Twenty years ago, tuberculosis (TB) was one of the least glamorous branches of medicine. The cause had long been known, as had the cure, so all that was left was the unromantic slog of reducing the poverty, hunger and overcrowding that fostered the disease, and working out better ways to get patients to comply with the lengthy course of treatment needed to cure it.
But in 1993 the sudden upsurge in TB cases associated with HIV and AIDS, and the growth of multidrug-resistant (MDR) strains of the bacterium, led the World Health Organization (WHO) to declare the disease a global emergency, which unlocked research funding. Now we are beginning to see the results.
Authors contributing to a special series of articles published by the London-based medical journal, The Lancet, note that "these investments have led to the most promising pool of new tuberculosis drug and vaccine candidates in more than 40 years, with several new drugs and drug regimens poised to enter late-stage clinical trials throughout the next few years."
The new drugs are not here yet, so much of the scientific debate centres on new tools for managing the MDR outbreak, used with the available drugs. One of the most promising, but also one of the most controversial, of these new tools is a diagnostic kit known as the GeneXpert MTB/RIF assay, endorsed by the WHO in 2010.
It works by identifying DNA sequences and their mutations, in this case of the TB bacterium and the changes that make it resistant to the most basic of TB drugs, Rifampicin. The GeneXpert is a lot more sensitive than the traditional microscope test for TB, and far quicker than more accurate tests where the bacteria are grown in a laboratory. Culture tests, used for smear-negative patients, take an average of 56 days from acquiring the sample to getting the patient started on a suitable treatment. The new machine cuts that delay to less than a week.
In the first article in The Lancet series, a group of researchers led by Prof Alimuddin Zumla, of University College, London, describe the testing kit as 'a landmark event in tuberculosis research', but debate whether the benefits are worth the very substantial development costs. Even at the most discounted price for the poorest countries, the equipment and software amount to $17,000, plus just under $10 for the cartridge needed for each individual test. In South Africa, which has gone furthest in adopting the technology, it is expected to increase the annual cost of the TB diagnosis programme by more than 50 percent.
The authors conclude that although the tests are very good, they are still far from perfect. Live bacteria can’t be distinguished from those killed by treatment, so tests can't be used to discover whether treatment has been successful. The technology also does not work as well on children or people co-infected with HIV, although this is also the case with older testing methods.
The GeneXpert tests are easy to do, and staff don't have to be trained lab technicians, but the equipment is delicate. It needs air-conditioned surroundings with constant power, and a good supply chain for the cartridges, which don't have a long shelf life. These requirements make it difficult to put the equipment where it is needed most - the clinics, often in rural areas, where patients first arrive with TB symptoms.
The study group points out that other diagnostic tools are in development, including hand-held systems the size of smartphones, urine dip-sticks, and even breathalyzers. "Several fully automated assays that compete with the Xpert MTB/RIF assay, and that will be more applicable for point-of-care, are likely to be developed in the future. However, how the donor assistance that has heavily subsidized the implementation of Xpert MTB/RIF in resource-limited settings will affect the development and entry of newer diagnostic assays to the marketplace in not clear. Commercially, funding is not a level playing field."
Other writers contributing to The Lancet series are more excited about the GeneXpert system's potential for tracking drug resistance, which is spreading at a frightening rate, especially in countries that can afford first-line TB drugs but have weak healthcare systems, such as India, China, Russia and Brazil. In Minsk, Belarus, almost 50 percent of TB cases are multidrug-resistant.
A group led by Dr Marco Schito, of the National Institutes of Health in Bethesda, Maryland, discusses how the test should be applied in a paper entitled 'Drug Susceptibility Testing, a Framework for Action'. Should every patient be tested for both the TB bacterium and the resistant strain? Test all patients diagnosed with TB? Or only those treated for TB in the past - a more economical approach when rates of resistance are not high?
The paper also argues that we need to develop tests for new drugs most likely to be the backbone of treatment in the future, so that surveillance work can track emerging drug resistance. "Generally, surveillance is restricted to activities that align with current rather than future treatment priorities," the authors comment. "Such data are insufficient to assess development and implementation priorities for new tuberculosis regimens and diagnostics."
The emergence of MDR and extremely drug-resistant (XDR) TB is alarming - at present, scientists can only guess how widespread these new forms of TB are. In 2011 less than 4 percent of new TB cases and 6 percent of previously treated cases were tested for resistance to first-line drugs. The new DNA-based assays could improve this dramatically, but would then raise the question of how to treat a possibly far higher number of drug-resistant patients.
The second-line treatments now available are lengthy, expensive, poorly tolerated and not very effective. People with strains of drug-resistant TB could spread these, but there is also no way that a large volume of patients could be kept in hospital for the length of time needed to effect a cure. New drugs and new combinations of drugs are urgently needed.
The Lancet series calls for visionary global leadership. "The global economic crisis and reduced investments in health services threaten national tuberculosis programmes and the gains made in global tuberculosis control. The world needs to acknowledge the serious threat of drug-resistant tuberculosis before it overwhelms health systems, as is being seen in several countries in the Soviet Union."