There's a mantra in AIDS treatment that every physician in the field knows by heart: When it comes to HIV, hit early and hit hard.
The idea, first put forth by leading AIDS researcher Dr. David Ho of the Aaron Diamond AIDS Research Center more than a decade go, is to blitz the virus in its first days of infecting a new human host, before it can establish a beachhead and launch a full-scale AIDS attack. And so far, the strategy seems to be working. Early treatment of newly infected patients has significantly reduced the death rate from AIDS in regions of the world where antiretroviral therapies (ART) are readily available. (Read about the surge in HIV/AIDS in Washington, D.C.)
The problem is that nobody, including the experts, knows how early is early enough. And now the largest study to date attempting to answer that question suggests that initiating anti-HIV therapy far earlier than current guidelines recommend could save more lives. The findings are setting off a lively debate in the AIDS community about whether those guidelines should be changed — and how soon.
Dr. Mari Kitahata, at the University of Washington, reports in the New England Journal of Medicine that HIV-positive patients enrolled in a nine-year study reduced their risk of dying as much as 94% by the trial's end if they began ART earlier, compared with patients who deferred treatment. "Our study adds to the weight of evidence accumulating that the balance between the potential benefit in survival of initiating therapy earlier outweighs the potential deleterious effects," says Kitahata, referring to concerns over the drugs' toxicity and possible long-term side effects.
Kitahata studied more than 17,000 HIV-positive patients who were being treated by physicians from 22 different research groups in 60 cities in North America between 1996 and 2005. She and her team essentially conducted two trials. In one, the scientists looked at patients who chose to initiate ART when their level of CD4 cells — infection-fighting immune cells that HIV uses to replicate and then systematically destroys — ranged between 351 and 500 cells per cubic mm of blood. These patients were compared with those who decided to defer therapy until their counts dipped below 350 cells per cubic mm, the level at which current guidelines recommend starting drug treatment.
In the second study, Kitahata's team looked at patients who chose to start ART when their CD4 count was 500 or above and compared them with patients who decided to defer treatment until their CD4 counts dropped below 500 cells. (In a normal, healthy adult, CD4 levels range from 600 to 1,200.) In both studies, the patients deferring treatment were more likely to have died by the 2005 end of the study than were their earlier-treated cohorts. HIV-positive patients beginning therapy at CD4 levels between 351 and 500 cells were 69% more likely to be alive at the end of the nine-year study, while those initiating drug treatment at CD4 counts of 500 or more were 94% more likely to have survived.
"I have a particularly strong view about this," says Ho about the early treatment of HIV, "so these results are what I would expect. You have a virus that is churning away actively, constantly destroying important immune cells, so how can it be good to let that go on unchecked by delaying therapy?" Ho is not the only expert impressed with the results. "This is a very good study that at least suggests strongly that there is a benefit to starting treatment early," says Dr. Anthony Fauci, director of the National Institute on Allergy and Infectious Diseases. But is it enough to change the current guidelines for when HIV-positive patients should start ART? "That is a question of debate now in the scientific and public-health community," he says.
In fact, when the potent ART combination therapy first emerged in the mid-1990s, government health officials recommended that anyone with a CD4 count of 500 cells or lower receive treatment. But in response to growing concerns over HIV's increasing ability to become resistant to the drugs, as well as worries over the drugs' toxicity and patients' inconsistent compliance with their regimen, the guidelines dropped to 200 before eventually settling at 350 cells — much further along in the progression of the disease.
None of these guidelines have been supported by the gold standard of medical evidence, the randomized controlled trial. And as convincing and as large as the current study is, Fauci notes that it too lacks this scientific imprimatur. In Kitahata's study, researchers followed patients as they and their doctors made their own decisions about when they would begin drug therapy. Those who chose to start early — before their CD4 counts reached 350 cells or 500 cells, for instance — may have simply been more health-conscious overall and therefore less likely to die, which could have confounded the study's results. Only a randomized and controlled trial in which patients are arbitrarily assigned either to initiate or defer therapy could determine any real benefit of early treatment.
Still, Fauci acknowledges that the sheer size of Kitahata's study gives its findings some weight. She presented the preliminary data to a government panel on HIV-treatment guidelines in February, and the results have since gotten HIV experts talking about whether waiting to begin treatment until the current threshold of 350 cells is reached is too late to improve HIV patients' survival.
Answering that question won't be easy. While there are clear benefits to starting anti-HIV medicines early in the progression of the disease, the drugs are not without side effects. Some studies have noted increased risk of certain cancers as well as toxic effects to the brain and other organs over the long term. "The real critical issue that everyone is struggling with is, What about the potential long-term deleterious effects of ART that might override the beneficial effects?" says Fauci.
While the medications currently prescribed are already much safer in the short term than the ones commonly used during the study period, their long-term effects on health are still unknown, since they simply haven't been circulating long enough for any damaging side effects to have surfaced. But, Ho notes, "I always felt the side effects of HIV are greater than the side effects of the drugs." After all, he says, "the side effect of unchecked HIV is death."