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Tenofovir To Prevent HIV Transmission
  "Despite Hope, Decade of Delay Afflicts Drug to Prevent AIDS"
Company's Caution, Protests Have Slowed Trials of Pill
But Pace Is Picking Up A Drenching With Fake Blood

Wall St Journal
May 18, 2006


In 1994, University of Washington scientists testing an experimental AIDS treatment in monkeys made a startling discovery: The drug, tenofovir, protected the monkeys from getting infected in the first place.
The finding, published in 1995 in the journal Science, was big news to AIDS researchers. It raised a tantalizing question: Might a simple pill slow or even halt the spread of the AIDS virus?
Eleven years later, that question remains unanswered. Tenofovir today is a top-selling AIDS drug for Gilead Sciences Inc. -- but only as a treatment for those who already have the disease, not as a protective measure for people who aren't infected.
The failure of the drug to get more rapid attention as a preventive step partly reflects the contentious politics of AIDS. Since 2004 protests and other issues have forced researchers to scrap trials in four nations in Asia and Africa.
Gilead also has had business reasons for focusing on tenofovir as a treatment drug. Regulatory hurdles to approval are lower when the people taking a drug are already sick, and so are legal risks. The company has sought to avoid being dragged into culture wars over whether an AIDS-prevention pill might encourage unsafe sex. "We always shied away from pursuing this ourselves," says Norbert Bischofberger, Gilead's research chief.
Behind the scenes, however, Gilead research officials have never abandoned the notion of using tenofovir to block infection by HIV, the AIDS virus. Two scientists at the company -- Dr. Bischofberger and Howard Jaffe, formerly a drug-development executive and now head of the Gilead Foundation -- strove to advance research and line up third parties to fund clinical trials.
That low-profile strategy may soon bear fruit. Researchers funded by the U.S. government and others have started new tests of tenofovir in about 5,000 volunteers, most in developing countries. If the trials pan out over the next three years, a once-a-day prevention pill might help slow the global AIDS epidemic, although few scientists think tenofovir can completely halt HIV transmission.
Interest in tenofovir is especially high because efforts to produce an AIDS vaccine have failed so far. HIV-prevention work with tenofovir "is probably the most important thing going on in AIDS today," says Martin Delaney, a longtime AIDS activist based in San Francisco.
Tenofovir's known side effects, including infrequent kidney problems and bone weakening, could derail the trials if they afflict healthy volunteers. Another potential roadblock: Some researchers worry that widespread use of tenofovir alone might spark the emergence of HIV strains resistant to the drug. Normally tenofovir is used as part of a cocktail of drugs, which reduces the odds that a resistant virus will evolve.
Even a safe and effective HIV-prevention pill won't be free of controversy, because it may lead people to abandon the caution that helps keep the virus in check. Already, anecdotal reports suggest some men on the gay-party circuit buy tenofovir with Viagra and other party drugs.
Gilead, based in Foster City, Calif., sells tenofovir under the brand name Viread. It also sells Truvada, a pill combining tenofovir with another AIDS medicine, emtricitabine or Emtriva. A year's supply of Viread costs about $5,300 and Truvada about $8,800. The drugs, which together recorded sales of $441 million in the first quarter of this year, have helped Gilead become a biotech success, with net income of $814 million in 2005.
The company insists it has no intention of adding to that bottom line by marketing Viread as a preventive drug. It says the ethical, legal and regulatory challenges in the U.S. would be too great. If Viread is ever used as a preventive in poor countries, Gilead says it will supply the drug at cost -- as it already pledges to do with AIDS treatments.
Gilead's foray into HIV prevention began by accident. In 1991, it acquired the rights to a new class of antiviral compounds that block an enzyme needed by the virus to multiply. Gilead chemists tweaked the compounds and produced several experimental drugs, including tenofovir.
Investigating the drug in infected monkeys presented a problem: At the time, testing virus levels in the blood was a crude process, obscuring whether the drug was working. Researchers decided instead to test whether tenofovir shielded healthy macaques from infection with SIV, a simian form of the AIDS virus. "Lo and behold, it was completely protective," Dr. Bischofberger says. Fifteen monkeys were treated with tenofovir, then exposed to SIV. All remained healthy. Ten monkeys given a placebo became infected within a few months.
Despite the results, the company was in no position to pursue the findings in humans. Just eight years old, it had no products or profits. Its focus in HIV was on winning approval for adefovir, a chemical cousin of tenofovir, as an AIDS treatment.
Outside the company, researchers were concentrating on other preventive steps such as an AIDS vaccine or a topical antiviral gel. For a time, Gilead thought a gel form of tenofovir might be its best hope for HIV prevention. The Gilead gel blocked simulated sexual transmission of SIV in monkeys. But work on the gel flagged, although it continues at a slower place. Gilead says it may soon assign its rights to the tenofovir gel to a nonprofit.
It wasn't until 2001 that interest finally revived in using tenofovir as a preventive pill. That year, Gilead won Food and Drug Administration approval for the drug, now named Viread, as a treatment for AIDS patients. (It dropped adefovir as an AIDS treatment in 1999, after kidney side effects derailed an FDA application.) In Africa, where AIDS drugs were in short supply, the epidemic grew catastrophic. Prospects for other prevention tools looked grim: Efforts to produce a vaccine stalled and a trial of a spermicide seen as protective showed it actually increased HIV-infection risk.
"We were really falling on our faces," says Mark Wainberg, an AIDS researcher at Montreal's McGill University. At a 2001 AIDS meeting in Buenos Aires, Dr. Wainberg proposed using antiviral drugs such as tenofovir to prevent HIV.
Inside Gilead, enthusiasm was rising again, led by Dr. Jaffe. He had stepped down from his research job at the company in 1999 but continued to work there part-time and promote tenofovir for prevention.
In September, 2001, Dr. Jaffe flew to the Durham, N.C., offices of the reproductive-health nonprofit Family Health International and sketched the potential for Viread's use as a preventive pill. "A light bulb went off," says Willard Cates Jr., president of the group's Institute for Family Health. He saw a parallel to the history of contraception, in which the birth-control pill overtook topical spermicides and condoms in preventing pregnancy.
John Mellors, a member of Gilead's scientific advisory board and a University of Pittsburgh AIDS researcher, also heard Dr. Jaffe's prevention pitch. "We said, 'Go for it,' " Dr. Mellors recalls. "We were frothing at the mouth."
Things seemed to be coming together. In October, Drs. Jaffe and Cates flew to Seattle to seek funding for prevention trials from the Bill and Melinda Gates Foundation. Officials started drawing up plans for studies in developing countries where HIV infection rates were far higher than in the U.S. Proving the effectiveness of a preventive drug would likely be faster in these countries.
Lie-Low Strategy
Gilead was turning down funding requests from all comers -- part of its lie-low strategy. At the University of California, San Francisco, AIDS researcher Robert Grant and colleagues were drawing up their own plans for a prevention trial and went straight to Gilead. "'Why not just give us the money, and we'll do a study?'" Dr. Grant recalls asking. "They said no."
Gilead wanted to remain in the wings, bringing together researchers and outside funders and providing free supplies of pills for trials. All this, Gilead hoped, might help it avoid the impression that it was seeking to profiteer from selling its pill in poor countries.
In October 2002, the Gates Foundation announced a $6.5 million grant to Family Health International for HIV-prevention trials of Viread in Cambodia and four African nations. The group joined forces the next year with UCSF researchers, who had received National Institutes of Health funding for their own trial in Cambodia.
Gilead's hopes that it could fly under the radar were soon dashed. In early 2004, activists in Cambodia's sex trade complained they hadn't been consulted on the Cambodia trial's planning. In August 2004, they joined French AIDS activists at a Bangkok AIDS conference, staging noisy demonstrations.
Activists charged that Gilead would encourage risky behavior among study participants to ensure infections and get data quickly. Gilead and researchers deny the charge. The activists also said anyone in the trial who ended up infected with HIV should receive a guarantee of lifetime treatment. Demonstrators attacked Gilead's trade booth, dousing displays with buckets of fake blood.
A few weeks later, Cambodian Prime Minister Hun Sen declared his opposition to unspecified drug trials in his country, effectively scuttling the Viread trial. In February 2005, Cameroon backed out of a trial amid claims that volunteers weren't getting enough medical care. A similar study in Nigeria then collapsed due to technical problems at local labs. Later, Malawi cancelled a prevention trial for fear it might give rise to Viread-resistant HIV.
In Shambles
The program lay in shambles. Only one of the first five study sites is still in business, in the Ghanaian port city of Tema. Safety data are expected by June. But the Ghana trial by itself may not yield statistically convincing proof of efficacy.
While overseas AIDS activists have blasted Gilead for going too fast, some doctors in the U.S. fault the pharmaceutical industry for moving too slowly. "The problem since the late 1980s is that these companies are so concerned about liability they won't promote vaccines or prophylactic drugs," says Marcus Conant, a San Francisco AIDS physician. He says he has prescribed preventive Viread to five or six patients who he fears are at high risk of contracting the virus.
Hope now rests on several trials of Viread or Truvada -- the combination pill containing Viread -- that have started recently or will do so soon. In Thailand, CDC researchers have enrolled half of a group of 1,600 intravenous-drug users.
Researchers say they're trying harder to get a commitment of support ahead of time from government leaders and nonprofit groups in each country. Dr. Grant of UCSF, who is lead researcher of a Peru trial funded by the NIH, says: "I'm proud that the community in Peru knew of our plans before NIH did."
Still unknown is how serious the side effects of Viread will be in people without HIV. The drug carries a prominent warning on its U.S. label regarding rare cases of lactic-acid buildup and liver enlargement, which can be fatal. Gilead says the warning covers the larger class of drugs that includes Viread and isn't specific to its drug. None of the drug's problems were big enough to outweigh the benefit for HIV-positive people, but the calculation is different for a prevention drug.
Recent research on Viread has led scientists to shift course slightly. A 2005 study showed Viread-treated monkeys eventually became infected after repeated exposure to a synthetic and particularly virulent form of the simian virus. The findings suggested that a single drug might not completely prevent HIV transmission. Even so, Viread slowed the rate of infection, lessening the chances of getting the virus from a single encounter.
Results were better in a study this year of monkeys taking Truvada. The combination drug shielded six monkeys even after repeated injections of the virus. Trials in Botswana and Peru now plan to use Truvada.
In the U.S., researchers have begun enrolling 400 HIV-negative gay men in a study of Viread. The goal is to test the drug's safety and measure whether it leads men to engage in more unsafe behavior.
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