Monday, July 06, 2015

Supercharged Tuberculosis, Made in India

A patient with extensively drug-resistant TB flew from Mumbai to Chicago, and the deadly disease could become an infamous export due to problems in India's public health system
By Jason Overdorf
Scientific American (July 2015)

MUMBAI, India—On a drizzly Monday afternoon here a few weeks ago, patients crowded around a door in a hallway in P. D. Hinduja Hospital—a private, nonprofit facility that caters to around 350,000 people per year. There is a loud, steady roar of voices, and patients and nurses have to shoulder past one another to get through the door, which leads to the office of lung specialist Zarir Udwadia. The walls are clean and white, and the air carries the tangy smell of disinfectant.

Against one of those white walls a grizzled old man with a breathing tube in his nose lies moaning on a stretcher. Nearby, clutching a sheaf of prescriptions, the father of a sick college student tries to catch the attention of one of Udwadia's assisting physicians. Several families have traveled thousands of kilometers to be here. Many of these patients, like 19-year-old Nisha, an engineering student from the central state of Madhya Pradesh, have tuberculosis (TB). Nisha, who asked that her real name be withheld, has been treated for lung problems for more than a year, only to learn that inaccurate diagnoses and prescription errors have supercharged the disease rather than curing it. “My doctors kept on changing the drugs,” says Nisha. Dressed in jeans and a floral-print blouse and black Buddy Holly–style horn-rimmed glasses, she speaks in a bright, optimistic voice, although her battle with TB has left her anorexic-thin.

By exposing Nisha's TB to various drugs without wiping it out, her doctors just made it stronger, a problem that Udwadia—the doctor who first identified extreme drug resistance in the germ—and other health experts say is becoming increasingly widespread in India. Too few diagnostic laboratories, too many poorly-trained health practitioners and thousands of infected people living in crowded, unsanitary conditions has made India home to the world's largest epidemic of drug-resistant TB. More than two million Indians every year get the highly contagious disease, and a patient dies every two minutes. Around 62,000 of these people harbor TB that is immune to at least four types of drugs, according to the World Health Organization, and as many as 15,000 may have an even more dangerous type called “extensively drug-resistant” TB that fights off almost every antibiotic in the medical arsenal.

Now, difficult-to-kill TB is no longer just India's nightmare. In June U.S. health authorities confirmed that an Indian patient carried this extreme form of the infection, called XDR-TB, across the ocean to Chicago. The patient drove from there to visit relatives as far away as Tennessee and Missouri. Health officials in several states are tracking down everyone with whom the patient—who is now quarantined and being treated at the National Institutes of Health in Maryland—had prolonged contact. The disease can be cured in only 30 percent of patients and sometimes requires surgery to remove infected parts of lungs. Although TB’s slow rate of infection makes explosive epidemics unlikely, the Chicago episode shows how easy it might be for the illness to become a worldwide export.

Yet until recently Indian public health officials remained reluctant to admit there's a problem, says Nerges Mistry, director of the Mumbai-based Foundation for Medical Research. “They were always trying to deny it [existed],” she says. (Neither the head of India's Revised National Tuberculosis Control Program (RNTCP) nor Mumbai's main tuberculosis control official—both of whom are new to their posts—responded to interview requests from Scientific American.)

Resisting a cure
Tuberculosis typically attacks the lungs, but can also develop in bones, the stomach or even the genitals. Unlike the Ebola virus, which can only be transmitted by direct contact with the bodily fluids of an infected person, TB can be transmitted via coughing, in airborne droplets from an infected person, though experts say it's harder to catch than viruses like influenza or chicken pox. (However, in 2013 Scientific American reported that some TB strains may be getting more virulent.) The typical symptoms of a TB lung infection include fever, night sweats and a chronic, hacking cough.

For an ordinary infection, the WHO-mandated treatment includes lengthy treatment with a cocktail of antibiotics: a two-month course of rifampicin, isoniazid, pyrazinamide and ethambutol followed by a four-month regimen of isoniazid and rifampicin alone. If the patient fails to complete the treatment or the TB bacilli in her system is already immune to one of those antibiotics, however, then some of the germs will survive, adapt and grow stronger. Some the hardier organisms can survive to pass on drug-resistant traits to their progeny, and those traits then spread to a wider group of descendants. That means it's crucial to kill off the entire population with the first course of treatment and hunt down and kill off any resistors.

The WHO defines drug-resistant TB as a strain of bacteria immune to one of the first-line drugs used to treat the disease. Multidrug resistant TB, or MDR-TB, does not respond to the two most powerful drugs, isoniazid and rifampicin. Finally, XDR-TB is resistant to those two drugs, plus any fluoroquinolone and at least one of the three injectable second-line drugs, capreomycin, kanamycin and amikacin.

In Nisha’s case her doctors never tested her for drug resistance, so she underwent treatment for more than a year with compounds doomed to failure. As a result, she suffered side effects from the antibiotics—which included hearing loss and joint pain so severe she couldn't get out of bed—without being cured. Worse, her infection grew stronger.

What concerns TB specialists like Udwadia is that India has been creating thousands of Nishas this way. And although it has begun to respond to the problem, the reaction is too small and too slow. A slim, fastidious man with a sharp nose and a thick shock of black hair, Udwadia doesn't look like an alarmist. He wears a conformist's pinstriped dress shirt and red tie as he puts Nisha through a brief examination. But Mistry and other health experts from nongovernmental organizations say his original identification of alarmingly resistant disease strains, and his continued pressure on the medical community to do something about it, are among the biggest reasons that India's culture of denial is beginning to show some cracks.

The country’s resistance problems have arisen, paradoxically, because India has made great strides against the nonresistant form of the disease. Beginning in the 1990s India adopted a WHO-developed program called “Directly Observed Treatment, Short Course,” or DOTS. It is designed to ensure poorly educated patients in the developing world properly complete the six-month-long, first-line TB treatment. Through a huge network of volunteer “DOT providers” the RNTCP has managed to dispense the free treatment to corners of the country where the nearest hospital lies hundreds of kilometers away. It boosted the detection rate for new cases above 70 percent in 2010 and it is targeting 90 percent this year. And it has achieved a treatment success rate of 88 percent for the patients it identifies, according to RNTCP documents.

In other ways, however, India’s performance has been less than stellar. Although public health spending has risen steadily since 2000 the federal share is still less than $5 per person, a perilously low level.** As a result, the country has fewer than one doctor per 1,000 people and an even more dramatic shortage of laboratories that can test for TB resistance. DOTS cannot substitute for testing infrastructure. As recently as 2008, less than one percent of high-risk patients were tested to see if they were susceptible to various anti-TB drugs. And private sector doctors screened for TB with blood tests that were notorious for false positives.* These errors simply meant that frontline antibiotics were overused, and overuse is the classic recipe for developing resistance.Number of multidrug-resistant TB cases estimated among known TB patients, 2013. Source: WHO

In December 2011 Udwadia decided that he had seen enough. The laboratory at Hinduja—one of the few Indian labs equipped to perform drug-susceptibility testing—identified a fourth patient infected with TB that was impervious to all 12 of the first-line, second-line and last-resort drugs that the hospital had at its disposal. He dashed off a two-page note to the medical journal Clinical Infectious Diseases, declaring an outbreak of what he called “totally drug-resistant TB.”

Italian scientists had made the same claim in 2006, and the bacteria’s capacity to develop drug-resistant strains was already well known. In a country that thought it was getting its TB problems under control, however, Udwadia’s article was as important as pulling the fire alarm when you see the building in flames.

The doctor, like the antibiotics he was trying to use, encountered resistance. WHO questioned the term “totally drug-resistant,” saying absolute imperviousness had not been demonstrated. The agency also hinted that Udwadia's laboratory results might be flawed. India's health ministry added doubts about the lab, noting that Hinduja Hospital had not received accreditation from the government to conduct drug-sensitivity tests for second-line drugs.

The dispute caught the attention of the press and the public. The Times of India and other newspapers launched lengthy discussions on the extent of drug resistance. Bollywood star Amir Khan devoted an hour-long episode of his wildly popular, Oprah-style talk show to Udwadia and TB. And other Indian medical experts came out to support him, accusing the health ministry of attacking the messenger. Citations of hisClinical Infectious Diseases article by other researchers skyrocketed.

The public outcry forced the government into action. It dramatically boosted the budget for the national tuberculosis control program and increased hospital and outreach staff fourfold. Authorities stopped using older, error-prone blood tests, and began a transition to molecular testing with new GeneXpert machines that identify genetic markers of resistant strains. Though still in short supply, the machines drastically reduced false positives and allowed doctors detect resistance to first-line drugs within two hours, rather than weeks. Where they've been implemented, the machines produce a fivefold increase in detection of rifampicin resistance, for instance, according to the largest Indian study to date. Cases that the machine flags as drug-resistant are referred to the district TB officer, and a committee of specialists decides on a treatment regime. “I don't think the push would have been sustainable if not for Zarir [Udwadia]'s reports in the newspapers,” Mistry says. “It forced people to come to terms with what was really happening in the city.”

An expanding problem

But machines alone will not solve the problem. Mumbai now boasts 18 GeneXpert machines. There are only 120 nationwide, though—not enough to test all patients suspected to have MDR-TB, as recommended by WHO. And even in Mumbai, government hospitals only conduct GeneXpert tests on patients that have failed to respond to the first two months of DOTS treatment, due to the high cost of the cartridges the machine uses.

Udwadia and other physicians voice a bigger concern. The GeneXpert test can only confirm resistance to rifampicin, they note. Because India doesn't have enough laboratories to conduct further drug-susceptibility tests, any patient flagged by the machines is immediately put on the national TB program recommended regimen for MDR-TB. This one-size-fits-all treatment does have an advantage; it makes it “easier for lower category people to supervise patients and easier for the patient to take the medicines regularly,” says Rajeshree Jadhav, chief medical officer at Mumbai's government-run Pandit Madan Mohan Malviya Hospital.

Yet the off-the-shelf regimen does not account for further, stronger drug resistance that has already spread in Mumbai. According to a yet unpublished study conducted by Udwadia and his colleagues at Hinduja, it would now only cure a third of the drug-resistant patients in the city. The rest would receive three or more useless drugs and thus become even more resistant. “In Mumbai it is absolutely critical to follow up GeneXpert with full drug-susceptibility testing,” says Madhukar Pai, an epidemiologist at McGill University in Montreal and a leading TB researcher. “Otherwise, patients might get inadequate treatment.

Nor does the country have a good sense of how big the resistance problem really is. Because of the small number of diagnostic laboratories there's no way of knowing how the proportion of XDR-TB patients here compares with central Asian and eastern European countries like Lithuania—where nearly a quarter of MDR-TB patients actually have XDR-TB. But the sheer numbers of new TB infections every year, together with the tardy government response, suggest the problem may soon be larger here. A nationwide drug-resistance survey should provide more data in 2016, according to Pai. But the evidence that is available suggests XDR-TB will be “a sizeable fraction of all MDR” in cities like Mumbai—although it will remain low in rural areas.

If there are indeed many people with resistant germs, it heightens the chances of those pathogens leaving the country for the rest of the world. Nearly a million Indians traveled to the U.S. in 2014, compared with less than three million from all of central Asia. More and more middle-class Indians are being diagnosed with TB, and although the patient who carried XDR-TB to the U.S. was immediately placed in isolation, India has no provisions for quarantines or travel restrictions.

The risk of an epidemic outbreak from a single traveler is low, since TB is transmitted from person to person through prolonged, close contact. Moreover, the US has both the resources and tuberculosis control programs to react swiftly, according to Neil Schluger, chief of pulmonary medicine at Columbia University Medical Center and a specialist in TB. However, the worldwide migration of drug resistant strains does worry him a good deal. "It is like Ebola in slow motion. Potentially it is a huge public health problem,” says Schluger, but it is likely to creep along rather than explode.

A difficult future
In India, the troubling situation is not without hope Udwadia has found that some XDR-TB strains can be treated with a cocktail of drugs including the broad-spectrum antibiotic meropenem–clavulanate and the antileprosy medications linezolid and clofazamine. Johnson & Johnson's bedaquiline, the first novel TB treatment to be released in some 40 years, can also be effective. But the chances of survival using bedaquiline are less than 50–50, depending on the severity of drug-resistance and how early treatment begins. The treatment is grueling because the drug itself is highly toxic. It has not yet been approved for use in India, so Udwadia has to lodge individual requests to treat each patient on what is called “compassionate basis.”

Whereas regular DOTS patients undergo a short course of chemotherapy, MDR- and XDR-TB patients may be subjected to it for as long as two years. Radical lung surgery is sometimes also required. And other second-line medications frequently cause nausea, joint pain, hearing failure and depression so severe that suicide is not uncommon.

In Udwadia’s office a stocky, lower-middle-class woman who asked to be called Vanita (not her real name) says she was diagnosed with XDR-TB some four years after she was first treated with DOTS. For months she has been striving to eat better so that she is strong enough to withstand bedaquiline. She is too shy to express her relief when one of Udwadia's assistants tells her that she's finally met the health criteria. But her eyes shine with grateful tears above the green cloth mask covering her mouth and nose. And her doctor, who pushed the concept of total resistance, insists that particular adjective does not determine fate. “‘Total’ never means ‘totally doomed,’” Udwadia says.