More than 50 years after the introduction of effective chemotherapy for tuberculosis, the disease remains unconquered and in many resource-poor countries, especially those blighted by HIV, alarmingly unstable. Although multidrug regimens are available that cure 95% of patients with active, drug-sensitive pulmonary tuberculosis, newer and better drugs are needed because of poor compliance with the 6 months of treatment, interactions with antiretroviral drugs, and the emerging issue of drug resistance.
Of these problems, the long duration of therapy is the most important to overcome, since shorter regimens would increase the proportion of patients who complete treatment, reduce the number who relapse, and improve the overall effectiveness of tuberculosis control programmes. Causes of non-compliance with complex treatment regimens include feeling well long before drugs can be safely set aside and the difficult conditions in most developing countries. In part because of these difficulties, WHO introduced their DOTS strategy in 1993. One of the crucial components of this strategy is the direct observation by trained personnel of patients taking their medications to ensure compliance and help prevent the emergence of drug resistance. Although important for treatment success, this strategy greatly increases the cost of delivering care. That said, regimens to treat multidrugresistant tuberculosis (MDR-TB) are badly tolerated, expensive, relatively ineffective, and must be taken for up to 2 years.
Other than by shortening treatment time, new agents would be considered an advance if they were able to penetrate sites that are difficult to treat, such as pulmonary cavities, empyema, or extrapulmonary locations, or had novel mechanisms of action that were active against infections that are either sensitive or resistant to current drugs. Drugs with long half-lives, allowing for simplification of therapy, are needed, as are those able to target tubercle bacilli in a dormant state, which many think are responsible for late relapse disease and latency. Treatment regimens that can be used safely concurrently with the commonly prescribed protease inhibitors and non-nucleoside reverse transcriptase inhibitors used in highly-active antiretroviral therapy for HIV are also an urgent research priority.
The decline in incidence of tuberculosis in the developed world has been accompanied by a fall in the commercial incentive for pharmaceutical companies to invest in antituberculosis drug research and development. This lack of investment over the past 30 years has resulted in a paucity of new drugs. Unanticipated by most, the explosive AIDS epidemic and deteriorating socioeconomic circumstances in many of the world’s poorest nations has fuelled a worsening of the global tuberculosis epidemic. In response, the Rockefeller Foundation convened a meeting in 2000, in Cape Town, South Africa, to investigate ways to stimulate drug development. From more than 120 attending organisations came the recommendation to form a not-for-profit public-private partnership—the Global Alliance for TB Drug Development (TB-Alliance)—responsible for the development of improved and affordable therapies. Coincident with the growth of the TB Alliance, three major pharmaceutical companies—AstraZeneca, GlaxoSmithKline, and Novartis—formed or developed discovery research units focused on tuberculosis. In the meantime, other companies and organisations, including Otsuka Pharmaceutical, Johnson and Johnson, Lupin, Sequella, the US National Institutes of Health (NIH), the Special Programme for Research and Training in Tropical Diseases (TDR) sponsored by WHO, and the Tuberculosis Trials Consortium (TBTC) sponsored by the US Centers for Disease Control and Prevention continued or initiated work aimed at finding and developing new therapies for tuberculosis.
This renewed interest in drug discovery and development has transformed a bleak picture into one of cautious optimism. There are now potentially useful agents at every stage of the development pipeline with multiple organisations doing clinical trials. The moxifloxacin programme, about to enter phase III, is being undertaken under an umbrella agreement between the TB Alliance and Bayer Pharmceutical, and is investigating the potential for shortening treatment duration by substituting moxifloxacin, in the current first-line regimen, for either ethambutol or isoniazid. Studies to investigate the treatment shortening potential of substituting gatifloxacin for ethambutol are also being done by a product development team supported by TDR and the European Commission. And there are compounds in preclinical development too.
Although this development pipeline is extremely encouraging, there remain many challenges. Development of a new drug active against Mycobacterium tuberculosis is only the start. As was discovered decades ago, the pathology of the disease and the biology of the causative organism mean that treatment with multidrug therapy is required. Thus, the role of new agents must be identified in the context of a treatment regimen. The fact that we now have several potential new agents in clinical trials means that we will soon need a complex series of studies to find the optimum treatment-shortening regimen. We need to devise innovative techniques to approach this challenge. The capacity to do large trials to high clinical-practice standards has diminished during the years of decline, and the infrastructure needed for rapid testing of new drugs needs to be re-established in high-burden countries. Finally, resources are needed, both financial and human, to allow us to take full advantage of and extend the progress made over the past few years.