The Slow-Motion Search for a New TB Treatment

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In this Monday, Oct. 22, 2012 photo, a tuberculosis patient is given medication at an Operation ASHA program center in New Delhi, India. Private companies, aid groups and the government have embarked on a flurry of innovation to modernize India's archaic anti-tuberculosis campaign and fight the spread of frightening new drug resistant strains threatening to cause a public health nightmare. (AP Photo/Kevin Frayer)

In this Monday, Oct. 22, 2012 photo, a tuberculosis patient is given medication at an Operation ASHA program center in New Delhi, India. (AP Photo/Kevin Frayer)

March 25, 2014

Doctors first noted that tuberculosis was resistant to some medication back in the 1940s. The bug has been evolving ever since.

Modern medicine, however, hasn’t always kept up.

The current treatment for non-resistant tuberculosis still works: a combination of four drugs taken daily for two months, followed by two drugs daily for about four more months. They’re what’s known as the first-line drugs for TB. The treatment can be difficult, causing nausea and stomach upset, but it’s still effective. It costs only about $20 per person for the entire course of drugs.

But multi-drug resistant TB, MDR, which is resistant to at least two of the most powerful anti-TB drugs, is on the rise. An estimated 9 million people became sick with the TB disease worldwide in 2012, and about 1.3 million die from it each year. The number of patients with MDR is difficult to tally because so few are tested, but it’s estimated to now afflict at least a half million people worldwide, and is much more difficult to treat.

TB can become drug-resistant in patients who don’t complete the proper treatment, and MDR-TB can also spread from patient to patient, infecting new people with the resistant strain. Most with MDR don’t receive a proper diagnosis, in part because the basic test for TB doesn’t reveal drug resistance. So especially in poor countries, patients can undergo months of useless treatment while their disease becomes more resistant to available drugs and spreads to others in the community.

Treating MDR is much more costly — up to $5,000 per person for the full course of mostly second-line drugs, so-called because they are so toxic. It’s estimated that less than half of the patients complete the grueling treatment, which involves daily injections for several months and at least four other drugs. The entire course, which totals more than 14,000 pills, takes two years to complete and side effects can include a risk of permanent hearing loss, psychiatric problems or seizures — and can even be lethal.

But the regimen is all that’s available today, and health experts say that among the global community, there’s little motivation to change that.

“There’s no urgency,” said Dr. Salmaan Keshavjee, director of Harvard Medical School’s program on infectious disease and social change. “The programs are chugging along, the Global Fund [to Fight AIDS, Tuberculosis and Malaria] gives money, there’s mediocre outcomes. It just hasn’t been on the agenda of policy makers.”

That’s in part because TB has largely been a disease of the marginalized, the poor, health experts say. “HIV, because it involved gay men in America who were able to organize, it involved transnational cities — Rio, Paris, Johannesburg — you end up having a much more vibrant civil society around it,” Keshavjee said. “There’s hardly any society around TB. Who would care? There’s no constituency that would care.”

The WHO estimates that it would take $7 to $8 billion to fully address the problem in low- and middle-income countries, excluding the research and development of new drugs, vaccines and diagnostics. In 2013, that funding was about $6 billion. Funding to develop new drugs in 2012 was only around $240 million, well short of the $740 million target, according to a 2013 report by the Treatment Action Group, which tracks spending on TB research and development.

Last year, the US spent about $9.8 billion in discretionary funding on global health in low- and middle-income countries, though only a small fraction of that — 2 percent — went toward fighting TB. The Obama administration’s proposed 2015 budget allocates $9.4 billion for global health, which includes a 19 percent drop in funding for TB, the largest reduction of any category. Even so, the U.S. government remains the top donor to TB research and development, according to the TAG report, with $169 million annually. The Bill and Melinda Gates Foundation is second with $111 million.

Brazil, Russia, India, China and South Africa, which have 40 percent of the world’s TB cases, don’t even make the top 10 list.

“Every time people say, ‘Well, we need more resources,’ the first response from public health authorities and experts is, ‘It costs too much,'” said Dr. Paul Farmer, Harvard Medical School professor of global health and social medicine, and a leading expert on TB. “Well, it costs too much to not do it. That’s the great agony of it.”

The private sector has also turned away from TB research: Globally, research and development on TB has declined, dropping by $30.4 million in 2012 compared with 2011. Pfizer, the world’s largest pharmaceutical company, no longer works on TB. AstraZeneca, another major drug company, said earlier this year that it planned to close its research and development center in Bangalore, India, where it had been conducting its TB research. Other companies, like Otsuka, have also pulled back.

The FDA did approve one new drug to combat MDR-TB in 2012. Bedaquiline, developed by Belgian pharmaceutical company Janssen, a subsidiary of Johnson & Johnson, is the first drug approved by the FDA to fight TB since 1971, according to the CDC. It’s been added to the drug regimen for MDR-TB.

But what doctors say they really need is a new multi-drug cocktail that will attack the bug in new ways and take less time to defeat it. The search for a cocktail is time-consuming. One advocacy group, the Critical Path to TB Drug Regimens, estimates it would take a quarter of a century to develop four brand-new drugs that work in concert.

TB Alliance, a nonprofit group, has begun to partner with companies to help them develop new TB drugs and test them in combination with one another, in the hopes of finding a more effective, and faster regimen to combat resistant TB. There are a handful of drug combinations in the Alliance pipeline now. But even if they all pass clinical trials, it will be several years before any new drugs are available for widespread use.

There is one vaccine for TB that can be administered to children. But it doesn’t protect against the pulmonary TB that adults contract, and can muddle test results for TB.  There are a few other potential vaccines in the pipeline, but those too will take time to develop.

And even as the race to fight MDR-TB continues, the bug continues to develop resistance to the few drugs left to treat it. Doctors have found cases of XDR — extremely drug-resistant TB that is resistant to more than two of the first-line drugs. And in India in 2011, Dr. Zarir Udwadia, a lung specialist, found patients who were TDR: totally resistant to all the first- and second-line drugs available to fight TB.

“If you accept that, and accept that these patients are out there spreading the disease, it will require three or four new classes of drugs at the same time” to treat the new TB strains, said Gail Cassel, vice president of TB drug development at Idri, a US-based nonprofit group that aids in research and development for infectious diseases. She added: “We need to have a much greater sense of urgency.”


Sarah Childress

Sarah Childress, Senior Editor & Director of Local Projects, FRONTLINE

Twitter:

@sarah_childress

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