Researchers have significantly strengthened the safety profile of a watershed treatment course for highly drug-resistant strains of tuberculosis — a heartening breakthrough set to change the lives of millions of MDR-TB patients around the world.

The results of a randomized-controlled trial published in the New England Journal of Medicine today showed the new oral TB antibiotic regimen BPaL had half as many side effects but maintained an efficacy rate of 91% after an adjustment to the course of one of the three component antibiotics in the regimen.

The breakthrough findings have already been hailed by experts as one of the most important developments in tuberculosis research this century.

Oral treatment can now safely replace injections

The findings mean the new oral regimen may safely replace the 18 to 24 months of intensive treatment via injections that was the standard of care until now — with a global success rate of just 52%.

This grueling process includes daily injections for at least 6 months, multiple daily IV infusions for up to 24 months, and 14,000 pills for a case of drug-resistant tuberculosis.

The new regimen was developed over two years by the TB Alliance, a not-for-profit product development partnership based in South Africa and the United States.

Dose of Linezolid halved in new trial to reduce side effects

The trial follows upon the March 2020 Nix-TB trial findings that demonstrated for the first time the efficacy of the all-oral antibiotic regimen. The trial achieved positive outcomes in 90% of its 109 patients over a period of just six to nine months.

That regimen also led to significant side effects, however, including peripheral neuropathy — nerve damage outside the brain and spinal cord — in 81% of patients.

Some 48% of patients also developed myelosuppression, a condition in which bone marrow activity is decreased, resulting in the production of fewer red and white blood cells, and platelets.  

Both conditions were linked to Linezolid, the antibiotic denoted by the “L” in BPaL, which has well-known side effects.

Today’s study results show halving the Linezolid dosage from 1200mg to 600mg achieves a reduction in incidence of peripheral neuropathy and myelosuppression by 56% and 46%, respectively, At the same time, efficacy remained stable at 91%.

WHO recommended new regimen based on early reports of data 

Privy to early reports from this trial and others, the World Health Organization in May 2022 recommended that the new 6-9-month oral BPaL regime replace the old intravenous one in the treatment of most drug-resistant tuberculosis.  

In addition to early results of the ZeNix trial published today, WHO based its recommendation on early reports from two other randomized control studies, which are still ongoing, about the safety and efficacy of BPaL: TB-PRACTECAL and NExT.

“We now have more and much better treatment options for people with drug-resistant TB thanks to research generating new evidence,” Dr Tereza Kasaeva, director of WHO’s Global TB Programme, said of the new guidance.

“This is major progress compared to what was available even a few years ago,” she said, “and will be of great benefit for people struggling with TB and drug-resistant TB, resulting in better outcomes, saving lives and reducing suffering.”

Accessibility Is key to the patent holder

Dr. Mel Spigelman, CEO of TB Alliance, said his organization is dedicated to discovering, developing, and delivering new therapies.

“And our mission is not complete until improved TB medicines reach every patient who needs them,” he told Health Policy Watch. “With enhanced commitment and global collaboration, we can advance the science and one day see a world where no one dies of TB.”

As one of the foremost experts on tuberculosis and TB drug development, Spigelman also sits on the Coordinating Board of the WHO Stop TB Partnership, which worked with TB Alliance in 2019 to make BPaL based regimens available to 150 low- and middle-income countries for just $364, or $2 a day.

For countries facing high drug-resistant tuberculosis burdens, this price point is a literal lifesaver.

Old generation treatment options for drug-resistant tuberculosis range from US$2,000–$8,000 for a full course through traditional distribution channels, and have long placed a heavy weight on the finances of health care systems on the front lines.

Through traditional market channels, BPaL-based regimens are available at US$700–$800, up to 10 times cheaper than the old generation alternatives.

The TB Alliance “will continue to innovate and fight for access until the days of lengthy and highly toxic therapies are over for every person with TB,” Spigelman said in a press release accompanying the release of the ZeNix trial’s results, 

Good news at a bad time

The advance in treatments comes at a time when global efforts to fight tuberculosis are still reeling from the devastating impacts of COVID-19.

Two years ago marked the first year on year increase in tuberculosis deaths since 2005, with fatal cases jumping by 100,000 to an estimated 1.5 million in 2020. In the same year, 1.4 million fewer people received care — a 21% reduction globally, and as much as 28% in the top 10 most affected countries.

WHO models project that COVID related disruptions to tuberculosis care and detection could have caused an additional half a million deaths in 2021.

The precise numbers remain unknown.

Tragically, this may not even paint the full picture.

WHO modeling for mortality in 2021 doesn’t account for exacerbations in social determinants such as extreme poverty and malnutrition that fuel the spread of tuberculosis.

The COVID-19 pandemic pushed 100 million people into poverty in 2019, and nearly 20% of global TB incidence is attributable to undernutrition.

In countries with high tuberculosis burdens, as in India, that number can be far higher, reaching more than 50% in many Indian states.

With the UN estimating that developing economies will have pandemic-related losses of $US12 trillion through 2025, undernutrition-driven tuberculosis could see a steep rise. 

An unimportant emergency

The world’s response to COVID-19 has also drummed up a lot of discussion in the world of TB advocacy and treatment. 

The sheer scale of financing and pace of scientific progress observed during the COVID-19 pandemic had two opposing effects: redefining the limits and hopes for what is possible to eradicate tuberculosis, and — by contrast — laying bare the persistent levels of neglect towards tuberculosis as a serious crisis since it was declared a public health emergency in 1993.

“The global response to TB has clearly failed to reflect the ‘public health emergency,’ which it is,” Spigelman said.

“It is now second only to COVID-19 as the greatest infectious disease killer in the world,” he said, “and unfortunately looks poised to regain the dubious distinction of again becoming the greatest single infectious disease killer.”

Even modest funding for tuberculosis fight could be game changing

In the first 11 months of the COVID-19 outbreak, US$104 billion was spent on research and development, resulting in more than a dozen vaccines receiving authorization within a year of the public health emergency declaration.

By contrast, US$5.5 billion has been spent on tuberculosis research and development over the last decade, and the century-old Calmette-Guérin vaccine — first approved for use in 1921  — is still used for tuberculosis.

Investments in new TB vaccines amount to US$100 million per year, and overall research and development investment reached US$900 million in 2020. That is far less than the US$2 billion funding goal — more than double current levels — set at the 2018 UN High-Level Meeting on TB Political Declaration.

A significant majority of countries that pledged to the agreement continue to fall short of their fair-share funding targets. 

“Given the modesty of the TB funding targets, the ongoing failure of global funders to meet even these low targets reflects the deep inequity in the global response to health challenges faced by poor communities versus wealthy ones,” says a joint report on tuberculosis research funding trends by Treatment Action Group and Stop TB Partnership, whose board includes Spigelman. 

“The result of this inequity manifests in the tools available to treat diseases,” it says, “where health systems and health care providers have an array of effective options for the management of some diseases, but must make do [for decades] with substandard or non-existent tools for others.”

The Global Fund, an organization responsible for providing 77% of all international tuberculosis funding, says the world is at a critical juncture and must increase investment in fighting TB — or accept it is abandoning UN goal to end the disease as a public health threat by 2030.

Spigelman said the world could dramatically improve the diagnosis, treatment and prevention of TB with far less funding than it has dedicated to COVID-19.

“In short, with adequate funding, TB could potentially be eradicated.”

Image Credits: Jonathan Torgovnik/Getty Images for TB Alliance.