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Case 2: Discussion

The case presented addresses four critical issues regarding postexposure prophylaxis (PEP): (1) initial management of an exposure, (2) timing of PEP, (3) basic versus expanded PEP regimens, and (4) testing and follow-up of the health care worker. The recommendations herein are based on the 2005 U.S. Public Health Service guidelines for the management of occupational exposures[1].

Initial Management of an Exposure

Initial management of a potential exposure to HIV should include immediate decontamination of the region involved in the exposure (washing with soap and water for percutaneous injuries, saline irrigation for splashes to the eye) and immediate evaluation for possible PEP[1]. Subsequent steps should include reporting the incident to the appropriate health care facility supervisor, performing baseline testing on the exposed health care worker for the blood-borne pathogen(s) in question, and, if PEP is initiated, baseline chemistry and hematology testing. These steps, however, should not interfere with timely administration of PEP medications. Because many antiretroviral agents, especially the protease inhibitors, have potential interactions with other medications, it is important to obtain a thorough medical history from the health care worker, including a list of their current medications. In the case presented, the medical resident should have received prompt evaluation rather than waiting 24 hours before going to employee health. During the initial evaluation of the exposure, it is important to determine whether initial management decisions should involve expert consultation; the 2005 U.S. Public Health Service guidelines outline specific circumstances for which expert consultation is advised (Figure 1)[1]. The initial assessment of the exposure should also include evaluation for the potential risk of transmission of other blood-borne pathogens, such as hepatitis B virus or hepatitis C virus. The following discussion, however, will only address the evaluation and management of occupational exposure to HIV.

Timing of PEP

How long after the exposure can PEP still provide significant benefit? This critical question arises often in the setting of PEP, but unfortunately, the answer to this question is not known with certainty. Animal models of PEP have suggested that the efficacy of PEP wanes with time following the exposure. Specifically, these data suggest that PEP is substantially less effective beyond 24-36 hours after the exposure and may be ineffective beyond 48 hours[5]. Similar studies involving human subjects have not been performed for obvious ethical reasons. A review of recent cases in which PEP failed to prevent HIV transmission in health care personnel did not establish a cut-off time, since most of these individuals received PEP within a few hours of their exposure[1]. Similarly, a retrospective case-control study published in 1997 that demonstrated the efficacy of zidovudine (Retrovir) PEP in reducing the risk of seroconversion did not identify a cut-off time for PEP efficacy[6]. An interesting case report published in 2000 suggested that PEP may have some efficacy in humans even if administered beyond 48 hours[7]. Taking all available data into consideration, the U.S. Public Health Service Guidelines recommend prompt initiation of PEP, but does not rule out consideration of PEP even if more than 36 hours have elapsed since the exposure[1]. If greater than 24-36 hours have elapsed since the exposure, expert consultation is recommended[1].

Basic and Expanded Regimens

The 2005 U.S. Public Health Service guidelines for the management of occupational exposures to HIV classify PEP regimens as either "basic" or "expanded" regimens (Figure 2Preferred Basic Regimens, Alternative Basic Regimens Preferred Expanded Regimen, Alternative Expanded Regimens Regimens Not Recommended, Regimens Recommended Only with Expert Consultation Acknowledgments)[1]. Basic regimens consist of two nucleoside reverse transcriptase inhibitors (NRTIs), or one NRTI plus a nucleotide reverse transcriptase inhibitor (NtRTI). An expanded regimen consists of the basic regimen plus one or more additional antiretroviral agent(s). The basic regimens are simple to take, and although side effects may occur, they can typically be managed in a way that allows the exposed health care worker to complete the PEP course. Expanded regimens provide greater potency, but there is no direct evidence that expanded PEP regimens are more effective in this setting than basic regimens, and expanded regimens typically involve a higher pill burden and more potential for adverse effects[8]. In addition, these guidelines classify regimens as either "preferred" or "alternative", as well as listing regimens that should not be given and those that require expert consultation (Figure 2Preferred Basic Regimens, Alternative Basic Regimens Preferred Expanded Regimen, Alternative Expanded Regimens Regimens Not Recommended, Regimens Recommended Only with Expert Consultation Acknowledgments).

Selection of Basic Versus Expanded Regimen

The selection of a basic versus an expanded regimen depends on characteristics of both the exposure and the source patient (Figure 3)[1]. Percutaneous exposures are classified as either less severe (solid needle, superficial injury) or more severe (large-bore hollow needle, deep puncture, visible blood on device, or needle used in patient's artery or vein). Mucocutaneous exposures are classified as either high volume (a major splash) or low volume (a few drops). The HIV-infected source patient is classified as either class 1 (asymptomatic or HIV RNA less than 1500 copies/ml) or class 2 (symptomatic HIV infection, AIDS, acute seroconversion, or known HIV RNA greater than 1500 copies/ml). For percutaneous exposures involving an HIV-infected source patient, the 2005 U.S. Public Health Service guidelines recommend using a basic PEP regimen if the exposure type is considered less severe and the source infection status is classified as low risk (HIV class 1) (Figure 4). For percutaneous exposures involving either a more severe exposure type or a high-risk source patient (HIV class 2), the 2005 U.S. Public Health Service PEP guidelines recommend using an expanded regimen.

Selection of Antiretroviral Medications

For persons with established HIV infection, dramatic advances in the field of antiretroviral therapy have occurred, and thus served as the catalyst for the 2005 U.S. Public Health Service revised guidelines for the management of occupational exposures to HIV (Figure 2Preferred Basic Regimens, Alternative Basic Regimens Preferred Expanded Regimen, Alternative Expanded Regimens Regimens Not Recommended, Regimens Recommended Only with Expert Consultation Acknowledgments)[1]. These 2005 guidelines include the addition of tenofovir DF (Viread) and emtricitabine (Emtriva) as preferred agents in the basic regimen. Tenofovir DF has several features that make it attractive as part of a PEP regimen, including excellent potency, a low rate of adverse effects, and convenient once daily dosing. In addition, it was effective in preventing SIV in monkeys when administered after they were exposed to SIV[3,5]. The 2005 guidelines recommend using the protease inhibitor lopinavir-ritonavir (Kaletra) as the preferred drug for the expanded regimen, primarily because of its excellent potency and reasonable tolerability. These 2005 guidelines for postexposure prophylaxis are now more consistent with the DHHS recommendations for the use of antiretroviral agents in persons with known HIV infection[10]. In the 2001 Guidelines, the previously used expanded regimens typically included either nelfinavir (Viracept) or indinavir (Crixivan)[9]. The use of indinavir in this setting gradually declined because of its complex dosing schedule and poor tolerance. Although nelfinavir replaced the use of indinavir in many centers, this drug has moderate potency, it often has reduced activity against protease inhibitor-resistant HIV, and frequently causes diarrhea. Further, in December 2007, following the discovery that nelfinavir manufactured in Europe contained high levels of the teratogen ethyl methane meslate (EMS), the U.S. Public Health Service issued a recommendation that pregnant women who need to begin antiretroviral therapy for PEP should not be offerred a regiment that contains nelfinavir[11].

Exposure Involving a Patient with Highly-Resistant HIV

For any health care worker who suffers an occupational exposure that involves a patient with highly-resistant HIV, expert consultation is strongly recommended. Prompt expert consultation is particularly important given the availability of newer medications, such as enfuvirtide (Fuzeon), darunavir (Prezista), raltegravir (Isentress), and etravirine, that may have activity against highly-resistant HIV[10]. Appropriate use of these newer medications in this setting should ideally be guided by recent resistance tests from the HIV-infected source patient. Obtaining resistance testing on the HIV-infected patient at the time of the exposure would not provide useful information in this setting, since it would take weeks to obtain the result from a genotype or phenotype test.

Duration of PEP

For exposures involving a known HIV-infected source patient, the exposed health care worker should take a 28-day course of PEP, regardless of which regimen is selected[1]. Animal studies suggest better efficacy with 28 days of PEP when compared with shorter duration of therapy (Figure 5)[5]. For mucocutaneous exposures, the 2005 U.S. Public Health Service PEP guidelines recommend using an expanded regimen if the exposure involves both a high-volume exposure and a high-risk source patient; basic regimens are recommended for other mucocutaneous exposures (Figure 6). The recommended duration of PEP for a mucocutaneous exposure is also 28 days.

Adverse Effects and Antiretroviral PEP Medications

The management of PEP medication adverse effects plays a very important role in helping the health care provider complete the full 28-day course of PEP therapy. Several studies have documented high rates of medication-related adverse effects among health care workers taking PEP, with nausea and fatigue being the most common symptoms[8,12]. Both can be side effects of zidovudine, and can sometimes be relieved with the substitution of an alternative agent, such as tenofovir DF. Several medications are not recommended for use either because of potential severe toxicity or poor efficacy. Multiple cases of severe hepatotoxicity associated with use of nevirapine (Viramune) for PEP have been reported[13]. Since patients with high CD4 counts (including HIV-negative individuals) appear to be at greater risk for nevirapine-associated hepatotoxicity, this drug is not recommended for use in PEP. Efavirenz (Sustiva) is much less likely to cause hepatotoxicity than nevirapine, but is infrequently used in this setting because of the neuropsychiatric side effects that often occur during the first weeks of therapy. The use of abacavir (Ziagen), or any combination drug that contains abacavir (Epzicom, Trizivir), is not recommended because of its potential to cause a hypersensitivity reaction. Side effects frequently occur with protease inhibitors, most often nausea and/or diarrhea. Lopinavir-ritonavir can cause nausea and/or diarrhea, though the latter is less common than with nelfinavir. The ritonavir (Norvir) component of many of the boosted protease-inhibitor regimens can cause significant drug-drug interactions. Atazanavir (Reyataz) is generally well tolerated, though it commonly causes indirect hyperbilirubinemia, which occasionally results in overt jaundice or scleral icterus. Indinavir is associated with nephrolithiasis, and clinically insignificant indirect hyperbilirubinemia. For health care workers who are pregnant (or possibly pregnant), efavirenz or nelfinavir should not be used.

Laboratory Testing and the Health Care Worker

Follow-up testing and evaluation of a health care worker following an exposure is recommended regardless of whether PEP is initiated (Figure 7). HIV antibody testing should be performed at baseline and at 6 weeks, 3 months, and 6 months postexposure; additional follow-up testing at 12 months is recommended for health care workers who contract HCV from a source patient co-infected with HIV and HCV. Because of the potential for false-positive results, HIV RNA testing is not recommended as a means to screen for seroconversion, unless the health care worker develops clinical symptoms that suggest acute HIV infection. At the time of this writing, documented failure with the use of combination antiretroviral therapy for postexposure prophylaxis has been reported in 6 individuals, with all but one of the cases involving a source patient who was receiving antiretroviral therapy[1].If PEP is administered, laboratory testing (CBC, renal panel, and hepatic transaminase levels) to monitor for toxicity should be performed at baseline, after two weeks of PEP, and as indicated for evaluation of signs and symptoms of potential medication toxicity.

Counseling the Health Care Worker

Counseling of the exposed health care worker is critical following an exposure. The psychological impact of an exposure can be significant, and professional help may be necessary regardless of the level of risk involved. In addition, counseling and management of PEP medication adverse effects plays a very important role in helping the health care provider complete the full 28-day course of PEP therapy. Measures to prevent secondary transmission of HIV should also be recommended during the follow-up period, particularly for the first 12 weeks following the exposure. These measures include sexual abstinence or barrier protection, and refraining from donating blood or other bodily fluids. Cessation of breast-feeding may be advisable for a woman who suffers a high-risk exposure and thus could transmit HIV to her infant. Health care providers are advised that they may continue working in their normal capacity during the follow-up period. If a health care worker were to acquire HIV from an occupational exposure, expert consultation would be indicated to determine the advisability of continuing work in the same capacity. Prompt evaluation of any acute illness that develops in the follow-up period should be encouraged, both to rule out possible acute HIV seroconversion and to assess the possibility of a serious adverse medication reaction[1].

Case Summary and PEP Recommendations

The case presented involved a high-risk percutaneous exposure (the injury involved a hollow-bore needle that had been in a vein) and a high-risk source patient (the patient had been diagnosed with AIDS). Accordingly, the 2005 U.S. Public Health Service PEP guidelines would recommend a 28-day course of an expanded, 3-drug PEP regimen for the exposed health care worker. In this case, suspected antiretroviral resistance did not play a role, since the source patient had not yet taken antiretroviral therapy. If, however, antiretroviral resistance is suspected in a source patient, the PEP regimen for the exposed health care worker should ideally consist of agents to which the source patient's virus is likely susceptible. Attempts to gather information concerning the likelihood of resistance in the source patient should not delay the timely administration of PEP to the health care worker, since the PEP regimen can be modified after PEP has been initiated. Expert consultation is advised if antiretroviral resistance is suspected. In addition, expert consultation should be obtained for any pregnant or breast-feeding woman for whom PEP is indicated. Management of exposures involving either an unknown source or a source patient whose HIV serostatus is not known at the time of the exposure is discussed in Case 3 in this Postexposure Prophylaxis section.

Resources for Expert Consultation

National Clinicians' Postexposure Prophylaxis Hotline (PEPline)
Phone: (888) 448-4911
Web Site: http://www.ucsf.edu/hivcntr/PEPline/index.html
Description: Immediate expert consultation regarding occupational exposures available to clinicians 24 hours/day, 7 days/week. Operated by the National HIV/AIDS Clinicians' Consultation Center (NCCC) at San Francisco General Hospital and supported by the HRSA Ryan White CARE Act, HIV/AIDS Bureau, AIDS Education & Training Centers, and the Centers for Disease Control & Prevention (CDC).

Hepatitis Hotline
Phone: (888) 443-7232
Web Site: http://www.cdc.gov/hepatitis/
Description: Information regarding hepatitis viruses, including hepatitis B and hepatitis C viruses.

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    Figure 1. Situations for Which Expert Consultation* is Advised

    *Expert Consultation either with local experts or by contacting the National Clinicians' Post- Exposure Prophylaxis Hotline (PEPline), telephone 888-448-4911.

    Adapted from Centers for Disease Control & Prevention. Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis. MMWR. 2005;54(No. RR-9):1-17.


    Figure 1
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    Figure 2: Recommended Postexposure Prophylaxis Regimens<br /> Image 1. Preferred Basic Regimens, Alternative Basic Regimens.
    Figure 2

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    Figure 3. Characteristics of High-Risk Exposures

    Adapted from Centers for Disease Control & Prevention. Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis. MMWR. 2005;54(No. RR-9):1-17.


    Figure 3
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    Figure 4. HIV PEP for Percutaneous Exposure based on Exposure Type and Source Infection Status

    Adapted from Centers for Disease Control & Prevention. Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis. MMWR. 2005;54(No. RR-9):1-17.


    Figure 4
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    Figure 5. Effect of Tenofovir DF as Postexposure Prophylaxis in Macaques Inoculated with SIV

    This study involved 24 cynomolgus macaques who were intravenously inoculated with either simian immunodeficiency virus (SIV) or a saline placebo. All animals were then followed for 46 weeks. Animals received either placebo or tenofovir DF subcutaneously for either 3, 10, or 28 days. The tenofovir DF was started 24, 48, or 72 hours after the SIV inoculation. The figure shows SIV seroconversion rate of macaques who started tenofovir DF 24 hours after inoculation of SIV). All controls, as expected, had seroconversion (data not shown). Based on data from Tsai CC, Emau P, Follis KE, et al. Effectiveness of postinoculation (R)-9-(2-phosphonylmethoxypropyl) adenine treatment for prevention of persistent simian immunodeficiency virus SIVmne infection depends critically on timing of initiation and duration of treatment. J Virol 1998; 72:4265-73.


    Figure 5
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    Figure 6. HIV PEP for Mucocutaneous Exposure based on Exposure Type and Source Infection Status

    Adapted from Centers for Disease Control & Prevention. Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis. MMWR. 2005;54(No. RR-9):1-17.


    Figure 6
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    Figure 7. Recommendations for Laboratory Monitoring following Occupational Exposure to HIV in Person Who Receives PEP

    *HIV antibody testing should be performed at 12 months if the health care worker acquires hepatitis C virus from the occupational exposure

    ^Only necessary to obtain these studies for health care workers who will receive postexposure prophylaxis to monitor for antiretroviral therapy toxicity

    #For women of reproductive age, especially if they will receive postexposure prophylaxis

    Adapted from Centers for Disease Control & Prevention. Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis. MMWR. 2005;54(No. RR-9):1-17.


    Figure 7