The World Health Organization's long-standing strategy for fighting tuberculosis is showing deadly unintended consequences: By focusing for years on the easiest-to-cure patients, it helped allow TB strains to spread that are now all but untreatable by modern medicine.
The WHO and a growing chorus of global health experts are now calling for a significant overhaul in the way nations with widespread drug-resistant TB combat the disease. It amounts to a de facto acknowledgment that the WHO's TB strategy, and the countries that use it, failed to adapt quickly enough as the disease formed more powerful, resistant strains.
"The TB community has been too conservative" on a global scale, said Puneet Dewan, until recently a senior officer in the WHO's India tuberculosis program. "We should have pushed sooner for a more aggressive, comprehensive approach" toward drug resistance, he said this month in an interview. "There was a cost in failing to do that. We're paying that cost today."
The WHO played a particularly sizable role in designing the tuberculosis program in India, which has seen a steep decline in regular TB. But India and other poor countries are now in the midst of an epidemic of drug-resistant strains - deadlier and harder-to-treat varieties of one of the world's top infectious-disease killers.
G.R. Khatri, who headed India's TB program more than a decade ago, called the epidemic of resistant TB in Mumbai "a recipe for disaster." The WHO should have known it was so bad and bears responsibility, he said. "What has the WHO been doing?"
In pilot testing across India this year of a new diagnostic method, some 6.6% of untreated TB patients were drug-resistant - suggesting far higher rates than the 2% to 3% levels India and the WHO have cited for years. The test was a collaboration of international aid groups and India's government.
At one clinic in Mumbai, research showed more than one quarter of 566 TB patients tested in recent months were resistant to the most powerful treatment, according to data obtained by The Wall Street Journal through India's Right to Information Act. The results are preliminary, but in the absence of any nationwide survey they offer a sense of what India's drug-resistance rates might be.
The WHO is in the midst of a "complete rethinking" of its strategy toward drug resistance that involves helping countries move more quickly to address their epidemics, said Mario Raviglione, the WHO's top tuberculosis official. Countries with the largest epidemics, such as India, China, South Africa and Russia, haven't moved rapidly enough against drug resistance, he said. "That is why you see no global progress."
Dr. Dewan said that perhaps he and others should have recognized Mumbai's epidemic sooner. But partly because drug-resistant TB was a slow-moving emergency, he said, it was hard to get a full sense of the scope.
"It's a bit like the frog in a pot on a stove," Dr. Dewan said. "If you turn up the heat fast, the frog jumps out. If you turn up the heat slowly, the frog doesn't jump out, it slowly dies."
Only now is India planning its first national survey of drug resistance in TB patients, according to Prahlad Kumar, director of the National Tuberculosis Institute, the government's Bangalore-based research center. A timetable hasn't yet been set.
The policy changes are vindication for Zarir Udwadia, a prominent Indian physician whose controversial findings earlier this year - he identified several patients in Mumbai who were so drug-resistant that virtually none of the usual medicines worked - helped sound the alarm. Patients like these reflect the way drug-resistant TB "is mismanaged in India," Dr. Udwadia said.
Dr. Dewan said he has been taken by surprise by "crazy" levels of resistance like those identified by Dr. Udwadia. Dr. Dewan's own views have shifted quickly: As recently as last year, he said at a presentation in India that there was too much "hype" regarding drug-resistant TB.
Globally, studies suggest that drug-resistant TB is likely far more common than the WHO's own estimate of 3.7% of previously untreated patients. Resistance is worsening in many countries, the research indicates, even as the WHO's widely praised program to fight regular TB has succeeded in reducing the overall number of TB cases since the 1990s.
For decades, the WHO, aid groups and nations have been fighting TB world-wide. But the governmental effort focused almost exclusively on traditional, treatable strains, which are inexpensive to diagnose and defeat with drugs. However, this approach largely ignored drug-resistant strains.
In India, that has left the lives of patients like 22-year-old Amol Dhuri hanging in the balance. In January he was diagnosed with extensive drug-resistance - but the lab that tested him hasn't yet been accredited by the government to do this kind of testing. In fact, Mumbai, India's largest city, doesn't yet have a single lab accredited to diagnose extensive drug-resistance.
Because India's government will give patients the more powerful drugs only if they are tested by an accredited lab, Mr. Dhuri hadn't until this week started taking the drugs that have a shot at curing his strain.
He was taking a cocktail of drugs provided by the government at no charge, most of which he was resistant to.
"I just don't understand why I'm taking these medicines and they're having no effect at all," Mr. Dhuri said.
Mr. Dhuri's drug regimen wasn't merely ineffective, it was potentially dangerous. Giving a patient medicines not strong enough to kill the TB bacteria increases the chance that it will mutate into drug-resistant strains.
It also left Mr. Dhuri wandering around, possibly spreading his drug-resistant disease to others. The average TB patient infects 10 to 15 people a year, according to the WHO.
Neither Ashok Kumar, head of India's TB program, nor P.K. Pradhan, secretary of the Ministry of Health & Family Welfare, returned calls seeking comment on Mr. Dhuri's case. But after the Journal's inquiries, Mr. Dhuri's drug-resistance report from an accredited lab elsewhere in the country showed up by email late last week, confirming his extensive drug resistance, Mumbai TB officials said. They said they would put him on the correct treatment this week.
The WHO, the United Nations agency dedicated to public health, once insisted that countries tackle only regular TB first before trying to treat resistant strains. Now, it urges poor countries to treat both simultaneously.
That, however, requires much more money. There will be a shortfall of $3 billion a year out of the $8 billion a year needed to fight TB in developing countries between 2013 and 2015, according to the WHO's Dr. Raviglione.
In India, medicines to treat regular TB cost $9 a month, compared with $2,000 for resistant strains.
Globally, TB receives much less money from international donors than other major deadly infectious diseases, according to data from the Institute for Health Metrics and Evaluation at the University of Washington. International assistance for TB was $1 billion in 2009. By contrast, malaria, which killed nearly half as many people, received $2 billion that same year. HIV received $6.5 billion, although HIV also costs more to treat and kills about 20% more people a year.
"There needs to be a giant leap in funding, thinking and innovation," said Soumya Swaminathan, director of the National Institute of Research in Tuberculosis, one of the Indian government's premier research centers.
Tuberculosis, an ancient, airborne disease that mostly affects the lungs, is spread by coughing and sneezing. In the 19th century, it was the biggest killer of adults in most of Europe.
In the 1940s researchers discovered they could cure it, over many months, with a cocktail of medicines. In many western nations, TB went into retreat. But in poor countries, it thrived and spread amid poverty and a lack of treatments and diagnostic tools.
The WHO in 1993 declared TB a global public-health emergency, following a resurgence driven largely by the HIV epidemic. At the time, there were approximately eight million cases a year world-wide.
Globally, there was almost no funding for TB, no unified strategy to fight it, and hundreds of treatment regimens in effect. Arata Kochi, the WHO's TB chief at the time, called it "treatment chaos."
The solution, many believed, was to devise a standard, simple-to-understand treatment cheap enough to work in the world's poorest places. The WHO developed a strategy known as DOTS, or Directly Observed Therapy Short-Course, so named because patients were to be directly supervised to make sure they took their medicine. Skipping doses, even briefly, gives the disease a chance to mutate and become drug-resistant.
The WHO, which produces health standards and policies, urged countries to adopt its DOTS program, though it can't oblige them.
The WHO played a particularly large role in India because of the size of the country's TB burden. Dozens of WHO consultants provided technical support nationwide.
Under DOTS, India relied on a rudimentary but affordable diagnostic - peering at a patient's spit under a microscope to spot the bacteria. Patients got a six-month treatment of four standard medicines. Anyone still sick went back on the same regimen for eight more months, plus one additional drug.
This could cure most people with regular TB. But it wasn't strong enough to cure multi-drug resistant, or MDR, strains.
The WHO decided that tackling MDR was unfeasible in places with poor infrastructure, little money and millions of patients lacking even basic treatment.
At that time, "there were two million new cases of TB in India each year" - almost none of which were being treated effectively - and "97% of them weren't MDR," said Thomas Frieden, the physician who spearheaded the India program on behalf of the WHO in its initial years. He is now director of the Centers for Disease Control and Prevention in Atlanta.
Dr. Khatri, who set up the India DOTS program with Dr. Frieden in 1997, agreed with the WHO's philosophy of treating regular TB first. "Every one minute, a patient was dying of TB in India," he said. "So I believed we should not plow a penny into MDR TB in India - and I did not." Dr. Khatri now heads the nonprofit World Lung Foundation for South Asia.
"It was well-intentioned reasoning in a resource-limited world," said Dr. Dewan, who left the WHO in recent weeks to join the Bill & Melinda Gates Foundation's TB program in India.
Dr. Raviglione, too, supports the WHO's original strategy. Without it, he said, drug resistance would now be "enormous." DOTS eliminated many of the slipshod medical practices that let the bacteria to mutate into super-resistant strains.
Meanwhile, however, evidence showed drug resistance emerging globally. Resistance was found in all 35 countries surveyed for a 1997 WHO-affiliated report. In 2000, a subsequent report found worrisome resistance rates in several countries, including parts of China and India.
In 2000, the WHO began a new program to tackle drug resistance and to "mop up" the damage caused by TB programs that had been "careless in how they treat the disease." But that program was never widely implemented, aside from some pilot programs.
This pilot program didn't even reach Mumbai, India's largest city, until mid-2010.
Around the same time, evidence emerged that resistant strains were more lethal than thought.
In one South Africa neighborhood, some 40% of patients with multi-drug-resistant TB - and 51% with higher levels of resistance - were dead within 30 days of their initial TB diagnosis, a 2010 study showed.
If that many people were dying within just 30 days, India's pilot program looked inadequate: It waited 14 months from initial diagnosis before even testing for resistance.
"We knew it was bad, but we didn't know it was this bad," Dr. Dewan said of the study.
Then, this year Dr. Udwadia and others at Mumbai's P.D. Hinduja National Hospital & Medical Research Center identified an even more menacing threat. The researchers called it "total drug resistance," because virtually none of the 12 treatments used to treat TB worked.
The report "sounded an alarm" globally, Dr. Dewan said. India quickly formulated a plan to increase its TB spending fourfold over five years, although that plan is still awaiting funding. It would establish more labs and 120 drug-resistance specialty centers.
Because most TB patients bypass the government's program when they first seek treatment, the new plan emphasizes engaging India's burgeoning private health-care providers.
Still, even this proposal falls short. By 2017, the plan says, India would only be able to treat fewer than half its estimated 100,000 multi-drug-resistant cases annually. Meanwhile India is home to the world's largest population of TB patients - 2.2 million of last year's 8.7 million new cases - and treatment delays remain typical.
Last year the WHO began overhauling its "global architecture" for fighting drug resistance, Dr. Raviglione said. Instead of one committee in Geneva advising the world, regional expert groups will work with governments to help them develop and fund programs to attack drug resistance.
The WHO is also helping countries implement a new test, GeneXpert, that can diagnose TB and a common form of resistance in just 100 minutes, instead of several weeks. This marks the first major diagnostic advance in more than a century.
Eleven new or repurposed TB drugs are also in clinical trials. Dr. Raviglione said a task force is now studying how best to use them without fostering more drug resistance. Meanwhile, India's central TB office says it has established 43 testing labs and plans to build 30 more by 2015.
--Shreya Shah contributed to this article.
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