Study shows poor tolerance of postexposure drugs

CDC to revise recommendations for HCWs

Preliminary results from a five-hospital study of HIV postexposure prophylaxis (PEP) among occupationally exposed health care workers show a high incidence of side effects and symptoms resulting from a two- and three-drug regimen recommended last year by the U.S. Public Health Service.

The PEP evaluation is part of the federal Centers for Disease Control and Prevention’s National Surveillance System for Hospital Health Care Workers (NaSH), a software system launched in 1994 to standardize and organize data on exposures to bloodborne pathogens, tuberculosis, and vaccine-preventable diseases, as well as noninfectious injuries or exposures such as falls or violence. (See Hospital Employee Health, October 1994, pp. 125-128.)

In June 1996, the Public Health Service published guidelines for chemoprophylaxis after occupational exposure to HIV. The guidelines outlined a plan for combination therapy with zidovudine (AZT, Retrovir), lamivudine (3TC, Epivir), and indinavir (IDV, Crixivan) for the highest-risk exposures, and AZT and 3TC for those who are lower-risk.1 (See Hospital Employee Health, August 1966, pp. 85-90.)

Despite the recommendations, toxicity and efficacy data are slim, especially for healthy people. However, the efficacy of combination therapy in HIV-infected individuals, as well as a 1995 CDC case-control study demonstrating AZT efficacy in preventing occupational HIV transmission,2 prompted officials to recommend combination therapy for HCWs who incur high-risk exposures.

"The PEP evaluation is a quick look at some of our NaSH hospitals in their experiences with PEP, but it was not designed to be a comprehensive toxicological study," says Scott Campbell, RN, MSPH, an epidemiologist in the CDC’s HIV infections branch of the hospital infections program. "We’re asking these questions as part of NaSH and hoping that with enough time, we can find out some meaningful things about toxicity. Right now we really don’t have enough information to say anything definitive."

Occupational health directors in hospitals using the NaSH software were asked to record information such as how many exposed HCWs were offered chemoprophylaxis, type of chemoprophylaxis offered, how many chose to take it, type of exposure, source patients’ HIV status, and symptoms reported during follow-ups.

The study period was June 1995 through May 1997. Most PEP drug combinations included zidovudine and lamivudine, with or without a protease inhibitor. During the study period, 1,039 blood exposures were reported. Of 956 known source patients, 122 (13%) were HIV-positive, 426 (45%) were HIV-negative, and 408 (43%) had unknown HIV status. PEP was offered to 619 (70%) of 889 HCWs, and was taken by 135 (22%).

Of the 135 HCWs who took PEP, 67 (50%) returned to the employee health department for at least one follow-up visit, and 34 (50%) of those reported one or more symptoms, including persistent nausea, fatigue, and headache.

Those results indicate that appropriate use of PEP should be further evaluated and side effects considered before prescribing it, says Campbell.

‘Who wants to be constantly nauseous?’

The number of HCWs who did not complete the drug regimen due to side effects is not available yet, but Campbell notes that they often chose not to finish, even in the presence of just one symptom, "because who wants to be constantly nauseous?"

Other data gleaned thus far from the study show that HCWs were more likely to be offered and to accept chemoprophylaxis after the 1996 recommendations for combination therapy were issued. Before June 1996, PEP (monotherapy with zidovudine) was offered to 280 of 465 exposed workers (60%), while after June 1996, combination therapy was offered to 339 of 425 exposed workers (80%). Prior to June 1996, PEP was taken by 50 of the 280 workers (18%), but after June 1996, 85 of 339 HCWs (25%) opted to accept it.

Overall, PEP was offered to 46 (55%) HCWs exposed to an unknown source, 96 (83%) workers exposed to an HIV-positive source, 274 (70%) exposed to a source that turned out to be HIV-negative, and 203 (66%) to a source patient with unknown HIV status. The frequency with which HCWs in each of those categories took PEP were 13%, 56%, 19%, and 12%, respectively.

For HCWs exposed to source patients with unknown or negative HIV status, PEP was offered (224/403 vs. 299/370) and taken (22/224 vs. 54/299) more often after June 1996.

"Before June 1996, some people were skeptical that taking AZT would be helpful to them, but after June ‘96, they thought it was more worthwhile, due to the CDC data. I think that influenced health care workers to decide to take what was being offered to them," Campbell says.

Health care workers with percutaneous injuries were offered PEP more often than those with mucocutaneous exposures (538/856 vs. 81/183); the proportion of HCWs taking PEP was the same for both groups, the data show.

Overall, physicians took PEP more often than other HCWs (76/251 vs. 60/368), but Campbell says he does not think it is because physicians’ exposures were more significant.

"Physicians generally are more aware of the recent literature out there regarding any type of chemotherapeutic regimens, this being one of them," he says. "Because they’re more aware of the risk reduction available to them through PEP, they’re probably more open-minded about subjecting themselves to taking some drugs for a while after an exposure."

Resident on PEP hospitalized

Specific data are not available on how many HCWs taking PEP became sick enough to lose days from work, but Campbell says "a considerable fraction" reported symptoms and complaints and became too sick to work. At least one worker was hospitalized, he adds. Campbell would not reveal the hospitals participating in the PEP study, but Hospital Employee Health has learned that Boston Medical Center (BMC) was one of those institutions, and the employer of the hospitalized worker.

BMC contributed data to the study for eight months beginning Sept. 28, 1996, the same day a hospital resident began taking PEP. Twenty days into treatment, she was hospitalized for severe pancytopenia "and wound up taking a year off to recover," say Robert Swotinsky, MD, MPH, director of BMC’s occupational health program and a study leader. "That was pretty eventful for us."

Although the resident’s severe reaction was "idiosyncratic," Swotinsky says the hospital’s data show a high incidence of side effects and a resulting inability to complete the 28-day drug regimen. The hospital’s protocol, based on PHS recommendations, calls for 200 mg zidovudine three times per day, 150 mg lamivudine twice per day, and 800 mg indinavir three times per day for the most significant blood exposures. The two-drug regimen (zidovudine and lamivudine) is offered for other exposures. The drugs are dispensed in two two-week quantities. Workers on PEP are followed up in the occupational health department once a week, where they receive blood tests and a brief interview to determine symptoms.

During the study period, 148 occupational exposures were reported. Of these, 46 (31%) initiated PEP (16 nurses, 15 physicians, six students, and nine others), and about two-thirds of them were taking the three-drug regimen. Overall, 28 (61%) reported side effects such as nausea, diarrhea, fatigue, and drug-related rash. One worker, a diabetic, had high blood sugar elevations on Crixivan, Swotinsky says. (For an FDA warning about protease inhibitors, see Hospital Employee Health, August 1997, p. 94.)

Sixteen workers (34%) discontinued PEP upon receiving HIV-negative source results, but they received PEP for an average of 6.4 days and reported numerous side effects.

Eleven of the 30 remaining workers (37%) prematurely discontinued PEP due to toxicity between two and 20 days into treatment, with a mean of 8.5 days.

"That percentage sounds awfully high to me," says Swotinsky. "If you have a protocol that cannot be completed by 37% of the people, that’s a problem."

Much of the problem lies in strict adherence to the antiretroviral PEP combination specified in the PHS recommendations, he maintains. An occupational health physician, Swotinsky says he has been learning from HIV/AIDS specialists that Crixivan is not the only or necessarily the most appropriate protease inhibitor to be used.

"There is a long list of drugs that could potentially be used if you understand how to use them, when to use them, when to switch, and the benefits of one vs. another, given the patient’s history. I wouldn’t say that the [PHS] recommendations are wrong, but I would say it’s too simplistic to tell people, ‘Here’s four weeks of something; take it or leave it.’ It’s much better to have the flexibility to switch and the knowledge of what to switch to."

More complete data from the PEP study will be presented at the Infectious Diseases Society of America’s 35th annual meeting in October, and Campbell says the CDC will issue updated recommendations for HCW postexposure chemoprophylaxis this fall, based on the PEP evaluation data and information obtained through the PEP data registry. HCWs taking PEP are urged to report their experiences to the registry by calling (888) PEP-4HIV. Information gathered is anonymous.

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 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.