We restricted our searches to reports published after Jan 1, 1996, in English. We did several searches of PubMed using the search term “tuberculosis” plus “clinical trials”, “biomarkers”, and “drug development”, and individual searches for each of the drugs Q203, SQ109, TBA-354, bedaquiline, delamanid, levofloxacin, moxifloxacin, pretomanid, pyrazinamide, rifapentine, rifampicin, and sutezolid (PNU-100480), and compounds identified by the Stop TB Partnership Working Group for New TB Drugs
ReviewTuberculosis—advances in development of new drugs, treatment regimens, host-directed therapies, and biomarkers
Introduction
WHO estimated that in 2014, 9·6 million people (5·4 million men, 3·2 million women, and 1 million children) fell ill with tuberculosis worldwide.1 The resulting 1·5 million deaths made tuberculosis the leading infectious cause of death globally.1 WHO further estimated 480000 cases (and 190000 deaths) were multidrug resistant (MDR; defined as resistant at a minimum to rifampicin and isoniazid; figure 1), and only a quarter of these cases were reported. An estimated 9·7% of cases of MDR tuberculosis were extensively drug resistant (XDR; defined as MDR plus additional resistance to at least one fluoroquinolone and one second-line injectable drug), and have been reported in 105 countries.1 In 2014, MDR tuberculosis accounted for 3·3% of new tuberculosis cases and 20% of previously treated cases.1 Only half of these patients will successfully complete treatment. Of those patients with outcome data, death (16%), loss to follow-up (16%), and treatment failure (10%) are common1 due to weaknesses in current regimens, national programmes, and operational challenges. MDR tuberculosis thus constitutes a major threat to global public health security. WHO's 2015 annual tuberculosis report1 states that “without new tuberculosis drugs and regimens, it will be very difficult to improve treatment outcomes in the near future”, adding “intensified research and development is one of the three pillars of WHO's Post-2015 Global Tuberculosis Strategy, and will play a crucial role in accelerating the reductions in tuberculosis incidence and mortality required to reach global tuberculosis targets by 2035”.
Many unmet medical needs exist for all forms of tuberculosis (panel). In this Review we describe how these needs can be addressed by recent developments in new and repurposed antimicrobial drugs and host-directed therapies, advances in biomarkers, strategies for regimen development, and opportunities afforded by regulatory innovation.
Section snippets
New and repurposed antimicrobial drugs
Regimens comprising entirely new drugs would be an important therapeutic advance, because they would reduce the present requirement for drug-susceptibility testing, thus simplifying patient care. The current tuberculosis antimicrobial drug pipeline shows eight drugs in phase 2–3 trials (figure 2). Two new drugs (bedaquiline and delamanid) are in confirmatory phase 3 trials, having received accelerated approvals for MDR tuberculosis based on phase 2 data in 2012, and 2014, respectively. However,
Host-directed therapeutics to eradicate infection and prevent lung damage
Scientific interest has recently increased in targeting of host factors to identify new treatments for MDR tuberculosis. Host-directed therapies (HDTs)—including new and repurposed drugs, biologics, and cellular therapies—have been proposed to shorten treatment duration, prevent resistance, and reduce lung injury, by promoting autophagy, antimicrobial peptide production, other macrophage effector mechanisms, and inhibiting mechanisms causing lung inflammation and matrix destruction.45, 46, 47
Advances in tuberculosis biomarkers
Biomarkers are measurable characteristics that can form the basis of surrogate endpoints, thereby accelerating drug development.73 However, progress in tuberculosis biomarkers has been slow.74, 75, 76 In 2015, a blueprint identified important research steps for advances in this area and emphasised collaboration and harmonisation of efforts.77 Four areas of particular interest for new tuberculosis regimens are sputum-culture status, PET, whole-blood bactericidal activity, and gene expression
Shortening of treatment in drug-susceptible tuberculosis
Relapse (the epigenetic persistence and subsequent reactivation of drug-susceptible but phenotypically tolerant, non-replicating bacilli) is the most common adverse clinical outcome in patients with drug-sensitive tuberculosis. The risk of relapse increases as the duration of treatment is reduced.80 Identification of shorter regimens that do not unacceptably increase the relapse risk has been a major research focus.
Efforts to shorten treatment have so far been diverse. Some trials have
Improvement of outcomes in patients with MDR tuberculosis
By contrast with drug-susceptible tuberculosis, poor outcomes in MDR tuberculosis more often are representative of treatment failure rather than relapse.101 Treatment failure precludes patient relapse.102 Relapses are less common in MDR tuberculosis than drug-sensitive tuberculosis, even after accounting for this competing endpoint.103 However, relapse will likely become more important in MDR tuberculosis trials as more effective regimens are studied and shorter treatment durations are judged.
Innovative strategies for new drugs, regimens, and research capacity in MDR tuberculosis
These previously stated observations illustrate the challenges faced by tuberculosis drug developers. In drug-sensitive tuberculosis, researchers must contend with a 6-month regimen that is relatively well tolerated and efficacious in trial conditions, even though it has been difficult to implement in real-world settings and yet more difficult to improve. In MDR tuberculosis, researchers must contend with control regimens requiring up to 3 years of treatment and follow-up, consisting of drugs
Search strategy and selection criteria
References (118)
- et al.
Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in patients with drug-susceptible or drug-resistant pulmonary tuberculosis
Lancet
(2015) - et al.
Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1-infected adults in Abidjan, Côte d'Ivoire: a randomised trial
Lancet
(1999) - et al.
Daily co-trimoxazole prophylaxis in severely immunosuppressed HIV-infected adults in Africa started on combination antiretroviral therapy: an observational analysis of the DART cohort
Lancet
(2010) - et al.
Chronic obstructive airways disease following treated pulmonary tuberculosis
Respir Med
(1989) - et al.
Corticosteroids for prevention of mortality in people with tuberculosis: a systematic review and meta-analysis
Lancet Infect Dis
(2013) - et al.
Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism
Cell
(2011) - et al.
Imatinib-sensitive tyrosine kinases regulate mycobacterial pathogenesis and represent therapeutic targets against tuberculosis
Cell Host Microbe
(2011) - et al.
Abl kinases regulate autophagy by promoting the trafficking and function of lysosomal components
J Biol Chem
(2008) - et al.
Large-scale imatinib dose-concentration-effect study in CML patients under routine care conditions
Leuk Res
(2014) - et al.
Phosphodiesterase-4 inhibition combined with isoniazid treatment of rabbits with pulmonary tuberculosis reduces macrophage activation and lung pathology
Am J Pathol
(2011)
Biomarkers and diagnostics for tuberculosis: a review of progress and current needs and translation into practice
Lancet
Sputum culture conversion as a prognostic marker for end-of-treatment outcome in patients with multidrug-resistant tuberculosis: a secondary analysis of data from two observational cohort studies
Lancet Respir Med
Imaging in tuberculosis
Int J Infect Dis
Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase II trial
Lancet
Global tuberculosis report 2015
Early phase evaluation of SQ109 alone and in combination with rifampicin in pulmonary TB patients
J Antimicrob Chemother
Daily rifapentine for treatment of pulmonary tuberculosis. A randomized, dose-ranging trial
Am J Respir Crit Care Med
Clofazimine for the treatment of multidrug-resistant tuberculosis: prospective, multicenter, randomized controlled study in China
Clin Infect Dis
Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis
N Engl J Med
A four-month gatifloxacin-containing regimen for treating tuberculosis
N Engl J Med
High-dose rifapentine with moxifloxacin for pulmonary tuberculosis
N Engl J Med
Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis
Eur Respir J
High cure rate with standardised short-course multidrug-resistant tuberculosis treatment in Niger: no relapses
Int J Tuberc Lung Dis
High effectiveness of a 12-month regimen for MDR-TB patients in Cameroon
Int J Tuberc Lung Dis
Linezolid for the treatment of chronic extensively drug-resistant tuberculosis
N Engl J Med
Susceptibility of clinical Mycobacterium tuberculosis isolates to a potentially less toxic derivate of linezolid, PNU-100480
Antimicrob Agents Chemother
Activity of PNU-100480 and its major metabolite in whole blood and broth culture models of tuberculosis
Am Soc Microbiol
Promising anti-tuberculosis activity of the oxazolidinone PNU-100480 relative to linezolid in the murine model
Antimicrob Agents Chemother
Addition of PNU-100480 to first-line drugs shortens the time needed to cure murine tuberculosis
Am J Respir Crit Care Med
Population pharmacokinetic/pharmacodynamic analysis of the bactericidal activities of sutezolid (pnu-100480) and its major metabolite against intracellular Mycobacterium tuberculosis in ex vivo whole-blood cultures of patients with pulmonary tuberculosis
Antimicrob Agents Chemother
Pharmacokinetics and whole blood bactericidal activity against Mycobacterium tuberculosis of single ascending doses of PNU-100480 in healthy volunteers
J Infect Dis
In vitro and in vivo activities of three oxazolidinones against nonreplicating Mycobacterium tuberculosis
Antimicrob Agents Chemother
Biomarker assisted dose selection for safety and efficacy in early development of PNU-100480 for tuberculosis
Antimicrob Agents Chemother
Mycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis
PLoS One
Controlled clinical trial of four short-course regimens of chemotherapy for two durations in the treatment of pulmonary tuberculosis. Second report
Tubercle
The rationale for using rifabutin in the treatment of MDR and XDR tuberculosis outbreaks
PLoS One
Predicting differential rifamycin resistance in clinical Mycobacterium tuberculosis isolates by specific rpoB mutations
Int J Tuberc Lung Dis
Rifabutin for treating pulmonary tuberculosis
Cochrane Database Syst Rev
Antituberculous activity of compound B-663
Ann Inst Pasteur (Paris)
Absorption, distribution and retention of the riminocompounds in the experimental animal
Ir J Med Sci
Double-blind controlled clinical trial of clofazimine in reactive phases of lepromatous leprosy
BMJ
Results of a standardised regimen for multidrug-resistant tuberculosis in Bangladesh
Int J Tuberc Lung Dis
Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis
Am J Respir Crit Care Med
Clofazimine shortens the duration of the first-line treatment regimen for experimental chemotherapy of tuberculosis
Proc Natl Acad Sci USA
Limited activity of clofazimine as a single drug in a mouse model of tuberculosis exhibiting caseous necrotic granulomas
Antimicrob Agents Chemother
ERS/WHO Tuberculosis Consilium assistance with extensively drug-resistant tuberculosis management in a child: case study of compassionate delamanid use
Eur Respir J
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