Last week, South Africa became the first country to replace injectable drugs with the new oral medicine bedaquiline in its standard regimen for treatment of rifampicin-resistant tuberculosis. In its estimate for 2016 — the latest available — the World Health Organisation (WHO) put the incidence of TB in South Africa at 438,000. India carries the world’s biggest TB burden; incidence in 2016 was estimated at 2.79 million, or a quarter of all cases worldwide.
Multi-Drug Resistant TB
A patient of MDR-TB stops reacting to the two strongest first-line anti-TB drugs, rifampicin and isoniazid. WHO’s 2018 Global Tuberculosis Report estimates India’s MDR-TB burden at 147,000.
Second-line treatment for MDR-TB includes daily intra-muscular injections for a minimum 9 months. The three commonly-used injectables, kanamycin, capreomycin and amikacin, have severe side effects, including kidney ailments, hearing disability, and general toxicity. A study of 100 MDR-TB patients in the UK published last year found 40% had stopped injectable treatment due to hearing loss, and 55% had experienced toxicity in the ear. (‘Adverse effects and choice between the injectable agents amikacin and capreomycin in multidrug-resistant tuberculosis’, Amber Arnold et. al, American Society for Microbiology, July 10, 2017) A patient who is resistant to isoniazid and rifampicin as well as to fluoroquinolones (levofloxacin or moxifloxacin), and to at least one of the three injectable second-line drugs is said to be suffering from extensively drug resistant (XDR) TB.
South Africa’s decision
In 2011, South Africa expanded the use of GeneXpert machines to diagnose a large number of MDR-TB patients and in 2013, the country’s Medicine Control Council approved use of bedaquiline, a new “magic drug” for patients who are resistant to most standard drugs. Two hundred pre-XDR and XDR patients were put on BDQ; by 2015, “favourable outcomes” were noted in 73% patients. As many as 15,000 patients — two-thirds the global consumption — are currently on bedaquiline. A retrospective cohort analysis found a “41% increase in treatment success and a three-fold reduction in mortality compared with those that did not get the medication (bedaquiline)”. On June 18, South Africa stopped injectables for all rifampicin-resistant patients and introduced bedaquiline, noting the severe toxic effects of injectables, which often led to treatment dropouts.
The WHO’s recommendation
For drug-resistant TB, it recommends use of injectables. Its guidelines on bedaquiline — based on limited studies — recommend use for pre-XDR or XDR patients under certain conditions. WHO will have a Guideline Development Group meeting in July to further discuss the new drugs bedaquiline and delamanid, as well as injectables.
Situation in India
India’s MDR-TB burden is estimated at 79,000. It uses injectables kanamycin, capreomycin and amikacin. Bedaquiline was rolled out in 2016 in a phase-wise control trial. Only 140 centres currently have access; about 1,000 patients have received the drug.
India is part of the global STREAM clinical trial to compare the effects of oral bedaquiline medication as opposed to a shorter regimen with injectable drugs. Thirty patients from Gujarat and Chennai have been enrolled since early 2018. “But the initial results will only come by 2021,” Dr Sarabjit Chadha, India’s deputy director of The Union, an international voluntary organisation against TB and lung disease, said.
“Injections are the aspect of MDR-TB treatment that patients and doctors hate the most. They are toxic and painful, but unavoidable because there were no options,” chest physician Zarir Udwadia of Mumbai’s P D Hinduja Hospital said. Udwadia said many resistant-TB patients are treated by importing bedaquiline on compassionate grounds, a process that sometimes takes months.
Dr Ramya Ananthakrishnan, executive director of TB advocacy group REACH, said private doctors are left with very few alternatives when dealing with second-line drugs. “If an injectable has massive side effects, a doctor has very few drug options for MDR-TB.”
Dr Chadha underlined the lack of data on bedaquiline. “South Africa took a decision based on an in-country trial. I am being cautious because that data needs to be studied. We can’t take an emotional decision,” he said.
Apart from South Africa, there are no randomised clinical trial results on bedaquiline. Existing studies have shown bedaquiline may have cardiotoxicity. “Injectables have side effects but they are also quickly absorbed by the body,” Dr Satish Pawar, in-charge of the TB cell in Maharashtra, said.