The worldwide epidemic of multidrug-resistant tuberculosis
WHO estimates that a third of the world's population is infected with Mycobacterium tuberculosis. In 2009, there were almost 9 million new cases of tuberculosis and the disease killed almost 1 million people around the world. Since the discovery of the BCG vaccine, and the development of new antibiotics in the 1950s, the incidence of tuberculosis has fallen substantially. From 1995 to 2009, about 49 million people received treatment for the disease, 41 million of whom were cured, saving up to 6 million. However, multidrug-resistant (MDR) tuberculosis—ie, resistance to two of the most potent drugs, rifampicin and isoniazid—threatens to turn the tide against the medical advances of the past century.
Although the problem of tuberculosis and drug resistance is commonly thought to be one that primarily affects developing countries in Africa, a report from the European Centre for Disease Prevention and Control (ECDC) and WHO, released for World Tuberculosis Day on March 24 and summarised by Talha Burki in this issue of The Lancet Infectious Diseases, shows that MDR tuberculosis is a growing problem in Europe. The number of patients with MDR disease in Europe is alarmingly high, with an overall absolute number of 27 765 patients in 2009.
In 2008, WHO estimated that there were 440 000 cases of MDR tuberculosis around the world; but because culture and PCR methods for diagnosis are unreliable for resistant disease, WHO estimates that only 11% of actual cases were detected in 2009. In the past 10 years, an estimated 5 million people developed MDR tuberculosis worldwide, of whom only 1% had access to treatment and almost 1·5 million people died. The global prevalence of MDR tuberculosis could be approaching 1 million.
Treatment of MDR tuberculosis is particularly difficult and costly. The most active drugs against MDR forms of tuberculosis are toxic and need to be taken for a long time. Furthermore, treatment needs to be tailored depending on the particular pattern of antibiotic resistance that has developed. The market for new drugs against tuberculosis is not an attractive one for drug developers because of patients' limited ability to pay for treatment.
How can this alarming rise in MDR tuberculosis be managed? The problem is not limited to particular regions and must be managed on a worldwide basis. The need for more effective treatments and improved diagnostic tools require immediate action. After many years of neglect, progress has been made and at least seven new compounds are under clinical development. A crucial aspect is whether new compounds should be used for the treatment of drug-susceptible tuberculosis or reserved for MDR tuberculosis. Incorporation of new drugs in first-line regimens for susceptible disease might immediately compromise their efficacy in the treatment of drug-resistant disease. Viewing of MDR tuberculosis as a separate entity to susceptible tuberculosis, rather than as a possible outcome of tuberculosis, will help to better curtail the disease and to deliver more targeted drugs.
Recently launched European research projects aim to discover and assess new compounds for the treatment of tuberculosis. More medicine for tuberculosis (MM4TB) aims to validate at least five new drug targets pharmacologically and to discover at least one candidate drug. The Open Collaborative Model for Tuberculosis Lead Optimisation (ORCHID) focuses on testing new drugs against drug-sensitive and drug-resistant tuberculosis. EDCTP is conducting phase 2 and phase 3 clinical trials for antituberculosis drugs and TBPAN-NET is aiming to improve understanding of MDR tuberculosis epidemiology by establishing and integrating basic science research projects. These advances are encouraging, but the outcomes are naturally uncertain and new drugs will not be available for at least 3—5 years.
The increasingly worrying picture of MDR tuberculosis in Europe and other middle-income and high-income countries might increase the interest of pharmaceutical companies in drug discovery projects. And a more competitive market for drugs would certainly benefit drug development and availability. At a national level, domestic funding mechanisms to reduce dependency on donors should be also reinforced. Although new diagnostic tools together with more drug discovery projects will help to control tuberculosis, long-term solutions will require more serious international political and economic commitment. MDR tuberculosis will retain its hold on Europe if the epidemic is not brought under control worldwide.