CDC creates two drug regimens to combat exposure to HI
New drugs spur revised recommendations for postexposure prophylaxis
Health care workers occupationally exposed to human immunodeficiency virus should be offered one of two prophylactic drug regimens depending upon HIV transmission risk and possible resistance to one or more antiretroviral agents, according to new guidelines released by the federal Centers for Disease Control and Prevention.
The latest CDC report updates and consolidates all previous Public Health Service recommendations for managing occupationally exposed HCWs, includes new recommendations for HIV postexposure prophylaxis (PEP), and discusses the scientific rationale for PEP.1 Since provisional recommendations were released in 19962, several new antiretroviral drugs have been approved, and more data are available about the use and safety of antiretroviral agents in exposed HCWs.3-6
In setting out the new guidelines, the CDC formulated a two-page algorithm (see algorithm, inserted in this issue) to help determine an "exposure code" and an "HIV status code." The algorithm is intended to help clinicians and HCWs decide whether PEP is warranted, and if so, whether the basic or expanded regimen should be used.
The basic regimen (see Table 1, p. 82) applies to occupational HIV exposures for which there is a recognized transmission risk. It consists of four weeks of both zidovudine (ZDV), 600 mg per day in two or three divided doses, and lamivudine (3TC), 150 mg twice daily. The expanded regimen is recommended for occupational HIV exposures that pose an increased risk for transmission, such as those involving a larger volume of blood and/or higher virus titer in blood. It combines the basic regimen with a protease inhibitor - either indinavir (IDV), 800 mg every eight hours, or nelfinavir (NEL), 750 mg three times a day.
The CDC's 1996 guidelines may have provided more questions than answers in some circumstances, with employee health and infection control personnel wondering about the use of chemoprophylaxis in situations not fully addressed in the provisional guidelines. Those included when not to offer PEP, what to do when the exposure source or HIV status of the exposure source is unknown, whether to offer PEP to HCWs who are or could be pregnant, and considerations for PEP when the source patient's virus is known or suspected to be resistant to one or more of the antiretroviral agents recommended for PEP. Many practitioners also have been concerned about drug toxicity and efficacy issues, as well as the need to initiate PEP within one or two hours postexposure. (See Hospital Employee Health, August 1996, pp. 85-92.)
While most of those questions are addressed in the updated guidelines, drug efficacy and toxicity in uninfected people remain largely unknown because there have been no clinical trials on that population, says Linda S. Martin, PhD, director of HIV activity for the National Institute for Occupational Safety and Health and a contributor to the document.
"We wanted to provide a very clear outline of PEP recommendations because these drugs are toxic. We now have more information on the toxicity of the drugs [from data related to treatment of HIV infection and disease], as well as on new drugs that weren't available when previous guidelines were written."
Martin notes that NIOSH was involved in preparing the guidelines because they relate to worker safety, but the agency usually is more involved in efforts to prevent exposures from occurring in the first place. In fact, the first sentence of the updated guidelines begins with the reminder that ". . . preventing blood exposures is the primary means of preventing occupationally acquired human immunodeficiency virus (HIV) infection. . ."
Leaders of the Washington, DC-based Service Employees International Union (SEIU), which represents about 500,000 HCWs, support the recommendations but had hoped for a stronger statement promoting the need for exposure prevention.
Jamie Cohen, SEIU's assistant director for occupational health and safety, says the reminder is "important, but kind of empty, because it doesn't give direction to health care facilities about how to prevent needlestick injuries."
When provisional recommendations were released two years ago, U.S. Occupational Safety and Health Administration officials had discussed taking action toward a new compliance directive or a change in the bloodborne pathogens standard. However, no action was taken at that time. Now that updated guidelines have been issued, "we expect to act on it," says OSHA spokeswoman Susan Fleming.
ZDV no longer to be used alone
Whether or not OSHA's action will turn the guidelines into law, this is the latest phase in the evolution of scientific information about PEP. In 1990, the CDC issued a statement on postexposure management that was largely neutral on the issue of chemoprophylaxis with ZDV due to a lack of efficacy data.7 Then, in 1995, a CDC case-control study revealed new evidence suggesting that ZDV was about 80% effective in preventing occupational HIV transmission.8 That study prompted the 1996 guidelines, which, for the first time, clearly recommended chemoprophylaxis for certain types of exposures. However, those guidelines allowed ZDV to be used alone for some exposures. That is no longer the case.
"We no longer recommend monotherapy with zidovudine," says Linda A. Chiarello, RN, MS, an epidemiologist in the HIV infections branch of the CDC's hospital infections program and coordinator of the report. "Zidovudine is the only drug shown to prevent transmission in humans, but on the other hand, the guideline for treating HIV infection or disease is to use combination therapy. Our recommendations are based on recommendations for treatment of people with established infection."
While the recommendations call for adding other antiretroviral drugs to ZDV, they also note that there are no data to directly show that other drugs are effective as part of a PEP regimen. The 1996 guidelines added 3TC as a second PEP agent for a number of exposure types based on greater antiretroviral activity of the combination and its activity against many ZDV-resistant HIV strains. In addition, data suggest that ZDV-resistant mutations develop more slowly in patients receiving the combination than in those receiving ZDV alone.9
Adding a protease inhibitor as a third drug in the expanded drug regimen for high-risk exposures is based on the site of activity in the viral replication cycle and demonstrated effectiveness in reducing viral burden, the guidelines state. IDV was recommended for PEP in the 1996 guidelines because of its increased bioavailability and more favorable toxicity profile compared with other protease inhibitors approved at the time. Since then, NEL has been approved for use and is included for treating primary HIV infection.
Based on dosage considerations - the recommended dose of the new soft-gel formulation of saquinavir requires taking 18 pills a day - the CDC recommends either IDV or NEL as first choice for inclusion in an expanded PEP regimen.
Closely monitor workers for toxicity
Toxicity remains a relevant consideration in prescribing PEP. The guidelines point out that all antiretroviral agents have been associated with side effects (which are noted in an appendix to the document), but they have been reported primarily for people with advanced disease and longer treatment courses "and therefore may not reflect the experience of persons with less advanced disease or those who are uninfected."10
Because protease inhibitors could have potentially serious drug interactions with certain other drugs, clinicians must carefully evaluate concomitant medications being used by an HCW before prescribing a protease inhibitor, and also must closely monitor workers for toxicity. Protease inhibitors have been associated with the onset or exacerbation of diabetes mellitus, nephrolithiasis, hemolytic anemia, and diarrhea, and may accelerate the clearance of certain drugs, including oral contraceptives. Common symptoms associated with ZDV include nausea, vomiting, malaise, fatigue, headache, and insomnia, as well as mild decreases in hemoglobin and absolute neutrophil count.
The recommendation for initiating PEP has changed slightly as well. While previous recommendations called for workers to begin taking the drugs one to two hours postexposure, the CDC now says "PEP should be initiated as soon as possible," noting that "the interval within which PEP should be started for optimal efficacy is not known."
Recommendations for managing potentially exposed HCWs call for written protocols for prompt reporting, evaluation, counseling, treatment, and follow-up. Employees must have access to postexposure care during all work shifts. Clinicians who provide postexposure counseling (see related story, p. 83) should be familiar with evaluation and treatment protocols and the facility's procedure for obtaining drugs for PEP.
If an exposure occurs, the exposure site should be treated (skin washed with soap and water, mucous membranes flushed with water) and information obtained for an exposure report. (See related story, above.) Both the source person and the exposed HCW should be evaluated to determine the need for PEP, according to an algorithm constructed for that purpose.
Exposed workers should be baseline-tested for HIV antibodies. If the source person is seronegative for HIV, baseline testing or further follow-up normally is not necessary. If the source person has recently engaged in behaviors associated with risk for HIV transmission, baseline and follow-up testing should be considered for the HCW. If considering PEP, the evaluation also should include information about medications the HCW may be taking and any current or underlying medical conditions or circumstances, such as pregnancy, breast-feeding, or renal or hepatic disease. Pregnancy testing should be offered to all women of childbearing age whose pregnancy status is unknown.
Pregnancy does not preclude use of PEP
If an exposed HCW is pregnant, the woman and her health care provider should discuss the potential benefits and risks of using antiretroviral drugs during pregnancy. "Pregnancy should not preclude the use of optimal PEP regimens, and PEP should not be denied to an HCW solely on the basis of pregnancy," the guidelines state. Exposed pregnant HCWs must be provided with all information about what is known and unknown regarding potential benefits and risks for her and her fetus associated with antiretroviral drugs. Considerations to be discussed include: the potential risk for HIV transmission based on type of exposure; the stage of pregnancy (the first trimester being the period of maximum organogenesis and risk for teratogenesis); and information about the pharmacokinetics, safety, and tolerability of the drugs in pregnancy.
Follow-up of all HCWs exposed to HIV should include counseling, postexposure testing, and medical evaluation. HIV-antibody testing should be performed for at least six months postexposure. If PEP is used, drug-toxicity monitoring should be performed at baseline and again two weeks after starting PEP. At a minimum, tests should include a complete blood count and renal and hepatic chemical function tests. HCWs whose regimens include a protease inhibitor should be monitored for evidence of hyperglycemia. Workers receiving IDV should be monitored for crystalluria, hematuria, hemolytic anemia, and hepatitis. Expert consultation is required if toxicity is noted.
Nausea and diarrhea sometimes prevent workers from completing the recommended regimen. Those symptoms often can be managed without changing the regimen by prescribing antimotility and antiemetic agents.
Health care providers are encouraged to enroll HCWs taking PEP in confidential registries to assess toxicity. They also should report severe or unusual toxicity to the Food and Drug Admini stration. A protocol has been developed to evaluate HIV seroconversion in HCWs who received PEP, and those events should be reported to the CDC. A National Clinicians' Post-Exposure Prophylaxis Hotline (PEP-line) is available to help clinicians manage occupational exposures. (For all telephone numbers, see Table 2, above.)
"The important message is that people who are prescribing postexposure prophylaxis need to be knowledgeable of the risk of transmission and need to have good counseling skills so they can guide health care workers in making a decision," says Chiarello. "I can't say [the guidelines] are a panacea by any means, but hopefully they will help people a little bit more in the decision-making process."
[Editor's note: To obtain a copy of the revised guidelines, contact the Centers for Disease Control and Prevention, National AIDS Clearinghouse, P.O. Box 6003, Rockville, MD 20850. Telephone: (800) 458-5231. The document also is available on the World Wide Web at http://www.cdc.gov/epo/mmwr/mmwr_rr. html.]
References
1. 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.
2. Centers for Disease Control and Prevention. Update: Provisional Public Health Service recommendations for chemoprophylaxis after occupational exposure to HIV. MMWR 1996; 45:468-472.
3. Ippolito G, Puro V, the Italian Registry of Antiretroviral Prophylaxis. Zidovudine toxicity in uninfected healthcare workers. Am J Med 1997; 102(suppl 5B):58-62.
4. Wang SA, the HIV PEP Registry Group. Human immunodeficiency virus (HIV) postexposure prophylaxis (PEP) following occupational HIV exposure: Findings from the HIV PEP registry [Abstract 482]. In: Program and abstracts of the Infectious Diseases Society of America 35th annual meeting. Alexandria, VA: Infectious Diseases Society of America; 1997.
5. Steger KA, Swotinsky R, Snyder S, et al. Recent experience with post-exposure prophylaxis (PEP) with combination antiretrovirals for occupational exposure (OE) to HIV [Abstract 480]. In: Program and abstracts of the Infectious Diseases Society of America 35th annual meeting. Alexandria, VA: Infectious Diseases Society of America; 1997.
6. Beekmann R, Fahrner R, Nelson L, et al. Combination post-exposure prophylaxis (PEP): A prospective study of HIV-exposed health care workers (HCW) [Abstract 481]. In: Program and abstracts of the Infectious Diseases Society of America 35th annual meeting. Alexandria, VA: Infectious Diseases Society of America; 1997.
7. 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).
8. 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.
9. Katlama C, Ingrand D, Loveday C, et al. Safety and efficacy of lamivudine-zidovudine combination therapy in antiretroviral naive patients: A randomized controlled comparison with zidovudine monotherapy. JAMA 1996; 276: 118-125.
10. Struble KA, Pratt RD, Gitterman SR. Toxicity of antiretroviral agents. Am J Med 1997; 102(suppl 5B):65-67.
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