It's not hard to see why the World Health Organization is reluctant to adopt the term "totally drug resistant" (TDR) to describe the growing number of strains of tuberculosis that seem to be proving unresponsive to any kind of drug therapy.

Cases of TDR-TB were reported by researchers in India in January this year. The term is not new – it had been used in Italy in 2007 and in Iran in 2009 to describe TB cases that were resistant to all second-line drug classes.

But there is some dispute over whether TDR is an appropriate description for these cases, or whether they represent the next iteration of what has been known since 2006 as "extensively drug-resistant" TB (XDR-TB).

The WHO is among those who believe there is not enough evidence as yet to adopt a new case definition, a position it says was taken at a meeting it held in Geneva on 21-22 March. The meeting concluded that current drug susceptibility testing (DST) lacks accuracy for several drugs used to treat multi-drug resistant TB (MDR-TB) and XDR-TB, and that there is not enough correlation of DST results with clinical response.

Furthermore, it noted, there are a number of new drugs in the pipeline that could offer an effective treatment for these unresponsive cases. The WHO will no doubt also be wary of adopting a term that gives the impression that, in the fight against TB, all is lost.

Gaining the upper hand

Nonetheless, in many parts of the world resistant TB strains do seem to be gaining the upper hand. In a statement issued just before World TB Day on 24 March, Médecins Sans Frontières said that 65% of the patients it treated in Uzbekistan in 2011 had MDR-TB, and of those, some 30-40% had presented to the clinic for the first time, indicating that drug resistance is not only fuelled by incorrect treatment of TB but is also transmitting in its own right.

In South Africa, MSF saw a 211% rise in TB diagnoses per month in its programme in KwaZulu Natal, with 13.2% of those cases resistant to rifampicin, one of the most effective first-line drugs. About 99,000 people are infected with MDR-TB each year in India, with only 1% receiving adequate treatment.

Experts at the Geneva meeting described the rise in resistant TB as "a wake-up call" to health ministries around the world. They said the TB community needed to make greater efforts to prevent drug resistance and scale up the provision of care and management to "avoid a scenario where TB becomes incurable".

The growth in resistant cases is indeed alarming. TB is already the second most common cause of death worldwide due to a single infectious agent, after HIV. 12 million are thought to have the disease. While TB cases in general have been in decline, the WHO predicts that by 2015 more than 2 million will have the MDR strain. MSF says that the global scope of MDR-TB is "much more vast than previously estimated", noting that fewer than 5% of TB patients have access to proper diagnosis for drug resistance.

The problem is that MDR-TB is caused by a multiplicity of factors: inappropriate and excessive use of medicines (many are available over the counter), failure to complete the six-month treatment course, and poor-quality or substandard drugs.

Moreover, according to MSF, fewer than 5% of patients worldwide have access to proper diagnosis of drug resistance. In 2010, only 20 of 36 countries with a high burden of TB or MDR-TB had at least one laboratory per 5 million people capable of performing TB culture and DST, with much of Africa and India poorly served, says WHO.

Lack of new drugs

Matters aren't helped by the lack of new treatments to replace those that no longer work. There are some products in the pipeline, but as with other anti-infective drugs, the low financial returns act to deter significant industry investment. Because of this, as well as the multifactorial nature of TB infection and the need for combination treatments, it looks as if future efforts will need to be made via routes such as public-private partnerships.

As reported recently ( scripintelligence.com, 20 March), the TB Alliance is running a Phase IIb trial assessing a three-drug oral regimen against MDR-TB, consisting of Novartis's nitroimidazole, PA-824, together with Bayer's moxifloxacin and pyranimide, in Africa and South America. The regimen is expected to reduce treatment time to four months and bring down treatment costs by 90%.

There is also a need for novel classes of drug to help overcome the resistance problem. One such product is in late-stage development: J&J's bedaquiline, a diarylquinoline that inhibits the ATPase enzyme that is vital in producing energy in TB bacteria. This product too is being developed by the TB Alliance under a royalty-free licence from the J&J subsidiary Tibotec. In a recent Phase II trial it reduced the time for sputum to become TB negative; the trial is to be extended to South Africa, Peru, Latvia, India, Brazil, Thailand, the Philippines and Russia.

Funding problems

But as with other diseases that predominantly affect the developing world, bringing new drugs to the market is of little benefit to resource-poor countries that cannot afford current treatments, not to mention the new rapid diagnostic tool.

Matters have not been helped by the decision in November 2011 by the Global Fund to fight AIDS, Tuberculosis and Malaria to cancel a round of funding grants, which MSF says "comes at a time when scale-up of DR-TB programmes is most needed". Without 'Round 11', no new grants for scale-up will be disbursed until 2014, "leaving countries unable to aggressively tackle their epidemics", it says.

Medicines access and poverty campaigners say the fund has been an invaluable resource in tackling the disease, and has helped to avert 4.1 million deaths. The UK anti-poverty group Results UK says that an expected $1.7 billion cut in funding for TB over the next five years means there is a risk of "severe backsliding" that could lead to 1.7 million more deaths.

More than 80% of external funding for TB control is channelled through the fund, which is credited with having helped to tackle the disease on a global level. Campaigners have called for donor governments to increase their contributions to the fund so that it can continue its work in this area. Governments will have the chance to do just that at the G20 summit in Mexico on June 18-19.