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Something was wrong with the death rates. They should have been lower.
The AIDS drugs were working. Most of the patients—impoverished rural people in Tugela Ferry, South Africa, who were taking seven pills every morning—had no detectable HIV in their blood. They were not cured, but they could expect to live for years.
And they were taking two additional pills, containing four different drugs for tuberculosis. In southern Africa, where HIV rates are the highest in the world, tuberculosis is the leading cause of death for people with HIV. AIDS specialist Gerald Friedland had been pushing for years to coordinate treatment for HIV and TB in South Africa. This study of 119 patients with both diseases was his chance to demonstrate that treating them together works. In the study's first year, only 10 percent of the patients had died—a huge drop from the 40 percent death rate typical for HIV patients getting TB treatment alone. Friedland had expected even better. But still, things were going well.
That is, it looked that way until January 11, 2005. That day, Friedland, a Yale medical school professor and director of Yale’s AIDS program, had scheduled a routine quarterly conference call with four fellow investigators. Their agenda was to review all deaths among the study subjects. This was simply a matter of good scientific procedure, and Friedland expected nothing out of the ordinary. Tony Moll, the doctor on-site at the hospital in Tugela Ferry, presented what he knew about the deaths, one by one. One patient had died from an unrelated gastrointestinal bleed. Another had died of drug-resistant tuberculosis. A third patient had been doing well, but had unexpectedly sickened and then died in a matter of weeks. She wasn’t the only one. Four or five others had also recently died.
“Whoa, what’s this all about?” Friedland remembers asking. “These people have non-detectable viral loads. We know they’re not dying of AIDS. What are they dying of?”
Infectious disease specialist Neel Gandhi, on the phone from Emory medical school in Atlanta, remembers going through the possible causes. “This is not about ordinary pneumonia,” said Gandhi, a former Yale postdoc. “We're treating for that. And it’s not an AIDS-related pneumonia like PCP, because their viral loads were undetectable and their CD4 counts were good. It doesn’t add up.”
“That’s when the light bulb started to go on,” says Friedland. He can’t recall who said it out loud. But by the end of the call, all five doctors had reached the same chilling conclusion: “They died of MDR TB.”
MDR TB is multidrug-resistant tuberculosis, TB that does not respond to the two most potent “first-line” drugs for the disease. It’s a familiar enough disease in Tugela Ferry, but the study had specifically excluded patients at risk for it. One case could slip through—but five or six? It didn’t make sense.
The implications were serious. Although three out of four otherwise healthy people will recover from MDR TB, for those with HIV, the death rate is 40 to 60 percent. And doctors in South Africa have only two or three other drugs to try on MDR TB—“second-line” drugs, which are more expensive and less effective. And if those drugs don’t work? “You die,” says Friedland.
For Tony Moll, that January phone call was the end of a kind of honeymoon. The previous year had been a year of optimism, the first in the 15 years of the AIDS epidemic in Africa.
Until the Yale-sponsored study began in October 2003, HIV-positive residents of his community who fell sick inevitably began a swift decline to death. “As physicians, we'd help them along, treating infections with antibiotics,” says Moll. “But it would just be a downward descent.”
About a third of the 250,000 people in Moll’s rural district of the province of KwaZulu-Natal could expect to die that way, sooner or later. The poverty of the area contributed to these deaths. In a place where most people live hand to mouth, without electricity or running water, the men leave. They generally go north to work in the mines, or east to Durban. When they visit, they often bring home HIV, and they pass it on. Men with HIV eventually come back to die, some in the Church of Scotland Hospital where Moll works, but most in the circular Zulu mud-and-thatch huts scattered among the hills and valleys. With the healthy men working away from home, this is a region of women and ailing men. When a woman becomes ill, Moll says, “everything collapses.”
The Yale study brought change. Financed by the Irene Diamond Fund, the Doris Duke Charitable Foundation, and Yale, the program provided Tugela Ferry patients, for the first time, with the antiretroviral drugs that had been keeping AIDS at bay in Western patients for years. People gained weight. Their vitality returned. When Moll and his colleagues asked community members to name the study, they called it Sizonqoba, Zulu for “We shall overcome.”
And in March 2004, reversing years of governmental resistance, South Africa began providing free antiretroviral medicines to all citizens who needed them. “We experienced these amazing turnarounds that we just had never seen before,” says Moll. “This really gave us new hope.”
But now, with this new outbreak of resistant TB, patients who had rebounded from AIDS were struggling—losing weight, having night sweats, their chest X-rays getting progressively worse. They were finally getting standard HIV drugs and tuberculosis treatment, and they were dying anyway.
A few weeks after the January conference call, Moll decided to find out how many patients were infected with resistant tuberculosis. He assigned the job to two visiting students from the Nelson R. Mandela School of Medicine in Durban. On February 7, they collected a sample of sputum from every patient in the hospital who could manage to cough some up—45 people in all. Moll sent the samples in a hospital van that travels every week, down the only paved road in town, to Durban, 125 miles away. Durban’s Nkosi Albert Luthuli Hospital has one of the few laboratories in all of Africa equipped for drug resistance tests.
The tests would take two to three months. The lab had to grow enough bacillus to track its vulnerability to several different drugs, and Mycobacterium tuberculosis grows slowly. While the cultures multiplied in glass vials, and while their responses to the drugs were recorded over several weeks, Moll’s patients remained at the Church of Scotland Hospital. The two 40-bed TB wards were ventilated only by opening the windows. Every cough or sneeze from a patient might spread the disease.
In late May, microbiologist Lynn Roux phoned from Durban. Moll vividly recalls the conversation: “You know, Dr. Moll,” Roux said, “out of 45 samples you submitted in February, ten of them have got resistance to every single drug that we tested against—a total of six drugs.”
Resistance to six drugs meant disease a quantum leap worse than any MDR TB Moll had seen before. What he didn’t know yet was that this strain of TB was part of something much bigger—a widespread phenomenon so new that the World Health Organization was still working to define it.
Moll did grasp immediately, and viscerally, what the test results meant for his staff. “I could feel something like a cold shiver going through my body,” he says. “Working with HIV patients is one thing, because the transmission of HIV from patient to worker is not something to be worried about. But with an airborne disease that is not treatable, it’s a completely different ballgame.”
And in fact, two of the people whose TB had tested resistant to every drug were hospital staff. Like 20 to 50 percent of the nursing staff, they were HIV-positive. By the time Roux called in May, both were dead.
It didn’t have to turn out this way. The TB bacillus is latent in about a third of the people on earth, but even with no treatment, only about 10 percent develop the disease. And the first-line TB drugs developed by the 1970s cured almost all patients who took them daily for six months. Armed with these highly effective antibiotics, doctors believed they could eradicate the disease worldwide.
Instead, the TB bacillus evolved to beat the drugs. Patients who quit taking their pills early—when they felt better but before their six months of treatment were over—failed to kill off all the TB in their systems. They effectively spared the toughest strains, bacilli that had mutated and become less susceptible to the drugs. The same thing happened en masse in poor countries where patients and clinics often could not afford high-quality drugs or enough of them, or the right drug combinations.
The advent of HIV in the 1980s made things worse. The TB bacillus activates in people with weak immunity, and TB, in turn, accelerates the replication of HIV. (Stephen Lewis, UN special envoy for HIV-AIDS in Africa, calls TB and HIV “a combination made in hell.”) The rise in TB cases increased the chances for resistance to develop.
These resistant bacilli compounded the challenges. They require longer treatment—at least two years—and second-line drugs are so toxic that patients often quit therapy prematurely. Nesri Padayatchi, deputy director of the Centre for the AIDS Programme of Research in South Africa, tells of 35 patients treated with a second-line drug that causes intense nausea. Eight of them, she says, “tried it and said, ‘I would rather die.’”
Gerald Friedland was working at Montefiore Medical Center in the Bronx in the late 1980s and early 1990s, when resistant TB sharply increased in New York City. Health officials quelled the outbreak with new strategies, such as supervising patients when they took their daily medicines. Since 1993, tuberculosis rates have steadily declined in the United States.
But as a result, Friedland says, researchers in the United States and other wealthy countries have been complacent. Diagnosis by sputum sample, still used in poor countries, has not changed since Robert Koch discovered the bacillus in 1882. And no new TB drugs have been developed for 35 years. Doctors whose patients face resistant TB can’t turn to “third-line” drugs: none exists.
At first, says epidemiologist Sarita Shah, the doctors studying TB in Tugela Ferry did not fully recognize the significance of what they were seeing. Shah specializes in TB. She is also Neel Gandhi’s wife, and when Gandhi took part in the January conference call, she happened to be working on a year-long survey of tuberculosis worldwide.
As early as 2000, the Green Light Committee, an international project to fight MDR TB, had begun seeing cases of TB that were resistant to virtually all second-line drugs. To find out how widespread and how frequent these cases were, Shah, at the Centers for Disease Control and Prevention (CDC), was collaborating with the World Health Organization to survey a global network of TB labs.
When Moll got the phone call in May alerting him to the ultra-resistant TB, Gandhi told his wife about it. He recalls her telling him that the outbreak wasn’t just a local crisis: “You guys don’t realize it,” Shah said, “but you're sitting on something incredibly important and incredibly dangerous.”
During the months that followed, Shah and her colleagues collected ultra-resistant bacilli in every region of the world. As alarming as MDR TB is in itself, they had to convey that this newly recognized TB was worse. At first the researchers called it “super-drug-resistant.” But Shah and her colleagues looked for an edgier and less positive name, to help attract the media, she says: “What comes with media attention is human and financial resources and political commitment.” They came up with “extensively drug-resistant”—XDR TB.
On March 24, 2006, the CDC reported their survey results. The researchers had found cases of XDR TB on all six continents, including 74 cases in the United States between 1993 and 2004. (See map.) Of 5,751 bacillus samples examined by TB laboratories in 2000-2004, 39 percent were MDR TB. Of those, 7 percent were XDR TB. These findings, said the report, raise “concerns of a future epidemic of virtually untreatable TB.” More than 150 stories on the report appeared in the U.S. media, from National Public Radio (“New Drug-Resistant TB Strain Menaces U.S.”) to the Kalamazoo Gazette (“Fight TB Abroad”).
Friedland and his colleagues, meanwhile, had tested 1,539 patients in KwaZulu-Natal, some with TB, some suspected to have TB. Of those, 544 tested positive. Close to half of these TB cases—41 percent—were MDR TB. And of those MDR TB cases, nearly a quarter—24 percent—were XDR TB.
In all, 53 patients had XDR TB. All of them also had either confirmed or suspected HIV. Of those 53 patients, 52 died. They survived, on average, less than a month after their sputum was taken. In August, when Gandhi reported these results at the 16th International Conference on AIDS in Toronto, Tugela Ferry made worldwide news. A South African epidemiologist said the study was “a jolt to reality. It gave a crisis perspective to a problem we all knew existed but were adopting an ostrich approach to.”
“What was repeated over and over again was the mortality rate: 98 percent,” says Friedland. “People are waking up. They are realizing that TB is a worldwide catastrophe.”
Since early 2005, TB has killed six people from the 270-person nursing staff at Church of Scotland Hospital. Four had MDR TB; two had XDR TB.
At any given time, Moll says, the hospital in Tugela Ferry is overseeing treatment of 900 patients with tuberculosis, though it has only 80 TB beds. So far, the hospital has identified 250 patients with XDR. About 15 percent have survived. Doctors are not sure what saved them.
The hospital staff now routinely wear high-tech face masks on the wards—something once frowned upon in the culture as unfriendly, but now accepted as lifesaving. (The Yale nursing and medical schools, which send students to the hospital to do rotations, say their students will take precautions.) And Moll’s urgent March 2006 request to the provincial government for an air-changing system to reduce the spread of infection was finally fulfilled last January.
But the isolation units he asked for were never built. And although the CDC offered to send consultants, at no cost, to give advice on how to manage the outbreak, the KwaZulu-Natal Department of Health never took up the offer.
Once a week, Moll sends patients who appear to be suffering from MDR TB to the province’s tuberculosis hospital in Durban for evaluation. Ideally, they should be admitted and kept for six months until they are no longer contagious. But the hospital, with only 200 beds, is overwhelmed. “They mostly get returned to us the same day,” says Moll. “We can’t do anything, because we don’t have isolation wards. So we have to send them back home.”
Two of Moll’s fellow physicians at the hospital recently developed TB; both had treatable strains and are recovering. Not long ago, Moll got sick, too. “I was really worried,” he says. “I did go for a chest X-ray.” It turned out to be bronchitis.
For Friedland, the scene in KwaZulu-Natal is reminiscent of what he experienced as an AIDS doctor in New Haven and in New York, where he began working with AIDS patients when the illness was first identified in 1981. “I saw in Tugela Ferry what I’d seen before, 20 years and 8,000 miles away. Wherever AIDS is in the world, there are more similarities than differences. It’s a stigmatized disease of young people. A very cruel disease.”
HIV infection becomes epidemic, says Friedland, where social factors have prepared the ground. “You need the virus, and that’s the seed. And you need the wind”—the socioeconomic factors—“to spread it.”
In South Africa, colonialism was “the social equivalent of a shooting gallery [where addicts share needles] or a bathhouse, where social circumstances are set up to incredibly effectively spread a sexually transmitted infection.” Apartheid and poverty undermined traditional societies and economies, and men living in all-male dormitories near mines and plantations sought out sex workers. HIV and TB, Friedland says, exemplify the bonds between biology and culture. These were the connections that drew him to medicine: “I think of medicine as a way to correct not just medical but social and health disparities.”
For Moll—who moved to Tugela Ferry to practice medicine, 20 years ago, “to show the love of God to the poorest of the poor”—“the link between poverty and HIV and TB is an undeniable reality that also has to be addressed in some way.” Is this happening? “Not really,” he says. “Not fast enough.”
If you think of the world’s population as a mega-patien t, the emergence of resistant TB is a serious relapse. The whole world will be affected. As the United States saw this May when Atlanta lawyer Andrew Speaker crossed the Atlantic—twice—while infected with XDR TB, the disease will not be contained within poor countries.
To Friedland, the delay before Speaker’s XDR TB was diagnosed (part of the reason Speaker was able to get on an international flight) illustrates the desperate need not only for new drugs but also for more rapid diagnostic tests. The United States must play a central role, he says. “One of the things we're best able to do is to address fundamental research questions in diseases that affect people all over the world. I think we have a moral responsibility to do it.”
The world is finally paying attention to TB since the media alarm over XDR, says Padayatchi of the Centre for the AIDS Programme of Research. (In part, she credits Friedland, whose “credibility and persistence have brought attention to this problem in South Africa.”) Still, Padayatchi believes new TB drugs are at least five years away. But studies on quicker modes of diagnosis are under way, and they are promising. Friedland, Moll, Gandhi, and Shah are starting a study this summer of a new, much faster diagnostic test.
Epidemiologists and clinicians have so far seen only the beginnings of XDR, and they can’t fully predict its course. Can they contain the problem, or could it become, asks Friedland, the “slow tsunami” that AIDS has been? He doesn’t know. But he feels now what he felt in the early days of AIDS: “a vague and yet very palpable feeling of dread that something very bad was happening.”
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