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.

Thursday, July 02, 2015

Inside India's Zodiac Murders

By Jason Overdorf
Newsweek (July 2015)

Kurapati Nagaraju is one of India’s wealthiest astrologers. He’s also very lucky. Several months ago, two gunmen on motorcycles skidded to a halt near his house, pumped three bullets into his gut and fled. Rushed to the hospital, Nagaraju survived—only to be jailed on murder charges.

Three of Nagaraju’s relatives—also wealthy astrologers—were much less fortunate. Last year, they were bumping down the highway outside of town when a Toyota minivan swung in behind them. Then it accelerated, roaring past the astrologers' Chevy and forcing it off the road. Three contract killers jumped out and sprayed the Chevy with bullets, killing everyone but the driver.

The victims should have seen it coming—and not because they were astrologers. A few months earlier, Nagaraju and his Gandham clan allegedly arranged the brutal murder of Durga Rao, the charismatic scion of the rival Buthams, and Durga’s relatives vowed revenge, according to a local police report. In separate reports, the police say Butham family members are suspects in the attempt on Nagaraju’s life and the murder of his relatives. Nagaraju has yet to face trial and says his enemies have framed him, according to a local prosecutor.

It’s suddenly dangerous to be a prosperous prognosticator in this country. In recent years, as astrologers and gurus have emerged as fixers and go-betweens for India's often-corrupt politicians, violence has grown increasingly common in that line of work. In 2012, hitmen dressed as police officers gunned down an astrologer who advised powerful politicians in the north Indian state of Uttar Pradesh. His murder, police say, was the result of disputes with rival kingmakers over local elections and construction contracts.

In the neighboring state of Haryana, a guru—who critics say operated with impunity for years because politicians relied on him to deliver votes from his devotees—faces charges of rape, murder and fraud, among other things. (He says his enemies fabricated the charges.) And last year, another Haryana guru barricaded himself in a compound with as many as 15,000 followers to avoid being arrested on a charge of conspiracy to commit murder, in connection with a clash between his group and another sect. He, too, is said to have long enjoyed the support of local politicians.

Residents say the Buthams and Gandhams also have enough clout to call in small favors from state-level politicians. And the bloodshed between the two families in the village of Pinakadimi, the police say, seems to be the result of that battle for money and influence. As one local police source, who asked for anonymity because he wasn’t authorized to speak to the press, put it, “Durga and his rival Nagaraju were vying for control of the local political machine.”

The Untouchable Astrologers

In a sign of the astrologers' new wealth, many villagers have multistory homes rather than the simple huts common in Indian villages. The garish pink houses of the Buthams and the gaudy blue homes of the Gandhams have satellite dishes and are decorated with expensive enamel tiles. Both families have set up lucrative fortune-telling businesses in Mumbai, New Delhi and other major Indian cities, and make frequent trips to meet clients in Australia, Japan and Singapore, among other places. Their customers, according to local journalists, include international businessman Lakshmi Mittal, as well as top local politicians and film stars.At first glance, Pinakadimi looks like a typical South Indian hamlet. Not far from the ditch where assassins threw Durga’s body, a handful of water buffalo amble across the village’s main street, a narrow dirt road. Piles of harvested corn dry in the sun in the adjacent field. But Pinakadimi is not a typical town; it’s known as “the village of the astrologers,” as many of its 500-odd families earn their living through astrology and fortune-telling, catering to clients across the country and even overseas. Not long after I arrive, a slim man with a neat mustache accosts me and offers an impromptu reading. “You will be rich,” he says. “You will have two wives and five children.” (He's zero for three so far, but I'm only 44.)

The rise of the two families represents a remarkable leap across caste barriers, experts say. For centuries, astrology was the domain of high-caste Brahmins. Traced to the ancient Hindu texts known as the Vedas, it was a priestly discipline, used for matchmaking and to identify auspicious days for weddings. So-called “remedial astrology”—which involves the sales of gems, charms and rituals as remedies to counter bad planetary alignments—is a more lucrative offshoot (astrologers sell both trinkets and advice). Such services were not available to the lowest castes, however, because the Brahmin priests considered them untouchable. So the Jangalu caste, which the Buthams and Gandhams belong to, had a vast audience for their predictions, rituals and remedies.

As long as that audience remained poor, the itinerant fortune-tellers couldn’t make much of a living. But since the 1990s, the lower castes have become a potent social and political force. The erstwhile untouchables and menial laboring castes together make up more than half of India’s population and have given rise to regional parties that have displaced both the Indian National Congress Party and the Hindu nationalist Bharatiya Janata Party—the country’s dominant political groups—in half a dozen states. This shift shrugged off centuries of prejudice, but it has created a Boss Tweed-style patronage system, as lower-caste leaders distributed contracts and government jobs to garner support.

Gandham clans is rooted in a fight for the spoils, police say. Already rivals in the astrology business and real estate speculation, the two families had also become embroiled in a long-running dispute, the result of a Romeo-and-Juliet-style romance gone wrong. In defiance of the traditional arranged marriages, Nagaraju’s niece ran away with Durga's nephew in 2006. After heated negotiations, the families reluctantly agreed to let the young couple marry. But there was no happily ever after.

Not long after the wedding, the relationship fell apart, and the marriage’s demise deepened the enmity between the two families and ended any hopes they might share political power. Both families donated heavily to rival campaigns for the local state assembly, and before the killings began last year, they backed competing candidates to head the local village council, a key conduit for government-funded projects. “The Gandhams were jealous of [Durga] because of his popularity,” says his widow, Tirupathamma. “He was always generous to the people of the village, and people of all communities came to him for help and advice.”

The police paint a less flattering portrait. Just before the local polls, Durga apparently ditched the candidate he'd been supporting in the race for village council chief and threw his money and support behind another man, said the local police officer. Police say the maneuver may also have been part of the motive for the attack.

‘He Was Covered in Blood’

Today, Tirupathamma is living under police protection. A solidly built woman with a broad face and long hair, she wears a bright-green sari printed with purple flowers and a dozen red and gold bangles on both wrists when I meet her on the porch of a massive bungalow. Standing between two armed police officers, she produces a smartphone and swipes through a series of professional-looking photos of her husband—a strikingly handsome man with the wavy, swept-back hair of a South Indian film star. Wearing black aviators and a tight-fitting shirt, he strides boldly toward the camera in one of the pics. In another, embossed with the Michael Jackson's name, he poses like the singer.

Tirupathamma's voice cracks and her eyelids flutter as she describes the night her husband was killed. (The police say at least four attackers stabbed him 16 times.) After his usual dinner of an apple and two chapatis, a type of unleavened bread, Durga went for a walk. Tirupathamma was washing the dishes when she heard people shouting outside. She stepped onto her balcony to see what was going on. “Durga has been attacked,” one of the villagers shouted. Durga's brother went out to find him, Tirupathamma says. When he came back, he was covered in blood. “He told me that Durga had been murdered, and he collapsed on the ground.”

Nagaraju’s first hearing is slated for August, at which time he’ll apply for bail. The trial itself may drag on for decades, due to the Indian court system’s glacial pace. For Tirupathamma, the resolution can’t come soon enough. As she speaks, a tear rolls down her cheek. “I vowed that I will not begin mourning until all my husband's killers have been eliminated.”