New chemoprophylaxis guidelines prompt federal discussion
NIOSH, union officials urge refocusing on prevention
New federal Public Health Service (PHS) recommendations for chemoprophylaxis after occupational exposure to HIV have triggered a flurry of activity among federal agencies as the U.S. Occupational Safety and Health Administration (OSHA) in Washington, DC, decides how to incorporate the guidelines into an enforcement policy.
Apparently complicating the matter is the fact that the three drugs recommended in the guidelines are licensed by the U.S. Food and Drug Administration (FDA) in Rockville, MD, for HIV treatment, not for prophylaxis following occupational exposure. That issue, which involves questions of the drugs' efficacy and toxicity in healthy people, also concerns hospital employee health practitioners. (See related story, p. 90.)
Federal officials apparently have concerns as well. Michelle Walker, a research specialist in OSHA's office of health compliance in Washington, DC, says the agency is considering the lack of FDA approval for the drugs as chemoprophylaxis as it ponders enforcement issues.
"What we're looking at right now is where the FDA would stand in reference to using the drugs as an approved chemoprophylaxis measure once an exposure occurs. We haven't taken a stand on [enforcement] because we don't know where the FDA stands," Walker says. "We're concerned about enforcement, and our main concern is the engineering controls aspect of the bloodborne pathogens standard, such as needlestick prevention."
OSHA officials are in the process of arranging meetings with representatives of the FDA and the federal Centers for Disease Control and Prevention in Atlanta to discuss policies, adds OSHA spokeswoman Susan Fleming.
"Following those discussions, we hope to make a decision as to what we should do," she says. "We don't know if the recommendations warrant a change in the [bloodborne pathogens] standard, or they may be considered advisory, so they would go into a compliance directive."
Although FDA officials remain tight-lipped about whether they might approve relabeling of the recommended drugs to reflect their use as chemoprophylaxis, spokeswoman Ivy Kupec says drugs commonly are used for purposes other than those for which they were approved, based on recommendations from federal public health agencies.
The new PHS-recommended combination therapy was published in guidelines recently issued by the CDC.1 The guidelines recommend use of zidovudine (AZT, Retrovir) combined with lamivudine (3TC, Epivir) and indinavir (IDV, Crixivan) for the highest-risk exposures, and state that AZT and 3TC should be offered for those that are lower risk. (See chart detailing the PHS postexposure chemoprophylaxis guidelines, p. 88.)
In 1990, PHS guidelines for postexposure management of HIV-exposed health care workers were largely neutral on the issue of chemoprophylaxis due to lack of efficacy data.2 AZT could be offered to workers prophylactically, the document stated, along with appropriate counseling about unknown efficacy. Without supporting data and a clear recommendation, however, many hospitals decided not to offer the drug.
Then in 1995, a CDC case-control study provided new evidence suggesting AZT is about 80% effective in preventing occupational HIV transmission.3 This study was the impetus for the revised guidelines which, for the first time, clearly recommend chemoprophylaxis for certain types of exposures.
Despite the recommendations, toxicity and efficacy data still are slim, especially for HIV-negative people. Although AZT has been available for nearly 10 years, 3TC has only been on the market since November 1995. IDV, one of the new protease inhibitors, was FDA-approved in March this year. Nevertheless, the efficacy of combination therapy in HIV-infected individuals, as well as case-control study demonstrating AZT efficacy, prompted PHS officials to recommend its use for HCWs who incur high-risk exposures.
AZT alone far from perfect
"The data now show definitively for the first time that chemoprophylaxis does diminish the risk of infection," says Steve Schnittman, MD, assistant director for clinical research at the National Institutes of Health in Bethesda, MD, a member of the interagency working group that formulated the guidelines.
The reason 3TC and IDV -- for which there are no data showing efficacy as chemoprophylaxis -- were added to the recommendation was that prevention with AZT alone "was far from perfect," Schnittman tells Hospital Employee Health.
"People could still become infected after taking AZT. Also, the virus is developing resistance to AZT, and in the settings where people are becoming infected, particularly in hospitals where they are taking care of late-stage AIDS patients, they are getting stuck with needles contaminated with the virus that has already seen AZT, so it was felt that these new potent agents could offer more reassurance. Also, we now know that these drugs in combination can lower viral load, not just a fewfold that AZT does alone, but on the order of a hundred- or a thousandfold when in double or triple combination. Taking all those things together, the impetus was to move to an expanded recommendation," he explains.
Although AZT is the only drug for which there are efficacy data in uninfected people, the CDC's expert consultants decided that in almost all cases, it should not be used alone, says David M. Bell, MD, chief of the HIV infections branch of the CDC's hospital infections program.
The AZT/3TC combination is more effective against HIV than AZT alone. Adding IDV is recommended for the highest-risk exposures and also can be considered for exposures involving HIV strains resistant to AZT, he says.
High-risk exposures defined
Exposure risk criteria largely were derived from the case-control study. According to the PHS guidelines, "highest risk" exposures include both a large volume of blood -- such as that from a deep injury with a large-diameter hollow needle previously in the source patient's vein or artery and involving an injection of the patient's blood -- and blood containing a high HIV titer, such as that from a patient with acute illness or late-stage AIDS. "Increased risk" exposures are those that involve either one of those elements.
"When we say the drugs are 'recommended,' that means the Public Health Service interagency working group has concluded that the drugs should be recommended for high-risk exposures despite the relatively limited information on toxicity, because when exposures are significantly high-risk, we feel it's worth it to take the drugs," Bell explains.
"For lower-risk exposures we say 'offer,' and this is a reflection of the need to balance the potential benefit of the drugs with the potential toxicities," he adds. "We think that the offer inherently involves a discussion with the worker, and we recommend that the worker be informed about the drugs and the available information."
Toxicity and efficacy of the new combined therapy are two major trouble spots for EHPs and other members of the health care community, as much as they had been for AZT chemoprophylaxis alone. Over the years, a number of EHPs noted the inability of HCWs on AZT to complete the regimen due to severe side effects. No one knows how workers will react to a combined-drug regimen.
"It's true that zidovudine is associated frequently with nausea, weakness, and headache in health care workers who take it after exposure," Bell admits, "but most of those [cases] involved higher doses than those currently recommended. Although we're not entirely sure, we think the current dose will be less toxic because it's lower."
The previous prophylactic dose of AZT was about one gram per day; current recommendations are for 600 milligrams per day.
Adding 3TC does not significantly increase toxicity for HIV-infected people, says Bell. "When you add the indinavir, you're in a totally different class of drugs, and indinavir has some known toxicities," he says. "The biggest reservation about indinavir is it's so new that there really isn't anywhere near as much information on toxicity as there is with the other drugs."
IDV clinical trials still are being conducted by manufacturer Merck & Co., in West Point, PA, but the drug's package insert states that nephrolithiasis (defined as flank pain, blood in urine, or kidney stones) was reported in about 4% of patients receiving the drug in preliminary clinical trials. It also lists the most frequently occurring clinical adverse effects of IDV combined with AZT (in less than 2% of patients) as nausea (32%), vomiting (12%), headache (12%), asthenia/fatigue (9%), abdominal pain (8%), diarrhea (4%), dizziness (4%), and taste perversion (4%).
According to Glaxo Wellcome in Research Triangle Park, NC, manufacturer of AZT and 3TC, adverse effects most frequently associated with the combination of those two drugs administered to HIV-infected adults in clinical trials included headache (35%), nausea (33%), malaise and fatigue (27%), nasal signs and symptoms (20%), diarrhea (18%), neuropathy (12%), low white blood cells (7.2%), and anemia (2.9%).
As more is known about the recommended drugs' toxicity and efficacy, as well as the risk factors for occupational HIV transmission, the PHS recommendations will be updated, perhaps as often as annually, Bell says.
"We don't know anywhere near what we'd like to know about what the risk is for different types of exposures," he states. "We encourage whenever possible that the recommendations be implemented in consultation with local infectious disease experts who can make further assessments. The word 'provisional' [in the guidelines' title] reflects that this is our first venture into this area, and although there is a lack of data on several aspects including risk, efficacy, and toxicity, there were enough data so that all the consultants and people in the interagency working group felt that it was justified to go forward."
Prevention is 'bigger issue'
Meanwhile, some experts warn that the real focus needs to be on preventing HCWs from sustaining potentially life-threatening needlesticks, instead of on medical treatment after the fact.
Officials of the Washington, DC-based Service Employees International Union (SEIU), which represents about 500,000 HCWs, say they support the recommendations, but they criticize the CDC for not providing equal leadership in exposure prevention.
"The recommendations raise a much bigger issue, which is the whole issue of prevention up front, and it's something the CDC did not adequately address," says Jamie Cohen, SEIU's assistant director for occupational health and safety. "They should always be getting out the latest scientific data that need to be in the hands of health care workers, but the agency also needs to provide leadership on the whole issue of prevention of these types of exposures."
The CDC should ensure that data on the efficacy of safer needle devices in preventing exposures are widely available to hospital employers and HCWs. In addition, the agency needs to publish information on how to select, trial, and provide inservices for safer devices, Cohen maintains.
"They're looking now at a very costly proposition. These drugs are expensive, and implementing an effective postexposure follow-up program costs money. They're talking about doing this at a time when hospitals are screaming about how they don't even have money to keep staff on board. It seems like it would be more cost-effective if the industry were preventing these exposures up front," she says.
Linda Martin, PhD, the Atlanta-based director of HIV activity for the National Institute for Occupational Safety and Health (NIOSH), in Washington, DC, agrees that more attention should be given to engineering controls, such as safer needle devices and sharps disposal containers, as well as HCW education.
"Prevention is always better than trying to fix it afterwards, particularly with something like HIV. In this case, hospitals may want to look a little more at engineering controls because it is going to be expensive to treat workers," she says.
Estimates are that the cost of chemoprophylaxis with combination therapy will cost between $700 and $900 per exposure.
"We don't know whether more workers will report a needlestick now that we have information showing that postexposure prophylaxis might actually work," Martin says. "We're really interested in what the impact is going to be, both on hospitals and the way they approach it, and on workers and how they perceive their risk and what they do about it."
[Editor's note: David Bell of the CDC calls attention to the hot line listed in the recommendations (see item 6, p. 89). He urges all health care providers who prescribe chemoprophylaxis to enroll workers in the anonymous registry developed by the CDC and the drug manufacturers. This will allow updated information to be available early next year. The registry is not just for reporting toxicity symptoms, he points out.]
References
1. Centers for Disease Control and Prevention. Update: Provisional Public Health Service recommendations for chemoprophylaxis after occupational exposure to HIV. MMWR 1996; 45:468-472.
2. Centers for Disease Control. Public Health Service statement on management of occupational exposure to human immunodeficiency virus, including considerations regarding zidovudine postexposure use. MMWR 1990; 39(No. RR-1):1-14.
3. Centers for Disease Control and Prevention. Case-control study of HIV seroconversion in health-care workers after percutaneous exposure to HIV-infected blood -- France, United Kingdom, and United States, January 1988-August 1994. MMWR 1995; 44:929-933. *
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