We searched English-language publications using PubMed and Google Scholar (articles published from Jan 1, 1940, to Jan 8, 2014), the Cochrane Library (published from Jan 1, 2001, to Dec 31, 2013), and Embase (published from Jan 1, 2001, to Dec 31, 2013) with the terms “tuberculosis”, “TB”, “mycobacterium tuberculosis”, “drugs”, “new drugs”, “repurposed drugs”, “re-engineering and drugs”, “treatment”, “regimens”, “treatment regimens”, “trials”, “clinical trials”, “EBA”, and “adjunct
ReviewNew antituberculosis drugs, regimens, and adjunct therapies: needs, advances, and future prospects
Introduction
In 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 8·6 million, including 2·9 million cases in women and 530 000 in children. Tuberculosis caused 1·3 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 fifth 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.
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Historical perspective
Aug 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 purified from Streptomyces griseus and the first substance with an effective bactericidal action against M tuberculosis.5 Within 1 year of its discovery, streptomycin provided the first hope for tuberculosis drug treatment.6 Results of small observational studies of
Need for new antituberculosis drugs and regimens
Although current treatment regimens for drug-sensitive tuberculosis are highly effective when adherence of patients is optimum and under trial conditions,9, 10, 11 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 first
Discovery of new tuberculosis drugs
In February, 2000, representatives from academia, industry, major government agencies, non-governmental 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
Advances in preclinical development
The discovery of entirely new and novel compounds remains challenging. After whole-genome sequencing of M tuberculosis, much effort was put into genome-derived, targeted approaches, which have yet to realise their potential.28 A major advance in the screening efficacy 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
Phase 2a early bactericidal studies
The 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 scaffolds 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 modified versions of oxazolidinone derivatives (sutezolid,
Advances in phase 2b and phase 3 trials
Recent 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 efficacy 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
Assessment of new drugs and doses in phase 2 trials
Phase 2 trials allow generation of important data for safety, dosing, and efficacy, 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 significantly 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
Drugs to eradicate persister populations of M tuberculosis
Investigators have described mechanisms and pathways for the formation of persister and dormant M tuberculosis populations,16, 17, 18, 19, 20 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 effective eradication of persister populations. Up to 90% of M tuberculosis isolates from untreated patients have evidence of lipid bodies—apparent in mycobacterial
Advances towards simpler and shorter tuberculosis treatments
The 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 effective 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 first presented in 1972 showed that a 6 month regimen of isoniazid, rifampicin, and
Combination evaluation
PA-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 moxifloxacin 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
Phase 3 selection
The novel multiarm multistage (MAMS) trial design compares several regimens simultaneously.78, 79, 80 Planned interim analyses act as intermediate checkpoints and are used to compare the experimental groups with common controls. Treatment groups that do not show sufficient evidence of benefit are dropped on the basis of previously prespecified values because weak regimens are unlikely to succeed in phase 3. This approach addresses the most relevant public health question: not which regimen can
Advances in biomarker development for clinical trials
At 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 effect of using this trial type is that sample sizes are very large.47 Through quantification of sequential viable count, it is possible
Advances in laboratory methods to support tuberculosis trials
Since 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
Optimum timing of ART in patients with HIV infection who have newly diagnosed tuberculosis
The treatment of patients with HIV who have newly diagnosed tuberculosis is complicated by toxic effects 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 effects, ART and antituberculosis drug interactions, or high pill burden.95 Immune reconstitution inflammatory syndrome occurs in up to 45% of patients with HIV who
Adjunct immunotherapies
Results 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 effect of adjunct therapy with mesenchymal stromal cells on microbiological, immunological, and clinical outcomes. Several other adjunct immunotherapy approaches that use a range of cytokines
Need for international cooperation and coordination
The importance of enhanced communication, coordination, and when appropriate, collaboration, among researchers, funding agencies, governments, and communities cannot be overstated.21, 116, 117, 118 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 clinical
Conclusion and perspectives
In 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 effective regimens that will banish the scourge of tuberculosis worldwide.
Search strategy and selection criteria
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