African AIDS drug trial stopped prematurely

By Dr. Ananya Mandal, MDApr 19 2011

One of the studies in three African countries where women were given an AIDS drug to prevent HIV infection is being stopped because the project is not working, researchers said Monday. These women on the trial were taking a daily dose of the drug Truvada or a look-alike placebo pill and had an equal chance of becoming infected. The ones taking Truvada were expected to have had a much lower infection rate.

The reason for the non-efficacy of the drug is not yet known. A study last year using it in homosexual men found that it reduced infections by 44 percent. Another study in which a similar drug was used in a vaginal gel reduced the HIV infection rate in women by 39 percent. Timothy Mastro, a physician at FHI - Family Health International, a nonprofit research institute in North Carolina that ran the study said, “This was a surprising and disappointing finding… At this point, we can’t conclude that these antiretrovirals will be effective.”

Truvada is a combination of two antiretroviral compounds, tenofovir and emtricitabine. It is intended to be used after infection in combination with other antiretroviral medicines. Two other studies are underway in sub-Saharan Africa to test the compounds in pill and gel form for HIV prevention in heterosexual men and women. If successful it would be a cheap and easy way for AIDS prevention. There is little likelihood that an AIDS vaccine will be available in the next decade. Many experts hope that pre-exposure prophylaxis (PrEP) with AIDS drugs could work as a vaccine equivalent for certain people.

Kevin Fenton, head of AIDS programs at the Centers for Disease Control and Prevention, which has conducted similar studies in the United States and abroad, said the strategy is worth pursuing. “These findings by no means suggest we should not do further PrEP trials in women,” Fenton said. “This really underscores the complexity of HIV prevention and the importance of doing multiple trials in different populations.”

The study called FEM-PrEP, enrolled 1,951 women in Kenya, South Africa and Tanzania starting in June 2009. Twenty-one percent of the women screened for participation were rejected because they were already infected. Participants were 18 to 35; 40 percent were married or living with a partner; and on average, they had had 3.7 acts of intercourse in the week before enrolment. All said they did not want to become pregnant, and more than 95 percent were using contraception (mostly birth control pills). The researchers predicted there would be 72 new HIV infections over the course of the study. When an independent monitoring board reviewed the results partway through, it found there had already been 56 infections. The Truvada and placebo groups each had 28 infections.

The reasons for failure may be that women were not actually taking the drugs. Another explanation could be that the pill’s active ingredients didn’t get into cervical and vaginal tissues in sufficient concentrations to have an effect. The third is that the strategy doesn’t work. The final explanation is that it works but by chance didn’t in that experiment.

By the time enrolment was stopped Friday, the average length of time a woman had been in the study was seven months. Overall, the women were becoming infected at the rate of about 5 percent per year. Nine percent were becoming pregnant, with the highest rate among women taking Truvada. It is possible the women who had been randomly assigned to Truvada missed an unusually large number of both birth control and Truvada pills.

An FHI news released said Truvada was “associated with some known side effects that were not serious.” The U.S. Agency for International Development and the Bill and Melinda Gates Foundation paid for the study, which was conducted in cooperation with local researchers in the three countries. It cost $26 million.

The question of when to commence therapy remains

In another new study it was found that HIV-infected patients are most likely to stay clear of AIDS longer if they start drug therapy when their immune systems are still relatively strong. However, starting treatment earlier, compared to waiting, didn't affect dying from AIDS. “There wasn't a clear benefit in terms of preventing death” by prescribing the drugs before some guidelines suggest, said Dr. Keith Henry, director of HIV clinical research at Hennepin County Medical Center in Minneapolis and co-author of a commentary accompanying the study, published in the April 19 edition of Annals of Internal Medicine.

The question of when to start therapy remains. If physicians wait to begin treatment, patients can delay the expense -- not to mention the side effects. But such delays may also give the virus a chance to become more powerful and better able to fend off medications. If they're not treated with drugs, HIV-infected people almost always go on to develop AIDS.

In the U.S., guidelines suggest that HIV-infected patients take them when the level of CD4 cells dips below 0.500 X 10⁹ cells per liter (cells/L). In Europe, the guideline number is frequently lower -- meaning a weaker immune system -- at under 0.350 X 10⁹ cells/L. In the new study, researchers examined how patients did when they began drug therapy with their CD4 cells at a variety of levels.

For the study the team examined the medical records of almost 21,000 HIV-infected patients who sought treatment in HIV clinics in Europe and through the Veterans Health Administration system in the United States. It was seen that death rate was about the same regardless of whether patients began treatment when their CD4 levels dipped under 0.500 X 10⁹ cells/L or if they waited until their immune systems deteriorated more and reached below the level of 0.350 X 10⁹ cells/L. However, the risk of death did rise when patients weren't treated until their CD4 cells fell to an even lower level: 0.200 X 10⁹ cells/L.

“To fully benefit from early initiation, patients must present for medical care while their CD4 cell counts are still above 500 cells,” said study lead author Lauren Cain, a research fellow at Harvard School of Public Health.