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© Brendan Bannon |
Drug-resistant TB is on the rise globally. The WHO estimates that around half a million new cases of multi-drug resistant TB (MDR-TB) emerge around the world each year. But only around 2% of those in need are receiving appropriate treatment.
There are many reasons that conspire to lead to this dire situation – treatment of MDR-TB presents enormous challenges for any national programme or medical organisation that takes it on – but the limited availability and irregular supply of drugs creates a major barrier for patients to get access to timely treatment.
Drugs for treating resistant TB: old, toxic and not very effective
A patient is defined as suffering from multidrug-resistant TB (MDR-TB) when they are resistant to at least rifampicin and isoniazid, the two most powerful first-line TB drugs. Patients on MDR-TB treatment are therefore obliged daily to take a combination of drugs from the list below, including one drug that must be injected daily (usually Capreomycin, Kanamycin or Amikacine).
Altogether patients may have to take up to 16 pills a day as well as the injectable and the drug taken in granular form, PAS. In addition patients may well need to take further medicines to counter the impact of the drugs' side effects. The drugs are old and not very effective - many of them had been abandoned because of their toxic side-effects but are now being used again in the absence of any better drug options. Treatment lasts up to 2 years
| Drug name | US FDA approval | Initial indication |
| PAS | 1946 | TB |
| Thiacetazone | 1946 | TB |
| Cycloserine | 1952 | TB |
| Ethionamide | 1956 | TB |
| Kanamycin | 1957 | Treatment of bacterial infections |
| Capreomycin | 1971 | MDR TB |
| Amikacin | 1972 | Treatment of bacterial infections |
| Clofazimine | 1986 | Leprosy |
| Moxifloxacin | 1991 | antimicrobial |
| Levofloxacin | 1993 | antimicrobial |
Individualized treatment – one size does not fit all.
Treating MDR-TB is extremely difficult because there is no standardized treatment. Instead patients must be individually tested to determine which of the TB drugs they have resistance to and their treatment tailored accordingly. Over time a patient may develop further resistances, in which case they will have to change to yet other drugs. Since many of these drugs have toxic side-effects, some patients may have to abandon using them. While it’s true that the pattern of resistance is often consistent within a country, all of this means that it very difficult to predict accurately the drug requirements in treatment projects or country-wide.
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© Braam/MSF |
Producing drugs for drug-resistant TB is not attractive to industry
Only four of the drugs used today to treat drug resistant TB were actually developed intentionally for TB and these all date back fifty years ago or more. They are not only fairly ineffective, they are also expensive. The pharmaceutical industry has largely lost interest in finding a treatment for a disease that hits people in poor countries hardest and has invested little time or resources to produce new drugs that could help patients with this disease
In fact, the age of these drugs could work to the advantage of patients: many of these drugs are no longer under patent and this means that there is no reason why more affordable generic versions could not be produced. But producing drugs to treat drug-resistant TB is not attractive to either originator or generic pharmaceutical companies for several reasons: Firstly, although drug resistant TB is on the rise globally, the comparative numbers of cases and so represents too small a market to attract companies to invest in products. Secondly, it is hard - for the reasons set out above - to obtain accurate forecasts of the demand for the drugs – so companies are reluctant to enter what they see as an unpredictable market. Thirdly the production of these drugs is often pharmaceutically complex and access to raw materials limited.
Few producers leads to high prices and unreliable supplies
What this all means is that there are very few producers in the field and that many of the drugs have only one producer. This has several implications for the availability of MDR-TB drugs – it means that prices remain high because of the lack of competition and it also means irregular supply with bottlenecks and delays. More drastically, if a company stops production, all supplies may dry up because there may be no immediate other source. Those companies that are producing the drugs, don’t produce enough to meet the rising demands. Nor has the generic industry risen to the challenge of filling the gaps – there are far too few new generic products in development to meet the challenge of treating MDR-TB.
“Our major problem now is that Moxifloxacin is not available here in India so we are obliged to purchase it in Europe and that creates a lot of logistical problems. We have another problem with the drug PAS because the formulation we get here is granules but not in individual sachets, so our nurses are packing the sachets themselves, but it requires a lot of time and it's not very precise. Capreomycin is used as an injectable in MDR TB treatment but the quality assured drug produced by Eli Lilly is not available in India – they don’t manufacture enough of the product and there are quality concerns over the only other source available to us.” MSF TB doctor in India
Expensive drugs
Because of the individualized treatment of MDR patients, it is hard to put a precise price on the cost of treatment but an average cost using drugs purchased through the Green Light Committee (GLC: see below) ranges between USD 1 800 and 2 100. Drugs purchased outside this procedure cost a great deal more.
In Cambodia, MSF is treating patients with second-line drugs that are not purchased through the GLC at a cost of around USD 7 300 per patient for a two year treatment course. MSF does negotiate with pharmaceutical companies to get price reductions so the cost of these drugs on the open market would be higher still.
These prices are far out of range of most health services in the developing world. But, as the overall numbers of people with MDR TB are still low, generic producers have not come forward in sufficient number to generate the competition needed to bring prices down
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© Donald Weber |
Quality concerns
Another issue that has inhibited the effective implementation of MDR-TB treatment programmes has been the absence of quality-assured drugs – at affordable prices. To date there are only two generic second-line drugs that have been approved by the WHO prequalification scheme, and a few more are waiting in the pipeline. This approval process needs to be accelerated as a matter as urgency, but even more importantly, manufacturers must be encouraged to submit their products for approval by WHO. The quality of drugs is a major concern when dealing with a bacteria that is already resistant to most of the drugs. By using non-quality assured drugs, the risk of amplification of resistance is even higher.
Green Light Committee established to address challenges
The Green Light Committee (GLC) was set up in 2000 by the Stop TB Partnership – MSF was a co-founder in order to try to meet some of these challenges. Its role is to approve MDR-TB treatment programmes and facilitate the procurement of quality-assured drugs at preferential prices negotiated with originator and generic companies. Treatment partners working with the GLC benefit from drugs with a quality assurance at affordable prices while pharmaceutical companies benefit from bulk purchase orders. However, the GLC process, as any bureaucratic process, is subject to delays with consequences for patients awaiting their drugs.
Additionally, some of these drugs have particularly short shelf lives of between 18 – 24 months. One of the practical implications is that sometimes when drugs do arrive, they can no longer be sent so some countries where the importation of any batch of drugs within six months to expiry is illegal.
As a result of GLC activities, treatment costs have come down and the number of overall treatment programmes has risen. The numbers of MDR-TB patients treated under this system has risen from around 10 000 in 2004 to 40 000 in 51 projects in 2007. Despite the progress, this number still falls far short of what is needed.
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