by pyrazinamide in the rst 2 months vs 6 months of isoniazid and rifampicin supplemented by pyrazinamide and ethambutol in the rst 2 months; all regimens given three times a week


OFLOTUB NCT00216385 4 months of isoniazid, rifampicin, and gati oxacin supplemented by pyrazinamide in the rst 2 months vs 6 months of isoniazid and rifampicin supplemented by pyrazinamide and ethambutol in the rst 2 months


REMoxTB NCT00864383 4 months of isoniazid, rifampicin, and moxi oxacin supplemented by pyrazinamide in the rst 2 months vs 4 months of rifampicin and moxi oxacin supplemented by pyrazinamide and ethambutol in the rst 2 months vs 6 months of isoniazid and rifampicin supplemented by pyrazinamide and ethambutol in the rst 2 months


NIRT daily CTRI/2008 /091/000024

3 months of isoniazid, rifampicin, pyrazinamide, ethambutol, and moxi oxacin vs 4 months of isoniazid, rifampicin, and moxi oxacin supplemented by pyrazinamide and ethambutol for the rst 2 months vs 4 months of isoniazid, rifampicin, and moxi oxacin supplemented by pyrazinamide and ethambutol for the rst 2 months and given three times a week in the last 2 months vs 4 months of isoniazid, rifampicin, moxi oxacin, and ethambutol supplemented by pyrazinamide for the rst 2 months and given three times a week in the last 2 monthsvs 6 months of isoniazid and rifampicin supplemented by pyrazinamide and ethambutol in the rst 2 months given three times a week throughout

3 Recruiting

SQ109

SQ109 EBA NCT01218217 SQ109 75 mg vs SQ109 150 mg vs SQ109 300 mg vs SQ109 150mg and rifampicin vs SQ109 300 mg and rifampicin vs rifampicin


Sutezolid

Sutezolid EBA NCT01225640 Sutezolid 600 mg twice a day vs 1200 mg four times a day vs isoniazid, rifampicin, pyrazinamide, and ethambutol


AZD-5847

AZD-5847 EBA

NCT01516203 500 mg four times a day vs 500 mg twice a day vs 1200 mg four times a day vs 800 mg twice a day vs isoniazid, rifampicin, pyrazinamide, and ethambutol


PA-824

NC-003 NCT01691534 Bedaquiline, PA-824, pyrazinamide, and clofazimine vs bedaquiline, PA-824, and pyrazinamide vs bedaquiline, PA-824, and clofazimine vs bedaquiline, pyrazinamide, and clofazimine vs pyrazinamide vs clofazimine vs isoniazid, rifampicin, pyrazinamide, and ethambutol


NC-002 NCT01498419 PA-824 (100 vs 200 mg), moxi oxacin, and pyrazinamide vs 2 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (includes cohort with multidrug resistance given PA-824 [200 mg], moxi oxacin, and pyrazinamide)


Paediatric tuberculosis

SHINE 2 months of isoniazid, rifampicin, and pyrazinamide (ethambutol in some settings), and then 4 months of isoniazid and rifampicin vs 2 months of isoniazid, rifampicin, pyrazinamide, and ethambutol, and then 2 months of isoniazid and rifampicin; population included children aged younger than 16 years with minimal disease

3 In development

If dose is not indicated, drugs given once a day. *Trial registration numbers from the following sources: NCT from ClinicalTrials.gov, ISRCTN from Current Controlled Trials, and CTRI from Clinical Trials Registry of India. Trial phases are as follows: phase 2a indicates a 7 or 14 day early bactericidal activity study; phase 2b indicates a study of microbiological endpoints over 812 weeks of treatment; phase 3 is a con rmatory e cacy trial with 1824 months of follow-up.

Table 1: Randomised clinical trials for drug-sensitive tuberculosis


Review

compounds that reduce ATP concentrations and thus are active against non-replicating M tuberculosis.66 Bryk and colleagues67 screened for inhibitors of dihydrolipoamide acyltrans ferase, an enzyme used by the bacterium to resist host-derived nitric oxide reactive oxygen intermediates. The search for inhibitors of M tuberculosis dihydrolipoamide acyltransferase to kill almost exclusively non-replicating mycobacteria led to identi- cation of the rhodanines. The nitroimidazoles, (delamanid and PA-824) and benzothiazinones (BTZ-043) also have some activity against persister mycobacteria. PA-824 was originally developed as an analogue of metronidazole, which kills organisms that had become dormant through anaerobiasis,68 yet this drug is being assessed successfully according to a standard develop-ment pathway.43 Pyrazinamide can be used to kill persisters.69 Furthermore, several drugs are now predicted to have activity against persister populationsnamely, clofazimine, bedaquiline, and the oxazolidonones (sutezolid and AZD-5847). Clinical data are needed to con rm these preclinical data. How a persister-directed or dormancy-directed drug might be assessed in clinical practice is not known.

Advances towards simpler and shorter tuberculosis treatmentsThe need to simplify and shorten treatment for tuberculosis is a long-standing priority. Initial Medical Research Council trials showed that treatment regimens that last 18 months or more were highly e ective when done in randomised trial conditions, but all too often had poor adherence and resulting unfavourable outcomes when applied in programme conditions.11 Trial results for a short-course chemotherapy rst presented in 1972 showed that a 6 month regimen of isoniazid, rifampicin, and streptomycin gave excellent results with respect to

relapse,10,11 which were comparable to or even better than those after an 18 month regimen. The authors emphasised the need to nd short-course regimens that readily lent themselves to practical application in routine treatment services.70

After this trial, researchers made several attempts to simplify the 6 month regimen, particularly to reduce the amount of rifampicin needed because of both its cost and their concern about the development of multidrug-resistant tuberculosis. One option adopted by WHO in their guidelines was to limit the use of rifampicin to the rst 2 months, but to extend the total treatment duration to 8 months by giving thioacetazone and isoniazid in the continuation phase, later changed to ethambutol and isoniazid. Each of these alternative regimens were inferior to the 6 month regimen,71 leading to WHO revising their guidelines in 2010,12 stating that new patients with pulmonary tuberculosis should receive a regimen containing 6 months of rifampicin.12 Expect for in patients with smear-negative disease,71 attempts to shorten duration to less than 6 months for some groups who might have needed less treatment (eg, those without cavitation and with culture conversion by 2 months) did not succeed.72 Internationally, people recognise that 6 months treatment is still too long and there is a need for new drugs to shorten duration.

Since 2000, results from several studies in mice, and later phase 2 trials in human beings, suggested that quinolones could shorten treatment duration.73 Several phase 3 trials were done to assess the role of various uoroquinolones (table 1). Results from three of these trials became available in 2013. The INTERTB consortium in southern Africa presented the results of the RIFAQUIN45 trial in March, 2013. Investigators showed that the 6 month regimen with a once-weekly continuation phase of moxi oxacin and high-dose



C208 NCT00449644 2 weeks of bedaquiline 400 mg, plus 22 weeks of bedaquiline three times a week 200 mg vs placebo plus background regimen

2b Results 2014

MARVEL Bedaquiline, PA824, pyrazinamide, and sutezolid (1200 mg, four times a day) vs bedaquiline, PA824, pyrazinamide, and sutezolid (600mg twice a day) vs bedaquiline, PA824, pyrazinamide, and levo oxacin (600 mg) vs standard of care

2b In development

Trial 204 NCT00685360 8 weeks of delamanid 200 mg twice a day vs 8 weeks of delamanid 100 mg twice a day vs placebo added to optimised background regimen

2b Results 2014

Trial 213 NCT01424670 2 months of delamanid (100 mg twice a day) and then 4 months of delamanid (200 mg four times a day) vs placebo added to optimised background regimen

3 Recruiting

STREAM ISRCTN78372190 9 months of moxi oxacin, clofazimine, ethambutol, and pyrazinamide, supplemented with kanamycin, isoniazid, and prothionamide for the rst 4 months vs local WHO-recommended regimen

3 Recruiting

OPTI-Q NCT01918397 8 weeks of levo oxacin (20 mg/kg vs 17 mg/kg vs 14 mg/kg vs 11 mg/kg), plus optimised background regimen

2b In development

If dose is not indicated, drugs given once a day. *Trial registration numbers from the following sources: NCT from ClinicalTrials.gov, ISRCTN from Current Controlled Trials. Trial phases are as follows: phase 2a indicates a 7 or 14 day early bactericidal activity study; phase 2b indicates a study of microbiological endpoints over 812 weeks of treatment; phase 3 is a con rmatory e cacy trial with 1824 months of follow-up.

Table 2: Randomised clinical trials for drug-resistant tuberculosis


Review

rifapentine was as e ective as the standard 6 month control regimen of daily rifampicin and isoniazid, whereas a 4 month regimen with twice-weekly moxi oxacin and high-dose rifapentine was signi cantly inferior. Although the 6 month regimen does not shorten treatment duration, once-weekly dosage provides the opportunity to simplify treatment and lower the cost of treatment supervision for both patients and health systems.

Two studies were done of whether substitution of a uoroquinolone for ethambutol in the initial intensive phase of the standard 6 month regimen and continuation of a uoroquinolone through the continuation phase could result in a successful, non-inferior, 4 month regimen.46,47 The National Institute for Tuberculosis Research (NIRT) in Chennai did the rst study,46 with investigators comparing one regimen using gati oxacin with one using moxi oxacin, both given for 4 months and, similar to the control regimen, given three times a week. The data and safety monitoring board stopped the trial prematurely, and the authors concluded that the groups given uoroquinolone for 4 months had higher recurrence rates than had controls, although data for the groups given moxi oxacin were not signi cantly inferior in the nal published results. Because of the early termination (and delayed start of the moxi oxacin group), results of the study are di cult to interpret, as readers comments show. The second, the OFLOTUB study,47 is similar in some respects to the REMoxTB trial because it tested a 4 month regimen that substituted gati oxacin for ethambutol in the rst 2 months compared with the standard tuberculosis treatment.47 In the study, 1836 patients in ve African countries (Benin, Guinea, Kenya, South Africa, and Senegal) were randomly allocated to the treatments. The study nished in 2011 and had very good patient retention, and the investigators reported the results at the World Lung Conference in Paris in November, 2013.48 The intervention did not show non-inferiority to controls based on a prespeci ed margin, but there was substantial heterogeneity between trial sites in di erent countries that needs further exploration.

At this stage, it would be premature to conclude that uoroquinolones cannot help to shorten treatment since results are still awaited from the REMoxTB trial (expected early 2014). REMoxTB74 is the rst regulatory phase 3 clinical trial of a treatment-shortening regimen. The investigators aim to nd out whether substitution of moxi oxacin for isoniazid or ethambutol could allow reductions in the duration of tuberculosis chemotherapy to only 4 months and whether this regimen is not inferior to that of the standard 6 month regimen. The primary endpoint is bacteriological failure and relapse. The trial is now completed and researchers report recruiting 1932 patients from Kenya, South Africa, Tanzania, and Zambia, and China, India, Malaysia, Mexico, and Thailand.

Analysis of the results of non-inferiority trials is challenging, particularly those that use composite endpoints.75 The full reports of the RIFAQUIN45 and OFLOTUB47 trials are expected to be published in early 2014, and these will provide more complete information to help interpretation of their results. However, it is important to consider the extent to which the results obtained so far con rm the predictions of what might have been expected to happen from earlier mouse and phase 2 trials. For example, studies in mice of intermittent rifapentine and moxi oxacin had particularly impressive results.76 Phase 2 studies with gati oxacin substituted for ethambutol suggested some evidence for a more rapid culture conversion, although the di erence in culture conversion rates between the gati oxacin and control regimens was much less in the OFLOTUB47 study than in the NIRT trial.46

Wallis and colleagues77 used a meta-regression model to predict that a new 4 month regimen would need to have 2 month culture positivity rates of only 12% of treated individuals to yield relapse rates of no more than 5% of patients, although few studies of duration less than 6 months in this model have been done, and culture positivity at 2 months is not a fully reliable surrogate.68 Although public funders of trials usually do not like dose-ranging studies and prefer rapidly successful phase 3 trials, analyses are needed for whether some of the continuing or completed phase 3 trials have used novel drugs without researchers establishing the appropriate and most e cient dose. Furthermore, potentially useful drugs or entire drug classes should not be dysregarded solely because they had been initially used in very low concentrations.

Combination evaluationPA-824 has now entered phase 2 trials, but as part of a regimen development programme. This scheme has the advantage that patients with multidrug-resistant tuberculosis can be included into the same recruitment process as those with treatment-sensitive tuberculosis. The regimen of PA-824 plus moxi oxacin and pyrazinamide was assessed successfully in an early bactericidal activity study43,44 and a larger trial of this regimen for 8 weeks has now completed. If results are promising, this combination might lead to the development of a phase 3 pivotal trial.

Phase 3 selectionThe novel multiarm multistage (MAMS) trial design compares several regimens simultaneously.7880 Planned interim analyses act as intermediate checkpoints and are used to compare the experimental groups with common controls. Treatment groups that do not show su cient evidence of bene t are dropped on the basis of previously prespeci ed values because weak regimens are unlikely to succeed in phase 3. This approach addresses the most relevant public health question: not which regimen can be used to treat


Review

tuberculosis, but which is the best regimen that clinicians can use to treat tuberculosis? The scale of the barrier is dependent on how much improvement is sought in the trial. As the study progresses, the hurdles are progressively raised for the subsequent interim analysis. This progression means that the analysis done at the end of the trial is based on the trial endpoints that would be used in a pivotal study. Through a series of increasing hurdles, investigators will only choose the best groups (treatments) for phase 3 trials.7880 The MAMS trial being done by the Pan African Consortium for Evaluation of Anti-tuberculosis Antibiotics (PanACEA) is currently recruiting in South Africa and Tanzania and should report results towards the end of 2014. The results of continuing trials will inform the next steps for the development of shorter regimens and the simpli cation of treatment. Approaches should include investigators revisiting the doses of existing drugs such as rifampicin, and carefully considering the use of new drugs such as bedaquiline and delamanid.

Advances in biomarker development for clinical trialsAt present, the endpoints of phase 3 clinical trials are combined failure and relapse. The lack of accurate surrogate biomarkers for trial endpoints necessitates that phase 3 trials involve large numbers of people, and are lengthy and invariably expensive. Because current treatment is 95% curative in trial conditions, non-inferiority designs are required.44 An e ect of using this trial type is that sample sizes are very large.47 Through quanti cation of sequential viable count, it is possible to distinguish between the killing e cacy of regimens,81 but whether these methods can predict success in the registered endpoint is not known. There is a widespread belief that culture conversion at 8 weeks predicts treatment failure and relapse.82 Yet, this relation is dependent on the sterilising e cacy of the regimen after 8 weeks, as was shown in study A in which all regimens were similar at 8 weeks, but the 8 month isoniazid and ethambutol continuation-phase regimen was signi cantly inferior.9

Clinicians can infer a decrease in viable organisms with a rise in the time to positivity using methods for automated mycobacterial culture such as mycobacteria growth indicator tube, which can be used in phase 2 studies.83,84 Detection of M tuberculosis viability by molecular means might make this process more rapid and allow results to be available in clinical real time.85 Investigators must choose the marker carefully because DNA-based tests, including the GeneXpert MTB-RIF assay, remain positive after an extended period,86 and mRNA tests revert to negativity rapidly.87,88 A marker based on rRNA seems to overcome several of these problems and follows viable counts closely; this method is now in assessment in a phase 2b study (MAMS-TB 001).89

Advances in laboratory methods to support tuberculosis trialsSince the original series of clinical trials, there has been a transformation in methods available.44 The importance of microbiological results for the outcome of trial endpoints and treatment has led to better standardisation of laboratory methods. The standard laboratory manual for the REMoxTB trial has been used as a basis of commercial and other academic trials57 and MAMS-TB.90 A template laboratory manual for general use in antituberculosis drug trials is nearing completion and will soon be made available through the Global Alliance. Such an approach must be incorporated widely to allow maximum comparability for phase 2 and 3 clinical trials done by di erent groups in di erent settings.

Automated liquid culture is not only more rapid, but more sensitive, changing the proportion of patients who are culture negative. The GeneXpert MTB-RIF assay is becoming widely adopted and might become the standard screening method for trial entry, as was tested in the MAMS-TB trial.91 Use of Xpert will reduce the risk of patients with multidrug-resistant tuberculosis being recruited because it is more sensitive than smear methods, but some patients will be recruited who are not culture positive. Other molecular susceptibility tests such as GenoType MTBC have helped to exclude patients with multidrug-resistant and extensively drug-resistant tuberculosis at sites in which drug resistance is common.57,91

Molecular technology has also a ected the use of relapse endpoints, with methods such as variable number of tandem repeats able to distinguish between relapse and reinfection.92,93 In a 2013 study, Bryant and colleagues94 did next-generation whole-genome sequencing of patients involved in a phase 3 trial and showed that the patients identi ed as relapsed had fewer than six single-nucleotide polymorphisms between the initial and recurrent M tuberculosis strains, whereas reinfection strains had many hundred single-nucleotide polymorphisms. They also showed that mixed infection was common (six of 47 patients), and that variable number of tandem repeats miscalled six relapse cases. In the future, the implications of these technologies will substantially change clinical trial design.94

Optimum timing of ART in patients with HIV infection who have newly diagnosed tuberculosisThe treatment of patients with HIV who have newly diagnosed tuberculosis is complicated by toxic e ects and pharmacokinetic interactions of tuberculosis and ART.28 Thus, time to initiation of ART is dependent on balance between the risk of HIV disease progression and the risk of having to discontinue treatment because of drug toxic e ects, ART and antituberculosis drug interactions, or high pill burden.95 Immune reconstitution in ammatory syndrome occurs in up to 45% of patients

For the REMoxTB trial see http://www.ucl.ac.uk/infection-immunity/research/res_ccm/ccm_ les/CCM_REMox

For more on the Pan African Consortium for Evaluation of Anti-tuberculosis Antibiotics (PanACEA) see http://panacea-tb.net/


Review

with HIV who start ART while receiving tuberculosis treatment.96 Delay of initiation of ART until after completion of tuberculosis treatment in people with HIV who have active tuberculosis is generally considered to be associated with increased mortality across a spectrum of immunode ciency. Three open-label clinical trials (SAPIT, CAMELIA, and STRIDE9698) assessed the timing of ART, showing that initiation of ART shortly after the start of antituberculosis therapy is associated with lower mortality, especially among people with HIV who have low baseline CD4 cell counts. Results of the TIME99 clinical trial in Thailand showed that, although early ART was not associated with survival advantage, there were trends towards this e ect in those with very low baseline CD4 T cell counts. Although WHO recommendations are that ART100 should be started as soon as possible in the rst 8 weeks of tuberculosis treatment, and that those with CD4 cell counts less than 50 cells per L should receive ART within the rst 2 weeks, the WHO guidelines also state that there is low quality of evidence for optimum timing of ART initiation in patient with HIV and tuberculosis who present with CD4 cell counts greater than 350 cells per L. The e ect of early or delayed initiation of ART on tuberculosis treatment outcomes in people with HIV with newly diagnosed, culture-con rmed tuberculosis is being assessed by investigators in a large phase 4, prospective, multicentre, multicountry (South Africa, Tanzania, Uganda, and Zambia), randomised, placebo-controlled trial (ISRCTN 77861053; results expected March, 2014).101

Adjunct treatments and host-directed therapiesAdjunct immunotherapiesResults of a phase 1 trial of autologous bone-marrow-derived stromal-cell infusions for adjunct treatment of terminally ill patients with multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis in Belarus show that the procedure is safe.102 Phase 2 trials are now planned to assess the e ect of adjunct therapy with mesenchymal stromal cells on microbiological, immunological, and clinical outcomes. Several other adjunct immunotherapy approaches that use a range of cytokines or their inhibitors, or chemical and biological immunomodulatory compounds, are being developed as an adjunct to drugs to improve treatment outcomes for multidrug-resistant tuberculosis, shorten duration of treatment, and prevent relapse.103 These treatments involve use of mycobacterial antigens or inactivated whole-cell environmental mycobacterial preparations to enhance cellular immune responses. Increases in anti-M-tuberculosis immune responses, which reduce collateral damage in in ammatory responses when given with antituberculosis drug regimens, tend to overlook the nutritional status of patients with tuberculosis. Malnutrition is associated with a de cient T-helper-1-type response, resulting in decreased ability to contain M tuberculosis.104 Vitamin D

receptor genotypes, and variations in the LTA4H locus a ect treatment outcomes and the responses to anti-in ammatory therapy in patients with tuberculosis meningitis.105 Various cytokine regimens, including interferon or interleukin 2, have been assessed with variable responses,79 underlining the need for clinically relevant biomarkers to de ne the best timepoint at which patients with tuberculosis are most likely to bene t from adjunct therapies. Reinfections, di erent exposures to M tuberculosis, infection with several M-tuberculosis strains, and the bimodal distribution of latent and active tuberculosis might occur in a patient,106,107 underlying the need to nd the optimum timing for adjunct therapies in the course of antituberculosis therapy.

The e ect of antituberculosis drugs on the immune system has not yet been su ciently addressed; uncertainty about this e ect has also challenged treatment of patients with several drugs simultaneously. The anti-in ammatory e ects of macrolide antibiotics are well known.108 Similar or other e ects mediated by antituberculosis drugs on complex cellular interactions need systematic study. Use of systems immunology in preclinical research and during drug development could help to improve clinical outcomes through personalised medicine and help to de ne clinically relevant patterns of immune reactivity.109 The future of personalised medicine for tuberculosis might also bene t from the use of whole-genome sequencing110 to show the patterns of antibiotic resistance in M tuberculosis strains isolated from patients, enabling highly individual-speci c treatment regimens.

Repurposing of drugs for tuberculosisNon-steroidal anti-in ammatory drugs (NSAIDs) can reduce M tuberculosis load and alleviate lung damage in mice,111 and they show anti-M-tuberculosis activity in phenotypical assays.112 E ux-pump inhibitors such as verapamil and reserpine can reduce macrophage-induced drug tolerance and their addition to standard tuberculosis therapy could potentially shorten the duration of curative treatment.113,114 Phosphodiesterase inhibitors cilostazol and sildena l, when added to the standard treatment, reduced tissue damage, quickened mycobacterial clearance, and shortened time to lung sterilisation by 1 month.115

Need for international cooperation and coordinationThe importance of enhanced communication, coordination, and when appropriate, collaboration, among researchers, funding agencies, governments, and communities cannot be overstated.21,116118 The ultimate therapeutic research goal is not development of single drugs or combinations, but to know which of several combinations, including at least two or three new drugs, will be the best to advance to phase 3. A phase 2 and 3 trial planning-coordination forum of non-commercial


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clinical research sponsors and trial groups was formed in 2012 with the aim of meeting this goal. For the past 2 years, the forum has discussed which combinations will be studied in phase 2 trials to be done by each partner and allows its participating research programmes to bene t from each others experience and to share study results as early as possible. Coordinated study planning avoids redundant projects and helps to achieve synergistic study outcomes, as well as optimum resource use in the era of scarce funding. Barriers to timely implementation of phase 2b trials are also addressed, including leads for studies of drugdrug interactions among tuberculosis drugs and with ART. This coordination allows more e cient discussions with pharmaceutical developers and regulatory authorities for the planning and im-plementation of trials. Furthermore, lack of regulatory capacity stops many countries from rapidly reviewing the new treatment regimens and doing post-marketing and pharmacovigilance surveillance.

The sponsors and research groups in the forum include the Global Alliance for Tuberculosis Drug Development, the National Institute of Allergy and Infectious Diseases and its AIDS Clinical Trials Group Network and Tuberculosis Research Unit, the US Centers for Disease Control and Prevention and its Tuberculosis Research Unit, the European and Developing Countries Clinical Trials Partnership and PanACEA, and the UK Medical Research Council and its funded investigators. The forum presently focused mainly on phase 2 studies and complements the objectives of the Critical Path to Tuberculosis Regimens (CPTR) to bring new combinations into phase 3 trials and gain regulatory approvals as soon as possible. A global trial outcomes registry would con rm safety and e ectiveness of new drugs and treatment regimens.117 There is also a need for

For the Critical Path to Tuberculosis Regimens see http://new.tballiance.org/cptr/

producers, purchasers, and providers to cooperate, and for governments to become more exible116 in adopting new regimens, so that all patients with multidrug-resistant tuberculosis can get second-line treatments without stock-outs of drugs. Achievement of this aim will require more community engagement in design, implementation, and uptake of research.

Conclusion and perspectivesIn the past decade, substantial progress has been made in tuberculosis drug development. Several compounds are in late clinical development and there have been innovative approaches to trials and laboratory methods. However, the pipeline remains inadequate and the specialty cannot be complacent since many more compounds and approaches will be needed to achieve shorter and more e ective regimens that will banish the scourge of tuberculosis worldwide.ContributorsAIZ, MM, and MS initiated the idea of the Review as a follow-up of The Lancet Infectious Diseases 2013 Tuberculosis Series, which they coordinated as guest editors. AIZ coordinated the Review and wrote the rst, subsequent, and nal drafts of the Review. All authors contributed their respective expertise to the text, gures, and references. All authors contributed to the revision and approved the nal version.

Declaration of interestsSTC is a named inventor on patents relevant to this Review (WO2012/066518, WO2009/010163). All other authors declare that they have no competing interests.

AcknowledgmentsFor development of table 1, we thank Michael J Vjecha, from the Institute for Clinical Research, Washington, DC, USA, and Executive Coordinator for US Centers for Disease Control and Prevention Tuberculosis Trials Consortium. We thank Adam Zumla (UCL School of Pharmacy, University College London, London, UK) for technical and administrative assistance. AIZ is supported by UK European Union FP7Rid-RTI programme grant; European Developing Countries Clinical Trials Partnership TB NEAT, PanACEA, and REMox grants; and grants from UBS Optimus Foundation, Switzerland, and National Institute for Health Research Biomedical Research Centre, University College London Hospitals, London, UK. STC is supported by European Communitys Seventh Framework Programme (FP7/200713) under grant agreement number 260872. MH is supported by BmBF grants, European Developing Countries Clinical Trials Partnership PanACEA 2007.32011.013, TB NEAT, PanACEA, and REMox grants. SHG and TDMH are supported by Global Alliance for Tuberculosis Drug Development; and European and Developing Country Clinical Trials Partnership (grants IP.2007.32011.011, IP.2007.32011.012, and IP.2007.32011.013), including TB NEAT, PanACEA, and REMox grants; and Innovative Medicines Initiative Joint Undertaking grant 115337. MM is supported by the European Developing Countries Clinical Trials Partnership, TB NEAT, Vetenskapsrdet, VINNOVA, and HLF (Heart and Lung foundation) Sweden. MS is supported by National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services under contract number HHSN272200800014C.

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Search strategy and selection criteria

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New antituberculosis drugs, regimens, and adjunct therapies: needs, advances, and future prospectsIntroductionHistorical perspectiveNeed for new antituberculosis drugs and regimensDiscovery of new tuberculosis drugsAdvances in preclinical developmentPhase 2a early bactericidal studiesAdvances in phase 2b and phase 3 trialsAssessment of new drugs and doses in phase 2 trialsDrugs to eradicate persister populations of M tuberculosisAdvances towards simpler and shorter tuberculosis treatmentsCombination evaluationPhase 3 selectionAdvances in biomarker development for clinical trialsAdvances in laboratory methods to support tuberculosis trialsOptimum timing of ART in patients with HIV infection who have newly diagnosed tuberculosisAdjunct treatments and host-directed therapiesAdjunct immunotherapiesRepurposing of drugs for tuberculosis

Need for international cooperation and coordinationConclusion and perspectivesAcknowledgmentsReferences

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Zumla Et Al 2014 New TB Drugs