The WHO’s deputy director general, Dr Soumya Swaminathan says that the new drug bedaquiline is highly recommended for certain patients suffering with drug resistant tuberculosis.
“There’s absolutely no doubt now that the benefits outweigh the risks. In fact, the cardiac toxicity noticed is extremely minor,” said Swaminathan. “It is extremely clear that TB patients on bedaquiline have half the mortality of those not on the drug.”
Swaminathan was referring to a recent WHO document that was the result of an expert committee’s deliberations. The committee recommended that debilitating injectables like kanamycin be replaced, in some TB regimens, with the new drug bedaquline. She was speaking on the sidelines of the Health Systems Global Summit in Liverpool last month.
The WHO will be releasing new recommendations for the treatment of multidrug-resistant and rifampicin resistant tuberculosis (MDR/RR-TB) later this year, which will speak in more detail about the usage of the new drugs bedaquiline and delamanid. Previously, the WHO had released evidence-based guidelines on the treatment of MDR-TB in 2016 and 2017.
Swaminathan said that the WHO expert committee’s recommendations were issued after studying a large volume of data. “Now we have data from a much larger number of patients. In fact Janssen has shared all their data with us, including their most recent data. South Africa has also shared as they have the largest number of patients (being treated with bedaquiline). Russian data has been looked at. India has also sent data,” she said.
However Janssen, the sole company making bedaquiline, has not yet released its phase 3 trial data. So far, the only data from their phase 2b trial has been released. This trial was conducted on a small cohort of just 161 patients. Drug regulators like the US’s Food and Drug Administration have given Janssen permission to sell it with the condition that the company release phase 3 data by 2022. While the company has been submitting this data for the WHO’s periodic reviews of evidence for their guidelines, it has not released this data publicly.
Meanwhile, both India’s and the global TB crisis continues to be urgent: India has the highest number of TB cases in the world. In 2016, India had 27.9 lakh new TB patients and 1.47 lakh new MDR-TB patients, according to the WHO’s Global TB Report 2017. This notwithstanding, the current NDA government has announced that TB will be eliminated in India by 2025.
The WHO has been growing increasingly confident of bedaquiline as a drug for some TB patients suffering with multi-drug resistant TB. As an oral drug, it comes with fewer side effects in comparison with drugs currently being given to these patients such as kanamycin, which are painful injections administered for at least nine months and can cause irreversible hearing damage, abscesses and neoprotoxicity. The WHO’s recommendations come after experts studied the data on the safety-benefit profile of these drugs.
“To the question of whether countries can start rolling out bedaquiline even without phase 3 clinical trial data, yes, we are fairly confident of the data now that the benefits far outweigh the potential risk,” said Swaminathan.
“The jury is in, as far as the safety of bedaquiline is concerned,” she said.
Medical and ethical questions on bedaquiline
Despite the medical confidence around bedaquiline, the ethical question of whether or not to wait for phase 3 data remains. India currently administers the drug through a highly controlled, government monitored programme. The Revised National Tuberculosis Programme (RNTCP) has been distributing the drug only in a few designated government centers and it is not widely available for purchase in the private sector.
WHO’s ‘Rapid Communication‘, released in August 2018, describes the changes it recommends in treatment regimens for MDR/RR-TB. One of the main takeaways of this document is that injectables like kanamycin and capreomycin are no longer recommended for lengthy treatment. Instead, an “all oral regimen” is preferred, which opens the door for bedaquiline. Drugs like bedaquiline, linezolid and clofazimine have risen in importance and ethionamide, prothionamide and the injectable agents (amikacin and streptomycin) have become less important.
On the issue of informed consent, its “treatment principles” says a WHO document. “Ahead of enrolment on MDR-TB treatment, all patients should receive appropriate counselling to enable informed and participatory decision-making,” she added.
Another WHO document says that, “Patients should be consulted regarding treatment decisions, and provided with updated information necessary to make an informed choice about whether they prefer the injectable-containing shorter MDR-TB regimen or an 18-20 month all oral regimen.” The WHO also says that there should be active drug safety monitoring and management for these patients.
However, the consent form that Indian TB patients are currently given has sparse information on the status of clinical trials and also says that patients will not be entitled to compensation in case of any adverse effects from bedaquiline.
The WHO says that “the decision about which regimen to use should be an informed decision”. This would include telling patients and clinicians complex things such as: “in eligible patients under trial conditions the shorter MDR-TB regimen showed similar efficacy to longer MDR-TB regimens without new drugs, but had the advantage of a much shorter duration and a lower likelihood of loss to follow-up.”
However patients also need to be conveyed that a regimen that includes bedaquiline and linezolid has a “lower risk of treatment failure, relapse and death,” says the same WHO document.
A second point of contention is the absence of phase 3 data and the collection of this data in a non-clinical trial framework through national programmes like India’s. The WHO addresses this and says that national programmes that do replace injectables with these new drugs like bedaquiline, linezolid and delamanid should also “collect and validate these data rigorously so that they may help inform future updates to the WHO guidelines.”
Bedaquiline is not being recommended by the WHO for short-course regimens (nine to twelve months). South Africa has been more ambitious, however, including bedaquiline even in the country’s short course regimens. The WHO says this is “not routinely recommended” and should be done only under “operational research conditions.” Long course regimens are between eighteen to twenty months and it is here that bedaquiline is being recommended by the WHO.
Anoo Bhuyan won a media-fellowship to attend the Health Systems Global conference in Liverpool. This report is the output of the author’s time attending the conference.