The Drugs Don’t Work

A girl swings her legs from the examination table and glances out the small square window of the doctor’s office. The breeze rolling in off Mumbai’s Mahim Bay ruffles the papers on the desk, where the girl’s grandmother has laid out her upturned hands imploringly. “Please help,” she says to Dr. Zarir Udwadia, a chest doctor. “I don’t know what to do.”

Udwadia glances through the papers that document the family’s months of attempts to treat the girl’s virulent case of tuberculosis. A lab has just delivered the test results that explain why she’s not getting better: the disease that has settled in the girl’s lungs is multidrug-resistant, or MDR, tuberculosis, and most medicine is useless against it. “Ten years ago, you would have been horrified,” Udwadia tells TIME, scratching out a prescription for yet another combination of TB drugs that may — or may not — work. As cases that are harder and harder to treat emerge, Udwadia says, patients who finally respond are a relief. “Now we say, At least she’s only MDR.”

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Some of the people waiting their turn to see Udwadia won’t be so lucky. Once a week, patients who have tried and failed to treat their tuberculosis line up, frustrated and frightened, outside his small office in Hinduja Hospital in India’s financial capital. Hinduja is where the first Indian cases of totally drug-resistant (TDR) TB were reported in late 2011, making the hospital a key battleground in India’s new war against a very old disease. What happens there concerns us all. For while the wily bacterium has been around for millennia, trade, migration, urban overcrowding and air travel mean that the disease has been able to spread like never before. And if TDR strains take hold in global populations, the resulting contagion could be catastrophic.

Doctors have been effectively fighting M. tuberculosis and other bacteria with antibiotics for decades. The global TB mortality rate has gone down 41% since 1990. But poor diagnosis and the misuse and mismanagement of powerful drugs have created strains that are getting harder to fight. When a TB patient is given the wrong prescription or starts but does not complete the full course of drugs, the bacterium can grow stronger. Nearly 4% of new TB patients have MDR strains of TB; among patients who had been treated for TB before, about 20% have MDR TB, according to the World Health Organization (WHO).

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A paper published last August in the Lancet reported that worldwide rates of MDR and extensively drug-resistant (XDR) tuberculosis are higher than anyone previously thought. (WHO identifies the cases that were reported at Hinduja as XDR, saying complete drug resistance in TB has not been clearly defined.) XDR TB has been found in 84 countries. East and Southeast Asia, Eastern Europe, South Africa, Russia and India have alarmingly high rates of drug resistance, and though only India, Italy and Iran have reported cases of TB that do not respond to any drugs, many experts believe that’s simply because more haven’t been found. “We are on the brink of another epidemic, and it has no treatment,” says Dr. Shelly Batra, president of Operation ASHA, a New Delhi — based NGO that fights TB. “If TDR spreads, we will go back to the Dark Ages.”

Tuberculosis — once known as consumption because of the severe weight loss it can cause — is a contagious, airborne disease that thrives in overcrowded places. It typically settles in the lungs but can attack other parts of the body as well, and its symptoms include coughing (often producing blood), fever, night sweats and chills. Malnourished people are particularly vulnerable to TB, as are those with HIV. Most TB infections are latent and asymptomatic, but once the infection becomes active, the mortality rate is high. A third of humans alive today carry TB bacteria. Only a relatively small number of them will get sick and become contagious, but it is still one of the world’s deadliest diseases, killing 1.4 million people in 2011. WHO estimates there will be over 2 million new cases of MDR TB from 2011 to 2015, yet today only 10% of new MDR cases get proper treatment. The ones who don’t inevitably spread the disease: a person with active TB can infect up to 15 others in a year.

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India, where about two people die every three minutes from TB, is on the front line of this global battle. Some 2 million Indians develop TB each year, leaving the Indian government with the unenviable task of managing roughly a quarter of the world’s TB cases. The more drug resistance, the more money must be spent on treatment, diverting funds and staff from addressing rampant but run-of-the-mill TB. That means the conditions creating drug resistance — when treatable cases go unnoticed or patients receive bad medicine — could get worse. “I’ve seen the resistance pattern changing,” says Udwadia. “Basically, we’re screwed.”

By we, he means all of us.

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Ground Zero
Mumbai is a crucible of bacterial opportunism. Perched on India’s west coast, it is one of the fastest-growing cities in the world, with Greater Mumbai’s population already at some 18 million. As more and more people pour into Mumbai, its edges have become a shifting horizon of rising and falling slums housing the migrant workers who make the city tick. In Ambujwadi, a cluster of some 8,000 people in north Mumbai, residents live like they do in most slums: in stiflingly close quarters, without running water or clean food. It’s just the kind of crowded, hardscrabble place where M. tuberculosis thrives — and where drug resistance is increasing.

Since 2006, India’s government has provided free TB medication nationwide, but to get it, patients need to go to a clinic, hospital or government drug provider three times a week. For day laborers, that means less money and less food. In India’s urban slums, as many as a third of TB patients stop taking their drugs before the standard six-month treatment is complete, according to Operation ASHA. New TB patients are prescribed six months of a combination of four medications, with two months of intensive treatment followed by four months of continuing care. Following the regimen is crucial. If patients don’t respond to that treatment, or if they test positive for drug resistance, they are given other, more powerful second-line drugs, which can be highly toxic and are part of a grueling two-year program. If a patient stops that, the bacterium gets stronger still.

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On one sweltering June morning, health worker Shilpa Kamble winds her way through Ambujwadi’s labyrinthine dirt lanes, past goats picking over garbage and open-air stalls hawking cookies and Coke. She stops outside a piece of cloth that serves as the front door of a lean-to home. In Mumbai and other parts of the country, the government has teamed up with NGOs like Navnirman Samaj Vikas Kendra, where Kamble works, to keep track of patients and to make sure they stick to their drug regimens. Inside the hot, airless hovel, a man named Nasim Mohammed rests on a dirt floor. He weakly props himself up to talk to Kamble, wiping away the fluid that seeps from his eyes. Mohammed has been taking government TB drugs for five months, but he isn’t getting better. “He doesn’t move around much,” says his wife Hasibunissa Shekh. “He sleeps most of the time.” Neighbors have been helping feed the couple since Mohammed has been too weak to work, but both husband and wife are alarmingly thin. Now they’re waiting for the test results to find out whether Mohammed’s TB is drug-resistant. That will take weeks; in the meantime, Shekh and anybody else Mohammed comes into close contact with could become infected.

When doctors at Hinduja first reported TDR cases in late 2011, the central government groused at them for being alarmist. But eventually New Delhi nearly doubled the budget of the national TB program. Now 529 of the nation’s 662 health districts are, at least on paper, equipped to treat drug-resistant cases, and last summer the government said the whole country would be covered by March. Says Dr. Minni Khetarpal, Mumbai’s deputy health executive officer: “After a year, I am confident the numbers will go down.”

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If You Build It, Will They Come?
At least in Mumbai there are options. Between the newly robust network of government clinics, NGOs, hospitals and labs, there is a reasonable chance that sufferers will get scooped into the system. But in rural areas — in other words, most of India — that possibility is worryingly remote. In Patna, the capital of Bihar state, which has one of India’s highest TB rates, 30 spartan beds are lined up in a new drug-resistant-TB ward. This is one of three facilities in Bihar where patients go to start government treatment for drug-resistant TB. Anil Kumar, a shy 18-year-old, sits on one of the beds with his father hovering over him. Kumar has been diagnosed with MDR TB. He was only tested after his sister, who had floated from private doctor to private doctor for years, finally died. Ajay Kumar Singh, the doctor on duty, says the boy almost certainly contracted the drug-resistant strain from his sister, and for that, he’s lucky. “His diagnosis was made at her sacrifice,” Singh says.

Thousands of families might not know to do the same. Finding a way to bring patients into the system is tricky in a place where mistrust of government services runs deep. Once bedeviled by insurgents, bandits and some of the worst infrastructure in the country, Bihar is still trying to shake its reputation as the nation’s basket case. Things have improved, but years of official neglect are hard to undo in far-flung villages that are waiting to catch up with a shinier India. “There’s [not enough] staff in the local hospital,” says Mohammed Ishaque, a villager whose wife has TB. “They just tell patients to go to private doctors.”

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And that’s exactly what most people in Bihar — and indeed most of India — do. Today there are about 57 doctors per 100,000 people, a number that the government says falls far short of what’s needed. The vast and unwieldy sector of private practitioners ranges from qualified professionals to unskilled entrepreneurs who sniff an opportunity to siphon off customers from crowded and generally loathed government facilities. Even patients with almost no money prefer to drop into a private neighborhood clinic than wait in line for hours at a public hospital. Thus, untold numbers of hole-in-the-wall providers are often the first point of contact in India’s battle against TB.

The government plans to make TB drugs free in the private as well as public sectors. If well implemented, the move could have an enormous impact on the spread of the disease and on drug resistance. If it’s not done right, wider use of powerful second-line drugs in particular could make resistance worse. India has also made the reporting of TB mandatory and became the first nation in the world to ban the import and use of an inexpensive but dangerously inaccurate TB blood test. (Without an effective system to communicate or enforce the new regulations, however, the test is still being widely used.) “More than 60% [of TB patients] are getting treated in the private sector, and it is totally unregulated,” says Khetarpal. Even in a major city like Mumbai, she admits, “regulating them is beyond our ability.”

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The Long Game
What happens in India could alter the course of one of the world’s oldest and deadliest diseases, but India is not the only country in the fight. In Belarus, where some of the highest rates of MDR TB have been detected, public-health experts are trying to contain the disease among needle-drug users. In Russia and Britain, drug resistance is rampant in prisons. Studies in other countries, including India’s neighbor Pakistan, show that getting the private sector involved is key to increasing the number of TB cases that get diagnosed — and therefore is key to containing the disease. “International policy has focused on the public sector,” says Salmaan Keshavjee, a professor at Harvard University who studies TB. “That might work in Canada, but in most of the world, people buy care from the private sector … If you don’t engage with it, you’re never going to get this disease under control.”

WHO estimates that TB costs the global economy nearly $12 billion a year in lost productivity and wages due to sickness and death, with India and China making up half that sum. Last March, the Bill & Melinda Gates Foundation gave a $220 million grant to the U.S. nonprofit biotech firm Aeras to develop new vaccines. In the first major TB-vaccine trial in decades, an initially promising Aeras vaccine was found to be ineffective — a serious setback — but now about a dozen new vaccines are being tested in clinical trials, according to the Stop TB Partnership. In December the U.S. Food and Drug Administration approved the first new TB drug in decades, and several other drugs are also in the pipeline that could help fight resistant strains, be taken for shorter periods, decrease side effects and be more effective for HIV/AIDS patients. Faster and more accurate diagnostic tools are on the way, including GeneXpert, a machine already in use in India and other parts of the world that tests for drug-resistant TB in hours, not weeks.

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For now, though, frontline staff are making do with the drugs they have. When TIME visited Udwadia’s airy Mumbai office, he sat facing portraits of Dr. Robert Koch, the scientist who discovered the TB bacterium, and American jazz great Miles Davis. As desperate patients who weren’t responding to drugs shuffled through his door, Udwadia appeared to take cues from the latter — by improvising treatments. Udwadia gestured to a longtime patient sitting at his desk. “At one stage, I told this man, ‘Go away. We can’t help you,'” he said. Owais Sheikh was one of the first patients Udwadia diagnosed as being TDR. He didn’t think anything would help the young father of two, who also has HIV. It was only because of Sheikh’s determination to get treated and eventually Udwadia’s willingness to try an unproven combination of drugs that Sheikh remained alive. “I’m very happy, my friend,” Udwadia said that day, looking at his smiling patient. “Totally drug-resistant does not mean totally doomed.”

Or perhaps it does. Because Sheikh has since suffered a relapse and Udwadia has been forced to seek yet another untried course that could leave the bacterium stronger if they don’t succeed in killing it. In the fight against TDR, hope and happy endings are tragically rare.

— with reporting by Shashikant Sawant / Mumbai

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