Cambodia Stops Important Tenofovir Prevention Trial

On August 11, 2004, the Cambodian government ordered researchers not to proceed with a trial to test whether once-daily use of tenofovir (brand name VIREAD), a drug already widely used to treat HIV, could prevent new infections in healthy people. The government had previously approved the study, which is funded primarily by the U.S. National Institutes of Health and the Bill & Melinda Gates Foundation. A Cambodian organization of sex workers had protested the trial, which was to recruit HIV-negative sex workers at high risk of infection, primarily because it did not include at least 30 years of insurance in case of side effects from the drug.

On August 15 I sent the following to ACT UP Philadelphia and other U.S. activists, to explain why this research is important.

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Stopping this trial is a serious setback to controlling the epidemic. The new prevention method being tested could save millions of lives if it works. Fortunately the study is being run not only in Cambodia but in other countries as well.

Experts say they will not have an HIV vaccine for at least ten years. Tenofovir (brand name Viread, from Gilead Sciences in California), the drug that was to be tested in Cambodia, is already in widespread use for treating HIV, so it is available now. In a small monkey study, an injectable form of tenofovir gave 100% protection against infection by SIV (simian immunodeficiency virus, which is like HIV). All the monkeys were deliberately exposed to SIV -- and every monkey that got tenofovir was protected, while all the others in the no-treatment control group became infected (Science, November 17, 1995, volume 270, page 1197).

If tenofovir works anywhere nearly this well in people, it could be at least as effective for preventing HIV as a vaccine. The drawback would be the need to take a pill once a day. So there could be a vaccine already for people at high risk, who might choose protection at the cost of the inconvenience and risk of side effects. Epidemiologists could watch where the epidemic is going and offer free drug to those most likely to become infected, for example, sex workers -- protecting not only them, but many others who could have been infected directly or indirectly through them. This new prevention tool, if used well, might possibly be enough to control the epidemic. But it won't be used at all unless it can be tested first.

If it works, tenofovir will be a form of prevention that women could control. They would not need to get men to put on condoms, nor tell men that they are using protection against HIV. And for both men and women, this kind of prevention would not require people to change their sexual behavior -- avoiding a major obstacle to the effectiveness of HIV prevention today. (Not much in human life is perfect, so behavior change will also be needed as well.)

Tenofovir has been approved as an HIV treatment for over two years in the U.S. and Europe, and has become widely used because it is one of the safest HIV drugs. The dose planned for the prevention trial is the same as that used for treatment. In an early study of tenofovir, eight volunteers took twice this dose for 28 days with no adverse effects. Almost all the experience with tenofovir so far has been in HIV-positive patients and volunteers -- but healthy, uninfected persons have if anything less problem with drug side effects than those who have HIV or other illness.

The group that objected to the trial, the Women's Network for Unity, "was established in June 2000 by a group of sex workers for sex workers," and says it has 5,000 members in Cambodia. Women's Network for Unity protested the tenofovir trial at a press conference in Phnom Penh on March 29, 2004, because the trial does not include insurance to treat drug side effects that may continue after the trial. It also protested at the Bangkok conference, with the support of ACT UP Paris. It appears to be an excellent organization; for more information, see http://www.swop-usa.org/world%20news/Cambodian_news.html

The demand for 30 years insurance is the main issue fueling the protests. There has been confusion in the press, with some researchers thinking the demand is for 30 year of general health care -- a large incentive that would raise ethical objections that participants were not consenting voluntarily to the trial. But from what I have seen in news reports, Women's Network for Unity only asked for treatment of any side effects of the drug being studied -- which is not an incentive to join the trial, so it does not raise questions of undue incentive interfering with voluntary consent.

Of course sponsors of clinical trials would worry about an arrangement that might give volunteers or their doctors 30 years of payments if they said the experimental drug made them sick. Often nobody knows the cause of an illness; a powerful incentive to blame the drug would not only raise the cost of doing a trial but, much worse for the sponsor, could affect the result, making any drug look more dangerous than it is. Probably for this reason, it is common practice in the United States to not guarantee medical care beyond the trial for side effects of the study drug. But U.S. volunteers have more access to medical care outside the trial than those in most poor countries.

The tenofovir prevention trial was developed collaboratively to meet current ethical standards. It passed ethical review in every country involved (unfortunately, many trials in developing countries do not). And if the drug is found to be effective for preventing HIV infection, all volunteers will be offered it free for two years after the trial, by which time other programs should be in place to supply it. The main issue that led to stopping this trial in Cambodia could affect any clinical trial in poor countries where people cannot get modern medical care.

Hopefully these issues can be resolved satisfactorily. Many people may live or die depending on whether the tenofovir HIV prevention trials are completed.

 

John S. James, AIDS Treatment News