The U.S., India and other nations are facing shortages of tuberculosis drugs - threatening to reverse decades of progress against a deadly disease that is becoming increasingly untreatable.
In India, some clinics are turning away sick children due to short supplies of pediatric doses, and in a risky move, adult pills are sometimes being split to approximate children's dosages. In the U.S., some patients who are infected, but not yet suffering symptoms, have lacked access to the most commonly used drug for that form of TB, leaving them instead to wait for the supply to improve or take another drug that doctors fear could worsen drug resistant TB if not properly used. The U.S. has also had repeated shortages of medicines that work against drug-resistant TB strains.
G.R. Khatri, the former head of India's Central TB Division, called the pediatric shortages "disastrous." Kenneth Castro, director of the division of TB elimination at the Centers for Disease Control and Prevention, called the continual U.S. shortages "exasperating."
World-wide, TB is becoming increasingly drug-resistant, and drug shortages are "one of the main reasons," said Lucica Ditiu, executive secretary of the Stop TB Partnership, which oversees a global drug-procurement facility used by more than 123 countries. If a patient starts and then stops taking a TB drug, even briefly, the disease can quickly become resistant to it.
"The huge gains we've made in reducing TB are at risk," said Bobby John, who heads Global Health Advocates, a New Delhi NGO.
Doctors in at least four other countries in Africa, South Asia and South America have reported drug shortages recently, according to Erica Lessem, assistant director of the TB/HIV Project at Treatment Action Group, a research and policy think tank. The shortages reflect fundamental problems including poor government-procurement systems, weak supply chains, poor profitability for some drugs and inadequate methods of gauging demand.
TB killed 990,000 people in 2011, excluding those also infected with HIV, according to the World Health Organization. The disease has been slowed in most Western nations; there were about 420 deaths in the U.S. in 2011, the most recent year reported, down from 1,800 in 1990.
In India, TB remains the biggest infectious-disease killer of adults. In 1997, in partnership with the WHO, India began a national program to beat TB by providing free treatment. TB killed 300,000 people in India in 2011, the most recent year for which the WHO reports, compared with 340,000 in 1990.
More than 1.5 million people currently receive free drugs at 13,000 Indian government centers nationwide. As many likely seek treatment at private Indian clinics, where they aren't registered, experts say.
India's supply woes arose soon after the planned expiration of a five-year grant from the British government providing TB drugs to a big portion of the country through the Stop TB Partnership's global drug-procurement facility. The Indian government needed to quickly begin the monthslong process of soliciting bids from companies to buy the vast volumes of drugs needed, but instead delayed, according to an official close to the Central TB Division, which manages the country's program.
Under India's TB program, the central government is in charge of buying drugs and distributing them to states. "Supply-chain management is a daunting challenge," said Anshu Prakash, the joint secretary at the Ministry of Health & Family Welfare, which oversees the Central TB Division. "There's nobody at fault."
Not only are pediatric dosages in short supply - with virtually none available in parts of Mumbai - but the central government has been unable to provide sufficient rifampicin, the most powerful TB drug, and two other medicines, streptomycin and kanamycin, according to Mr. Prakash and several state and local officials.
Mr. Prakash acknowledged the shortage of children's drugs as "a cause for worry."
He said India had solved the shortages of adult dosages by letting states buy the medicines themselves from private suppliers and by making emergency purchases. But that doesn't work for children's medicines, the official close to the TB Division said, because private suppliers offer mainly daily dosages that differ from the government's treatment plan, which is designed around alternate-day medication.
The official close to the TB Division said the government feels it is too difficult to retrain TB workers to administer pills daily to kids when the system is set up for every-other-day regimens.
Mr. Prakash said India's "dip in stock" would be solved by the end of June. "We'll have more than sufficient stock," he said.
Government TB officers in several state and local programs say they began experiencing shortages late last year in streptomycin. By January, some state and local officials say, they were also short of some rifampicin doses.
Also in January, they say, they saw pediatric shortages. In some clinics in Mumbai, which is experiencing an epidemic of drug-resistant TB, virtually no pediatric dosages are available, a senior Mumbai TB official said.
H.H. Chavan, the state TB officer in Maharashtra, where Mumbai is located, said his state would be unable to treat all children if no drugs were provided in a month.
When Rizwana Sheikh brought her adopted daughter Reshma Khan to a government clinic in Mumbai a few weeks ago, the child's neck was swollen with plum-size lymph nodes. Because the clinic was out of pediatric supplies for the smallest patients, the little 3-year-old - weighing just 18 pounds and so weak she could barely walk - was turned away without medicine, her family and a government TB worker familiar with her case say.
Back in her one-room home, Mrs. Sheikh wiped pus from the open wounds on the girl's neck and worried how her family could keep paying for the medicines on her husband's 3,000-rupee, or $60-a-month, income as a barber. The family is treating the child with drugs it purchases from a private pharmacy.
In a corner, Mrs. Sheikh's sister-in-law, 32, lay coughing. Both she and Reshma are suspected of having "multidrug resistant" or MDR-TB, in which the two most powerful medicines don't work, medical records say. MDR-TB is much costlier and tougher to cure than regular TB.
A senior Mumbai TB official said officials were doing their best treat kids despite shortages. She said her staff were, among other things, retrieving pills from dead patients.
Complicating matters, she said, she is overwhelmed with arranging treatment for the city's 3,600 patients with MDR-TB. Two years ago Mumbai treated only 280 such patients.
Officials in the states of Gujarat and Madhya Pradesh said they also weren't receiving enough medicines to treat all of their sick kids. Dr. Pradip Patel, Gujarat's head of drug distribution, said his staff has been breaking up adult dosages and giving them to children, but this isn't ideal because the precise dosage is unclear. The WHO specifically warns that giving kids too low a dose can lead to drug resistance.
"It is really problematic," he said. "There is no way you can justify the dosage."
Mario Raviglione, the WHO's TB chief, said India's problem is surprising because Indian drug makers supply the vast majority of the world's TB patients. "In India, this shouldn't happen," he said. "You are a producer of drugs."
In the U.S., the shortage of isoniazid, which was reported to the CDC last fall, is just one of several shortfalls that doctors have faced the past few years, said Dr. Castro of the CDC. There have also been "chronic shortages" of medicines used against drug-resistant strains, Dr. Castro said.
Shortages this spring of a common TB skin test, tubersol, have slowed down diagnosis in some cases. A spokesman for Sanofi Pasteur Inc., maker of tubersol, said a testing delay caused a shortage earlier this year.
One version of tubersol became available again in late April, and the other is expected to be available this week. But supplies may be limited "into the summer months" due to pent-up demand, the spokesman said.
"We need a long-term plan," Dr. Castro said. "One week I learn about isoniazid, the next week the tubersol shortage." The Food and Drug Administration and CDC are working on possible solutions to the shortage problem, including a plan to import needed TB drugs.
According to a January survey by the U.S. National Tuberculosis Controllers Association, 79% of participating health departments had difficulties procuring isoniazid, and 15% said they were out of it. A spokeswoman for Novartis said the company's Sandoz division, a U.S. supplier of isoniazid, "quickly ramped up its production in an effort to help meet patient need."
Teva Pharmaceuticals USA Inc., another isoniazid maker, also boosted production and established an emergency reserve, a spokeswoman there said.
The extent of global shortages is difficult to assess for some of the very reasons shortages occur: poor tracking of drug supply and a lack of good global reporting systems.
In Kenya, a woman with "extensively drug-resistant," or XDR TB - a very dangerous category - went several weeks last year without one of the few drugs that actually worked against her strain because of shortages, according to Jennifer Cohn, a medical coordinator with Médecins Sans Frontières, who helped treat the woman last year.
"We counsel patients, 'You have to stay on the drugs, it's life or death,' and then we come back and say, 'Actually, we don't have that drug,' " she said.
Drug stockouts "can arise at any one of many stages in the supply chain," said Amir Shroufi, deputy medical coordinator for MSF South Africa and Lesotho, which helped alleviate a shortage of AIDS and pediatric TB drugs caused by a strike at a distribution depot in part of the Eastern Cape of South Africa earlier this year.
The Global Drug Facility, the big TB drug-procurement organization, is working on reducing bottlenecks with new forecasting tools, an early warning system for stockouts and other measures, said Joel Keravec, special adviser. The GDF and the Global Fund to Fight AIDS, Tuberculosis and Malaria say they are also working on ways to consolidate orders for TB drugs, to create steadier demand so manufacturers aren't flooded with last-minute orders.
"If we can't plan very well, they can't manufacture very well," said Christopher Game, the Global Fund's chief procurement officer. The goal, he said, is to become a "customer of choice" for drug makers.
That may be more difficult than it sounds. At present, drug makers say governments order so erratically and estimate demand so poorly that it is hard to manufacture the right amount. Governments aren't often customers of choice because they drive prices down so low that the market isn't profitable, said J.P. Parswani, executive director of Cadila Pharmaceuticals Ltd., an Indian TB-drug maker.
"It is not a commercially interesting market," he said. "Prices are always under pressure."
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