New DHHS treatment guidelines green light earlier HIV treatment

Evidence shows benefit of early ART

HIV clinicians now are advised to consider HIV antiretroviral treatment for patients who have CD4 counts greater than 350 cells/mm3 and perhaps even upon diagnosis.

The revised antiretroviral treatment guidelines published by the U.S. Department of Health and Human Services (DHHS) bring current HIV treatment in greater alignment with national expert recommendations. (See guidelines' initiating ART recommendations.)

"The guidelines are sort of catching up with how many of us have been practicing," says Douglas Richman, MD, who is a professor of pathology and medicine at the University of California — San Diego and who is also with the San Diego VA Healthcare System.

"The guidelines are a little bit slower than the way many of us practice because they had to acquire consensus and some kind of evidence-based medicine support, which takes time," Richman says.

"The data now support what many of us have been thinking," he adds. "We've been treating earlier and earlier as we figure out which drugs have the toxicities that discourage people from starting early and as we find regimens that are well-tolerated."

Earlier HIV treatment makes sense, says Daniel R. Kuritzkes, MD, professor of medicine at Harvard Medical School and Brigham and Women's Hospital in Boston, MA. Kuritzkes is on the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents — A Working Group of the Office of AIDS Research Advisory Council, which developed the guidelines.

"The more we learn about the pathogenesis of HIV and its role in non-AIDS-related complications, the more sense we're getting that ongoing replication has cumulative health effects," Kuritzkes explains. "So reducing inflammation and stopping reproduction are providing health benefits, and that's why people should consider initiating therapy for all patients."

The guidelines make the new threshold of starting therapy at a CD4 count of 500 cells/mm3, notes John Bartlett, MD, professor in the division of infectious diseases at Johns Hopkins University School of Medicine in Baltimore, MD. Also, Bartlett is an editorial advisory board member of AIDS Alert and he is co-chair of the DHHS panel that developed the guidelines.

'Then, above 500, what we said was that the panel was divided as to whether this was a recommendation or whether it should be made optional," Bartlett says. "And that reflects the opinions of most of the physicians who are dealing with HIV infection, in general."

So while clinicians might choose to initiate treatment early on with their HIV patients, there is one other important consideration, Bartlett notes.

HIV physicians should make certain their patients are resolved to take antiretroviral drugs for the rest of their lives, he says.

"That's a very important part of this that is often forgotten," he adds. "They have to understand it's a lifelong commitment, and they shouldn't stop their medication."

Richman assesses patients' motivation toward adherence soon after they're diagnosed.

"If someone presents early, you sit down and talk with them," he says. "I want them to show up two to three consecutive times in the clinic before starting antiretroviral treatment."

If patients have substance abuse problems or mental health illnesses that might make adherence a problem, or if they simply have no interest in taking the drugs, then it doesn't make sense to start ART, Richman says.

"You want to make sure this is something they want to commit to," he adds.

New view of opportunistic infections

The guidelines' revisions result from mounting data that opportunistic infections, which occur later in the disease process, might not be the biggest clinical concern in the ART era, says H. Clifford Lane, MD, deputy director for clinical research and special projects at the National Institute of Allergies and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) in Bethesda, MD. Lane is co-chair of the DHHS panel that developed the guidelines.

Evidence increasingly shows that untreated HIV infection can cause inflammatory disease problems earlier on than previously thought.

"There might be benefits to early therapy," Lane says.

HIV clinicians should note another important change in the revised guidelines: the way initial antiretroviral treatment is listed has changed, Lane says.

"It used to be that the guidelines would say to pick one drug from column A and one from column B, and now what we're giving are four to five regimens, and each one of these has the same nucleoside analog backlog," Lane says. "There are good clinical trial results to support the use of these drugs together rather than selecting from one column and then another column."

The revised guidelines recommend the specific antiretroviral drug combinations that have had the best outcomes. (See ART recommendations.)

"We inserted Raltegravir as a preferred agent," Bartlett says. "We recommended four regimens that are the regimens that have never been beaten, and they have extensive data out to 96 weeks."

The factors that helped the panel make this decision were the regimens' good tolerance and their relatively low pill burden, he adds.

These recommendations are a critical change from a clinician's perspective, Richman says.

"In the original guidelines they didn't want to promote one drug over another," Richman says. "But it's clear that some drugs are more effective and less toxic than others."

Clinicians should consider both pros and cons of initiating therapy early.

Also, research increasingly shows that immune activation problems can be very damaging over time in HIV patients.

"We used to be worried about pneumocystis," Bartlett says. "Now we're also worried about the consequences of immune-activation impacting a variety of different organs."

Immune activation is associated with more cardiovascular disease, neurocognitive impairment, hepatic complications, and non-AIDS-defining malignancies, Richman says.

"The downside is we don't know the long-term complications of having patients on therapy," Lane says. "And if we ran into a situation where for whatever reasons resistant viruses started to show up and come through the regimens being used then you could be in a very difficult situation."

But the barriers to early therapy are dissolving and the benefits appear strong.

"There has been a lot of angst from the past about early therapy, and this has been somewhat obliterated or reduced as a result of the newer drugs," Bartlett says. "We have better success in therapy, better tolerance of drugs, better experience with long-term treatment, and lower rates of resistance than were feared."

Another possible benefit of early treatment is a reduction in HIV transmission.

"There are so far only indirect data on that point, but certainly more and more information is accumulating and making a strong case that treating people who are infected will prevent the spread of HIV infection to their partners," Kuritzkes says.

Some people have made a strong case for treating everyone to prevent the spread of HIV, Lane notes.

And there's no question that if someone reduces their viral load, they reduce the probability of transmitting HIV, Bartlett says.

"But we don't know whether trying to do this in the whole population will reduce the rates of HIV infection," he says.

It's still a hypothesis that needs to be tested, Lane says.

"There are a lot of strong opinions about this," Lane says. "I think the panel weighed all of this information."

One strategy would be to test and treat everyone and even giving ART to uninfected, at-risk patients as a pre-exposure prophylaxis, he says.

"But from the guidelines panel's perspective, we're really focused on treating patients who are in front of the doctor today," Lane says. "So we mentioned those other things for the public to be aware of, but we don't use them as a deciding factor in whether or not an individual patient should be treated."

Unfortunately, the guidelines' landmark shift toward earlier HIV treatment is a moot point for many patients.

"I offer treatment at the time of the diagnosis," Kuritzkes says. "And most of the patients we see are coming in with lower CD4s because, unfortunately, too many are still being diagnosed late."