A tuberculosis (TB) patient

Earlier, treatment for drug-resistant forms of TB lasted for 20 to 24 months duration or more, and treatment success rate hovered around 50% or less, with very high rates of drug toxicities and side effects. But this new six months therapy (of BPaL - Bedaquiline, Pretomanid and Linezolid) shows that treatment success rate can be over 90%.

With less than 100 months left to end TB globally (and less than 40 months left to end TB in India), there is no doubt that we need more effective and less toxic treatments to cure TB, which continues to be among the top deadly infectious diseases today. It is therefore imperative that game-changing scientific breakthroughs must translate into public health gains in terms of reduced human suffering and deaths related to TB.

Shorter and more effective treatment for drug-resistant TB

Science has proven that it is possible to reduce the duration of treatment of highly drug-resistant forms of TB from around 2 years to 6 months, reduce the toxic side effects of the medicines and significantly improve treatment outcomes.

But first, let us understand why do we need new medicines and why do older medicines stop being affective against disease-causing germs, such as, TB bacteria? Antimicrobial resistance, also known as drug resistance, makes an infectious agent (such as the TB causing bacteria) resistant to medicines. So, when TB bacteria become resistant to a medicine, they cannot be killed by it. That is why we need a different combination of medicines (to which the bacteria are sensitive) to treat the disease. Choice of medicines to treat is limited, treatment is long, risk of severe illness and dying is high, and a host of other issues, like drug toxicity, side effects, and even post-treatment disabilities at times, are other challenges.

But there is good news too. Thanks to rigorous scientific research, we have shorter, safer, and more effective therapies for treating drug-resistant TB now.

Watershed moment in TB treatment science

The final phase-3 results of the ZeNix study were published in New England Journal of Medicine which show that BPaL treatment regimen consisting of three medicines - Bedaquiline, Pretomanid, and Linezolid - is not only highly effective against drug-resistant forms of TB, but this high effectiveness can also be maintained with reduction in dosing and/or duration of Linezolid. Reduction in dosing and duration of Linezolid means people on this therapy faced less Linezolid-related side-effects - so treatment becomes more tolerable.

This ZeNix study was led by TB Alliance and took place in eleven sites across Georgia, Moldova, Russia, and South Africa.

Why ZeNix study results are important and build upon the evidence of previously done Nix-TB study?

The Nix-TB Study results, which were published in New England Journal of Medicine in 2020, had shown very high treatment success rate of over 90% when all-oral BPaL treatment regimen was used for six months to treat drug-resistant forms of TB. But the Linezolid-related side effects were very alarming.

High treatment effectiveness of BPaL regimen in Nix-TB study “came at the cost with very high rates of toxicity - 81% of the patients, who had one or more episodes of peripheral neuropathy, required the regimen to be either dose-adjusted, interrupted or abandoned altogether, and 48% of participants experienced one or more episode of myelosuppression so a reduction in haemoglobin (red blood cells), white blood cells or platelets,” said Dr Conor Tweed, Honorary Clinical Lecturer, Medical Research Council, Clinical Trials Unit at University College London (UCL), who was in conversation with CNS. Jessica Wiggs, Senior Communication Specialist of TB Alliance also joined the conversation.

That is why ZeNix Study was conducted to check if Linezolid related side effects could be reduced with reduced Linezolid dosing and/or duration of therapy, and how this would impact the effectiveness of the BPaL regimen.

In ZeNix study, there were four groups of people, all of whom had drug-resistant forms of TB, and who were treated using the all oral, six months long BPaL regimen of Bedaquiline, Pretomanid and Linezolid. The only difference between these four groups was in the duration and/or dosing of Linezolid.

The first group received 1200mg of Linezolid for six months; second group received 1200mg of Linezolid for two months; third group received 600mg of Linezolid for six months, and the fourth group received 600mg of Linezolid for two months, shared Dr Tweed.

Overall treatment efficacy across the four groups ranged between 93% and 84% - with 93% among those who received 1200mg of Linezolid for six months and 84% among those who received 600mg of Linezolid for two months. It is important to note that the group with 600mg of Linezolid for six months had 91% efficacy – very similar to the highest efficacy of 93% - but drastically reduced levels of Linezolid-related toxicity - such as peripheral neuropathy which was reported in only 24%, and myelosuppression reported in only 2% patients in the study.

Dr Tweed shared that this study had had a life influencing impact on those enrolled. There were 181 people who took part in ZeNix study (about 20% of them in each of the four groups were people living with HIV). All of them had highly drug-resistant TB - a form of TB that previously required 20 to 24 months to treat with associated cure rates between 40-50% in the field, and alarmingly high rates of toxicity. This study demonstrated that treatment success rate with the all oral BPaL regimen was over 90%, treatment duration was reduced to one-fourth of the previous regimen (6 months compared to 20-24 months), and much reduced drug-related toxicities. There is still work to be done for even better treatments.

The BPaL regimen to treat highly drug resistant forms of TB has been endorsed by the UN health agency, the World Health Organization (WHO) for use under operational research conditions. Earlier, United States FDA and European regulators had already given the green signal for the use of this regimen. Recently the Indian regulators have also given a thumbs up to Pretomanid and shorter regimens.

However, we have to remember that the number of participants in ZeNix study was relatively small, given the burden of TB in the real world. Dr Conor cautioned that “we do not think we feel comfortable making a definitive casual statement about the relationship between the different doses of Linezolid and the incidence of toxicity, but I think we would feel confident to draw attention to the association between higher rates of toxicity with the higher doses of Linezolid.”

He added that “it is unacceptable for people to die from an infection that could theoretically be treated”.

TB could also be prevented as we have the tools to prevent TB but are failing to do so because of which over 10 million people suffer from active TB disease every year.

As this study was done on those with drug resistant forms of TB of the lungs (and not extrapulmonary TB), Dr Tweed remarked that it was done so, as TB of the lungs (pulmonary TB) is easier to diagnose, monitor, and confirm cure. Also three out of four TB patients suffer from TB of the lungs.

Larger goal

The larger goal is to have many novel TB treatment regimens, which can be tailored as per the drug resistance profile of a person (individualised therapy), said Dr Tweed.

But we have to tread with caution as many drugs developed in the past century have lost their efficacy due to drug resistance. Sadly, resistance to the relatively new wonder drug Bedaquiline is already getting reported from South Africa, for instance.

“There is no such thing as a magic bullet when we are dealing with drug resistance. Any novel regimen has to be taken with the perspective of programmatic adjustments of what is needed. Moreover, there needs to be a big increase in funding for TB programming in the most hard-hit areas. We also need to see an improvement in TB diagnostics - not just in developing new technology, but also in its rollout. We need to see better awareness and we do need global development cooperation to make this work,” said Dr Tweed.