COMMENTARY

HIV Prophylaxis Following Occupational Exposure: Guideline and Commentary

Barry S. Zingman, MD

Disclosures

January 30, 2013

In This Article

Recommended PEP Regimen

Recommendations:

The preferred PEP regimen is tenofovir + emtricitabine plus raltegravir (see Table 3 for dosing and Appendix A for description of each drug). Zidovudine is no longer recommended in the preferred PEP regimen. The first dose should be given as soon as possible after exposure, ideally within 2 hours. The recommended duration of PEP is 28 days. (Lamivudine may be substituted for emtricitabine.)

If the source patient is known to be HIV-infected and information is immediately available regarding past and present ART experience, current level of viral suppression, or resistance profile, the treating clinician, in consultation with a clinician experienced in managing PEP, should individualize the PEP regimen to maximize potential effectiveness against the exposed HIV strain. (AII) Initiation of the first dose and continuation of PEP should never be delayed while awaiting this information. (AII) If indicated, the regimen can be changed when more information becomes available.

Table 4 and Table 5 list recommended alternative PEP regimens that should be used in the setting of potential HIV resistance, toxicity risks, clinician preference, or constraints on the availability of particular agents. (AII)

Clinicians should switch exposed workers to an alternative regimen if the initial or subsequent PEP regimen is not well tolerated (see Appendix A for potential adverse events).

Treating clinicians should consult with a clinician experienced in managing PEP when alternative agents are prescribed or if there is doubt as to whether PEP should be continued after the first dose.

The prescribing clinician should ensure that the exposed worker has access to the full 28-day recommended course of antiretroviral medications (AIII) and is appropriately monitored for toxicities during the treatment (see the section above entitled Responsibilities of Employers and the section below entitled Follow-Up and Monitoring of the Exposed Worker Following Occupational Exposure).

Treating clinicians who do not have access to experienced HIV clinicians should call the National Clinicians' Consultation Center PEP Line at 1-888-448-4911. When using the PEP Line, providers from New York State should identify themselves as such.

Table 3. Recommended Regimen for HIV PEP Following Occupational Exposurea

Tenofovirb 300 mg PO qd + Emtricitabineb,c 200 mg PO qd
Plus
Raltegravird 400 mg PO bid

a When the source is known to be HIV-infected, past and current ART experience, viral load data, and genotypic or phenotypic resistance data (if available) may indicate the use of an alternative PEP regimen. Consult with a clinician experienced in managing PEP. See Tables 4 and 5. b The dosing of tenofovir and emtricitabine/lamivudine should be adjusted in patients with baseline creatinine clearance < 50 mL/min (see Appendix A for dosing recommendations). Tenofovir should be used with caution in exposed workers with renal insufficiency or who are taking concomitant nephrotoxic medications. Fixed-dose combinations should not be used in patients who need dose adjustment due to renal failure. c Lamivudine 300 mg PO qd may be substituted for emtricitabine. However, a fixed-dose combination is available when tenofovir is used with emtricitabine (Truvada 1 PO qd). d The dosing of raltegravir should be adjusted when co-administered with rifampin (see Appendix A for dosing recommendations).

Duration of PEP Regimen

Recommendations:

  • When the source patient is confirmed to be HIV-negative, clinicians should discontinue the PEP regimen before completion (see the section above entitled HIV Testing of the Source Patient).

  • If the exposed worker's baseline test shows evidence of HIV infection acquired before the exposure and initiation of PEP, decisions regarding continuation of ART should be based on current treatment guidelines (see Antiretroviral Therapy). However, the PEP regimen should not be discontinued until the positive result is repeated with a confirmatory assay.

  • If the exposed worker's week 4 post-exposure HIV test results are indeterminate or the exposed worker has symptoms suggestive of acute HIV infection, clinicians should continue ART beyond 28 days until a definitive diagnosis is established.

The recommended 28-day treatment duration is based on limited animal data and expert opinion.[19] When the source patient is confirmed to be HIV-negative, the PEP regimen should be discontinued before completion (see the section above entitled HIV Testing of the Source Patient).

If at any time acute HIV infection is suspected, consultation with a clinician experienced in managing acute HIV infection should occur immediately (also see Diagnosis and Management of Acute HIV Infection). Clinicians who do not have access to experienced HIV clinicians should call the National Clinicians' Consultation Center PEP Line at 1-888-448-4911. When using the PEP Line, providers from New York State should identify themselves as such.

Rationale for Recommended PEP Regimen

This Committee now recommends tenofovir plus emtricitabine and raltegravir as the preferred initial PEP regimen because of its excellent tolerability, proven potency in established HIV infection, and ease of administration. (Lamivudine may be substituted for emtricitabine.)

The recommended regimen has a favorable side effect profile, fewer potential drug-drug interactions, and an expected efficacy similar to PEP regimens containing zidovudine or protease inhibitors. Studies have shown increased rates of adherence and regimen completion when tenofovir + either emtricitabine or lamivudine have been used as components of the PEP regimen.[20,21] Limited data show similar improved tolerability with tenofovir + emtricitabine plus raltegravir.[22,23] Additionally, tenofovir + emtricitabine has been highly successful in recent studies of pre-exposure prophylaxis.[24,25,26]

This Committee no longer recommends that zidovudine must be included in PEP regimens because it is believed to have no clear advantage in expected efficacy over tenofovir while having significantly higher rates of treatment-limiting side effects. As experience with PEP continues to accumulate, it has become increasingly clear that tolerability is one of the most important factors in selecting a PEP regimen, especially when the source patient is not available for testing and the patient will need to complete the full 28-day course.

Unlike protease inhibitors, which block HIV replication in steps after integration with cellular DNA, all three drugs in the recommended regimen (tenofovir, emtricitabine, raltegravir) act before viral integration with cellular DNA, providing a theoretical advantage in preventing establishment of HIV infection.

Use of a Three-Drug PEP Regimen

Once a decision has been made that a significant risk exposure (see the section above entitled Evaluating the Exposure) has occurred and that PEP is warranted, this Committee recommends a three-drug regimen as the preferred option.

Preferred Alternative PEP Regimens

Recommendations:

  • The preferred alternative PEP regimen is tenofovir + emtricitabine plus ritonavir-boosted darunavir, atazanavir, or fosamprenavir (see Table 4). (Lamivudine may be substituted for emtricitabine.)

  • Clinicians should carefully assess for potential drug interactions between these agents and other medications (including prescription medications and over-the-counter drugs, such as proton pump inhibitors and H2-blockers) that the patient may be taking. See Appendix A for information regarding dosing, adverse effects, and drug interactions.

  • Clinicians should consult a clinician experienced in managing PEP or an occupational health clinician experienced in providing PEP when using alternative PEP regimens (AII). If consultation cannot be immediately obtained, the first dose of the regimen should be given rather than delaying initiation, with consultation occurring as soon as possible thereafter (AII). Clinicians who do not have access to experienced HIV clinicians should call the National Clinicians’ Consultation Center PEP Line at 1-888-448-4911. When using the PEP Line, providers from New York State should identify themselves as such.

The alternative regimens in Table 4 are expected to be less well tolerated than the preferred regimen of tenofovir + emtricitabine plus raltegravir, but significantly better tolerated than regimens containing zidovudine or lopinavir/ritonavir. Efficacy of the preferred alternative regimens is expected to be equivalent to other alternative regimens (see the section below entitled Other Alternative PEP Regimens), unless the source patient's HIV strain is resistant to one or more of the agents.

Table 4. Preferred Alternative PEP Regimens Following Occupational Exposure

Tenofovira 300 mg PO qd + Emtricitabinea,b 200 mg PO qd
Plus
Darunavir 800 mg PO qdc or Atazanavir 300 mg PO qdc or Fosamprenavir 1400 mg PO qdc
and
Ritonavir 100 mg PO qdc

a The dosing of lamivudine/emtricitabine, and tenofovir should be adjusted in patients with baseline creatinine clearance < 50 mL/min (see Appendix A for dosing recommendations). Tenofovir should be used with caution in exposed workers with renal insufficiency or who are taking concomitant nephrotoxic medications. Fixed-dose combinations should not be used in patients who need dose adjustment due to renal failure. b Lamivudine 300 mg PO qd may be substituted for emtricitabine. However, a fixed-dose combination is available when tenofovir is used with emtricitabine (Truvada 1 PO qd). c See Appendix A for dosing recommendations for protease inhibitors in exposed workers with hepatic impairment.

Potential for drug interactions in patients receiving protease inhibitors is increased due to the extensive cytochrome P450 interactions. For example, proton pump inhibitors may adversely affect the absorption of atazanavir. Clinicians should assess for potential interactions before prescribing a PEP regimen.

The following online resources provide information about antiretroviral drug interactions:

Other Alternative PEP Regimens

Other alternative PEP regimens are listed in Table 5 and may be acceptable in certain situations.

Some clinicians continue to favor use of zidovudine in PEP regimens based on the results of a retrospective study supporting the efficacy of the agent[3] and from long-term experience in occupational PEP. Clinicians continuing to prescribe zidovudine in this setting should recognize and inform patients that the drug has significant side effects and that better-tolerated agents are available (see Appendix A for side effects associated with alternative PEP agents).

Some clinicians may favor use of lopinavir/ritonavir due to long-term experience in occupational PEP. It should be recognized that this agent has greater potential for drug interactions and side effects than raltegravir or the preferred protease inhibitors (darunavir, atazanavir, or fosamprenavir; each taken with ritonavir 100 mg daily), with little added efficacy benefit expected. Recent studies have demonstrated decreasing protease inhibitor resistance among HIV strains,[27] suggesting that there may be diminishing benefit to choosing lopinavir/ritonavir for its activity against resistant HIV strains. The other recommended ritonavir-boosted protease inhibitor regimens listed in Table 4 also have excellent activity against protease inhibitor-resistant strains and are better tolerated than lopinavir/ritonavir.

Table 5. Alternative PEP Regimens Following Occupational Exposurea

  • Tenofovir + Emtricitabineb + Zidovudine

  • Tenofovir + Emtricitabineb + Lopinavir/ritonavir

  • Zidovudine + Lamivudinec + one of the following ritonavir-boosted protease inhibitors: Darunavir, Atazanavir, Fosamprenavir, or Lopinavir

a See Appendix A for full dosing information for alternative ARV agents that may be used in the PEP regimen. Also see HIV Drug-Drug Interactions for important drug interactions. Dosing interval of zidovudine should be adjusted in patients with baseline creatinine clearance < 15 mL/min. The dosing interval of lamivudine, emtricitabine, and tenofovir should be adjusted in patients with baseline creatinine clearance < 50 mL/min. (see Appendix A for dosing recommendations in patients with renal impairment). Fixed-dose combinations should not be used in patients who need dose adjustment due to renal failure. b Lamivudine 300 mg PO qd may be substituted for emtricitabine. However, a fixed-dose combination is available when tenofovir is used with emtricitabine (Truvada 1 PO qd). c Emtricitabine 200 mg PO qd may be substituted for lamivudine. However, a fixed-dose combination is available when zidovudine is used with lamivudine (Combivir 1 PO qd).

Although the committee recommends a three-drug regimen, the PEP regimen could be reduced to a two-drug regimen if tolerability was a concern. Use of a two-drug regimen would be preferred to discontinuing the regimen completely. An early case control study of occupational exposure demonstrated an 81% reduction in seroconversion with the use of zidovudine monotherapy alone,[3] suggesting that treatment with any active antiretroviral agent is beneficial in reducing risk.

Antiretroviral Drugs to Avoid as PEP Components

Consultation with a clinician experienced in managing PEP is recommended before using any of the following non-preferred antiretroviral drugs in a PEP regimen (see below for drugs to avoid in exposed workers who are pregnant or breastfeeding):

  • Efavirenz: Although efavirenz is considered a preferred agent for treatment of chronic HIV infection, it is not recommended as part of an initial PEP regimen for several reasons: (1) central nervous system (CNS) side effects are common, complicating the need to provide a first dose at any time of the day; (2) CNS side effects may impair work after the initial and subsequent doses; (3) efavirenz should be avoided in pregnant women, women intending to become pregnant, or women of childbearing potential who are not using effective contraception; and (4) substantial efavirenz resistance continues to be found in community HIV isolates. If efavirenz is used in women of childbearing potential, a pregnancy test should be obtained before initiation and the woman should be counseled about the use of effective contraception while taking efavirenz.

  • Nevirapine is contraindicated for use in PEP due to the potential for severe hepatotoxicity[28]

  • Abacavir should not be used due to the potential for hypersensitivity reactions

  • Stavudine and Didanosine should not be used due to the possibility of toxicities

  • Nelfinavir and Indinavir are generally poorly tolerated

  • CCR5 co-receptor antagonists should not be used due to lack of activity against potential CXCR4 tropic virus

  • Rilpivirine and Etravirine have not been commonly used in PEP

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