Researchers note changing patterns of HIV morbidity

Study suggests benefit to starting ART early

It's well known that HIV patients have been healthier and have lived longer since the advent of highly active antiretroviral therapy (HAART) in the mid-1990s. But as the population now ages and stays on these potent drugs for decades, there are many concerns about the impact of drug toxicity on long-term HIV patients.

"We realized some years ago that there may be some toxicities associated with long-term use of HIV treatment," says James D. Neaton, PhD, professor of biostatistics at the University of Minnesota in Minneapolis, MN. Neaton also is the principal investigator of Insight Network, an HIV network sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). Neaton spoke about changing HIV morbidity and mortality patterns at the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention, held July 22-25, 2007, in Sydney, Australia.

"Several large cohort studies a few years ago pointed to cardiovascular disease risk increasing with long-term treatment, as well as metabolic changes," Neaton says. "What's happened is people with HIV are dying less of AIDS and more often from end-stage organ diseases, such as heart disease, cancer, and renal disease."

For HIV-infected people who start treatment late, their risk remains high for morbidity related to opportunistic infections and AIDS-defining illness. For those who start treatment early, their morbidity and mortality is associated with end-organ diseases, Neaton explains.

"So we initiated a large trial called SMART, with the motivating hypothesis that if we spared patients the use of antiretroviral therapy when their CD4 cell counts were high and only put them on treatment when the CD4 counts dropped and the patients were at risk for OIs, then we could spare them toxicity," Neaton says.

The treatment was interrupted when CD4 cell counts were over 350, and they were started again when the CD4 counts dropped to 250, he explains.

"The trial found that you can't interrupt therapy like that," Neaton says. "It increased the risk of AIDS."

But there also was another surprise finding: "The non-AIDS deaths, including cardiovascular, renal, and liver morbidity rates were much higher in the group with interrupted therapy," Neaton says.

"This was serious morbidity, including heart attacks, strokes, end-stage renal disease requiring dialysis, and end-stage liver disease," Neaton says. "And these occurred more with the interrupted treatment arm."

These findings coincided with study results from large cohorts in Europe in which long-term follow-up research found that liver disease, cancer, non-AIDS deaths generally were lower among patients who had higher CD4 cell counts, Neaton says.

"So this suggests that antiretroviral therapy (ART) may have effects way beyond opportunistic infections," he says.

"ART may be associated with some risks, as we've previously identified in some of the large cohorts, but it appears the benefits could potentially outweigh the risks," Neaton says.

These studies have opened up a new line of thinking in research and motivate trials that involve starting ART earlier, he adds.

From a public health perspective, it may be important to start ART earlier to prevent HIV transmission, but it also may benefit patients by preventing or delaying serious disease, Neaton says.

"In the SMART study we've undertaken a series of biomarker analyses to understand why risk may be increased to these other end-organ diseases," Neaton says. "It's possible that HIV and an inflammatory process that initiates activation of coagulation markers may offer in some part a marker of what's going on here."

Researchers still don't understand all of the benefits and risks of giving ART early because there have been no trials where it's been started early, Neaton notes.

"There was a small subset of people from SMART who came in and were treatment naïve," he says. "If they were assigned to the interruption arm, they didn't start therapy, but if they were assigned to the viral treatment arm, they started therapy, and it mimicked a trial of early treatment."

For this subgroup of people in the SMART study, both AIDS events and non-AIDS events were lower with therapy, Neaton says.

"It's clear there is a risk-benefit here that we don't understand," Neaton says. "Therapy probably is associated with long-term risk, but those risks potentially may be outweighed by other benefits."

The most compelling scientific question resulting from the SMART study is whether the ART guidelines should recommend earlier treatment, he says.

"The only direct data to answering that question is a small subset," he adds.

But the consensus may be swinging in that direction, particularly since the newest ART involves drugs with less cross resistance to existing medications, which means that if patients start early and begin to fail on one regimen, there are more treatment options available to them, Neaton says.

"You would not want to start treatment early unless there was compelling data from a randomized trial that looked at when these end-stage diseases began," he says.

"It may be reasonable to start therapy earlier for older HIV patients," Neaton says. "There are clearly a lot of other risk factors that people with HIV have."

It wouldn't be prudent to start early ART for every patient until more data are available, he notes.

"The National Institutes of Health will sponsor a pilot study we'll undertake later this year, starting people with CD4 cell counts of 500 on treatment," Neaton says.

If this study and future studies suggest this treatment method might work best, then it could prompt a shift in treatment strategy, similar to what happened 20-30 years ago when studies showed that providers were better off treating patients with mild, stage one hypertension than they were to wait until patients' blood pressure increased to moderate or high levels, he adds.

"I just hope the pendulum doesn't swing too quickly until we get more data," Neaton says.