CHASING BLACK FEVER

Seven hundred miles beyond Delhi, on the plains of India's Bihar state, the 21st century is hard to distinguish from the 11th. There isn't a tractor on the horizon as you travel north from the Ganges River toward Nepal. Peasants cultivate wheat and rice at the whim of the annual monsoon, using wooden carts and water buffalo. The villages look bucolic from a distance--all thatched huts, bright saris and swarms of curious kids. But the romance is illusory. In Rajwara, a community of 3,000, whole families survive on $300 a year. The adults are illiterate, the children malnourished and the misery is compounded by a growing sense of dread. As a local crowd converges on Dr. Shyam Sundar, a soft-faced physician who has traveled from the district capital of Muzaffarpur, people don't complain about their worms, malaria or dysentery. What has everyone so frightened is kala azar, or "black fever."

As Sundar wanders Rajwara's dusty lanes, villagers emerge from one hut after another, begging him to examine a family member whose failing health has defied all local remedies. Local healers can treat most fevers, but they're largely powerless against kala azar, a parasitic infection spread by tiny, biting sand flies. The disease is always fatal if left untreated, but the conventional cure no longer works in this part of the world. A sufferer's best hope of survival is a month of intravenous infusions in a distant hospital, at a cost that can run to several hundred dollars. "People will sell their land, their homes, even their utensils to pay for the treatment," Sundar explains as he presses villagers' abdomens to check for telltale swelling of the spleen. Within a few hours, he has identified nine likely sufferers and promised each of them a free bed at the small charitable hospital he runs four hours away in Muzaffarpur. Sundar saves about 600 lives a year this way. But, as he likes to say, "this is a very drop in the ocean." In the area he serves, kala azar kills 100,000.

Kala azar--technically, visceral leishmaniasis--is what health experts describe as a neglected disease. It strikes a half-million people each year, killing at least 200,000. If it took that toll in the United States, it would rank just behind heart disease and cancer as a cause of death. But kala azar is concentrated in the poorest rural areas of India, Nepal, Bangladesh, Sudan and Brazil--and the lack of prosperous patients has kept drugmakers from pursuing need-ed treatments. This problem isn't unique to kala azar. Of the nearly 1,400 drugs brought to market between 1975 and 1999, only 13 target tropical diseases. But change may finally be at hand. Corporations, relief groups and international donors have recently launched a flurry of efforts to correct the market's failures. This is the story of one such initiative. Its goal--the resurrection of an old antibiotic called paromomycin--may sound modest. But for millions of people now threatened by kala azar, success could mean life instead of death.

The paromomycin initiative was seeded five years ago by an American scientist named Victoria Hale, but the crisis it addresses dates back to 1976. That's when doctors in Bihar discovered that kala azar was becoming untreatable. The standard remedy--an antibiotic based on the heavy-metal antimony--was toxic and sometimes lethal, but it had always worked. "You know that damn bug is got to be dying inside you because you feel like you are dying, too," says a U.S. soldier who endured a full 28-day course of antimony injections during the first gulf war. Unfortunately, few people in Bihar could afford a full course, and the state lacked a health system that could provide it. Patients relied on private healers, who would sell a few shots at a time to counter the symptoms. The practice bred drug-resistant parasites--and sand flies spread them from person to person. "We tried administering larger doses of antimony," says Dr. T. K. Jha, a veteran infectious-disease specialist in Muzaffarpur, "but we reached a point where the therapy was killing more people than it helped."

As antimony lost its punch, Bihar's best doctors turned to an antifungal medicine called amphotericin B, or Fungizone--the $200 cure that Jha and Sundar still use in their clinics. Fungizone can rescue almost any patient who's strong enough to withstand four weeks of infusion therapy, and lucky enough to have access to it. Sundar has made it his mission to treat the unlucky. The son of a middle-class textile merchant, he runs his 50-bed clinic as a trust, using family donations and his own research grants to cover his patients' costs. As he walks though Rajwara, former patients acknowledge him by presenting their tattered discharge certificates. And when a distraught mother admits that she lacks 100 rupees ($2.30) to bus her stricken child to his clinic, Sundar finds the fare in his pocket. "We celebrate every day because we are so happy we can provide this care," he says the next day, standing in one of his clinic's teeming open wards. "But [Fungizone] requires facilities that don't exist outside of a few select hospitals. We need an affordable drug that is safe enough to use in the field."

That's exactly what Medecins sans Frontieres (Doctors Without Borders) was looking for when kala azar ripped through southern Sudan in the early 1990s, killing more than half of the population in some districts. The old antimonial treatment still worked in East Africa, but MSF couldn't get enough of it to meet the burgeoning need, and Fungizone was out of the question in that setting. "We ran out of medicine at least five times," says Dr. Jill Seaman, an MSF physician who worked on the front lines. "If people heard we were setting up a treatment station, they would walk for two weeks to get there. We would have 1,500 people crowded into a tiny village with one latrine, and the patients would end up with dysentery." As an emergency measure, the MSF docs tried combining half doses of antimony with paromomycin, a cheap antibiotic developed back in the 1950s to treat intestinal parasites. To their delight, the experiment worked. The two-drug regimen was less toxic than antimony alone, and it cut treatment time from 28 days to 17. "We couldn't gather publishable data," Seaman says, "but we were curing more people."

The Sudan story thrilled the world's kala azar experts (who call themselves leishmaniacs), but the pharmaceutical industry didn't share their enthusiasm. Just as paromomycin's potential was coming to light, the drug's sole manufacturer--the now defunct Pharmacia--decided to take it off the market. The drug's patent had expired, there were newer treatments for intestinal bugs and kala azar had little commercial potential. MSF worked with a Netherlands-based company to sustain its own African relief efforts during the 1990s, and to support preliminary studies in India. But production stopped again when the Dutch firm changed hands. By the end of the decade, MSF's dwindling stockpile was all that the world had left. A drug with the potential to save millions was going extinct.

Victoria Hale was only dimly aware of kala azar during these years, and she'd never been to India or Africa. She'd grown up in Baltimore, the dutiful daughter of two civil servants, then earned a Ph.D. in pharmaceutical chemistry and spent her 30s at the Food and Drug Administration and at Genentech, in San Francisco. She reveled in the science and politics of drug development, but she'd grown frustrated by the gaps in the system. "There was a whole set of promising compounds that weren't being developed," she says, "and diseases that weren't being tackled." In 1998, Hale quit her job to think about starting her own pharmaceutical company--one that would measure success in lives saved instead of dollars earned. "I felt confident that I could develop drugs," she says. "I just needed one to start on."

During her search, she heard Shyam Sundar speak at a conference in Belgium. He was explaining how India's kala azar epidemic could explode as HIV moved into Bihar, leaving infected people defenseless against the leishmania parasite. Hale had heard about MSF's experience with paromomycin, and she was mesmerized by Sundar's talk. So she introduced herself, and asked if she might visit his clinic. She got her tour a few weeks later, and it shook her to the core. "I had never seen such hopelessness in people's faces," she recalls. "We walked through the villages; he would explain to me over and over, 'This person has been fighting kala azar for some time and is now losing the ability. Yet it's possible to cure him'." Hale went home by way of Calcutta, and remembers breaking down in her hotel room as she realized she had found her drug and her calling. "I knew it was going to change my life and my family's life," she says. "I called my husband, sobbing, and said, 'This is it. I'm doing it.' And he said, 'Of course you are. Come back and we'll do what we need to'."

The to-do list was daunting--form a company, organize a large clinical trial, push paromomycin through the approval process and find a way to manufacture it--but things happened fast. Hale's husband, Dr. Ahvie Herskowitz of the University of California, San Francisco, stepped in as chief medical officer, and the World Health Organization's longtime leishmaniasis coordinator, Dr. Philippe Desjeux, scrapped his retirement plans to serve as a full-time adviser. Their new company--the grandly named Institute for OneWorld Health--secured $5 million in seed money from the Gates Foundation in 2002, and by 2003 the stage was set for a full-dress paromomycin study. MSF raided its warehouses to provide the medication, and Hale recruited four Indian physicians--Sundar, Jha and two others--to run the trial out of their clinics in Bihar.

Would paromomycin work as a first-line therapy in India? To find out, the researchers recruited 666 patients and gave 500 of them three weeks of daily injections. The other patients got Fungizone, the monthlong infusion therapy. The findings, unveiled this spring, were everything the leishmaniacs could have hoped for. Paromomycin's 95 percent cure rate nearly matched Fungizone's, and it was far less poisonous. Only 9 percent of the recipients suffered adverse reactions, versus 66 percent of the comparison group. Hale's team is now using the results to get paromomycin approved as a remedy for kala azar, and the Gates Foundation is outfitting an Indian firm to produce large quantities at low cost. If all goes as planned, paromomycin will soon be available for $10 a cure--just one twentieth of what treatment now costs in Bihar.

It will be a sweet victory for Hale and a godsend to the world's poorest people. But huge hurdles remain. The communities that most need paromomycin still lack health systems that can deploy it, so experts are scrambling to devise a treatment program that relief workers can manage independently. The initial challenge is to ensure that anyone starting treatment gets a full course. The larger one is to change the conditions that make villages like Rajwara such hotbeds for kala azar. The needed measures are often staggeringly simple--clearing the cow dung that sand flies thrive on, providing people with insecticide-impregnated bed nets. But none of that is happening at the moment. As Sundar moves from hut to hut, feeling people's spleens, he asks the adults if they know what causes kala azar, or what can be done to prevent it. Except for a couple of village elders, not one has any idea.