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Nonoccupational HIV PostexposureProphylaxis: A New Role for the Emergency Roland Clayton Merchant, MD
Despite numerous primary prevention campaigns, new cases of HIV infection are occurring at high rates. Postexposure prophylaxis (PEP) after possible HIV exposures from sexual encounters or Received for publicationNovember 15, 1999. Revisions injection drug use may prove to be a worthwhile means of re- ducing HIV infection. Although there are no studies that directly demonstrate its efficacy, indirect support comes from animal and human studies. Multiple animal studies have shown that Address for reprints: Roland
Clayton Merchant, MD, Department
antiretroviral medications can reduce simian immunodeficiency virus infections if given early and for a prolonged period. A Sinai Medical Center, One Gustave L. study of health care workers suggests that zidovudine taken Levy Place, New York, NY 10029;212-659-1653; fax 212-426-1946; after needlestick injuries can dramatically reduce HIV serocon- version. Zidovudine and nevirapine use recently showed great reductions in perinatal HIV transmission. Studies of dendritic and T-cell processing of simian immunodeficiency virus and HIV indicate that antiretroviral medications taken soon after a viral 47/1/109511
exposure may terminate viral replication. Regimens of 2 or 3 antiretroviral medications have been suggested as prophylacticmeasures after certain exposures. Even though limited experienceexists with these populations, HIV PEP is most likely safe inpregnancy and for children. Emergency departments are en-couraged to anticipate the probable demands for nonoccupa-tional HIV PEP by establishing protocols for its rapid provisionand ensuring proper follow-up care.
[Merchant RC. Nonoccupational HIV postexposure prophylaxis:a new role for the emergency department. Ann Emerg Med.
October 2000;36:366-375.] According to current HIV-AIDS statistics, an estimated33.6 million persons in the world are living with HIV-AIDS, approximately 650,000 to 900,000 in the UnitedStates have HIV-AIDS, and 20,000 new adult HIV infec-tions occurred in 33 states reporting data to the Centersfor Disease Control and Prevention from July 1998 to A N N A L S O F E M E R G E N C Y M E D I C I N E 3 6 : 4 O C T O B E R 2 0 0 0
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1999.1-3 Nearly 100% of new adult HIV infections in In 1994, the Working Group on HIV Testing, Counseling, these states resulted from sexual or intravenous drug con- and Prophylaxis After Sexual Assault considered zidovu- tacts.3 Reports from San Francisco and Sydney indicate dine to have a possible prophylactic role.23 In 1998, the that rates of unprotected male-male anal intercourse may PHS first commented on PEP after sexual assault, stating be on the rise.4,5 Almost half of the risky sexual encoun- that “A recommendation cannot be made, on the basis of ters reported in the San Francisco study occurred between available information, regarding the appropriateness of partners with unknown HIV status or sero-opposite part- post-exposure antiretroviral therapy after sexual expo- ners.4 These new HIV infections and unsafe sexual prac- sure to HIV.”24 Other groups have proposed specific rec- tices are persisting despite numerous primary prevention ommendations. Bamberger et al25 of San Francisco stated programs. As an adjunct to HIV prevention, nonoccupa- that “Post-exposure prophylaxis for HIV should be a part tional HIV postexposure prophylaxis (PEP) has been pro- of a comprehensive rape treatment program,” and in their article provide a PEP model. The AIDS Institute of the In a recent convenience sampling of homosexual men New York State Department of Health considers that “HIV at a Gay Pride event in Atlanta, 14% of attendees knew of PEP should be recommended when significant exposure persons who had been prescribed PEP after a sexual expo- may have occurred, as defined by direct contact of the sure to HIV, and 3% had used it themselves.6 This survey, vagina, anus, or mouth with the semen or blood of the a recent case example,7 and several newspaper articles8-11 perpetrator, with or without physical injury, tissue dam- demonstrate both public knowledge and use of this new age, or presence of blood at the site of the assault.”26 form of secondary HIV prevention. It is likely that emer- In 1997 and 1998, 2 prominent leaders in HIV preven- gency departments will be faced with demands for PEP tion, Dr. Julie Gerberding of the University of California, after nonoccupational exposures as public knowledge of San Francisco, and Dr. Mitchell Katz, of the San Francisco it grows. In this article, the historical and scientific back- Department of Public Health, wrote the first comprehen- ground of nonoccupational HIV PEP and its purported sive articles on nonoccupational HIV PEP.27,28 In their mechanisms, indications, and regimens are discussed, as articles, Drs. Gerberding and Katz called for an expansion well as recommendations for its provision from the ED.
of current PEP use to include certain sexual and intrave-nous needle exposures. Stating that “we believe that the available data are robust enough to support the use ofpostexposure prophylaxis,”27 Drs. Gerberding and Katz The US Public Health Service (PHS) recently classified suggested a complete nonoccupational PEP program, in- prophylaxis after HIV exposures into 2 types: occupa- cluding selection criteria, medication regimens, monitor- tional and nonoccupational.12 Occupational exposures ing, and HIV–sexually transmitted disease (STD) preven- primarily refer to needlestick injuries incurred by health care workers. Nonoccupational exposures include sexual In 1998, the PHS issued a statement on PEP for nonoc- and intravenous needle exposures to HIV.
cupational HIV exposures.12 In its statement, the PHS The first reported use of antiretroviral medications first reiterated that PEP cannot replace primary HIV pre- after a needlestick injury appeared in 1988,13 the initial vention and cautioned against the routine and cavalier PHS statement on occupational PEP appeared in 1990,14 use of PEP as a “morning-after pill” after risky sexual be- and the first controlled study was released in 1995.15,16 haviors. The PHS, although outlining the possible scien- In 1996, a PHS workshop of professionals from different tific rationale and providing some commentary on initiating aspects of HIV management reviewed a large amount of nonoccupational PEP, did not endorse or dissuade its use.
data regarding occupational PEP and issued guidelines onits use.17 The PHS issued recommendations in 1996 on the basis of the workshop’s findings and updated them in1998. These are now standard practice guidelines in most The evidence supporting the concept of PEP after nonoc- medical institutions for occupational PEP.18,19 cupational HIV exposures relies on animal studies of HIV infection after sexual assault was first reported in simian immunodeficiency virus (SIV) examining various 1989 after a young woman in London was raped by a chemoprophylactic regimens and their timing, animal known HIV-positive assailant.20 Proposed prophylactic SIV transmission studies, human HIV chemoprophylac- therapies then were vinegar douches and nonoxynol 9. It tic studies in occupational and perinatal exposures, HIV was also suggested that zidovudine might be helpful.20-22 transmission studies, and some preliminary PEP center O C T O B E R 2 0 0 0
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data. Most of the evidence lends indirect support because sures could not be objectively measured. Fourth, the study the extent that animal and perinatal studies can be relied on health care workers to take the zidovudine as applied to nonoccupational HIV exposures is unclear.
recommended, which did not occur in all cases. Fifth, In several studies with primates intravenously exposed Evans et al38 observed that the control subjects were from to SIV, zidovudine delayed or reduced SIV viral replica- different populations, that the case reporting methods tion and occasionally prevented SIV infection.29-32 In a differed between patients and control subjects, and that study by Tsai et al,33,34 a nonlicensed nucleotide ana- the 81% reduction in seroconversion after zidovudine logue, (R)-9-(2-phosphonyl methoxypropyl) adenine, therapy seems very high given that the source patients prevented SIV infection in 100% of macaques intrave- probably carried zidovudine-resistant HIV strains.
nously injected with SIV. Tsai et al noted that prevention There are no other controlled studies with PEP after of SIV infection only occurred when treatment was ren- occupational HIV exposures. An attempt to conduct a dered within 24 hours and continued for 28 days. In a prospective, placebo-controlled study was terminated study with a different experimental medication, nucleo- early because too few people volunteered.39 side analogue 2´,3´-dideoxy-3´-hydroxymethyl cytidine PEP has also been used to prevent the perinatal trans- (BEA-005), SIV infection was prevented in macaques mission of HIV. In the Pediatric AIDS Clinical Trial Group when BEA-005 was given within 8 hours of exposure and Protocol 076 Study Group randomized, prospective, administered for 3 days.35 This study is noteworthy be- placebo-controlled trial, HIV-infected women were given cause it included vaginal exposures to SIV.
zidovudine orally, starting between 14 and 34 weeks’ ges- While examining the mechanism and timing of SIV tation, and intravenously while in labor.40 Their infants transmission in Rhesus macaques intravaginally inocu- received zidovudine syrup for 6 weeks after delivery. The lated with SIV, investigators discovered that a 2-day lag researchers observed a 67.5% risk reduction (95% CI, occurs before SIV-infected cells appear in regional lymph 40.7% to 82.1%) of perinatal HIV infection. Analyses of nodes and a 5-day lag occurs before the virus is detected this study suggest that the reduction of maternal HIV viral in the blood.36 The investigators postulated that den- load only partially accounts for the observed reduction.41 dritic cells in the lamina propria may be the first receptors If zidovudine crossed the placenta during the prepartum and mediators of SIV infection. A recent article in Science and peripartum intervals, it is possible that zidovudine disputed this postulated mechanism. Zhang et al37 found acted as either a preexposure or postexposure prophylac- that T cells of the lamina propria were the first cells in tic agent against transplacental HIV transmission. A sepa- which SIV RNA could be detected and that the dendritic rate prospective trial in Thailand with a simpler, shorter, cells did not mediate their infection. Zhang et al did ob- and cheaper regimen of oral zidovudine twice daily, start- serve a 3-day delay before the first T cells showed evi- ing at 36 weeks’ gestation and every 3 hours during deliv- ery, showed a 51% reduction (95% CI, 15% to 71%) in Only one controlled study exists that examined PEP in human subjects possibly occupationally exposed to An examination of 939 HIV-exposed infants in New HIV.15,16 Cardo et al16 reviewed more than 700 health care York state who received partial zidovudine regimens when worker needlestick injuries compiled from France, Italy, their mothers received none, gives more compelling evi- the United Kingdom, and the United States from 1987 to dence of its postexposure prophylactic effect, as well as 1994. The cases comprised health care workers in whom further support to the importance of the timing of its initi- seroconversion occurred after exposure to HIV, whereas ation.44 Eight (9.3%; 95% CI 4.1% to 17.5%) of 86 HIV- the control subjects were nonseroconverters. Nine exposed infants who received zidovudine initially within patients and 172 control subjects who were offered 48 hours of birth had a positive HIV test result within 180 zidovudine took it. The researchers observed an 81% days of birth compared with 63 (26.6%; 95% CI 21.1% to reduction in the odds of HIV infection among control sub- 32.7%) of 237 HIV-exposed infants who did not receive jects who took zidovudine (95% confidence interval [CI], any perinatal zidovudine prophylaxis. Of 38 HIV-exposed 48% to 94%). The researchers concluded that prophylaxis infants who received zidovudine initially from 3 to 42 days with zidovudine after percutaneous injuries involving of life, seroconversion to HIV occurred in 18.4% (95% CI HIV-infected blood “appears to be protective.”15,16 The study by Cardo et al16 has several limitations. First, Nevirapine recently demonstrated even greater effi- the study was retrospective. Second, there were only 33 cacy than zidovudine in reducing perinatal HIV transmis- persons in the case group. Third, the severity of the expo- sion.45 In this trial, HIV-infected pregnant women were A N N A L S O F E M E R G E N C Y M E D I C I N E 3 6 : 4 O C T O B E R 2 0 0 0
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randomly assigned to receive either a single dose of nevi- and a protease inhibitor, and 73% completed 28 days of rapine, 200 mg, at the onset of labor while their infants treatment. None of their patients had positive HIV test received a single oral dose of nevirapine, 2 mg/kg, within 72 hours of birth; or they received zidovudine, 600 mg bymouth, at the onset of labor and 300 mg every 3 hours P O S S I B L E M E C H A N I S M O F H I V P O S T E X P O S U R E until parturition while their infants received 4 mg/kg twice daily for 7 days. Almost 99% of the women in bothgroups breast-fed initially, and 96% continued to breast- If a time lag occurs between an exposure to HIV and feed by the end of the study at 14 to 16 weeks. Compared when human cells become infected, an opportunity for with zidovudine, nevirapine lowered the risk of perinatal prophylaxis may exist.27,28 Chemoprophylaxis, such as HIV infection at 14 to 16 weeks of age by 47%.
with antiretroviral medications, taken shortly after a pos- Recent work on human tissue may help explain the sible HIV exposure may halt HIV replication. The body time course and method of HIV transmission after skin could possibly then destroy the virus by means of various and mucosal exposures. Until the recent article by Zhang immune mechanisms. Support for this concept arises et al,37 the prevailing hypothesis has been that when HIV from a study showing that treatment of cultures with invades the skin or mucosa, such as after anal or vaginal zidovudine prevented T-cell infection when HIV was receptive intercourse, dendritic cells receive the virus added to cultures of dendritic cells and T cells.46 first. Dendritic cells then travel through the skin to the Presumably, both the T cells and the dendritic cells lymph nodes and present the virus to the T cells.46 For incorporated zidovudine before the introduction of HIV ordinary antigens, and presumably also HIV, it takes into the culture and consequently terminated its replica- about 12 to 24 hours for dendritic cells to travel from the skin to the lymph nodes and about 48 to 72 hours for T More support comes from a study of health care work- cells to be infected.46 Zhang et al disagree with the ers occupationally exposed to HIV in whom seroconver- hypothesized intermediary role of dendritic cells and sion did not occur.50,51 Health care workers who took propose that T cells may be directly infected by HIV.
antiretrovirals had a lower immune memory response in Regardless of the mechanism of infection, the observed cytotoxic T cells than those who did not take antiretrovi- rals. Presumably, in the health care workers taking anti- PEP centers at San Francisco and Boston recently re- retrovirals, the medications reduced viral replication so ported their experiences with providing nonoccupational that the amount of virus presented to their T cells was low.
PEP. From San Francisco, Martin et al47 reported that of Low amounts of virus meant that fewer T cells came in 401 persons studied, 94% received nonoccupational PEP contact with the virus and hence there was a lower im- after a sexual exposure and the remainder after intrave- mune memory. Cellular immune mechanisms, humoral nous (2%) accidental needlestick, assault, and other ex- immune mechanisms, or both possibly cleared the body posures. Forty percent of the sexual exposures involved receptive anal intercourse. Condoms were not used in Timing to initiation of PEP appears to be critical. As 64% of the sexual exposures. Forty-one percent knew noted previously, perinatal studies suggest a reduced ben- that their partner was infected with HIV. Eighty-eight efit in PEP after 48 hours, animal studies with SIV indi- percent took zidovudine and lamivudine, and only 3% cate PEP must be begun within 24 to 36 hours postexpo- took a protease inhibitor, typically nelfinavir. Eighty sure, and cellular studies of SIV and HIV show that the percent completed 28 days of treatment. Also from San window period to T-cell infection may be up to 72 hours.
Francisco, Roland et al48 reported that of 401 people The optimal timing for PEP is unknown, but these obser- receiving nonoccupational PEP, 4 displayed HIV serocon- vations indicate that the sooner chemoprophylaxis with version within 6 months of receiving PEP. Each of these 4 antiretroviral medications is begun after an HIV expo- persons engaged in high-risk sexual activities during this Kwong et al,49 from Boston’s Fenway Community N O N O C C U P A T I O N A L P O S T E X P O S U R E Health Center, have treated more than 60 persons with P R O P H Y L A X I S I N D I C A T I O N S PEP since 1997. Most of their patients requested PEP aftermale-male sexual exposures, the majority received 2 There are no clearly accepted indications for PEP after nucleoside reductase transcription inhibitors (NRTIs) nonoccupational HIV exposures. Katz and Gerberding28 O C T O B E R 2 0 0 0
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recommend prescribing PEP if (1) an HIV exposure is at N O N O C C U P A T I O N A L H I V P R O P H Y L A X I S high risk, such as unprotected anal or vaginal intercourse and receptive fellatio with ejaculation; (2) the patient’spartner is known to be infected with HIV or in an HIV risk The optimal regimen of nonoccupational HIV PEP is un- group (eg, men who have sex with men, injection drug known. The recommendations of Katz and Gerberding,27,28 users, and commercial sex workers); (3) the exposure is with some modifications, are presented in Table 1. Other isolated (not part of a distinctive pattern) or the patient regimens are possible and may or may not be more effec- commits to safer sexual practices; and (4) the exposure tive. The PHS does not make specific medication propos- occurred within the previous 72 hours.
als but advises that physicians prescribing PEP should do For nonoccupational HIV PEP, the PHS recommends so in consultation with an expert in the use of antiretrovi- considering (1) the risk of HIV transmission, such as HIV status of the source; (2) the type and risk assessment of Multiple studies have demonstrated a greater reduc- the exposure (eg, unprotected sex, condom breakage, tion in HIV viral load by using various combinations of sexual acts performed, and sharing of injection drug para- antiretrovirals over monotherapy.66 The NRTIs zidovu- phernalia); and (3) any factors that might modify the risk dine and lamivudine are consistently preferred as first- from the exposure (eg, vaginal or anal tears or bleeding, line treatment in HIV infection and are frequently used in ulcers, presence of STDs, and bleaching of syringes).12 prophylactic regimens.14-19,25-28 For occupational HIV The PHS also advises that PEP after nonoccupational exposures, the PHS advocates using zidovudine and lami- exposures may be most effective within 1 to 2 hours of vudine on the basis of its greater antiretroviral activity exposure and no later than 24 to 36 hours but adds that the “interval during which therapy can be beneficial for The utility of protease inhibitors in HIV prophylaxis humans is unknown.”12 In their occupational PEP recom- is of unknown effectiveness. Protease inhibitors are ex- mendations, but not in their nonoccupational PEP state- tremely effective in combination with NRTIs in reducing ment, the PHS states that “Initiating therapy after a longer HIV viral load in persons infected with HIV.66 The PHS interval (eg, 1 to 2 weeks) may be considered for expo- currently suggests their use in occupational HIV expo- sures that represent an increased risk for transmission; sures when there is an increased risk of HIV transmis- even if infection is not prevented, early treatment of acute sion (eg, larger volumes of blood in the exposure, higher HIV infection may be beneficial.”19 Lurie et al52 advise HIV viral loads from the source, or both).19 Katz and that ethical, practical, and community factors, such as Gerberding27,28 prescribe protease inhibitors when the cost, expected compliance, and HIV prevalence, may source has a known high HIV viral load, such as in have a bearing on prescribing PEP and should be consid- advanced AIDS, or when he or she is or has been treated with NRTIs. Bamberger et al25 only recommend protease If the true risk of seroconverting after a particular HIV inhibitors after sexual assault when the assailant is exposure were known, patients could be adequately infected with HIV resistant to NRTIs.
selected for PEP. Several studies have attempted to quan- Despite the recent success of nevirapine in reducing tify the risk of HIV transmission from various routes.53-65 perinatal HIV transmission, nonnucleoside reverse tran- The quoted risks may not be reliable; the ranges are quite scriptase inhibitors (NNRTIs) are not currently recom- broad, the populations observed differ, and the methods mended in a PEP regimen. NNRTIs are an attractive con- of assessing the risks (eg, per-person versus per-contact) sideration for PEP, however, given their potent activity vary. Furthermore, multiple host factors, such as circum- early in HIV infection.50 However, resistance to NNRTIs cision, concurrent infections, and genetic variations of develops rapidly, especially when used alone.50,67-70 cellular receptors, and source factors, such as stage of Resistant HIV strains can develop and overwhelm the viral infectivity (eg, viral load) and use of antiretroviral medi- population within 28 days after beginning NNRTIs.71 cations, may change the risks dramatically for a particular The PHS considers the toxicity of NNRTIs and their rapid exposure.63 Nonetheless, some of the data available sug- loss of effectiveness to be major detractors for their use in gest a 5 to 30 in 1,000 risk for unprotected receptive anal intercourse per sexual contact64 and a 0.5 to 1.5 in 1,000 Two approaches to providing PEP are possible. First, risk for receptive vaginal intercourse per sexual contact.53 as shown in Table 1, exposure history can dictate the need Needlestick injuries may confer a 3.2 in 1,000 risk of for PEP and the medications required.27,28 Given that vital exposure history elements, such as the source’s HIV A N N A L S O F E M E R G E N C Y M E D I C I N E 3 6 : 4 O C T O B E R 2 0 0 0
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status, may be unknown at initial presentation, the ap- combination therapy in their suggested regimens for proach proposed in Table 2 may be more appropriate for occupational PEP. The value of initial triple-drug therapy the ED. In this proposed regimen, all persons possibly is not universally accepted. Bamberger et al,25 Katz and exposed to HIV are provided with an initial 3-drug antivi- Gerberding,27,28 and the PHS do not promote this alterna- ral treatment. During follow-up, preferably within 72 tive regimen because of concerns over the cost, toxicity, hours, the regimen can be modified if indicated.
and lack of data supporting the use of protease inhibitors.
The regimen proposed in Table 2 is advised by the New These concerns may not be relevant for an initial short York State Department of Health for HIV PEP after sexual course prescribed from the ED because a 72-hour supply assault.26 Manion and Hirsch66 also advocated triple- of protease inhibitors adds only about $50 (retail) to theregimen, and no long-term adverse sequelae should resultfrom short-term use.
The PHS established the National Nonoccupational HIV Postexposure Prophylaxis Registry for reporting patient data from health care providers who consider, prescribe, orreceive requests for nonoccupational PEP.12,72 This registry Exposure to person or persons known to be HIV infected:
provides a toll-free telephone number (877-HIV-1PEP), fax •If medication regimen of source patient is unknown, prescribe:
(877-HIV-7PEP), Internet site (http://www.hivpepreg- istry.org), and mailing address (HIV PEP Registry, 44 Indinavir (Crixivan) 800 mg PO q8h or nelfinavir (Viracept) 1,250 mg PO bid or Farnsworth Street, 7th Floor, Boston, MA 02217). Health Combivir 1 tablet PO bid may be substituted for zidovudine and lamivudine care providers are strongly encouraged to contact the reg- •If medication regimen of source patient is known:
istry so that more information on this topic can be gathered.
Prescribe 2 NRTIs and 1 protease inhibitor that are different from the source patient’s regimen. Possible substitutes for zidovudine or lamivudine: S P E C I A L C O N S I D E R A T I O N S Stavudine (d4T/Zerit) 40 mg PO bid for >60 kg, 30 mg for <60 kgDidanosine (ddI/Videx) 200 mg PO bid for >60 kg, 125 mg for <60 kg For occupational exposures to HIV in the pregnant Exception: Zidovudine and stavudine should not be used together
Exposure to person or persons of unknown HIV status but who probably
patient, the PHS recommends that “the evaluation of risk have high HIV risk factors*:
and need for PEP should be approached as with any other [health care worker] who has had an HIV exposure” but Treat as if an exposure to a known HIV-infected person with an unknown medication regimen, as above.
that the risks and benefits of PEP to her and her fetus should •Exposures that might result in HIV infection‡: be discussed.19 For nonoccupational exposures, the PHS Treat with zidovudine and lamuvidine without a protease inhibitor.
advises that the need for PEP “be evaluated before anti- Exposure to person or persons of unknown HIV status but who probably
have low HIV risk factors:
retroviral therapy is initiated in consultation with physi- •Significant exposures: Treat with zidovudine and lamivudine. A protease cians expert in the care of HIV infection during preg- inhibitor could be added if the patient requests it, if the provider believes that the nancy.”12 However, knowledge of nonoccupational PEP exposure history is unclear, other exposures also occurred, or if other factors relating to exposure history or HIV status are compelling.
in pregnancy is limited. Dr. Mitchell Katz of the San Fran- •Exposures that might result in HIV infection: cisco Department of Public Health and Dr. Kenneth Mayer Treat with zidovudine and lamivudine without a protease inhibitor.
of the Fenway Community Health Center acknowledge Additional caveats:
•PEP should not be provided to patients whose exposure history has no known that no pregnant woman has requested PEP from their centers (personal communications, August 1999).
•PEP should not be given to persons already infected with HIV.
•Providers may consider PEP for any patient who appears to be at risk after an HIV exposure but whose circumstances are not delineated in the above categories.
Providers are reminded that PEP should only be prescribed as part of a comprehensive pro-
gram to reduce future HIV risk–related behaviors. Multiple prescription requests for PEP
should be strongly discouraged and must be averted through risk reduction counseling.
*High HIV risk factors: trading sex for drugs or money, intravenous drug use, unprotected anal
or vaginal intercourse with persons with HIV risk factors.
†Significant exposures include the following: anal or vaginal intercourse without a condom or with condom breakage; exposure to semen or blood onto mucosal or nonintact surfaces; and Indinavir (Crixivan) 800 mg PO or nelfinavir (Viracept) 750 mg PO tid or 1,250 mg ‡Examples of exposures that might result in HIV infection are as follows: cunnilingus, fellatio, semen or blood on healing skin wounds.
Combivir 1 tablet PO bid may be substituted for zidovudine and lamivudine O C T O B E R 2 0 0 0
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Much of the data to date support the contention that type, nature, components of the exposure as discussed antiretroviral therapy is probably safe during pregnancy.
previously, and possible indications for PEP. Treatment Connor et al40 did not observe an increase in perinatal regimens outlined in Table 1 or 2 may be considered for maternal or fetal morbidity or mortality with zidovudine this protocol. If possible, baseline laboratory testing, use in their study. In a retrospective review of protease including a CBC count, chemistry, liver enzyme, and HIV inhibitors given during all 3 trimesters, Morris et al73 testing, could be conducted or could be deferred to an noted no adverse effects on the fetus or the pregnancy outpatient visit within 72 hours. A pregnancy test should attributable to protease inhibitors. The Antiretroviral Pregnancy Registry has not found an increase in the num- A starter pack of PEP medications of at least a 72-hour ber of birth defects in live infants exposed to any anti- supply may be dispensed from the ED. One group, The retroviral-containing regimen in the first trimester among British Columbia Centre for Excellence in HIV-AIDS, pro- vides a free starter kit of 5 days of zidovudine and lamivu- The PHS recently revised their 1998 recommendations on the use of antiretroviral medications in HIV-infected The management of nonoccupational PEP for pregnant pregnant women. These guidelines provide a summary of and pediatric patients may be challenging to ED providers some of the most recent data on antiretroviral regimens, given the limited knowledge of PEP for these populations.
efficacy, and adverse effects.75 The guidelines are frequently ED protocols should be constructed by using the avail- updated and are available on the HIV/AIDS Treatment able data to date in case such patients present. Pregnant Information Service Web site (http://www.hivatis.org).76 patients should be informed of the unknown risks and Although there has been extensive work with anti- benefits of PEP to themselves and their fetuses, the possi- retrovirals in HIV infection in children,77 there are no bility that some of the side effects of antiretroviral medi- known studies on nonoccupational PEP in the pediatric cations may be enhanced during pregnancy, and that they population and no guidelines for its use. Experience with are above all free to choose or decline therapy. pediatric PEP at PEP centers has been limited (Mitchell H.
Patients who receive PEP should be referred to physi- Katz and Kenneth H. Mayer, personal communications, cians knowledgeable in the management of antiretroviral August 1999). The PHS recommends that for patients medications and PEP within 72 hours. As per the recom- younger than 16 years, “clinicians expert in the specific mendations of the PHS,12 Katz and Gerberding,27,28 medical needs, consent issues, and other factors (eg, sex- Bamberger et al,25 and others, follow-up should consist ual abuse) involved in their treatment, including the use of the following: (1) reevaluation of the patient’s need for of antiretroviral medicines for children and adolescents PEP, (2) as-required modification of the patient’s current be involved before therapy is initiated.”12 A summary ofdosing adjustments for nonoccupational PEP medica-tions is provided in Table 3.
Pediatric dosing for PEP medications. E M E R G E N C Y D E P A R T M E N T C O N S I D E R A T I O N S The ED may be the logical place to begin nonoccupational HIV PEP. Most EDs in the United States are open 24 hours 180 mg/m2 PO q6h, ages 3 mo–12 y. Adult dosing after a day and possess providers trained in medical and social concerns related to sexual assault, STDs, and other mat- 4 mg/kg PO bid, 3 mo–16 y. Oral solution available.66 ters relevant to PEP. Persons possibly exposed to HIV Currently not recommended for pediatric use (<16 y).
could receive their initial evaluation and treatment rapidly Substitute nelfinavir (Viracept) for indinavir.68 Adult in the ED, and appropriate follow-up can be coordinated.
Because animal and human studies of SIV and HIV in- 20–30 mg/kg per dose PO tid, ages 2–13 y. Use adult dosing for >13 y. Powder form is available. Powder may dicate that antiretroviral medication should be initiated be mixed with milk, soy, or water but not juice.69 quickly after an exposure, EDs should consider develop- Didanosine (dDI/Videx) 120 mg/m2 PO bid. A powdered solution, with different ing triage, evaluation, and treatment protocols that re- options, is also available. Consult the prescribing information for didanosine for these regimens.70 duce “door-to-drug” time. Triage protocols should focus 1 mg/kg per dose PO for <30 kg. Use adult dosages for on identifying persons who may have had an HIV expo- sure. Evaluation should include an assessment of the A N N A L S O F E M E R G E N C Y M E D I C I N E 3 6 : 4 O C T O B E R 2 0 0 0
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PEP regimen, (3) HIV testing, (4) appropriate evaluation Patients who receive PEP must also be informed that a and treatment of the results of laboratory testing con- month’s supply of zidovudine, lamivudine, and indinavir, ducted in the ED, (5) HIV-STD counseling, (6) baseline for example, costs approximately $1,000.12,27,28 Patients and follow-up laboratory testing for monitoring of PEP may have to bear the cost of their medications and treat- medications, (7) further counseling and instruction ments, unless local arrangements exist or insurance plans regarding PEP, and (8) attention to special situations (eg, pay for it. In the clinic setting, Martin et al47 report suc- cessful billing of PEP to third-party payers.
Patients are ideally followed weekly for at least 4 weeks In summary, the provision of nonoccupational PEP is to monitor their regimen and side effects, encourage their controversial. Although indirect evidence supports its use, compliance, and counsel them regarding safer sexual its efficacy is unknown, the initial cost is high, and several practices. The PHS recommends that HIV testing should aspects of it are unclear. However, PEP may be the only be conducted at baseline, 4 weeks, 3 months, and at least chance of averting an HIV infection in persons possibly 6 months with appropriate treatment for those in whom exposed from nonoccupational sources. As knowledge of nonoccupational PEP expands in the general population, Critical to the success of PEP are clear instructions and requests for it will undoubtedly rise, and the ED will be a dialogue between the patient and the ED physician. An likely destination for persons seeking PEP. EDs should now adaptation of the PHS12 and Katz and Gerberding’s27,28 be proactive in establishing protocols for nonoccupational recommendations are presented here. First of all, patients PEP in anticipation of these requests. As a first provider in should be informed that PEP has unknown efficacy and public health care, the ED may produce an important effect may not prevent HIV infection. Second, patients must on the reduction of HIV through this measure.
understand that PEP does not prevent further HIV infec-tion and that HIV prevention through safer sexual prac- I thank the following for their assistance and advice in the creation of this review: Robert tices (and/or cessation of intravenous drug use) is essen- Colligan, MD, Jeff Jacobson, MD, Sheldon Jacobson, MD, Andy Jagoda, MD, Mitchell tial. The physician should also instruct the patient on the Katz, MD, Marla Keller, MD, Kenneth Mayer, MD, Barbara Merchant, Edwin Meyer, LynneRichardson, MD, Sandra Sallustio, MD, and Oren Townsend, MD.
types and possibilities of adverse effects (Table 4), thenecessity for compliance with 28 days of PEP and strictfollow-up, as well as the need to attend to other medical and social matters (eg, sexual assault) that were evaluated Joint United Nations Programme on HIV/AIDS and The World Health Organization. Report on the Global HIV/AIDS Epidemic—December 1999. Geneva, Switzerland: United NationsProgramme on HIV/AIDS; December 1999.
Centers for Disease Control and Prevention. National Center for HIV, STD and TB prevention Web site. Available at: http://www.cdc.gov/hiv/hivinfo.htm. Accessed April 4, 2000.
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Van de Ven P, Prestage G, French J, et al. Increase in unprotected anal intercourse with casual partners among Sydney gay men in 1996-98. Aust N Z J Public Health. 1998;22:814-818.
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after meals. Must drink at least 48 oz of water per day.
Rifampin, astemizole, terfenadine, cisapride, midazolam, San Francisco Chronicle. October 14, 1997:A2.
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