Drug-resistant TB: Are we converting scientific breakthroughs into public health gains?

Bobby Ramakant *

Undoubtedly, among the most important scientific breakthroughs for the diagnosis and treatment of drug-resistant tuberculosis (TB) have happened in the past few years. But are we able to convert the scientific breakthroughs into public health gains quickly enough - by diagnosing every person with drug-resistant TB, and treating them with safe and effective medicines?

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 toxicity of the medicines, and significantly improve treatment outcomes. A big challenge indeed is to translate these scientific advancements into public health gains. Clock is ticking!

Know more on drug resistance

“Antimicrobial resistance, also known as drug resistance, makes an infectious agent (such as TB causing bacteria) resistant to medicines. So, when TB bacteria becomes resistant to a medicine, then it cannot be killed by it. That is why, we need a different combination of medicines (to which bacteria is sensitive to) to treat the disease. Choice of medicines left to treat is limited, treatment is longer, risk of severe illness and dying is higher, and host of issues such as, drug toxicity, side effects, and sometimes post-treatment disabilities, 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. We need to ensure that standard and best possible treatment options reach everyone in need without any delay. No excuse for inaction,” said Shobha Shukla, founder Executive Director of CNS who was moderating The Dose Podcast.

The Dose Podcast

The latest episode of The Dose Podcast, which premiered on 2022 World TB Day (launched by the Working Group of New TB Drugs of Stop TB Partnership), featured two TB science leaders who have been instrumental in advancing scientific research for highly drug-resistant TB.

“Highly drug-resistant TB as it was referred to in the Nix-TB and ZeNix scientific studies, was the combination of either XDR-TB or pre-XDR-TB (using the pre-2021 definitions) or MDR-TB with treatment intolerance or non-responsive MDR-TB,” said Dr Gustavo Velasquez, Assistant Professor in the Division of HIV Infectious Diseases and Global Medicine at University of California.

Watershed moment: Increasing treatment success rate from 58% to 90%

“Treatment success for highly drug-resistant TB has been highly variable over time and very specific to cohorts and geography. Latest WHO Global TB Report (of 2021) cited data from across the world that the treatment success rate for MDR-TB was 59% in 2018,” said Dr Gustavo. Treatment success rate for MDR-TB in 2012 was around 50%.

But two studies (Nix-TB and ZeNix) have provided strong scientific evidence that treatment success rate can be much better (90%).

90% treatment success rate for drug-resistant TB

“The Nix-TB study showed an extraordinarily high rate of success [with BPaL regimen of Bedaquiline, Pretomanid and Linezolid]. I work in South Africa and at that time the success rate for those with highly drug-resistant TB was less than 40%. The Nix-TB study showed that we could successfully treat 90% of our patients with the short all-oral regimen,” said Dr Francesca Conradie, who is the principal investigator of the two studies (Nix-TB and ZeNix) that have evaluated one of the most promising treatment options for people with highly drug-resistant TB (BPaL regimen with Bedaquiline, Pretomanid and Linezolid drugs).

Ninety percent treatment success rate for highly drug-resistant TB has given a new hope to many.

“I think this was a watershed moment in the treatment of drug-resistant TB but it did come at a cost. There was a high rate of adverse events associated with the older drug used in this regimen – Linezolid. Because of higher dosage of Linezolid, we saw a frequent occurrence of peripheral neuropathy. We had two cases of optic neuropathy and more cases when Linezolid suppressed the bone marrow (which resulted in drop of haemoglobin),” said Dr Francesca.

Safer, all-oral and more effective treatment becomes even better!

Following Nix-TB study, another study called ZeNix study aimed to find if it was possible to maintain high rate of 90% efficacy but also increase the safety (by looking at various doses of Linezolid that caused adverse events in Nix-TB study).

ZeNix study had 4 groups of people who got BPaL (Bedaquiline, Pretomanid and Linezolid) regimen for six months but there were differences in dosage and duration of Linezolid given.
- In the first group, 1200mg of Linezolid was part of the regimen for entire six months
- In the second group, 1200mg of Linezolid was part of the regimen for the two months
- In the third group, 600mg of Linezolid was part of the regimen for entire six months
- In the fourth group, 600mg of Linezolid part of the regimen for two months

“What was striking about ZeNix study is that it demonstrated that the Nix-TB study was not a flash-in-the-pan. Across the four groups, the rate of treatment success was around 90%. We also noted that with the decreasing dose and duration of Linezolid while maintaining the efficacy of the regimen, we saw a decrease in the adverse events,” informed Dr Francesca.

ZeNix study was conducted in European nations as well as South Africa, and higher treatment success rate was seen in all study sites.

“Many of the patients that I treat have very poor social circumstances and the quicker that we can get them treated and back into the communities the better” said Dr Francesca underlining the importance of six-months, all-oral and highly effective regimen for people with highly drug-resistant TB.

ZeNix study also shows that HIV positive patients with highly drug-resistant TB who are on antiretroviral therapy (and virally suppressed), do as well with BPaL regimen as those who are not HIV co-infected. “So, being HIV co-infected is not an indication for not giving this particular regimen,” said Dr Francesca.

The US FDA had approved BPaL regimen for treating highly drug-resistant TB, followed by the WHO that issued consolidated 2020 TB guidelines recommending 6 to 9 months of BPaL regimen under operational research conditions for treating highly drug-resistant TB.

“ZeNix has contributed very important new evidence on the dose and duration related toxicities of Linezolid,” said Dr Gustavo in The Dose Podcast.

He cautioned: "For treatment of highly drug-resistant TB globally, Linezolid remains a toxic drug. It will continue to be important to think about how we will monitor and manage Linezolid toxicity in programmatic settings. Evidence provided by the ZeNix study is important. I hope it will also be complemented by ongoing studies that are going to further look at optimization of Linezolid in this type of regimen but also in different combination of drugs."

Low diagnostic capacity to detect drug resistance cripples us further

Important new diagnostics for highly drug-resistant TB have come forth in the last decade. Gene Xpert, Xpert Ultra to Xpert XDR, are among the technological advancements that have made it possible to detect drug resistance quickly and accurately. But molecular diagnostics to detect resistance against new medicines like Bedaquiline for example, are yet to come. As of now, we have the older phenotypic methods which takes six to eight weeks for results to come.

“The diagnosis of Bedaquiline resistance is laborious. At this stage there is no molecular diagnostics to detect Bedaquiline resistance. In our BPaL clinical access programme in South Africa we have enrolled 70 patients. We have detected two patients with Bedaquiline resistance. Both of them have been exposed to Bedaquiline for a short period of time and were lost to the programme because of COVID-19,” said Dr Francesca. “Bedaquline has a very long half-life so particularly if you are lost to the programme early on in treatment you end up being on Bedaquiline monotherapy for a while.”

There was another study published by Dr Nazir A Ismail from National Institute for Communicable Diseases, Johannesburg, South Africa, in which about two percent of patients with rifampicin-resistant TB had concomitant Bedaquiline resistance.

Dr Gustavo rightly pointed out that more work needs to be done to scale up latest diagnostic technologies worldwide. While we are rightly demanding latest molecular diagnostics to be accessible and available everywhere, the ground reality is that not even phenotypic testing is widely available everywhere.

Time to act is now!

"The time for action is here. There is sufficient clinical trial data for us to start implementing better treatment options in select populations," asserts Dr Francesca.

"We hope that the new regimens on the horizon will mean relief for people with highly drug-resistant TB, reduce human pain and suffering, and avert untimely deaths," said Shobha Shukla, who also leads Asia Pacific Media Alliance for Health and Development.

Definitions of MDR-TB, XDR-TB and Pre-XDR-TB:

- When TB bacteria is resistant to two of the most potent first-line anti-TB drugs, Isoniazid and Rifampin (outside of the US this medicine is called Rifampicin) then it is referred to as multidrug-resistant TB (MDR-TB).

- When in addition to Isoniazid and Rifampin, the TB bacteria also gets resistant to fluroquinolones and second-line injectables, then it is referred to as extensively drug-resistant TB (XDR-TB).

- If TB bacteria is resistant to Isoniazid and Rifampin, and in addition to either fluoroquinolones or second-line injectable, then it is referred to as Pre-XDR-TB.

Definitions of XDR-TB and Pre-XDR-TB went some change in January 2021 because all-oral regimen became a reality (and second-line injectables are no longer as highly prioritised, thankfully!). Now, XDR-TB is defined as resistance to Isoniazid and Rifampin, fluoroquinolones, and at least one other group of drugs, or drug (Bedaquiline or Linezolid). Pre-XDR-TB is a simpler definition now because it is resistance to Isoniazid and Rifampin, and fluoroquinolones.