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Efavirenz & Nonoccupational HIV Postexposure Prophylaxis
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JAMA
October 5, 2005
To the Editor: We agree with the perspective of Drs Merchant and Mayer in their Commentary1 that the new Centers for Disease Control and Prevention (CDC) guidelines for provision of human immunodeficiency virus (HIV) nonoccupational postexposure prophylaxis (HIV NPEP)2 represents an important initial step in advising clinicians. However, we note an important caveat with regard to the choice of antiretroviral agents, as discussed in the clinical guidelines developed by the New York State Department of Health AIDS Institute (NYSDOH AI) in 1997 and updated in December 2004.3-4
The CDC now endorses 3-drug HIV NPEP regimens rather than 2-drug regimens, as does the NYSDOH AI. Yet, the CDC's suggestion of efavirenz as an anchor of the simplest 3-drug regimens is concerning. In some resource-limited countries, efavirenz may be the only viable option to complete a postexposure prophylaxis regimen. However, in the United States, the Food and Drug Administration recently reclassified efavirenz as a category D agent (positive evidence of fetal risk) for pregnant women.5 Since much of HIV NPEP is likely prescribed for women exposed to HIV through sexual assault, recommendation of 28-day therapy with a category D agent will require more attention to contraception than simply testing for pregnancy and providing emergency postexposure contraception at the time of NPEP initiation. Furthermore, the therapeutic index of efavirenz in this context seems unfavorable, since the incide1nce of central nervous system adverse effects approaches 25%.6
The alternative regimen of tenofovir, zidovudine, and lamivudine that is suggested in the NYSDOH AI guidelines for HIV NPEP3-4 may offer a potentially less toxic option that maintains a low pill burden (3 pills/d) and also is supported by at least some experimental evidence from animal models.7 This alternative regimen, in the context of explicit instructions and algorithms for its use (as contained in the NYSDOH AI guidelines), may better serve patients with nonoccupational exposure to HIV, especially those who have been exposed through sexual assault, as well as the practitioners asked to care for them.
We also note that clinicians practicing in local jurisdictions in which HIV NPEP guidelines have been created (eg, California, Massachusetts, New York, Rhode Island) should be aware that federal guidelines do not necessarily replace or supplant local medical standards of care.
Financial Disclosures: None reported.
Geoffrey A. Weinberg, MD
geoff_weinberg@urmc.rochester.edu
Department of Pediatrics
Amneris E. Luque, MD
Department of Medicine
University of Rochester School of Medicine & Dentistry
Rochester, NY
Sheldon T. Brown, MD
Department of Medicine
Mount Sinai School of Medicine
New York, NY
Nonoccupational HIV Postexposure Prophylaxis-Reply
JAMA Oct 5, 2005
In Reply: We agree with Drs Weinberg, Luque, and Brown that efavirenz is not an optimal choice for nonoccupational HIV NPEP in women who are or may become pregnant. Unfortunately for clinicians' decision-making, data are limited on the relative efficacy of any HIV NPEP regimen. This limitation forces clinicians to choose regimens based on the best available evidence that can be extracted from studies involving persons already infected with HIV, as well as from mother-to-child HIV transmission prevention studies, basic science research, and HIV NPEP investigations that are not randomized, controlled trials. For example, Schechter et al1 educated a cohort of men who had sex with men to take zidovudine/lamivudine for NPEP after high-risk exposures and demonstrated a lower incidence of HIV seroconversion compared with those who did not take HIV NPEP; however, the trial did not include other HIV NPEP regimens. As a result, this study provides additional proof-of-concept for HIV NPEP but not direction on which regimen is best.
We also agree that tenofovir has many attractive features, including an excellent safety and tolerability profile, substantial animal data corroborating its use for prophylaxis, and human studies using tenofovir for NPEP that support its ease of use in HIV NPEP. In an open-label phase 4 observational study at Fenway Community Health in Boston, Mass, comparing zidovudine/tenofovir to historical controls that used zidovudine/lamivudine-based regimens, the tenofovir-based regimens were better tolerated and were more likely to be taken for the entire treatment period.2 In a recent study from Sydney, Australia, Winston et al3 compared zidovudine/lamivudine with and without nelfinavir to a tenofovir/lamivudine/stavudine regimen for HIV NPEP. Completion of the regimen was nearly 3-fold greater for the tenofovir vs the nelfinavir-based regimen, and reported adverse effects were less for patients taking tenofovir. Although no HIV seroconversions were observed in these 2 studies, the likelihood of detecting such an uncommon event would be exceedingly low, given that only 515 people were involved in these 2 trials.
In the absence of clinical trials and large registries that could help compare the advantages and disadvantages of 3 drug regimens using tenofovir, efavirenz, or any other HIV NPEP regimen, meaningful comparisons regarding their efficacy are not feasible. We are left with other HIV NPEP-related considerations-cost, compliance, and adverse-effect profiles-that can be extracted from these and other studies. Continued maintenance of national registries in Europe, Canada, and Australia may further inform this field eventually. We are hopeful that clinicians will continue to report their patients' experience with these medications used for HIV NPEP and look forward to trials that can assist us with future decisions regarding HIV NPEP regimens.
Financial Disclosures: None reported.
Kenneth H. Mayer, MD
Department of Medicine
Roland C. Merchant, MD, MPH
rmerchant@lifespan.org
Department of Emergency Medicine
Brown Medical School
Providence, RI
Perspectives on New Recommendations for Nonoccupational HIV Postexposure Prophylaxis
Roland C. Merchant, MD, MPH; Kenneth H. Mayer, MD
JAMA. May 2005;293:2407-2409.
In an important initial step for providing advice to US clinicians on this complex subject, the Centers for Disease Control and Prevention (CDC) recently released national guidelines for provision of human immunodeficiency virus (HIV) nonoccupational postexposure prophylaxis (HIV NPEP).1 In the guidelines, the CDC defines nonoccupational exposure as
any direct mucosal, percutaneous, or intravenous contact with potentially infectious body fluids that occurs outside perinatal or occupational situations (eg, health care, sanitation, public safety, or laboratory employment). Potentially infectious body fluids are blood, semen, vaginal secretions, rectal secretions, breast milk, or other body fluid that is contaminated with visible blood.
These guidelines, which were constructed through a multiyear consultation process, endorse and make recommendations for the use of antiretroviral medications following sexual, injection drug, and other nonoccupational exposures to HIV.
The new CDC guidelines replace a 1998 CDC advisory to clinicians on HIV NPEP in which the CDC did not recommend either for or against the use of HIV NPEP but instead offered "considerations" of when and how it might be used.2 The new guidelines serve to complement the twice-revised guidelines on HIV PEP for occupational use (ie, health care worker exposures) that were first published in 1996.3-5 The CDC occupational HIV PEP guidelines have been the national standard by which postexposure care has been delivered to health care workers and related persons exposed to HIV while at work. This distinction both places a large burden on these new HIV NPEP guidelines and creates a great deal of hope that they will become an equal standardof care for people exposed to HIV through much more common means-namely, sexual contact and use of injection drugs.
Of interest to the clinician, the CDC HIV NPEP guidelines discuss the evaluation, medications, testing, monitoring, and counseling involved in HIV NPEP provision. The guidelines explicitly state that HIV NPEP is recommended for HIV-uninfected persons who sustained significant exposures (eg, unprotected vaginal or anal intercourse) to individuals known to be HIV-infected and who present for care within 72 hours after the exposure. The CDC recommends several antiretroviral medication regimens for HIV NPEP for exposed persons, 2 of which are preferred by the CDC: a nonnucleoside reverse transcriptase inhibitor-based regimen (efavirenz plus lamivudine or emtricitabine with zidovudine or tenofovir) and a protease inhibitor-based regimen (lopinavir/ritonavir plus lamivudine or emtricitabine with zidovudine). Just as for occupational HIV PEP, patients should take these medications for 28 days and should be monitored for adverse effects through clinical evaluation and measurement of liver enzyme, renal function, and hematologic parameters. Clinicians should also search for an as-yet undiagnosed HIV infection in these patients and observe for signs and symptoms of an acute HIV infection. The only real departure from occupational HIV PEP is the suggestion for clinicians to use HIV NPEP as an "educable moment" to counsel patients on reducing future risky behaviors that lead to HIV exposures.
The preferred CDC regimens for HIV NPEP echo the Department of Health and Human Services' advice to health care professionals on the use of antiretroviral medications for newly diagnosed HIV-infected persons.6 This stance prompts an important question-are these really the best regimens, in terms of content and quantity, for HIV NPEP? As acknowledged by the CDC in the guidelines, this question remains unanswered by the CDC or any group, since randomized controlled trials of PEP for any group have not been conducted. Of note, although there are no clinical trials demonstrating the superior efficacy of a 3-drug vs a 2-drug HIV PEP regimen, the CDC endorses a 3-drug regimen for HIV NPEP for nonoccupational exposures to known HIV-infected sources. This philosophy is grounded in animal and human studies that suggest a multidrug approach is superior for suppressing HIV replication in persons known to be HIV infected. Whether HIV replication will be suppressed or halted when these recommended medications are used for HIV NPEP is not known. Of course, more drugs mean higher cost, more complexity, and the potential for greater nonadherence. When Bassett et al7 modeled HIV PEP regimens after health care worker exposures to known HIV-infected sources, a 2-drug regimen appeared to be favored, given the expected nonadherence due to adverse effects with a 3-drug regimen. Whether the balance favors a 3-drug approach in HIV NPEP is unclear. Perhaps newer, better-tolerated regimens may shift this balance.
In distinct contrast to their direction on exposures to known HIV-infected sources, the CDC advice on the management of exposures to sources of unknown status is not explicit. In the guidelines, the CDC states that "no recommendations are made either for against the use of" HIV NPEP when the HIV status of the source is unknown.1 Clinicians are advised to consider prescribing HIV NPEP on a "case-by-case basis," essentially considering the risk of infection from what is known about the source and exposure. The steps clinicians should take in this consideration are not outlined, but the guidelines offer some direction on assessing the nature of the exposure, determining the source's HIV status, and estimating the likelihood of infection.
The explicit advice to clinicians regarding HIV NPEP for exposures to known HIV-infected sources will be applicable to few patients. The vast majority of patients who present for care after an exposure, eg, after sexual assault, do not know-and may never know-the HIV status of the source of their exposure. In a retrospective study of 1436 patients with exposures to blood or body fluids and presenting to the Rhode Island Hospital emergency department, less than 2% reported at the time of evaluation that their exposure source was known to be HIV infected.8 For the much larger group of patients whose source is of unknown HIV status, clinicians will have to extrapolate from well-delineated care plans for patients exposed to known HIV-infected sources. It is probable, then, that the "case-by-case basis" will be the norm rather than the exception.
From a public policy perspective, the guidelines are a marked improvement. There now exists a national blueprint for managing HIV exposures for the group who represent almost all new, existing, and prior HIV infections-ie, persons exposed to HIV through sexual contact or use of injection drugs. Health care workers exposed to HIV while at work, even though covered by national guidelines on HIV PEP, comprise a tiny fraction of the legions of HIV-infected persons. These policies now address those in the majority and most at risk for HIV, similar to earlier policies implemented in Europe.9 In addition, the federal government has rightfully assumed responsibility for a problem left to the states in the absence of national guidelines. Rhode Island, New York, and recently California developed state guidelines on HIV NPEP; Massachusetts created a clinical advisory on the subject; and New York and California previously released HIV NPEP guidelines specific to sexual assault.10-15 The eventual creation of 50 state guidelines would have led to uneven practices and a lack of a coherent standard. Worse still, some states might not have developed guidelines and would have left their citizens without due attention on this topic.
It is hoped that the CDC HIV NPEP guidelines will be as successful as the occupational HIV PEP guidelines, which clinicians and administrators at clinical sites transformed into clear policies that over time became part of improvements to worker safety. Reductions in HIV transmission may be substantial if clinical entities were held equally responsible to ensure decreases in HIV exposures among non-health care workers. In reality, clinicians can incorporate the larger goal of HIV NPEP for all patients at risk for an HIV infection by finding ways to reduce their personal risk of acquiring HIV.
However, HIV NPEP is rightly a second means of defense against HIV because it is intended for those for whom primary preventive methods failed or were unavailable. It is therefore likely that HIV NPEP will not be dispensed frequently. For example, as estimated in 1 study, only 14 pediatric sexual assault patients per year presenting to the Hasbro Children's Hospital emergency department (>40 000 annual patient visits) would even be eligible for HIV NPEP.8
For the clinician who has been prescribing HIV NPEP, the guidelines are welcome. Clinicians practicing in areas without HIV NPEP state or local guidelines had assumed a low but nonnegligible risk of using as-yet unendorsed therapeutic measures. Their only defense would have been to cite the various medical society and expert opinion-generated commentaries and recommendations on use of HIV NPEP. These national guidelines support their good intentions.
The greatest value of guidelines like these is the codification of a reasonable means of practice. An obvious problem of their absence was the lack of use of HIV NPEP when it should have been prescribed and its use when it should not have been given. The clinician is now held to know when HIV NPEP is appropriate. As a result, this knowledge should translate into improved practice. The challenge that remains, however, is determining how to best educate clinicians on the implementation of these guidelines and also to work on the larger task of helping clinicians reduce their patients' risk of becoming HIV infected.
These new guidelines are an important step. What must now be resolved is how to make them a part of standard practice and how to find ways to make explicit the steps clinicians should follow for patients exposed to sources with unknown HIV status. Furthermore, states and other locales should now determine how to supplement the guidelines with information and resources for clinicians and patients by creating or modifying centers for HIV NPEP evaluations and follow-up, allowing for access to rapid HIV testing, and making available HIV NPEP medications for those unable to afford them. This is the next challenge and one that helps redirect the focus toward persons at greatest risk of acquiring HIV.
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