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Tuberculosis treatment and management—An update on treatment

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Article  in  The Lancet Respiratory Medicine · March 2015

DOI: 10.1016/S2213-2600(15)00063-6

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 Rapid Review
Lancet Respir Med 2015;
3: 220–34
Division of Infection and
Immunity, University College
London and National Institute
for Health Research (NIHR)
Biomedical Research Centre,
UCL Hospitals NHS Foundation
Trust, London, UK
(Prof A Zumla FRCP); Kenya
Medical Research Institute,
Nairobi, Kenya (J Chakaya MD);
WHO Collaborating Centre for
Tuberculosis and Lung
Diseases, Fondazione
Salvatorie Maugeri, Care and
Research Institute, Tradate,
Italy (R Centis ME,
L D’Ambrosio MA,
Prof G B Migliori FRCP);
European Developing Countries
Clinical Trials Partnership, Cape
Town, South Africa
(T Nyirenda MD); UNZA-UCLMS
Research and Training Project,
University Teaching Hospital,
Lusaka, Zambia (M Bates PhD,
D Chanda MMed,
P Mwaba FRCP, Prof A Zumla);
National Tuberculosis
Programme, Ministry of
Community Development,
Ministry of Health, Lusaka,
Zambia (N Kapata MMed);
National Institute for Medical
Research, Muhumbili, Tanzania
(S Mfinanga PhD); Division of
Infectious Diseases and Tropical
Medicine, Medical Centre of the
University of Munich, and
German Center for Infection
Research (DZIF), partner site
Munich, Munich, Germany
(Prof M Hoelscher FRCP); and
Therapeutic Immunology,
Departments of Laboratory
Medicine, Karolinska Institutet
and Center for Allogeneic Stem
Cell Transplantation, CAST,
Karolinska Hospital,
Stockholm, Sweden
(Prof M Maeurer FRCP)
Correspondence to:
Prof Alimuddin Zumla, Centre for
Clinical Microbiology, UCL
Division of Infection and
Immunity, Royal Free Hospital,
London NW3 2PF, UK
a.zumla@ucl.ac.uk
220
Tuberculosis treatment and management—an update on
treatment regimens, trials, new drugs, and adjunct therapies
Alimuddin Zumla, Jeremiah Chakaya, Rosella Centis, Lia D’Ambrosio, Peter Mwaba, Matthew Bates, Nathan Kapata, Thomas Nyirenda,
Duncan Chanda, Sayoki Mfinanga, Michael Hoelscher, Markus Maeurer, Giovanni Battista Migliori
WHO estimates that 9 million people developed active tuberculosis in 2013 and 1·5 million people died from it.
Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis continue to spread worldwide with an
estimated 480 000 new cases in 2013. Treatment success rates of MDR and XDR tuberculosis are still low and
development of new, more effective tuberculosis drugs and adjunct therapies to improve treatment outcomes are
urgently needed. Although standard therapy for drug-sensitive tuberculosis is highly effective, shorter, more effective
treatment regimens are needed to reduce the burden of infectious cases. We review the latest WHO guidelines and
global recommendations for treatment and management of drug-sensitive and drug-resistant tuberculosis, and
provide an update on new drug development, results of several phase 2 and phase 3 tuberculosis treatment trials, and
other emerging adjunct therapeutic options for MDR and XDR tuberculosis. The use of fluoroquinolone-containing
(moxifloxacin and gatifloxacin) regimens have failed to shorten duration of therapy, and the new tuberculosis drug
pipeline is sparse. Scale-up of existing interventions with increased investments into tuberculosis health services,
development of new antituberculosis drugs, adjunct therapies and vaccines, coupled with visionary political
leadership, are still our best chance to change the unacceptable status quo of the tuberculosis situation worldwide and
the growing problem of drug-resistant tuberculosis.
Introduction from 8·6 million estimated in 2012. The western Pacific
Tuberculosis is still a global emergency.1 The WHO 2014 and southeast Asia regions had 56% of tuberculosis
global tuberculosis report2 estimates that in 2013 cases, with India (24%) and China (11%) bearing the
9 million new cases of tuberculosis occurred, an increase highest burden. 25% of cases were from the WHO Africa
region. An estimated 1·1 million of the 9 million new
tuberculosis cases (13%) were in people with HIV. In
Key messages 2013, of an estimated 1·5 million deaths attributable to
tuberculosis, 510 000 were in women, 80 000 in children,
• An estimated 9 million people develop active tuberculosis
and 1·5 million people die of it each year and 400 000 in people with HIV. Although standard
• Multidrug-resistant (MDR) and extensively drug-resistant therapy for drug-sensitive tuberculosis is highly effective,
(XDR) tuberculosis continue to spread relentlessly, and shorter, more effective treatment regimens are needed to
reduce the burden of infectious cases.
treatment outcomes are still poor
• More effective treatment regimens are needed to reduce The number of new cases of multidrug-resistant
the burden of infectious cases (MDR) tuberculosis (caused by Mycobacterium tuberculosis
• Trials have shown that fluoroquinolone-containing strains resistant to at least rifampicin and isoniazid) and
of extensively drug-resistant (XDR) tuberculosis (defined
regimens (moxifloxacin and gatifloxacin) do not shorten
the present 6-month duration of therapy by resistance to rifampicin, isoniazid, plus any
• Apart from two new drugs rapidly approved under licence fluoroquinolone and at least one of the three injectable
(bedaquiline and delamanid) for use in MDR disease, the second-line tuberculosis drugs, amikacin, kanamycin,
new tuberculosis drug pipeline remains sparse and capreomycin) continue to increase. An estimated
• Scale-up of existing interventions and improving 480 000 new cases of MDR tuberculosis occurred in 2013,
tuberculosis health services is still the best option to making up 3·5% of the estimated 9 million people who
manage and control the unacceptable status quo of developed tuberculosis that year.2 Of these patients, only
tuberculosis and the growing problem of drug-resistant 97 000 started treatment and 39 000 were on waiting lists,
disease thus leaving a huge number of people untreated.
• WHO global guidelines and recommendations are Treatment success rates for MDR tuberculosis regimens
important and provide evidence-based principles of are still low for both individualised and standard
tuberculosis care in the public and private sectors regimens, resulting in high death rates. MDR and XDR
worldwide, to ensure that an accurate diagnosis is tuberculosis now greatly complicate patient management,
established and proven acceptable treatment regimens particularly in resource-poor national tuberculosis
are used under supervision programmes. The dismal treatment outcomes of MDR
• With dwindling drug treatment options, the need to and XDR tuberculosis highlight the urgent need for
explore other adjunct treatment options, including development of new antituberculosis drugs, treatment
host-directed therapies is growing regimens, and other adjunct treatment approaches to
improve treatment outcomes.
www.thelancet.com/respiratory Vol 3 March 2015
 Rapid Review

We review the latest WHO guidelines and global surveillance of antituberculosis drug resistance and not for
recommendations for treatment and management of management of individual patients. Patients who have
drug-sensitive and drug-resistant tuberculosis and provide received previous antituberculosis treatment, and who
updates from the past 2 years’ literature on the drug- now require retreatment, need special attention because of
development pipeline, results of tuberculosis treatment the risk of inducing drug resistance. Rapid tests for drug-
trials, and adjunct host-directed therapies. susceptibility should be used whenever available to ensure
the appropriate treatment regimen is prescribed. While See Online for appendix
Treatment of drug-susceptible tuberculosis
Guidelines and recommendations for management of Recommended daily dosage Frequent adverse events
tuberculosis are updated regularly, including the
Group 1: First-line oral antituberculosis drugs
WHO-recommended treatment regimens, approved
Isoniazid 5 mg/kg once a day CNS toxicity; increase of liver
antituberculosis drugs, and the dosage of antituberculosis enzymes; gastrointestinal
drugs (table 1 and appendix). Figure 1 shows the clinical intolerance; hepatitis; peripheral
management algorithm for treatment of tuberculosis. neuropathy
Present WHO recommendations3 make a clear Rifampicin 10 mg/kg once a day Discolouration of body fluids;
increase of liver enzymes; fever;
distinction between new cases (ie, patients diagnosed
gastrointestinal intolerance;
with tuberculosis, who have never had tuberculosis hepatitis; hypersensitivity;
treatment or had previously received antituberculosis thrombocytopenia
drugs for less than 30 days) and retreatment cases (ie, Ethambutol 15–25 mg/kg once a day Optic neuritis
those treated previously for more than 30 days). New Pyrazinamide 25 mg/kg (range 20–30 mg/kg) once a day Arthralgia; gastrointestinal
tuberculosis cases (irrespective of HIV status) should be intolerance; hepatitis;
hyperuricaemia
treated with a 6-month regimen of isoniazid, rifampicin,
Group 2: Injectable antituberculosis drugs
pyrazinamide, and ethambutol for the first 2 months
Streptomycin, 15–20 mg/kg Allergy; auditory and vestibular
(intensive phase), followed by isoniazid and rifampicin amikacin, capreomycin, nerve damage; nausea;
for the remaining 4 months (continuation phase).3 kanamycin neuromuscular blockade; renal
Longer duration treatment (ie, more than 6 months) is failure; skin rash
not recommended because it does not show clinical Group 3: Fluoroquinolones
superiority.3 Ofloxacin, levofloxacin 750 (800)–1000 mg once a day CNS toxicity; gastrointestinal
Daily dosing is recommended for the entire duration of intolerance; hypersensitivity
therapy, particularly during the intensive phase of Moxifloxacin 400 mg once a day Dizziness; increase of liver
enzymes; gastrointestinal
treatment; however, a three-times per week dosing intolerance; hallucinations;
regimen can be used provided that directly observed headache; QT prolongation
therapy is done. However the emergence of rifampicin Group 4: Oral bacteriostatic second-line antituberculosis drugs
resistance in HIV-infected isoniazid homozygous rapid Ethionamide, 500 mg for bodyweight <50 kg once a day; CNS toxicity; gastrointestinal
acetylators receiving intermittent treatment is of concern; protionamide 750 mg for bodyweight >50 kg once a day; intolerance; hepatitis
rapid acetylators rapidly inactivate isoniazid thus resulting 1000 mg for bodyweight >70 kg once a day

in favouring rifampicin resistance. Cycloserine 500 mg for bodyweight <50 kg once a day; CNS toxicity; dizziness; psychosis
750 mg for bodyweight >50 kg once a day;
Antituberculosis drugs are available as single-drug 1000 mg for bodyweight >70 kg once a day
loose formulations or as fixed-dose combination Para-aminosalicylic 8 g for bodyweight <70 kg once a day; Gastrointestinal
formulations. Both are recommended for the treatment acid 8–12 g for bodyweight >70 kg once a day intolerance; hypersensitivity
of tuberculosis although the fixed-dose combination is
preferred because it is easier to give, and taking all drugs
Terizidone 600 mg for bodyweight <70 kg once a day; CNS toxicity; dizziness; psychosis
prevents development of drug resistance. Several trials
900 mg for bodyweight >70 kg once a day
have assessed the efficacy, tolerability, and treatment
Group 5: Antituberculosis drugs with unclear efficacy or toxicity, or under assessment for use in
outcomes of loose versus fixed-dose combination. A multidrug-resistant disease
systematic review of these trials4 showed no significant Clofazimine 100–300 mg once a day Discolouration of the skin;
differences between the two formulations in patient gastrointestinal intolerance;
adherence, side-effects, acquired drug resistance, culture ichthyosis
conversion at 2 months, or cure rates. Amoxicillin with 875/125 mg twice a day or 500/250 mg three Gastrointestinal intolerance; rash
clavulanate acid times a day
As part of the new WHO End Tuberculosis Strategy,2
Clarithromycin 500 mg twice a day Gastrointestinal intolerance
universal drug-susceptibility testing (rapid or conventional)
Linezolid 600 mg once a day Anaemia; neuropathy;
is strongly recommended before prescription of an thrombocytopenia
antituberculosis regimen, although this is not universally
Thioacetazone 150 mg once a day Gastrointestinal intolerance;
available in most developing countries and, where the hepatitis; hypersensitivity; vertigo
testing is available, it is limited to referral or tuberculosis
Table 1: First-line and second-line antituberculosis drugs, recommended drug doses, and frequent
research laboratories only. The results of drug-susceptibility
adverse events
testing in this scenario are thus used for routine

www.thelancet.com/respiratory Vol 3 March 2015 221

 Rapid Review
Tuberculosis diagnosis
New tuberculosis case Previously treated tuberculosis case
Treatment regimen Medium/low risk High risk
2 HRZE/4HR (2 months of HRZE multidrug-resistant multidrug-resistant
and 4 months of HR) tuberculosis tuberculosis
Month 2: SS/C evaluation
Month 5/6: SS/C evaluation
If SS+ at month 2 obtain sputum
again at month 3
If SS+ at month 3 obtain culture
and drug susceptibility testing
See appendix table 1
Treatment regimen Regimen design
2 HRZES/1 HRZE/SHRE (2 months of HRZES, 1 month of HRZE, Empirical multidrug-resistant tuberculosis regimen to be changed
and 5 months of HRE, to be changed once drug susceptibility once drug susceptibility testing results are available
testing results are available) See appendix table 1
Month 3: SS/C evaluation
Month 5: SS/C evaluation
Month 8: SS/C evaluation
See appendix table 1
Figure 1: Treatment regimens and monitoring in new, previously treated, and MDR tuberculosis cases
For more details on the tables cited in this figure, please see table 1 in the online appendix (WHO recommended treatment regimens for new and previously treated patients) and table 2 in this Review
(WHO-recommended stepwise approach to design an regimen for multidrug-resistant tuberculosis). H=isoniazid. R=rifampicin. Z=pyrazinamide. E=ethambutol. S=streptomycin. SS/C=sputum smear/
culture. SS+=sputum smear positive.
awaiting results of drug-susceptibility testing, these
patients could be initially treated with an empirical
regimen (ie, isoniazid, rifampicin, pyrazinamide,
ethambutol, and streptomycin for 2 months, followed by
isoniazid, rifampicin, pyrazinamide, and ethambutol for a
month, and isoniazid, rifampicin, and ethambutol for
5 months) in case of medium and low probability of MDR
tuberculosis.
Treatment of drug-resistant tuberculosis
Standardised and individualised treatment
Strategies for the treatment of drug-resistant tuberculosis
have been recently updated.5 The treatment of monodrug-
resistant and polydrug-resistant tuberculosis is addressed
and is largely based on the recommendations from the
2011 WHO guidelines for the programmatic management
of drug-resistant tuberculosis, which underwent systematic
review and analysis of the best data available.6 Table 2
summarises the stepwise approach recommended for the
design of treatment regimens. Thus, tuberculosis
programmes end up using a combination of standardised
and individualised approaches to the treatment of drug-
resistant tuberculosis.
In standardised treatment, suspected MDR tuberculosis
cases should be confirmed by drug-susceptibility testing
222
Multidrug-resistant tuberculosis case
Regimen design Treatment duration
Use at least 4 drugs certain to be effective Treatment should be given for at least
Include drugs from groups 1-5 in a hierarchical order based 20 months, the recommended intensive
on potency phase of treatment being 8 months
Use any of the first-line oral drugs (group 1) that are likely to SS/C evaluation: monthly
be effective
Use an effective injectable agent (group 2)
Use a higher generation of fluoroquinolone (group 3)
Use the remaining group 4 drugs to complete a regimen of
at least four effective drugs
For regimen with fewer then four effective drugs, consider
adding two group 5 drugs
The total number of drugs will depend on the degree of
uncertainty, and regimens often contain five to seven
See table 2
whenever possible. In the absence of patient-specific
drug-susceptibility testing, data from representative
patient populations are used to develop and design
empirical treatment regimens. In individualised
treatment, each treatment regimen is designed on the
basis of the patient’s past history of tuberculosis treatment
and individual results of drug-susceptibility testing.
Where drug-susceptibility testing is unavailable or
restricted to only one or two first-line drugs, a standardised
empirical regimen should be used.
Treatment regimens for MDR tuberculosis
The recommended empirical regimen for MDR
tuberculosis treatment should include at least four
potentially active drugs (table 2): a later generation
fluoroquinolone (moxifloxacin, gatifloxacin, or
levofloxacin) and an injectable aminoglycoside (amikacin,
capreomycin, or kanamycin), plus any first-line drug to
which the isolate is susceptible, such as pyrazinamide,
plus the addition of one group 4 drug (cycloserine, para-
aminosalicylic acid, terizidone, protionamide, or
ethionamide). The drugs classified as WHO group 5
should be included only if four potential active drugs are
unavailable. Thus at least four drugs to which
M tuberculosis is likely to be susceptible are used.
www.thelancet.com/respiratory Vol 3 March 2015
 Rapid Review

The duration of the intensive phase (with injectables) is

Actions needed Drug to consider Notes
a minimum of 8 months, followed by a continuation
phase of 12–18 months. WHO recommends a treatment Step 1 Choose an injectable Kanamycin; amikacin; capreomycin Streptomycin is generally not used
(group 2) drug based on because of high rates of resistance
duration of at least 20 months, with duration of treatment drug-susceptibility in patients with MDR disease
being guided by culture conversion, continuing for testing and treatment
18 months after the date of the first negative culture. history
When patients show no clinical response and cultures Step 2 Choose a higher Levofloxacin; moxifloxacin If levofloxacin (or ofloxacin)
generation of resistance is documented, use
are consistently M tuberculosis positive, the underlying fluoroquinolone moxifloxacin; avoid moxifloxacin
causes should be investigated, such as incorrect drug (group 3) if possible when using bedaquiline
dose, poor quality of drug supply, non-adherence factors, Step 3 Add two or more Cycloserine/terizidone; para- Ethionamide and protionamide
malabsorption, and comorbidities. group 4 drugs until there aminosalicylic acid; ethionamide/ are considered the most effective
The treatment outcomes of present MDR tuberculosis are at least four second- protionamide group 4 drugs; consider treatment
line antituberculosis history side-effect profile and cost;
regimens under operational conditions are still poor; a drugs likely to be drug-susceptibility testing is not
meta-analysis of ten studies from community based effective considered reliable for the drugs in
treatment programmes showed cure rates of only 65% this group
(with 13% dying, 15% defaulting, and 7% treatment Step 4 Add group 1 drugs Pyrazinamide; ethambutol Pyrazinamide is routinely added in
most regimens; ethambutol can
failures).7 Antituberculosis drugs used for MDR disease be added if the criteria for an
can cause several side-effects (table 1) that might lower effective drug are met*; if
patient adherence, and increase the probability of susceptibility to isoniazid is
treatment failure and development of further resistance unknown or pending it can be
added to the regimen until drug-
to second-line antituberculosis drugs. Several ancillary susceptibility testing results
drugs are recommended to counter specific side-effects become available
(appendix). Step 5 Consider adding group 5 Bedaquiline; linezolid; clofazimine; If drugs are needed from this
drugs if four second-line amoxicillin/clavulanate; imipenem group, two or more should be
antituberculosis drugs and cilastatin plus clavulanate; added; drug-susceptibility testing
Treatment of XDR tuberculosis are not likely to be meropenem plus clavulanate; high- is not standardised for the drugs in
The role and optimum number of individual drugs for effective from dose isoniazid; clarithromycin; this group
the treatment of XDR tuberculosis has not yet been groups 2–4 thioacetazone
ascertained since it depends on several variables,
*An antituberculosis drug is thought likely to be effective when the drug has not been used in a regimen that failed to
including host immune status, extent of tissue damage, cure the patient; drug-susceptibility testing done on the patient’s M. tuberculosis strain shows that it is susceptible to
virulence, and resistance patterns of infecting strain of the drug (drug-susceptibility testing for isoniazid, rifampicin, and group 2 and 3 drugs is deemed reliable; drug-
M tuberculosis. Thus, most regimens are tailored for susceptibility testing for all other drugs is judged not reliable enough for individual patient management); no known
resistance to drugs with high cross-resistance; no known close contacts with resistance to the drug; and drug resistance
individual patients, based on drug susceptibility testing surveys show that resistance is rare to the drug in patients with similar tuberculosis history. This final criterion is
results.8 relevant in the absence of drug-susceptibility testing or for drugs in which individual drug-susceptibility testing is not
In the intensive phase of treatment, based on the reliable. Information from all five criteria is not always possible to be ascertained. Therefore, clinical judgment is often
necessary on whether to count a drug as likely to be effective.
evidence from a large cohort of more than 9000 MDR
tuberculosis and 400 XDR tuberculosis cases, at least Table 2: WHO-recommended stepwise approach to design a regimen for multidrug-resistant tuberculosis4
four drugs should be used to treat MDR disease and at
least six active drugs (or more) for XDR disease.6 For the
continuation phase, three drugs are recommended for Randomised controlled trials assessing the efficacy of
MDR disease and four for XDR disease. Patients with adjunctive surgical therapy for the treatment of
quinolone-sensitive strains of M tuberculosis have tuberculosis have not been done and are needed.
improved cure rates. However, cure rates for XDR
tuberculosis cases are still suboptimum. HIV co-infected Implementation of WHO guidelines
patients harbouring MDR and XDR strains of Translation of WHO guidelines into optimum standards
M tuberculosis should be prescribed antiretroviral therapy of care worldwide faces operational difficulties due to lack
because this approach improves survival in this group.9 of adequate laboratory diagnostic services and trained
personnel, difficulties in designing the treatment regimen
Surgical treatment for MDR and XDR tuberculosis for MDR and XDR disease on full spectrum drug-
Surgical excision of diseased lung tissue was used for susceptibility testing, poor availability of second-line
treatment of tuberculosis long before the introduction of tuberculosis drugs, and patient adherence and follow-up
antituberculosis drugs. Surgery for treatment of difficult- issues. The essence of tuberculosis treatment is early case
to-treat MDR or XDR tuberculosis cases is now routinely detection, initiation of appropriate therapy, and guarantee
considered10–12 with variable degrees of success. A systematic of treatment completion and cure. Adherence to 6 months’
review and meta-analysis of 15 clinical studies using tuberculosis treatment is determined by several factors
pulmonary resection for patients with MDR tuberculosis related to patients, health-care providers, and caregivers.
showed an estimated pooled treatment success rate of One of the concerns of treatment has been non-adherence
84%,10 although there were several confounding variables. in the population at large and in specific subgroups of the

www.thelancet.com/respiratory Vol 3 March 2015 223

 Rapid Review

population such as those with comorbidities or those who drugs needs to be carefully monitored. There are well
are homeless, substance misusers, prisoners, refugees, known pharmacological interactions (table 3), and drug–
migrants, or displaced people. Poor adherence is drug interactions are associated with an increased
determined by structural factors, poverty, economic status, probability of adverse events.14–17 For example, the
gender discrimination, social context, health-service concomitant administration of drugs such as tenofovir and
factors and personal factors, and patients’ knowledge second-line injectable aminoglycosides are nephrotoxic,
about tuberculosis. WHO recommendations are important thus baseline assessment of liver and kidney function and
and form a sound basis for national health services to careful regular clinical monitoring are necessary.
formulate and modify their tuberculosis management The most frequent and serious adverse events described
policies for use by a wide range of health-care personnel in co-infected patients are liver dysfunction (mainly in
involved in the diagnosis and management of patients patients treated with non-nucleoside reverse transcriptase
with tuberculosis. Such guidelines also prevent wide inhibitors, isoniazid, pyrazinamide, and rifampicin),
variability in the quality of care provided. Present WHO peripheral neuropathy (mainly associated with stavudine,
global guidelines and recommendations are important didanosine, and isoniazid), gastrointestinal problems,
and provide all national health services and tuberculosis CNS problems, haematological disorders, and hyper-
programmes the same optimum evidence-based principles sensitivity events.14 Gastrointestinal side-effects such as
of tuberculosis care in the public and private sectors, and diarrhoea and malabsorption can hinder achievement of
ensure that an accurate diagnosis is established and proven optimum blood concentrations of antituberculosis drugs.
acceptable treatment regimens are used under supervision. Rifampicin and protease inhibitors are well known
WHO guidelines and the International Standards for inducers and inhibitors of hepatic cytochrome CYP450,
For the Patients’ Charter for tuberculosis care (which includes the Patients’ Charter for leading to inhibition or induction of drug metabolism.
Tuberculosis Care, patients’ Tuberculosis Care, patients’ rights and responsibilities) Increased rifampicin-related glucuronidation reduces the
rights and responsibilities see
represent an opportunity to tackle the challenges of patient blood concentration of zidovudine.14
www.istcweb.org/documents/
istccharter.pdf adherence and follow-up. Interactions between rifampicin and protease
inhibitors,14–17 non-nucleoside reverse transcriptase
Treatment of tuberculosis in patients with HIV inhibitors,16 integrase inhibitors,17 and CCR5 receptor
Drug interactions antagonists14 are well documented. Despite these
Tuberculosis is the most common cause of death in HIV- interactions and their potential clinical consequences,
positive patients.1,13 The widespread rollout and clinical rifampicin-sparing regimens were ineffective in HIV-co-
efficacy of antiretroviral drugs has led to substantial infected patients.14 The reduced peak and trough
reduction in mortality and has contributed to the reduction concentrations of efavirenz and nevirapine and the
in the incidence of opportunistic infections.13 The co- expected reduced pharmacodynamic effect can be
administration of tuberculosis drugs with antiretroviral bypassed by an increase of the anti-HIV drug
concentration, although adverse events are likely to
occur.14 The effect of rifampicin on lowering HIV-protease
Antiretroviral drugs Adverse event inhibitors concentration can be overcome by concomitant
Isoniazid; linezolid Didanosine; Peripheral neuropathy delivery of high-dose ritonavir owing to the increased
stavudine half-life of the coadministered protease inhibitors.
Bedaquiline; isoniazid; para-aminosalicylic acid; Efavirenz; Liver dysfunction Therapeutic drug monitoring when available should be
pyrazinamide; rifampicin etravirine;
maraviroc;
used to optimise dosing. This individualised approach
nevirapine; reduces the risk of adverse events.
ritonavir and protease
inhibitors Optimum timing of antiretroviral drug treatment in
Amikacin; amoxicillin and clavulanate; Abacavir; Skin rash patients with HIV and newly diagnosed tuberculosis
fluoroquinolones; isoniazid; kanamycin; rifampicin; efavirenz;
streptomycin; thiacetazone etravirine; Treatment of patients with HIV and newly diagnosed
nevirapine tuberculosis remains challenging because of the demands
Bedaquiline; pyrazinamide; thiacetazone ·· Arthromyalgia of multidrug therapy with antiretroviral drugs and
Amikacin; capreomycin; kanamycin; streptomycin Indinavir; Renal dysfuction antituberculosis drugs on patient adherence, overlapping
Tenofovir side-effects, drug–drug interactions between the
Amikacin; capreomycin; kanamycin; streptomycin ·· Vestibular and auditory rifampicin-based tuberculosis treatment and antiretroviral
dysfunction drugs such as nevirapine or ritonavir-boosted protease
Amoxicillin and clavulanate; bedaquiline; Didanosine; Gastrointestinal disorders, inhibitors, and increased frequency of tuberculosis-
clarithromycin; clofazimine; ethionamide; protease inhibitors; nausea, vomiting,
fluoroquinolones; linezolid; prothionamide; para- stavudine; diarrhoea, and abdominal associated immune reconstitution inflammatory
aminosalicylic acid; terizidone; thiacetazone zidovudine pain syndrome. The optimum timing of antiretroviral therapy
Cycloserine; fluoroquinolones; terizidone Efavirenz Psychosis initiation in individuals with HIV and newly diagnosed
tuberculosis commencing antituberculosis drug treatment
Table 3: Adverse events attributed to antituberculosis and antiretroviral drugs
needs further definition. Several reported trials18–22

224 www.thelancet.com/respiratory Vol 3 March 2015

 Rapid Review

suggested that early antiretroviral therapy leads to improved
survival of patients with HIV and tuberculosis, especially
those with low CD4+ T cell counts. WHO guidelines
recommend that all patients with HIV and tuberculosis
should be offered antiretroviral therapy irrespective of
CD4+ T cell counts and that tuberculosis treatment should
be started first and followed by antiretroviral therapy as
soon as possible within the first 8 weeks of starting
antituberculosis treatment, and within the first 2 weeks for
those with profound immunosuppression (CD4+ T cell
count <50 cells per μL).23 The guidelines have a specific
caution that there is low-quality of evidence on optimum
timing of antiretroviral therapy initiation in patients with
HIV and tuberculosis who present with preserved
immunity, especially those presenting with CD4+ T cell
counts greater than 350 cells per μL.
A large, multicountry, randomised, double-blind,
placebo-controlled clinical trial24 done under
programmatic settings within health services in sub-
Saharan Africa assessed the effectiveness and safety of
early antiretroviral therapy (initiated 2 weeks after
starting tuberculosis treatment) versus delayed
antiretroviral therapy (initiated at the end of 6 months
tuberculosis treatment) in patients with HIV with smear-
positive culture-confirmed tuberculosis. Randomisation
was by two strata: lower CD4+ T cell strata (220–349 cells
per μL) and higher CD4+ T cell strata (≥350 cells per μL).
The primary endpoint was a composite of tuberculosis
treatment failure, tuberculosis recurrence, and death
within 12 months of initiation of tuberculosis treatment.
Initiation of antiretroviral therapy during tuberculosis
treatment in patients with CD4+ T cell counts of more
than 220 cells per μL did not affect tuberculosis treatment
outcomes of failure, recurrence, or death.24
Treatment of latent tuberculosis infection in
high-risk groups
Latent M tuberculosis infection (LTBI) is defined as a state
of persistent immune response to stimulation by
M tuberculosis antigens without evidence of any clinical
manifestations of active tuberculosis.25 Individuals with
LTBI usually have no signs or symptoms of tuberculosis
but are at risk of developing active tuberculosis disease
when they are immunosuppressed from any cause.
Prevention of LTBI from developing into active
tuberculosis is important in some risk groups. Systematic
testing and treatment of LTBI should be done in people
with HIV, adult and child contacts of pulmonary
tuberculosis cases, patients starting anti-tumour necrosis
factor (TNF) treatment, patients receiving dialysis,
patients preparing for organ or haematological
transplantation, and patients with silicosis. Either
interferon-γ release assays (IGRA) or Mantoux tuberculin
skin test should be used to test for LTBI.25
Testing and treatment of LTBI should be considered
for prisoners, health-care workers, migrants from
countries with high tuberculosis burden, homeless
people, and illicit drug users. Other considerations for
treating LTBI are pregnancy and immunosuppression
due to any cause. In these high-risk groups, LTBI
should be treated to avoid LTBI re-activating to clinical
disease.26 The latest WHO guidelines on LTBI
management (table 4) recommend the following
regimens: 6-month isoniazid; 9-month isoniazid;
3-month regimen of once per week rifapentine plus
isoniazid; 3–4 months’ isoniazid plus rifampicin; or
3–4 months’ rifampicin alone. Individuals should be
asked about symptoms of tuberculosis before being
tested for LTBI and chest radiography should be done

Main recommendations Strength of recommendations

High-income and upper middle-income
countries with estimated tuberculosis
incidence less than 100 per 100 000 population pulmonary tuberculosis cases, patients starting anti-TNF
Resource-limited countries and other middle-
income countries not belonging to the
previous category
Systematic testing and treatment of LTBI should be Strong recommendation
done in people with HIV, adult and child contacts of (low-to-very-low quality of evidence)
treatment, patients receiving dialysis, patients preparing
for organ or haematological transplantation, and
patients with silicosis; either IGRA or TST should be used
to test for LTBI
Systematic testing and treatment of LTBI should be Conditional recommendation
considered for prisoners, health workers, immigrants (low-to-very-low quality of evidence)
from high tuberculosis burden countries, homeless
people, and illicit drug users; either IGRA or TST should
be used to test for LTBI
Systematic testing for LTBI is not recommended in Conditional recommendation
people with diabetes, people with harmful alcohol use, (low-to-very-low quality of evidence)
tobacco smokers, and underweight people unless they
are already included in the above recommendations
People with HIV and children younger than 5 years who Strong recommendation
are household or close contacts of people with (high quality of evidence)
tuberculosis and who, after an appropriate clinical
assessment, are found not to have active tuberculosis
but have LTBI should be treated

LTBI=latent Mycobacterium tuberculosis infection. TNF=tumour necrosis factor. IGRA=interferon-γ release assays. TST=Mantoux tuberculin skin test.

Table 4: Summary of recommendations of indications for LTBI screening and treatment setting18

www.thelancet.com/respiratory Vol 3 March 2015 225

 Rapid Review

Discovery Preclinical development Clinical development

with an increased sputum culture conversion at 2 months
in patients with MDR tuberculosis. Another study31 showed
Good efficacy of delamanid in MDR cases and its ability to reduce
laboratory
Lead optimisation
Preclinical
practice Phase 1 Phase 2 Phase 3 mortality in these difficult-to-treat cases, and more recently
development
Toxicity the drug was used to treat XDR tuberculosis in a child.33
studies
The efficacy and safety of bedaquiline was assessed in a
Cyclopeptides CPZEN-45 PBTZ169 AZD-5847 Delamanid phase 2b trial with a 2-year follow-up of 47 patients with
Diarylquinolines BTZ043 TBA-354 Bedaquiline (OPC-67683)
DprE inhibitors DC-159* Q203 (TMC-207)
MDR disease.34 The proportion of adverse events was low,
InhA inhibitor SQ609 Linezolid with the only exception being nausea.
Indazoles LeuRS SQ641 Novel regimens† In this trial,34 bedaquiline added to the background
inhibitors TBI-166 PA-824
Ureas, macrolides Rifapentine regimen reduced the median time to culture conversion,
Azaindoles SQ-109 compared with placebo, from 125 days to 83 days (hazard
Mycobacterial gyrase inhibitors Sutezolid
Pyrazinamide analogues (PNU-100480)
ratio in the bedaquiline group, 2·44; 95% CI 1·57–3·80,
Ruthenium(II) complexes Tedizolid p<0·001 by Cox regression analysis) and increased the rate
Spectinamides SPR-10199 of culture conversion at 24 weeks (79% vs 58%, p=0·008)
Translocase-1 inhibitors
and at 120 weeks (62% vs 44%, p=0·04). The overall
Chemical classes: incidence of adverse events was similar in the two
Rifamycin; oxazolidinone; nitroimidazole; diarylquinoline; benzothiazinone; ethylenediamine
groups, with ten deaths in the bedaquiline group and two
Figure 2: Tuberculosis drug development pipeline in the placebo group, with no identified relation with the
DprE=decaprenylphosphoryl-β-D-ribose2’-epimerase. InhA=inhibin alpha. LeuRS=Leucyl-tRNA synthetase. study drug.34
*Details for projects listed can be found at http://www.newtbdrugs.org/pipeline.php and continuing projects In terms of new regimens, Diacon and colleagues32,35
without a lead compound series identified can be viewed at http://www.newtbdrugs.org/pipeline-discovery.php.
†Combination regimens: NC-001-(J-M-Pa-Z), Phase IIa, NCT01215851; NC-002-(M-Pa-Z), Phase IIb, assessed the 14-day early bactericidal activity of a regimen
NCT01498419; NC-003-(C-J-Pa-Z), Phase IIa, NCT01691534; PanACEA-MAMS-TB-01-(H-R-Z-E-Q-M), Phase IIb, composed of pretomanid (previously known as Pa-824),
NCT01785186. © WHO 2014 Report. All rights reserved.2 moxifloxacin, and pyrazinamide, which proved to be
significantly higher than that of bedaquiline alone,
to exclude active tuberculosis. Individuals with bedaquiline plus pyrazinamide, bedaquiline plus
tuberculosis symptoms or any radiological abnormality pretomanid, but not to pretomanid plus pyrazinamide
should be investigated further for active tuberculosis.25 and comparable to that of the standard treatment regimen
A major dilemma regarding treatment of LTBI is (isoniazid, rifampicin, and pyrazinamide with strepto-
uncertainty regarding the sensitivity of the infecting mycin or ethambutol). An additional, important finding of
M tuberculosis strain to tuberculosis drugs.27 Strict the study is that the addition of pyrazinamide increased
clinical observation and close monitoring for the the activity of both bedaquiline and pretomanid. This
development of active tuberculosis disease for at least innovative method, which is able to test several drugs at
2 years is recommended as preventive treatment for the same time, opened the way to a new approach in
contacts of MDR tuberculosis cases. antituberculosis treatment, proposing a universal regimen
that would be equally effective on drug-susceptible and
Drug development and treatment trials MDR strains.33 Because rifampicin was not part of the
New drugs regimen, interactions with antiretroviral drugs are not
Figure 2 shows the present tuberculosis drug expected, which solves one of the major clinical problems
developmental pipeline. For the first time in more than in treatment of individuals with both HIV and tuberculosis.
50 years, two new tuberculosis drugs, delamanid and A phase 2b trial36 compared the bactericidal activity of an
bedaquiline,28–32 have been approved by the US and 8-week regimen composed of moxifloxacin, pretomanid,
European regulatory authorities and are now recommended and pyrazinamide (MPa100Z or MPa200Z) with the
by WHO for use as part of combination therapy for MDR standard antituberculosis regimen for drug-susceptible
tuberculosis. In 2013, the European Medicines Agency tuberculosis in sputum smear-positive patients with drug-
(EMA) approved conditional marketing authorisation for susceptible and drug-resistant tuberculosis. The
use of delamanid in adults with MDR tuberculosis as an bactericidal activity in drug-susceptible cases was
addition to a background treatment regimen designed as significantly higher compared with that of the WHO-
per WHO recommendations.6,29 In 2014, the EMA granted recommended regimen after 2 months of treatment. The
conditional marketing authorisation for bedaquiline on experimental treatment was well tolerated and no
the same principles. WHO have put in place policy cardiotoxicity episode of QT interval exceeding 500 ms
guidance for safe and rational use of bedaquiline and was identified.36 Bedaquiline is associated with sudden
delamanid to treat MDR tuberculosis.6 unexpected death and mortality data appear in the product
The first evidence on the effectiveness of delamanid was label including a boxed warning. The use of bedaquiline is
provided by Gler and colleagues,30 who showed that this therefore limited to patients with MDR tuberculosis for
new drug, in combination with a background regimen whom resistance to several other drugs necessitates the
developed according to WHO guidelines,3,5 is associated inclusion of bedaquiline in the treatment regimen.

226 www.thelancet.com/respiratory Vol 3 March 2015


Ongoing trials
Several antituberculosis drug-treatment trials assessing
various combinations of new, repurposed and existing
antituberculosis drugs are being developed or are in
progress (table 5). A phase 3 trial (NCT01424670) is
assessing delamanid (OPC-67683) as an adjunct to an
optimised background regimen for the treatment of
MDR tuberculosis, comparing the outcomes of patients
treated with optimised background regimen plus
delamanid for 6 months versus placebo plus optimised
background regimen. Unique aspects of this trial are that
after the induction phase (2 months), delamanid is
prescribed only once daily, moxifloxacin is part of the
optimised background regimen, and HIV-positive
patients on antiretroviral therapy are included in a sub-
study in Africa. The enrolment of about 500 patients has
been completed, follow up is underway, and the trial
results will be available in 2016.
The use of delamanid for treatment of paediatric MDR
tuberculosis is being assessed in two clinical trials
(NCT01859923 and NCT01856634) that are expected to
end in 2017. In an open-label pharmacokinetic study,
delamanid is added to optimised background regimen
for 10 days. Children successfully completing the study
will be requested to participate in a second study
assessing pharmacokinetic characteristics, safety,
tolerability, and efficacy of delamanid added to optimised
background regimen for 6 months.
Repurposed drugs
Several existing antibiotics are now being repurposed for
treatment of tuberculosis46–48 and some of these are listed
under WHO group 5 drugs (table 1). Linezolid,
meropenem, and co-trimoxazole are being used in off-
label clinical practice to treat pulmonary tuberculosis.
Linezolid is effective, but its use is unfortunately
hampered by severe adverse events.46,47 Meropenem
showed promising efficacy, safety, and tolerability in a
case-control study48 when added to linezolid-containing
regimens. Co-trimoxazole, an old drug used for other
bacterial and protozoal infections, has also shown
potential for treatment of MDR tuberculosis.49
Trials to shorten treatment of drug-susceptible
tuberculosis
Tuberculosis treatment regimens recommended by
WHO for drug-susceptible tuberculosis are highly
effective with cure rates of up to 90% in individuals with
HIV.2 However, they have several inherent difficulties
associated with the long duration of treatment, frequency
of drug administration, and patient adherence. Treatment
shortening could lead to a breakthrough in achievement
of faster tuberculosis control. A major research priority
for the past decade has been development of new
tuberculosis drugs or new treatment regimens that could
shorten the duration of treatment from the current
6–8 month regimens for drug-sensitive tuberculosis.
www.thelancet.com/respiratory Vol 3 March 2015
Rapid Review
Early-phase animal and phase 2 studies50,51 suggested
that fluoroquinolone-containing regimens might allow
for shortening of treatment of uncomplicated, smear-
positive pulmonary tuberculosis. Results have been
published from three large, multicountry, non-inferiority
phase 3 clinical trials39,41,42 designed to assess safety and
test whether the inclusion of a fluoroquinolone in a
modified treatment regimen could shorten the duration
of treatment for drug-susceptible tuberculosis. The high
expectations raised by promising phase 2 data were not
borne out in all three trials.
The Rapid Evaluation of Moxifloxacin in Tuberculosis
(REMoxTB) consortium did the first regulatory
phase 3 clinical trial of a treatment-shortening regimen.42
The study was a randomised, placebo-controlled, double-
blind, phase 3 trial assessing the non-inferiority of two
moxifloxacin-containing regimens in three groups of
patients. The first group of patients (control group)
received isoniazid, rifampin, pyrazinamide, and
ethambutol for 8 weeks, followed by 18 weeks of isoniazid
and rifampin. In the second group, ethambutol was
replaced with moxifloxacin for 17 weeks, followed by
9 weeks of placebo (isoniazid group). In the third group,
isoniazid was replaced with moxifloxacin for 17 weeks,
followed by 9 weeks of placebo (ethambutol group). The
primary endpoint was treatment failure or relapse within
18 months after randomisation. The two moxifloxacin-
containing regimens produced a more rapid initial
decline in bacterial load, compared with the control
group. However, non-inferiority for these regimens was
not shown, which suggests that although replacing one
of the drugs in the standard 6-month treatment regimen
with moxifloxacin caused a more rapid decrease in
mycobacterial load, it does not allow the treatment time
for tuberculosis patients to be shortened to 4 months.
The OFLOTUB trial41 assessed a standard 6-month
regimen that included ethambutol during the 2-month
intensive phase compared with a 4-month regimen in
which ethambutol was substituted with gatifloxacin during
the intensive phase and continued, along with rifampicin
and isoniazid, during the continuation phase. The primary
efficacy endpoint was an unfavourable outcome (treatment
failure, recurrence, death or study dropout during
treatment) measured 24 months after the end of treatment.
The researchers concluded that non-inferiority of the
4-month regimen to the standard regimen with respect to
the primary efficacy endpoint was not shown.
The RIFAQUIN Trial39 assessed two regimens in
which moxifloxacin replaced isoniazid in an intensive
phase followed by either 2 months of standard-dose
rifapentine and moxifloxacin twice per week, or
4 months of high-dose rifapentine and moxifloxacin
once per week. The investigators compared the standard
6-month regimen with two study regimens: 2 months of
daily ethambutol, moxifloxacin, rifampicin, and
pyrazinamide followed by 2 months of twice-per-week
moxifloxacin and rifapentine (2EMRZ/2PM2); or
227
 Rapid Review

Trial registration number Description of study groups Phase Funder/sponsor/group Present status
Patients with drug-sensitive tuberculosis
High-dose rifampicin (R)
HIGHRIF1 NCT01392911 R 10 vs 20 vs 25 vs 30 vs 35 mg/kg 2A European Developing Countries Clinical Trials Partnership/ Published 201537
(dose escalating study) Radboud University Nijmegen Medical Center/Pan African
Consortium for the Evaluation of Anti-tuberculosis Antibiotics
RIFATOX ISRCTN55670677 2HRZE/4HR (20 vs 15 vs 10 mg/kg) 2B St. George’s, University of London/ International Consortium for Completed
Trials of Chemotherapeutic Agents in Tuberculosis (INTERTB)
HIGHRIF2 NCT00760149 2HRZE/4HR (1200 mg vs 900 mg 2B European Developing Countries Clinical Trials Partnership Completed
vs 600 mg) Radboud University Nijmegen Medical Center/Pan African
Consortium for the Evaluation of Anti-tuberculosis Antibiotics
HIRIF NCT01408914 2HRZE/4HR (20 vs 15 vs 10 mg/kg) 2B US National Institutes for Health/Harvard Recruiting
High-dose rifampicin (R) plus moxifloxacin and SQ109
MAMS-TB-01 NCT01785186 HR(35 mg/kg)ZE vs HRZQ vs 2B European Developing Countries Clinical Trials Partnership/ Recruiting
HR(20 mg/kg)ZQ vs HR(20 mg/kg) Ludwig-Maximilians University Munich/Pan African Consortium
ZM vs HRZE for the Evaluation of Anti-tuberculosis Antibiotics
High-dose isoniazid (H)
A5312 NCT01936831 H 15 vs 10 vs 5 mg/kg (includes 2A US National Institutes for Health AIDS Clinical Trials Group In development
inhA mutation)
Rifapentine (P)
Tuberculosis Trials NCT00694629 HPZE (20 vs 15 vs 10 mg/kg) vs 2B Tuberculosis Trials Consortium and Centers for Disease Control Published 201538
Consortium Study 29 HRZE and Prevention
RPT Study NCT00814671 HPZE (600 vs 450 mg) vs HRZE 2B John Hopkin’s Universit/University of Cape Town Results 2015
Rifapentine (P) plus moxifloxacin;
RioMAR NCT00728507 HPZM (7·5 mg/kg) vs HRZE 2B John Hopkin’s University and Universidade Federal do Rio de Results 2015
Janeiro
RIFAQUIN ISRCTN44153044 2MRZE/2M2P2 900 mg vs 3 European Developing Countries Clinical Trials Partnership/St Published 201439
2MRZE/4M1P1 1200 mg vs George’s, University of London/INTERTB
2HRZE/4HR
Fluoroquinolones: gatifloxacin and moxifloxacin
A5307 NCT01589497 MRZE vs RZE vs HRZE 2A US National Institutes for Health AIDS Clinical Trials Group Recruiting
National Institute for CTRI/2012/10/003060 2(HRZG)3/2(HRG)3 3 National Institute for Research in Tuberculosis, India/Indian Published 201340
Research in Tuberculosis, vs2(HRZM)3/2(HRM)3 Council of Medical Research
India 3-per week vs2(HRZE)3/4(HR)3
OFLOTUB NCT00216385 2HRZG/2HRG vs 2HRZE/4HR 3 Institut de Recherche pour le Développement (IRD)/WHO Published 201441
Research and Training in Tropical Diseases
REMoxTB NCT00864383 2HRZM/2HRM vs 2RMZE/2MR 3 Global Alliance for Tuberculosis Drug Development/European Published 201442
vs2HRZE/4HR Developing Countries Clinical Trials Partnership/Pan African
Consortium for the Evaluation of Anti-tuberculosis Antibiotics
SQ-109 (Q)
SQ109-01 NCT01218217 Q 75 mg vs Q 150 mg vs Q 300 mg 2A European Developing Countries Clinical Trials Partnership/ Published 201543
vs RQ150 mg vs RQ300 mg vs R Ludwig-Maximilians University Munich/Pan African Consortium
for the Evaluation of Anti-tuberculosis Antibiotics
Sutezolid (U)
Sutezolid EBA and WBA NCT01225640 U 600 mg twice a day vs 1200 mg 2A Pfizer Published 201444
four times a day vs HRZE
AZD-5847
AZD-5847 EBA NCT01516203 500 mg once a day vs 500 mg 2A US National Institutes for Health, National Institute of Allergy Recruiting
twice a day vs 1200 mg one a day and Infectious Diseases
vs 800 mg twice a day vs HRZE
Pa-824 (Pa) plus bedaquiline and clofazimine;
NC-003 NCT01691534 BPaZC vs BpaZ vs BpaC vs BZC vs Z 2A Global Alliance for Tuberculosis Drug Development Published 201537
vs C vs HRZE
Pa-824 (Pa) plus moxifloxacin
NC-002 NCT01498419 Pa (100 vs 200 mg)MZ vs 2HRZE 2B Global Alliance for TB Tuberculosis Drug Development Results 2015
(includes multidrug-resistant
cohort on PaMZ 200 mg )
(Table 5 continues on next page)

228 www.thelancet.com/respiratory Vol 3 March 2015

 Rapid Review

Trial registration number Description of study groups Phase Funder/sponsor/group Present status
(Continued from previous page)
Paediatric tuberculosis
SHINE ISRCTN63579542 2HRZ(E)/4HR vs 2HRZ(E)/2HR 3 Medical Research Council, UK/Wellcome Trust/UK Department for In development
(children younger than 16 years International Development/University College London
with minimal disease)
Patients with multidrug resistant tuberculosis
Bedaquiline (B)
TMC207-TiDP13-C208 NCT00449644 2 weeks B 400 mg plus 22 weeks B3 2B* Janssen Pharmaceuticals Published 201435
200 mg vs placebo plus
background regimen
Delamanid (D)
Trial 204 NCT00685360 200 mg twice a day vs 100 mg 2B Otsuka Pharmaceutical Development & Commercialization, Inc. Published 201231
twice a day vs placebo plus
optimised background regimen
Trial 213 NCT01424670 2D (100 mg twice a day)/ 4D 3 Otsuka Pharmaceutical Development & Commercialization, Inc. Recruiting
(200 mg once a day) plus
optimised background regimen
Other drugs
Moxifloxacin, clofazimine, ethambutol, pyrazinamide, kanamycin, isoniazid, prothionamide
STREAM ISRCTN78372190 4MCEZKHPro/5MCEZ vs local 3 US Agency for International Development/International Union Published 201445
WHO-recommended regimen Against TB Tuberculosis and Lung Disease/Medical Research
Council, UK
Levofloxacin
OPTI-Q NCT01918397 L (20 vs 17 vs 14 vs 11 mg/kg) plus 2B US National Institutes for Health/Boston University Recruiting
optimised background regimen

For trial phases, phase 2A indicates 7-day or 14-day early bactericidal activity (EBA) studies, phase 2B indicates studies with microbiological endpoints over 8–12 weeks of treatment (*24 weeks of treatment),
and phase 3 indicates confirmatory efficacy trials with 18–24 months of follow-up. For phase 3 trials, the leading number shows the duration of the phase in months with the subscripted number showing the
frequency of dosing per week when less than daily. Pk=pharmacokinetics. EBA=early bactericidal activity. SSCC=serial sputum colony counts. WBA=whole blood assay. DS=drug sensitive. DR=drug resistant.
OB =optimised background regimen. R=rifampicin. P=rifapentine. RBT=rifabutin. H=isoniazid. Z=pyrazinamide. E=ethambutol, M=moxifloxacin. G=gatifloxacin. C=clofazamine, K=kanamycin, L=levofloxacin.
Pro=prothionamide. Q=SQ109. B=bedaquiline. Pa=Pa-824. U=sutezolid. OPC=delamanid. AZD=AZD-5847. LPV/r=Lopinavir plus Ritonavir. EFV=efavirenz.

Table 5: Selected list of randomised clinical trials for drug-susceptible and drug-resistant tuberculosis

4 months of once-per-week moxifloxacin and rifapentine
(2EMRZ/4PM1) in a maintenance phase. The researchers
found that a 6-month regimen that included once-per-
week administration of high-dose rifapentine and
moxifloxacin was as effective as the control regimen.
However, the 4-month regimen was not non-inferior to
the control regimen. This trial shows that although the
regimen cannot be used to shorten duration of therapy,
the 6-month study regimen might turn out to be more
convenient than the present standard of care regimen in
that if directly observed, it will operationally be more
convenient to give from the third month of treatment.
The high costs will be a barrier to general adoption.
In all three trials,39,41,42 observed culture conversion rates
at 2 months were within the predicted confidence
intervals of the phase 2 data, suggesting that
fluoroquinolone-containing regimens were likely to be
superior. The discrepancy between the promising phase 2
trial data, which were used to develop these trials, and
the disappointing phase 3 trial results highlight the fact
that small sample sizes limit the value of predicting the
success of phase 3 treatment-shortening regimens.
These results also show that culture conversion at
2 months can predict potency of the regimen to clear
M tuberculosis bacilli from sputum, but it cannot predict
relapse, which was the major cause for the inferiority of
the fluoroquinolone-containing regimens. Shortening of
tuberculosis treatment is still a worldwide priority and
will be crucial to the achievement of tuberculosis control.
As shown by the REMoxTB and OFLOTUB trials,41,42
phase 3 trials need enormous financial investment and
take many years to complete. Although the studies
described here have established the capacity for large,
multicentre trials across disease-endemic countries, the
design and selection of future experimental regimens
will need to incorporate a triage process that can mitigate
risks while enabling the accelerated assessment of
treatment-shortening regimens.
A phase 3 trial to investigate the safety and efficacy of
bedaquiline when used in combination with short MDR
tuberculosis regimens of 9 and 6 months’ duration
respectively was scheduled to start before the end of 2014.
The trial will take place under the umbrella of the STREAM
trial,45 in which a short regimen of 9 months’ duration
(group B) is being compared with the WHO recommended
standard of care for MDR tuberculosis (group A). Two new
bedaquiline-containing arms will be added: group C is a
9-month oral-only regimen in which bedaquiline replaces
kanamycin, and group D is a shortened simplified 6-month
regimen containing bedaquiline.

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 Rapid Review
The use of four drugs to which the M tuberculosis
isolate is susceptible offers a reasonable probability of
success and prevents selection of additional drug
resistance.34 The availability of the new drugs delamanid
and bedaquiline, either under compassionate use or
purchased (in countries where this is possible and
affordable), poses specific challenges, particularly with
regard to potential toxicities and in the grey area of
concern about their combined use as referred to by
WHO.34,52 No information is presently available about the
potential advantages or combined toxicity of delamanid
and bedaquiline if used together. In a phase 2b trial,
compared with placebo, addition of bedaquiline to a
preferred background regimen for 24 weeks resulted in
faster culture conversion and in significantly more (62%
vs 44%, p=0·04) culture conversions at 120 weeks.
However, compared with the placebo group there were
more deaths in the bedaquiline group. The unexplained
excess mortality identified in the bedaquiline treatment
group,35 and the known effect of the drug in increasing
the QT interval, indicate caution when this drug is added
to complex treatment regimens. WHO has developed
guidance on how to use delamanid and bedaquiline,53–55
and on the programmatic background requirements that
are necessary to prevent toxicity and further development
of drug resistance. Several clinical trials are being
planned to assess the potential of these two new drugs
for shortening treatment regimens, improving treatment
outcomes for MDR tuberculosis, and their toxicities and
interactions with other antituberculosis drugs.
Other clinical presentations of tuberculosis
Apart from drug-resistant tuberculosis, there are several
other clinical presentations of tuberculosis that are
associated with difficulties of diagnosis and poor treatment
outcomes, and for which new treatment regimens and
adjunct therapeutic interventions are needed to improve
management outcomes. These presentations include
tuberculosis-associated immune reconstitution inflam-
matory syndrome, miliary tuberculosis, tuberculosis
meningitis, CNS tuberculomas, spinal and bone
tuberculosis, tuberculosis pericarditis, genitourinary
tuberculosis, abdominal tuberculosis, and ocular
tuberculosis. Any of these conditions can present as
comorbidities with diabetes, chronic liver and kidney
diseases, HIV, and other immunosuppressive states, and
thus be easily overlooked and result in increased morbidity
and mortality.56–58 There have been few advances in the
management of these disorders and further research into
them is needed. Trial data have emerged on tuberculosis
pericarditis, which is a very common presentation to all
points of care in developing countries. Tuberculosis
pericarditis is associated with high morbidity and mortality
even when antituberculosis therapy is given.59,60
Tuberculosis pericarditis is associated with substantial
inflammatory and immune responses,61 which can
paradoxically cause injury to cardiac tissues. The prevailing
230
view is that adjunct host-directed therapies, such as use of
corticosteroids62 or immune-modifying treatment with
environmental mycobacteria,63 could attenuate destructive
inflammatory responses and improve morbidity and
mortality rates. Guidelines for treatment of tuberculosis
pericarditis61 recommend treatment with glucocorticoids
in addition to antituberculosis drugs, although the
evidence base for this recommendation is poor. The IMPI
Trial64 assessed the effects of adjunctive glucocorticoid
therapy and Mycobacterium indicus pranii immunotherapy63
in patients with tuberculosis pericarditis. The trial64 used a
two-by-two factorial design, randomly assigning 1400
patients (two-thirds of them HIV-positive) with definite or
probable tuberculosis pericarditis to either prednisolone or
placebo for 6 weeks and to either M indicus pranii or
placebo, given in five injections over the course of
3 months. The primary efficacy outcome was a composite
of death, cardiac tamponade necessitating peri-
cardiocentesis, or constrictive pericarditis. The results
showed that neither prednisolone nor M indicus pranii had
a significant effect on the composite endpoint.64 New
therapeutic interventions are urgently needed for the
treatment of tuberculosis pericarditis.
Where next?
Tuberculosis differs from most other bacterial
infectious diseases in human beings by requiring
therapy that lasts for at least 6 months for drug-sensitive
tuberculosis and 20 months for drug-resistant
tuberculosis, often complicated by adverse drug events
and pharmacokinetic interactions with other drugs.
Poor treatment outcomes for MDR and XDR
tuberculosis are dependent on several variables, such
as genetic background, nutritional status, extent of
inflammatory and immune response and associated
tissue destruction, the virulence of the infecting
M tuberculosis strain, and other risk factors such as
immunosuppressive therapy and comorbidities.
Available drug treatment and continuing development
of new tuberculosis drugs65 need to be supplemented
with an increased focus on other promising adjunct
therapies. Many questions about MDR and XDR
tuberculosis are still unanswered5 and need serious
political and funding attention to support the
development of new approaches to treatment apart
from new drug development to optimise
antituberculosis therapy and management.
The very high rates of pyrazinamide and ethambutol
resistance in patients with MDR tuberculosis and the
high fluoroquinolone resistance levels in developing
countries is of concern. Particularly, the use of
standardised MDR tuberculosis regimens in the absence
of complete drug-susceptibility testing information (a
situation unfortunately common in several developing
countries) exposes the patient to the risk of treatment
failure and death, and favours the development of
additional drug resistance.5,6
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Worryingly, the success rate of MDR tuberculosis
treatment is only 48% worldwide.2 Weaknesses in
health systems, shortages of resources, and ineffective
treatment regimens coupled with other operational
treatment challenges all contribute to the low cure
rates. The importance of good governance and
improvement of the quality of health services in
preventing the development and spread of MDR and
XDR tuberculosis needs to be emphasised. Otherwise,
we risk losing new tuberculosis drugs soon after they
are introduced. Apart from studies on the optimum
ways of enhancing the effects of newly emerging drugs,
optimum formulations, drug dosing, treatment
duration, route of administration, and phasing drug
combinations, adjunct host-directed therapies are now
being actively explored.
Host-directed therapies
With the restrictions of MDR tuberculosis therapy,
increasing MDR and XDR cases worldwide and drug
treatment options running out, attention has focused on
adjunct host-directed therapy (using repurposed drugs and
immunotherapy) approaches to treatment of MDR and
XDR tuberculosis.65–71 An effective immune system is
crucial to eradicate or contain M tuberculosis infection as
LTBI. In cases of active tuberculosis, M tuberculosis
replication is sometimes associated with excess, ineffective
immune responses and consequential tissue destruction
leading to further ineffective immune responses. Various
ways to reduce these responses or augment protective
responses are being explored in animal and human studies
with widely used drugs.65–75 Analgesic or anti-inflammatory
drugs such as ibuprofen, steroids, leukotriene inhibitors,
and the phosphodiesterase inhibitors cilostazol and
sildenafil, are showing promise in animal models. Efflux-
pump inhibitors such as verapamil71,72 and reserpine,73,76
partly restore susceptibility to antituberculosis drugs, and
decrease inflammation by enhancing autophagy.
Helminthic drugs such as ivermectin augment immune
responses.77
Various immunomodulatory drugs have the potential
to enhance immune responses and need assessment for
their usefulness as adjunct therapies with antituberculosis
drugs to improve cure rates for MDR disease, shorten
duration of therapy, and prevent recurrence. These
include mycobacterial antigens or whole-cell inactivated
environmental mycobacteria and cytokines (interleukin
2, interleukin 7, and interferon γ).75,78
Adjunct cellular therapy using the patient’s own bone-
marrow-derived mesenchymal stromal cells (MSCs)
now presents a viable option for treatment of drug-
resistant tuberculosis since they modulate immune
responses with beneficial trophic activity on damaged
tissues.75,78–80 The anti-inflammatory and tissue-repairing
effects of MSCs might improve management outcomes
in both immunocompromised and immunocompetent
individuals. MSCs interact with the target tissue and the
www.thelancet.com/respiratory Vol 3 March 2015
Rapid Review
patient’s immune system in several ways including
mitochondrial transfer to injured cells.81 MSCs exposed
to a pro-inflammatory environment, such as high TNFα
concentrations in the lungs, produce prostaglandin E2,
which helps to decrease unproductive inflammation.82
A prostaglandin E2 driven profile has been instrumental
in restricting access of interferon type I production
linked to disease exacerbation and increased
M tuberculosis proliferation.83 Clinical treatments with
mesenchymal stem cells, especially for non-infectious
diseases, seem far ahead of the science.84 Thus interest
has focused on infusion of autologous bone-marrow-
derived MSCs for adjunct treatment of MDR and XDR
tuberculosis. Infusion of MSCs was safe in a phase 1
trial in patients from Belarus with MDR and XDR
tuberculosis,80 and randomised placebo-controlled
phase 2 and 3 clinical trials are now needed for
treatment of MDR-tuberculosis in various geographical
settings.
Adjunct cellular therapy is also being considered for
treatment of cardiac diseases including tuberculosis
pericarditis.85
Conclusion
Present WHO global guidelines and recommendations
are important and provide evidence-based principles of
tuberculosis care in the public and private sectors
worldwide, and ensure that an accurate diagnosis is
established and proven acceptable treatment regimens
are used under supervision. With the failure of
fluoroquinolones to shorten duration of chemotherapy,
very sparse pipeline of new tuberculosis drug
Search strategy and selection criteria
We searched publications in English language in PubMed, the
Cochrane Library, Embase, and Google Scholar for the period
Jan 31, 2000, to Jan 31, 2015, to obtain background
information. Since this is a rapid update review of recent
progress, we focused on publications from Jan 1, 2013, to
Jan 31, 2015). The search terms used were “tuberculosis”,
“Mycobacterium tuberculosis”, “TB”, combined with the terms
“drugs”, “new drugs”, “treatment”, “regimens”, “treatment
regimens”, “trials”, “clinical trials”, “EBA”, “adjunct therapy”,
“repurposed drugs”. This search was complemented by
searching publications from Jan 1, 2013, to Jan 31, 2015, on
tuberculosis from the WHO Global TB Department, US Centers
for Disease Control and Prevention, and European Centre for
Disease Prevention and Control websites, the International
Unions Against Tuberculosis and Lung Disease, and searches
on websites of antituberculosis drugs manufacturers and that
of the TB Alliance. We also reviewed studies for the same
period cited by articles identified by this search strategy and
selected those we identified as relevant. Selected review
articles are cited to provide readers with more details and
references than this Review can accommodate.
231
 Rapid Review
development, and dwindling drug treatment options for
MDR tuberculosis, new drug development is urgently
needed, as well as exploration of other adjunct treatment
options, including host-directed therapies. Although
investigations into the basic biology and pathogenesis of
M tuberculosis86 continue, and new tuberculosis drugs
and other therapeutic options are being explored, scale
up of existing interventions, tools, and tuberculosis
health services87 coupled with visionary political
leadership88 is still our best chance to manage and control
the unacceptable status quo of tuberculosis and the
growing problem of drug-resistant tuberculosis.
Contributors
AZ and MM initiated the idea for this Review and together with GBM
developed the first draft of the manuscript. All authors contributed to
further drafts and finalised the manuscript.
Declaration of interests
We declare no competing interests.
Acknowledgments
AZ receives support from the European Union FW7 RiD-RTI Project,
European Developing Countries Clinical trials Partnership (EDCTP), and
the National Institute for Health Research Biomedical Research Centre at
UCL Hospital, London, UK. MH is supported by BmBF grants,
EDCTP—Pan African Consortium for the Evaluation of Anti-tuberculosis
Antibiotics (PanACEA) 2007 32011 013. MM is supported by the EDCTP,
Vetenskapsrådet (VR), Vinnova, and the Heart and Lung Foundation,
Sweden. We thank Michael J Vjecha, Institute for Clinical Research Inc,
Washington DC, USA for supplying information for table 5.
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