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CDC stressing hazards of unnecessary PEP
Concerned that health care workers are being unnecessarily treated with powerful and potentially toxic HIV drugs, the Centers for Disease Control and Prevention will try to end the overkill with new guidance for post-exposure prophylaxis (PEP), Hospital Infection Control has learned.
Slated for release in early June 2001, the new guidelines were the subject of discussion recently in Toronto at the annual meeting of the Society for Healthcare Epidemiology of America (SHEA).
"I think what has changed most dramatically is the philosophy of the guidance," said Julie Gerberding, MD, MPH, director of the CDC division of healthcare quality promotion. "[We are trying] to bring the pendulum of treat, treat, treat’ back to a more rational position of treat when there is a risk, but don’t overtreat.’ . . . People are having a really hard time saying no. We are trying to provide a better framework for people to [limit PEP] to situations where true risk is evident."
By the same token, the CDC must strike a balance to ensure PEP is given when appropriate. The low but real risk to health care workers was underscored at SHEA by the reporting of the 57th case of documented HIV transmission to a health care worker. In a development that could cloud the CDC’s message about preserving PEP for serious exposures (i.e., needlesticks), the latest case involved a worker with prolonged blood and body fluid exposures to cracked and damaged skin on her hands. (See related story, p. 64.)
But with PEP drugs potentially toxic enough to induce life-threatening liver failure, public health officials are concerned that two- and three-drug regimens are being routinely administered following minor exposures. The CDC recently reported near-death PEP in two health care workers — one who had a liver transplant — after the use of the drug nevirapine for PEP.1 In one of the cases, the decision to administer PEP was questionable, as the 38-year-old physician involved had a mucous membrane exposure to a nonbloody body fluid.
"We always worried about overprescribing and the potential for toxicity," said David Henderson, MD, a medical epidemiologist at the National Institutes of Health Clinical Center in Bethesda, MD. "Now we have some hard and fast evidence that that is what’s happening."
Calls to the national PEP hotline suggest a similar trend, as inquiring clinicians are usually told not to administer PEP for the case they are describing, he added. "For two or three years running, [for about] 60% who call for help, the advice of the PEP line is to either stop the medication that they have already started or don’t give any medicine at all," Henderson said.
PEP decisions could get considerably easier with the highly anticipated return of rapid HIV tests to the market, as clinicians will be able to quickly determine the serostatus of the source patient. (See HIC March 2001 under archives at www.HIConline.com.)
"My information from the [Food and Drug Administration] is that there are several new rapid tests that are going to be approved soon and should be available," Elise Beltrami, MD, medical epidemiologist in the CDC division of healthcare quality promotion, told HIC. "One way to minimize the exposure of health care workers to unnecessary PEP is the use of rapid HIV testing to more quickly determine that source patients are HIV-negative."
The new guidelines will emphasize that workers who have HIV-positive exposures should be encouraged to take PEP and complete the full course of drugs. The CDC also will recommend a regimen of antinausea and antidiarrhea agents to minimize side effects of those undergoing prophylaxis, she said.
Infection control professionals, particularly those working in low HIV prevalence settings, first should rely on clinical and epidemiologic evaluation of the source patient, Gerberding said. Certainly, the assumption should not be that all blood exposures are HIV-positive and require treatment, she noted. While the fear of HIV infection is not to be underestimated, it is wise to remember that even needlestick exposures to HIV-positive blood result in transmission only .3% of the time.
"We are already starting with 99.7% chance that nothing bad is going to happen to the exposure recipient," Gerberding says. "We are trying again to find the subset of the risky exposures and treat those with the best regimens [we can devise]."
In its 1998 guidelines, the CDC emphasized that the risk for HIV transmission appears to increase for needlestick exposures involving larger quantities of blood from an infected source patient.2 Markers for that include visible contamination of the device with the patient’s blood, a procedure that involved a needle placed directly in a vein or artery, or a deep injury. In addition, the CDC emphasized in those guidelines that the likelihood of transmission after a mucous membrane exposure to HIV-positive blood is a miniscule 0.09%. Exposures to intact skin are thought to be at even lower risk than that.
In general, risk is thought to increase for any exposure if the source patient is in the latter stages of AIDS and has a high titer of virus in the blood. Nevertheless, it is risky to make PEP decisions based on HIV viral load in the patient’s blood, Gerberding warned. Though common sense would suggest high viral load translates to higher risk of transmission, the issue is complicated because HIV has been transmitted from people with little evidence of circulating virus.
"We don’t want to assume that there is no risk with a low viral load in the source patient," she said. "Although you would suspect that."
Even after deciding that the exposure entails true risk and PEP should be administered, a new round of questions opens up. These include, as evidenced by SHEA discussions, how soon should therapy begin, and when is it too late to give it? A two-hour time frame became ingrained in the clinical mindset in earlier CDC guidelines, but the truth is nobody knows.
"I think there was a misunderstanding in previous guidelines," Gerberding said. "There was concern that if you did not treat within two hours, there were significant changes in the efficacy of the regimen. Generally, there is no finite line between this is good’ and this is bad.’"
Henderson added, "I don’t think of this as a light switch. It’s a continuum. The longer you wait, the higher the risk. So the earlier [PEP is given], the better." If there is significant concern that an exposure has occurred and the clock is ticking, go ahead and administer the first PEP dose and then continue to investigate the exposure, he recommended. Clinicians must follow up and determine whether it was a legitimate exposure to HIV-positive blood rather than just continue the PEP regimen, he emphasized.
Some clinicians may be tempted to stagger the introduction of PEP drugs in an attempt to minimize side effects. When starting a PEP regimen, determine what drugs you are going to use and then administer the regimen in full, Gerberding emphasized.
"I would not start one drug and add a second drug two or three days later," she said.
"Everything we know about [HIV treatment] suggests that is bad idea. If you are going to treat, treat with the regimen that you think will be effective. And if you are not going to treat, don’t start anything. It is not a good idea to stagger. If it really were an HIV exposure and you had a resistant virus, then what you have done is really set the stage for [emergence of that] resistance," Gerberding explained.
If the exposure is to a known HIV patient under treatment with antiviral drugs, one approach to concocting an effective PEP regimen and staving off resistance is to give the same drugs to the worker.
"Nobody can figure out how to manage the patient with this [resistance] problem, let alone the occupationally exposed health care worker," Gerberding added. "I think the philosophy of post-exposure prophylaxis is conservative. What is [the patient] taking now? I would try to craft a complementary antiviral regimen."
However, another caveat arises: Three-drug regimens are not necessarily better than using two PEP drugs. Thus, there is no reason to unleash every weapon at your disposal for every health care worker exposure.
"We don’t know that three drugs are more efficacious than two drugs for prophylaxis," Gerberding said. "The number of drugs is primarily driven by the probably of resistance [in the source patient]. So the reason we don’t use AZT alone is because some communities have potential for viruses with AZT resistance. The second drug was added to try and ensure that you have at least one active drug onboard."
Similarly, the third drug in a regimen is often added for high-risk exposures in an attempt to increase the odds of successful prophylaxis. "We know the more drugs you have, the less likely you are to get clinical breakthrough," she said. "There is still a recommendation [in the new guidelines] for using more antiretrovirals in the really high-volume exposures."
A common confounder to that approach, however, is that the likelihood of the worker completing the PEP regimen drops sharply when the full three-drug regimen is used. The third drug is usually a protease inhibitor, and side effects can be significant. "In the new guidelines, there is more emphasis on [using] three-drug therapy in the really high-risk exposures where you have the obvious dramatic risk factors," Gerberding said. "[But don’t] take the default position that three or four drugs are good for our AIDS patients, so we should be treating our health care workers with three or four drugs."
1. Centers for Disease Control and Prevention. Serious adverse events attributed to nevirapine regimens for postexposure prophylaxis after HIV exposures — worldwide, 1997-2000. MMWR 2001; 49:1,153-1,156.
2. Centers for Disease Control and Prevention. Public Health Service. Guidelines for the management of health-care worker exposures to HIV and recommendations for postexposure prophylaxis. MMWR 1998; 47(No. RR-7):1-33. n