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The changing face of therapy for HIV

How soon should asymptomatic HIV patients begin antiretroviral therapy?

From the October ACP-ASIM Observer, copyright 2001 by the American College of Physicians-American Society of Internal Medicine.

By Margie Patlak

Like something out of "Hamlet," to treat or not to treat is a major question vexing physicians who see asymptomatic HIV patients.

Many of these patients and their doctors are grappling with the frequent and sometimes deadly complications linked to highly active antiretroviral therapy (HAART). Those side effects, combined with the sobering reality that the drugs offer no cure and must be taken for life, have led many to question whether they should treat HIV infection like other infectious diseases and hit it early and hard, or delay treatment instead.

"The HIV clinician is confronted with a real quandary," said Scott Holmberg, MD, chief of CDC's clinical epidemiology section of its HIV/AIDS prevention division. "This big question of when to start therapy remains a complicated, frustrating problem."

Adding to the complexity are the continually evolving HIV treatment guidelines put forth by the HHS and the Henry J. Kaiser Family Foundation. In February of this year, those guidelines raised the threshold for starting treatment for HIV-infected patients who are asymptomatic. But by recognizing the need to be flexible, the guidelines offered support for both the "treat early" and "treat late" camps.

"The initial hope for eradicating the virus with HAART led to a willingness to tolerate its toxic effects, just as with cancer drugs," noted Anthony S. Fauci, MACP, director of the National Institute of Allergy and Infectious Diseases and a co-chair of the HHS panel that issued the February guidelines. "But now we have to rethink the drugs' risk-benefit equation. The guidelines show the need to be flexible because we can't cure HIV infection with current regimens.

"We're in the middle of an evolving discipline of treatment," Dr. Fauci added. "Since new drugs and new regimens are emerging, it's a moving target. We don't know anything definitively."

Limited clinical evidence

The question of when to treat asymptomatic HIV infected patients is complex in part because there are good arguments for treating these individuals earlier—when their CD4 counts are high (350 per cubic millimeter or greater)—as well as for delaying treatment until their CD4 counts dip as low as 200 cells/mm3.

In addition, there are no large, well-controlled, long-term studies that can show which approach works best. As a result, experts look to more limited studies to support their opinions. As Dr. Holmberg pointed out, figuring out which camp has more data to back it up "is like weighing two feathers" because the data are so sparse.

Supporters of a more aggressive approach say that early treatment can delay or prevent the virus' insidious destruction of the immune system. Even when patients have relatively high CD4 counts, the virus can disrupt the normal architecture of the thymus and lymph nodes and eat away at the arsenal of lymphocytes targeted to fight specific infections. HAART may be able to raise CD4 counts, but it is not likely to reverse all previous damage.

Some studies also suggest that it is easier to bring down viral loads to low or undetectable levels and maintain low levels when HAART is started earlier in HIV infection. Still other researchers have shown that starting HAART early stems the number of circulating viruses over time. In theory, at least, that should lessen the risk of transmission.

The downsides of HAART

Early therapy, however, has shown some serious downsides. For one, the long-term accumulation of adverse drug effects puts patients at a greater risk of developing life-threatening disorders.

Protease inhibitors (PIs), for example, frequently disrupt normal fat metabolism. As a result, HAART patients may be more prone to develop diabetes and heart disease. PIs also appear to disrupt bone metabolism, perhaps boosting the risk of hip and spinal compression fractures.

Some HAART patients also undergo disfiguring body fat changes, in which their extremities show a marked loss of subcutaneous fat, which is deposited in excessive amounts in the abdomen and, in women, the breasts. This lipodystrophy commonly produces buffalo humps or huge abdominal paunches and often appears to be irreversible even when patients stop taking PIs. Lipodystrophy afflicts about one quarter of patients who take these drugs for an extended period of time.

Although PI-induced body changes may not be life-threatening, clinicians say physicians need to consider them when prescribing the drugs. "We have to take these body changes very seriously because they drive people to not take their medications," added Johns Hopkins University HIV clinician Joel E. Gallant, FACP.

"It's a tough thing to live with," noted Charles Carpenter, MACP, an HIV clinician at Brown University in Providence, R.I. "It's distressing to patients and has a bad effect on their body image."

In addition, prolonged use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) can cause long-term complications, including episodes of lactic acidosis and hepatomegaly with steatosis that, although rare, are often fatal. Even if patients elude these deadly toxicities, studies suggest more than half of patients on HAART find that the treatment seriously interferes with their quality of life.

The case for delaying treatment

Delaying treatment of HIV infection can lessen or even prevent some of these complications of HAART. It might also delay the development of drug resistance and preserve treatment options until patients' immune systems start to fail later in the course of the disease.

Although patients who conscientiously take all their medicines have so far been able to stave off drug resistance, most patients are not so diligent, noted Dr. Gallant. "I encounter drug resistance in patients every day," he said.

Recognizing these concerns, the February treatment guidelines from the NIH take a middle-of-the-road approach. They suggest that physicians start treating HIV-infected patients when their CD4 counts dip below 350 cells/mm3, the halfway point between 200 and 500.

To support this recommendation, the guidelines cite a few limited studies that show that patients, at least in the short term, do just as well if they start treatment when their CD4 count slips under 350 as they do when their counts fall just below 500. (In its 1998 HIV treatment guidelines, HHS recommended starting HAART at 500 cells/mm3.)

As Dr. Fauci pointed out, "If starting at 500 vs. 350 doesn't add any benefit, why subject the person to several more years of antiretroviral therapy that in the cumulative sense might be detrimental?"

But the number 350 is somewhat arbitrary. Studies show that patients do well as long as they start their antiretroviral therapy at CD4 counts greater than 200.

At the International AIDS Society meeting held in Buenos Aires last July, the antiretroviral guidelines panel of the International AIDS Society-USA went even further than the NIH panel and concluded that there are no strong reasons to start treating most HIV patients with CD4 counts above 200, according to Dr. Carpenter, who served on the NIH panel and presented the recommendations at the meeting. He said he suspects that the next HHS guidelines, which are expected to be issued early next year, will follow these recommendations. He emphasized, however, that the decision to start therapy must be individualized for each patient, and that some patients may benefit from earlier initiation of therapy.

How much of a delay?

Nearly all experts agree that doctors should start treating patients once their CD4 counts fall below 200. How high above that level physicians should begin treatment, however, is "a debatable and hot topic," according to Dr. Holmberg.

Several clinicians argue, for example, that it is too risky to wait until patients' CD4 counts drop to 200 before initiating therapy. The worry is that physicians will overshoot the target, especially if patients skip office visits.

"You want some margin of comfort," Dr. Carpenter said. "There's no scientific basis for a threshold above 200, but you want to provide a safety zone so people don't fall below 200 before they start. You also want to give patients the opportunity to start early if they prefer."

Both the HHS guidelines and many clinicians stress that when to start treatment—as long as CD4 counts aren't below 200—is largely an individual decision. Many say that a patient's willingness to start treatment should play a major role in the decision.

"If we treat patients who aren't ready for the treatment and don't take their medicines and get resistance, then we create this difficult, untreatable population," pointed out Dr. Gallant. "I hope the guideline changes make the internist a little more cautious about starting HAART, because we can make big mistakes by being too aggressive with therapy.

"It's easier to say, 'Oops, your CD4 count is 180, let's start you today' than it is to say 'I started you five years too early and now you're completely drug resistant.' You can't fix that problem."

Also affecting the decision of when to start treatment is a patient's viral load, which clinicians view as an indicator of how rapidly a person's CD4 counts will likely drop.

"The correct time to start treatment is when CD4 counts are somewhere between 200 and 350," said Dr. Gallant. "Viral load tells you whether you start closer to 350 or closer to 200."

If patients' CD4 counts are greater than 350 and viral loads are more than 30,000 copies per mL when using the branched DNA test, the February guidelines from the NIH recommend starting treatment. Previous guidelines had recommended therapy be initiated at 10,000 copies per mL.

Although the guidelines are unclear about exactly when to start treating chronically infected HIV patients, they continue to recommend starting HAART in the rare patient with recognized acute HIV infection and in patients who have seroconverted within the last six months.

"We know that in acute infection, the virus sometimes goes up to tens of millions of copies, and that absolutely can't be good for the immune system," noted Dr. Fauci. "It's common sense to try to blunt that initial massive destruction of the immune system, although we don't know for sure what the long-term effect of that early treatment is going to be."

Dr. Fauci pointed out that the body's immune response can be preserved to at least some degree in those who start HAART during acute HIV infection. He added that the same benefit has not been seen in patients who start antiretroviral therapy years after they are first infected with the virus.

Drug holidays

One question that the guidelines do not adequately address, most experts agree, is what to do with patients who started HAART when their CD4 counts were above 350.

"Most of us feel that if patients are lucky enough not to have side effects, they should just continue HAART," said Dr. Carpenter. "If the patient is experiencing side effects, then you'd want to advise him to stop taking HAART. Even if his viral load shoots up when he stops treatment, if his CD4 count is high and stable, he's safe in staying off medication at this point."

Dr. Carpenter noted that he monitors patients frequently for the first six months after they stop HAART. Dr. Gallant, on the other hand, said he opts to treat them the same as patients who had never started therapy, and that he uses the same parameters to decide when to restart their treatment. "Most of these patients have done fine without therapy and are enjoying their treatment vacations," he said.

Dr. Gallant added that such interruptions in HAART actually give him a vacation of sorts as well. "When I take patients off HAART," he explained, "they stop calling me because they are not developing side effects. I don't have to play with their lipid- or glucose-lowering agents or worry about their hips. They are a lot happier and easier to manage."

Margie Patlak is a freelance science writer in Elkins Park, Pa.

The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP-ASIM.

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