SA ahead of World Health Organisation in recommending new TB medicine

The Department of Health this week announced it will be making a new tuberculosis medicine available more widely than recommended by the World Health Organization (WHO). The department deserves credit for this brave decision that will both save lives and prevent many patients from suffering irreversible hearing loss.

There has been substantial debate in recent years on how to best use the only two new drugs registered for the treatment of TB in the last half-a-century. Evidence for the use of these drugs have been slow in accumulating and in the generally conservative world of TB, people have opted to stick with the drugs they know, which are mainly drugs developed around the middle of the 20^th century.

This conservatism in TB treatment has been particularly disturbing when it comes to the treatment of multi-drug resistant TB – that is TB for which two of the most widely used TB medicines no longer work. Even today, the WHO recommends treating people with MDR-TB with a set of old, and pretty toxic medicines. These medicines may save your life about half of the time, but they may also cause irreversible hearing loss – with studies estimating hearing loss in as many as 50% of people taking the so-called injectables (also known as aminoglycosides). Medicines in the injectable class include amikacin, capreomycin, and kanamycin.

The current WHO guidelines recommend that most people take a combination of medicines including an injectable until a change in treatment is forced by side effects. In practice, that often means that you wait until someone has some level of irreversible hearing loss, and only then do you take them off the medicines that cause the hearing loss. It should also be noted that the injectables literally refer to medicines that are injected into the body. The toll taken by months of daily, often painful, injections is surely something people should only be exposed to if it is truly essential to their health and survival.

Over the last few years many have suggested replacing the hearing loss-causing injectables with one of the two new TB medicines called bedaquiline. Bedaquiline is registered in South Africa, the United States, and a number of other countries, even though its phase III trial has not yet reported – usually drugs only get registered after phase III results are available.

Through some smaller studies, through pre-approval access, and an ambitious treatment programme in South Africa, we have learnt a lot about bedaquiline. We can say with a high level of confidence that it has a better side-effect profile than the injectables and on balance it seems likely that it is more effective than the injectables – although the latter point has not definitively been proven either way. Just this week South Africa’s Department of Health reported findings suggesting that people receiving bedaquiline were much more likely to be cured of MDR-TB and to survive the disease than people taking older medicines. We now know that bedaquiline’s impact on heart rhythms is not as clinically relevant as we feared it might be. We also now know that deaths that occurred in a phase II trial of the drug was most probably a statistical fluke. Maybe most importantly, bedaquiline is not injected and does not cause hearing loss.

Even so, as scientific evidence goes, the MDR-TB waters are still murkier than the waters in most fields of medicine. Yet, with only about half of people being cured with current treatments, waiting for the waters to clear up is not a luxury we have – we have to make the best decisions we can based on the currently available evidence. Some ongoing studies will clarify how to best use bedaquiline in the treatment of MDR-TB, but results from those studies will only start coming in in 2019, and some of the most important ones only in 2021.

It is in this context that the Department of Health’s decision this week to make bedaquiline part of the standard treatment for MDR-TB in South Africa should be seen. While the Department could probably have gotten away with waiting for the WHO to first update its guidelines, they did not. They applied their minds to the available evidence, considered the seriousness of the side effects, and made a decision that is both scientifically sound and humane. For this they deserve credit.

In February this year the Global TB Community Advisory Board and over 30 organisations wrote to the WHO urging them to update their guidelines to recommend the wider use of bedaquiline – but the response from the WHO has until now been lukewarm. New MDR-TB treatment guidelines are however expected from the WHO in the next few months. It is not a foregone conclusion that they will follow South Africa’s lead and recommend wider use of bedaquiline.

Most serious TB doctors and researchers I’ve spoken to have no doubt that if they were diagnosed with MDR-TB, they would prefer to be treated with a drug combination that includes bedaquiline and that excludes the injectables. A sober assessment of the limited evidence available supports this view – and yet the WHO has dithered and failed to update its guidelines. It is hard not to see in the WHO’s failure a reflection of the fact that poor people’s lives, and poor people’s hearing loss, is implicitly considered by many not to matter as much as those of wealthy people. Hopefully, in the year of the first UN High Level Meeting on TB, this underlying double standard in our global response to TB will be abandoned and we will start giving all patients the option of being treated with the same medicines we would choose for ourselves.

Some technical details

• The regimen: The Department of Health’s statement this week not only indicates that bedaquiline will replace the injectables, but also that it will replace the injectables in the shortened regimen. In response to Spotlight, Department of Health Director of Communications Foster Mohale explained that the short regimen referred to is essentially that used in the STREAM stage I trial and that it contains the following medicines: Kanamycin, Moxifloxacin, Ethionamide, Clofazimine, High dose Isoniazid, Ethambutol and Pyrazinamide. We assume bedaquiline will replace Kanamycin in this regimen.
• Timeline: Mohale told Spotlight that introduction of the new regimen will start on 1 July 2018 at “a significant number” of initiation sites that are ready and then “rapidly scale-up at sites that are not ready”.
• Price: Mohale says the department is currently purchasing a six-month course of bedaquiline (188 tablets) for R 9950. “Between 2013 and 2015 we used a donation for 200 patients who were enrolled in the Bedaquiline Clinical Access Programme,” says Mohale. “In 2015 when we started purchasing bedaquiline the price was $ US 1000; by then 1 US $ was equal to R 9,95. The price has not increased, it has decreased from $ US 1000 to $ US 820.” Research conducted at the University of Liverpool suggests that bedaquiline can be sold profitably at a price of $98 for a six-month course.
• Savings: Mohale claims that by introducing the shortened MDR-TB regimen the department is making huge savings on medicines and laboratory costs. “Laboratory tests that were done over a 24 months period are now done for 9 months for most patients. Also, medicines are administered for 9 months instead of 24 months, “says Mohale. “These gains will absorb the price increase due to bedaquiline.”

 

Note: Low is a member of the Global TB Community Advisory Board, which is mentioned in this article. He is writing in his personal capacity.