CDC guidance expected for high-risk sexual exposure

Conference previews HIV treatment guidelines

In response to the most recent developments in combination HIV therapy, federal health officials are further updating recommendations for post-exposure prophylaxis for exposed health care workers and discussing possible guidelines for offering similar preventive treatment to people sexually exposed to the virus.

The announcement of the recommendations by the Centers for Disease Control and Prevention was made recently at a Boston conference during which a renowned AIDS researcher presented a general overview of the soon-to-be-issued Public Health Service (PHS) guidelines for HIV treatment.

Speaking at a conference sponsored by the Cambridge, MA-based Whitehead Institute and Massachusetts General Hospital in Boston, Martin Hirsch, MD, director of AIDS clinical research at Massachusetts General and a member of the PHS recommendations panel, reported that the CDC was expanding the post-exposure prophylaxis protocol for health care workers to include other three-drug combinations. The guidelines issued late last year offered a combination of zidovudine, 3TC, and indinavir for severe exposures to the virus. "After meeting last week, it is likely they will expand the recommendation to include some of the newer drugs, such as nelfinavir, in their decision making," he said. Nelfinavir is the latest of four protease inhibitors approved by the FDA.

In a related step, CDC officials planned to meet in early June to discuss the possibility of making recommendations for treatment of people who have been exposed to the virus through sexual contact. Hirsch said the CDC had sidestepped the sexual-exposure issue when it issued the updated guidelines for health care workers, even though many clinicians would treat high-risk sexual exposures as well. At the same time, the PHS panel also has addressed the issue in its new guidelines, he added.

"This has become well-accepted practice in health care worker occupational exposure, and I think we are at a point now where we have to decide whether these recommendations should cover other exposures as well," he said. "I don’t want to speculate as to what they will come out with, but I think they [panel members] have raised in rather vague terms that one should consider exposure for high-risk individuals."

Although data are limited, the risk of transmission from HIV-infected semen is estimated to be similar to the risk of health care workers exposed to infected blood — about one in 300. Candidates for therapy would be people who have been raped, or partners unwittingly exposed by a person with AIDS, he said. The effectiveness of this type of "morning-after pill" is unknown, as research data would be difficult to obtain. Yet, it makes theoretical sense based on the effect of AZT prophylaxis for exposed health care workers. Issues the CDC would have to grapple with include under what circumstances therapy would be warranted, how soon it would have to be administered after exposure, and for how long. No one, however, is recommending pre-exposure prophylaxis, he clarified.

As for the PHS panel guidelines on HIV treatment, Hirsch said the recommendations would suggest treatment for patients with primary infection syndrome, established infection, RNA viral load greater than 5,000 to 10,000 copies, rapidly falling CD4 counts, or deteriorating clinical conditions, as well as for HIV-positive pregnant women, occupationally exposed health care workers, and in some cases, sexually exposed people. Therapy should be considered, as opposed to automatically recommended, for patients with CD4 counts below 500 or any detectable RNA viral load.

Patients should be started on a three-drug regimen, the most favorable being AZT, 3TC, and one of the four approved protease inhibitors. A combination of AZT, ddI, and nevirapine, a non-nucleoside reverse transcriptase inhibitor, also is a preferred regimen.

Monotherapy is not acceptable

For patients who cannot tolerate three drugs or protease inhibitors, the two-drug regimens of choice are AZT and 3TC, AZT and ddI, and AZT and ddC. "What is not acceptable is monotherapy of any kind and several two-drug combinations, such as AZT and d4T," Hirsch added.

As a caveat, he noted that protease inhibitors should be recommended only if the goal of treatment is to reduce the virus to nondetectable levels. Anything short of that goal increases the risk of the development of resistance. Likewise, because 3TC and nevirapine are agents that select rapidly for single mutations that confer high-level resistance, clinicians probably shouldn’t use those drugs unless they’re aiming for complete suppression.

"What has been widely done, and what is still being widely done in the United States and elsewhere, is using an AZT-3TC combination, and you may be doing more harm than good if you use that combination by itself because 3TC resistance will more rapidly develop and you won’t be able to use that agent as a benefit down the road," he explained.

Change all drugs in failing regimen

As for changing therapy, Hirsch noted that while virus dropped to undetectable levels in 80% to 90% of people using new combinations of therapy in clinical trials, factors in the real world may make the response rate lower. If patients do fail therapy, as measured by increased viral load levels, dropping CD4 counts, symptomatic disease progression, or intolerance, then changing therapy is warranted, he said. The panel recommends that all drugs in a failing regimen be changed, and not just one or two.

"The most common mistake in the treatment of HIV infection today is adding a protease inhibitor if you are failing with two drugs. That means you are really treating with one drug and you’re likely to induce resistance to that drug. So try to change not only the protease inhibitor but the other drugs as well," he said.

Because compliance with combination regimens is so critical, researchers are trying to determine whether HIV treatment can work like cancer treatment, whereby initial combination therapy is followed by a maintenance stage during which one or two drugs are phased out. To answer that question, Hirsch and other researchers at Massachusetts General Hospital and Harvard University are participating in a trial (ACTG 343) in which patients are put on three drugs for up to six months. After achieving nondetectable levels of virus for several months, some patients will continue with only one or two drugs to see whether a more manageable regimen is adequate to suppress the virus indefinitely, he said.

So far, the longest time for which patients’ viruses have remained undetectable as a result of triple combination therapy is 68 weeks. If research shows that these drugs can reach not only plasma viral RNA but also latently infected virus as well as virus in the lymph nodes and central nervous system, the study might discontinue all drugs in selected patients to determine if long-term suppression can indeed result in total eradication of the virus. But as Hirsch warned, "To my knowledge not a single person has had virus eradicated from his or her body through therapy. So far it is only theoretical."

In the meantime, researchers are optimistic that improvements in drug development will make it easier for patients to tolerate and comply with therapy. High on the priority list is development of regimens that require fewer drugs, drugs that can be taken only once or twice a day, drugs that don’t interfere with eating and sleeping habits, and drugs that penetrate better or target different entry points into the virus. Without improved therapies, clinicians must consider whether patients who cannot meet the rigid requirements of compliance should be offered the drugs, Hirsch noted.

"You really have to have patients signing off on this because it is very tough for someone who has a CD4 count of 400 and feels perfectly well to be told they have to take 20 to 30 pills a day around the clock. So it’s really better not treating at all the patients who do not take the drugs regularly, rather than treat someone with something that is ineffective."

Hirsch’s colleague, Deborah Cotton, MD, associate professor of medicine at Harvard University and a physician treating AIDS patients at Massachusetts General Hospital, said denying treatment to patients categorically if they’re in populations that are notoriously noncompliant with therapy is not good practice. However, she does draw the line with drug users who are not in drug treatment. "I just don’t believe that patients in that frame of mind can keep track of these very difficult regimens over the long run," she said.