When should HIV medications be started?

The key question: Sooner or later?

It has to do with when to initiate antiretroviral therapy in patients with HIV.

And recently, debate over the answer is being fueled by a growing body of data indicating that starting earlier might produce fewer side effects and better outcomes.

"Is there a right time or a better time when these drugs should be given?" asked Michael Mugavero, MD, assistant professor of infectious diseases at the University of Alabama at Birmingham.

This issue has been a matter of dispute since it became possible to treat HIV. The most recent guidelines, which were developed by the International AIDS Society-USA and published in the Aug. 16 Journal of the American Medical Association, recommend that all patients experiencing symptoms start therapy.

For those who are asymptomatic, therapy should be initiated after the CD4 count dips below 350 but before it hits 200. Therapy can be started earlier if this number is declining rapidly or the viral load is high.

The recommendations are supported by solid evidence, although many physicians say they try to start closer to 350 than 200 or even at higher numbers if appropriate. And some wonder whether it is wise to wait at all.

"If you know somebody is infected, why would you allow the organism to expand in the person?" asked Ken Lichtenstein, MD, professor of infectious diseases at the University of Colorado Health Sciences Center in Denver. "Being infected is really an indication to treat."

Large observational studies appear to support this conclusion. A handful of papers on the subject were presented at last month's XVI International AIDS Conference in Toronto.

The topic also was explored in a study given at the 13th Conference on Retroviruses and Opportunistic Infections in Denver in February.

This paper reported that participants in the HIV Outpatient Study who started therapy at higher CD4 counts were less likely to develop complications from the drugs, including renal insufficiency, peripheral neuropathy and lipatrophy. They also were less likely to die and develop AIDS-defining illnesses. These data are expected to be published in a journal later this year.

"Patients who start therapy at a later time in their disease don't do as well," said Dr. Lichtenstein, lead author and one of the principal investigators of the project, which is funded by the Centers for Disease Control and Prevention.

Key factors

Hesitation to start therapy, particularly before symptoms appear, usually has centered around the fact that HIV regimens have been incredibly complex and highly toxic. But those in favor of this approach argue that because regimens have been simplified and cause fewer side effects, earlier treatment is gaining momentum.

In July, the Food and Drug Administration approved a once-a-day HIV pill that includes three medications. Several recent studies also have suggested that such regimens might be just as effective as more complicated ones.

"The pendulum may be swinging back toward earlier therapy. It used to be 25 pills a day. The drugs are so much easier to take, and the inconvenience is no longer there," said Frank Palella, MD, associate professor in the division of infectious diseases at Northwestern University's Feinberg School of Medicine in Chicago. "And there are fewer short- and long-term side effects."

For example, a paper published in the Aug. 16 Journal of the American Medical Association found that a three-drug regimen worked as well as four for the initial treatment.

Another preliminary study in the same issue suggested that it might be possible to use as few as two drugs to maintain patients who have achieved suppression of the virus on heartier regimens.

Still, while this issue is being intensely discussed and one of the most common questions asked in publications targeting those infected with this virus, most experts believe that it will never be definitively answered. A randomized trial is needed not only to answer the question but also to dictate physician practice, many say.

Most add, though, that such a study would be too large and too lengthy to be practical. "The challenges in doing such a trial are nearly insurmountable," said Daniel Kuritzkes, MD, chair of the board of the HIV Medicine Assn. and director of AIDS research at Brigham and Women's Hospital in Boston.

Experts also maintain that, for many patients, the question is moot. The most important factor, they say, is patient willingness to start, and many don't want to. Or they can't afford it. Many more aren't even diagnosed until their CD4 count is low. HIV also might not be the only problem they're facing, or even the most pressing.

"Many of these patients have other issues. They are mentally ill or have substance abuse issues. They're in poverty, worried about where their next meal is coming from, and trying to stay one step from child protective services," said Dr. Susan Swindells, medical director of the HIV Clinic at the University of Nebraska Medical Center in Omaha. "Taking medicine is way down the list of priorities for them."