By guest contributor Rudolf Abugnaba-Abanga The Climate and Health Network for Collaboration and Engagement (CHANCE) organized its second annual conference from the…
By guest contributor Catherine Berry
“I’m not sure if the cure is worse than the disease.”
That was my first thought when I started working in multi-drug resistant tuberculosis in 2014. At that time, treatment was 18 to 24 months including 8 months of a painful intramuscular injection.
The people I met with TB had unparalleled resilience. Sometimes walking for miles to their DOTS corner, often vomiting every day, unable to work or study, often finding it hard to just concentrate on the day to day. The long treatment meant I had the privilege to get to know families over many months. I recall stories of a spectre that had gone through generation after generation – that rested in a new chest every few years – starting as a “flu” but then never getting better. The cough would persist and the realisation would gradually sink in. Sooner – and sometimes much later – a trip to the TB dispensary would confirm the truth. They had seen their family go through it – now it was their turn.
The programmatic management of drug resistant TB had been around a while, the so-called DOTS-plus program launched in 1999. Early success, in what had initially been thought to be an incurable disease, became harder to replicate with scale-up. The long, toxic and poorly efficacious treatment barely cured 50% of those starting treatment.
My colleagues in MSF had already seen enough – new drugs like bedaquiline and delamanid were slowly coming through the pipeline but had only been tested with these long 18-month treatments. Communities we worked with were telling us this wasn’t acceptable. We were left asking – if drug-sensitive TB could be cured in 6 months, surely this was possible in drug-resistant TB too?
MSF took the unprecedented step to sponsor not just one, but three clinical trials: TB-PRACTECAL, endTB and endTB-Q. TB-PRACTECAL will be the first to report having been terminated early for efficacy. BPaLM or bedaquiline (B), moxifloxacin (M), linezolid (L) and the recently approved, pretomanid (Pa) used in combination for 6 months showed an 89% successful outcome rate compared to 52% in the standard of care in the initial analysis. The data was provided to the World Health Organisation who, in May 2022, have recommended BPaLM to be used for most kinds of rifampicin-resistant tuberculosis. Forms of RR/MDR-TB with fluoroquinolone resistance can also be treated with BPaL.
What do we know about this regimen? From TB-PRACTECAL and ZeNIX, we know its much less toxic than standard of care. The regimen still works well with linezolid dosed at 600mg/day compared with 1200mg/day used in the NIX-TB study. The toxicity of linezolid is well known with effects on bone marrow, peripheral neuropathy and, more rarely, optic neuropathy and pancreatitis. These were generally manageable with dose adjustments, and most patients completed treatment with few recurrences – so far none at all seen in the BPaLM arm. Concerns around QT-prolongation esp. related to bedaquiline were also shown to be manageable. The addition of moxifloxacin did not seem to have a significant impact with similar mean corrected-QT (QTcF) at week 24 in the BPaL and BPaLM arms (adjusted for site and baseline QTcF). The initial concerns around hepatotoxicity related to pretomanid were not seen in PRACTECAL or ZeNIX but liver dysfunction is an adverse effect which needs to be monitored.
What don’t we know about this regimen? We don’t know if BPaLM works in severe extra-pulmonary TB – its not been tested in those with meningitis or osteomyelitis. We have very little data in pregnant women. Dose finding trials for pretomanid in children will start in late 2022. The 9-month regimen will continue to be an option in these last two groups and we welcome a linezolid-based shorter regimen that means pregnant women can use a regimen without prothionamide.
Also a new spectre – resistance to bedaquiline or linezolid – is also growing. We need to look after these drugs but desperately need more agents in the pipeline.
So what’s next? We, as MSF, want this regimen to reach as many people with MDR/RR-TB as soon as possible. Operational research is already underway but we would like to see it rolled out programmatically wherever feasible. 6-month treatment for all TB care has the possibility revolutionise and free up resources in TB programs and provide care to those even in unstable settings.
People with drug-resistant TB deserve shorter, better and kinder treatments and for the first time we have clinical trials which say they work.
Now we need action.
Catherine Berry is the Global Principal Investigator for TB-PRACTECAL. She is a practicing infectious diseases physician (FRACP) and currently a conjoint lecturer with the University of Newcastle. Whilst completing a Masters in Public Health and Tropical Medicine, she joined MSF in 2014 working in Uzbekistan, Belarus, and South Africa. She has extensive experience in research coordination as well as the care of MDR-TB patients. She Tweets at @catherineeberry