Changes to Initial Postexposure Prophylaxis Regimens Between the Emergency Department and Clinic

To the Editors: Postexposure prophylaxis (PEP) is an effective mode of HIV prevention following occupational and nonoccupational exposures.1–3 World Health Organization and Center for Disease Control and Prevention guidelines recommend PEP be initiated as soon as possible (within 72 hours) after a high-risk exposure and continued for 28 days.4,5 Patients commonly present to the emergency department (ED) for evaluation after potential HIV exposures. Nonoccupational postexposure prophylaxis (nPEP) is usually prescribed by ED physicians when an exposure to potentially infectious bodily fluids is substantial enough to warrant prophylactic antiretroviral therapy (ART). Patients are typically provided with an ART “starter pack” with enough medications until an initial outpatient clinic appointment with a specialist familiar with nPEP is arranged, at which point the patient is reevaluated and the decision to continue, stop, or change ART is made.4 The choice of ART provided in the ED is occasionally modified at the initial outpatient clinic appointment. Common reasons for modifying ART regimens include drug side effects, drug interactions, or additional patient information that alters care. Knowledge of the prevalence of specific starting regimens and reasons for switching medications at follow-up visits will help optimize choice of first-line regimens. We prospectively evaluated modifications of ART PEP regimens between the ED and first clinic appointment. We conducted a prospective observational cohort study at Massachusetts General and Brigham and Women's Hospitals, both in Boston, MA. Ethical approval was granted by the Institutional Review Board for Partners Healthcare (a health care system to which both hospitals belong). The study enrolled all patients aged 18 years and older who presented to the ED for nPEP at either hospital from July 2010 to June 2011 and who attended their first clinic appointment. Patients presenting to the ED after a potential HIV exposure were evaluated by an ED clinician who then contacted the on-call HIV consultant to discuss the case. Based on this consultation, an initial ART “starter pack” was provided with the choice of drug determined by history provided to the ED clinician and relayed to the HIV consultant. The fixed-dose combination of tenofovir–emtricitabine (TDF/FTC) with or without lopinavir-boosted (LPV/r) was used as the first-line regimen at the time of this study. Raltegravir (RAL) was substituted for LPV/r based on clinical context at the discretion of the HIV consultant and ED physician, often due to drug interactions. Patients were provided with written and verbal instructions on how to follow-up in clinic. They were also contacted by phone if they did not attend their scheduled appointment. At the initial clinic appointment 2–5 days after the ED visit, patients underwent clinical evaluation and the decision to stop, change, or continue ART was made. Data pertaining to the initial ART regimen, changes to the regimen, and reasons for change were prospectively collected with a standardized data collection tool. Descriptive statistics were used for data analysis. The risk of regimen modification was examined in a primary analysis: LPV/r-containing regimens were compared with non–LPV/r-containing regimens. The primary outcome was a post hoc analysis of the frequency of regimen stops or switches for LPV/r-containing regimens vs. TDF/FTC with or without RAL. Fisher exact tests were used with a P value cutoff of 0.05 for statistical significance. There were 180 patients referred for nPEP from the ED, 98 (54.4%) of whom attended their first clinic appointment (Table 1). Details of clinic adherence are presented elsewhere.6 Ninety-one of the 98 individuals had nPEP prescribed, and the 2 most common regimens prescribed were TDF/FTC alone (40 individuals, 40.8%) and TDF/FTC + LPV/r (40 individuals, 40.8%). Eight individuals (8.2%) received TDF/FTC plus RAL, 7 individuals (7.1%) received no nPEP, and 3 individuals (3.1%) received other regimens. Of 98 individuals who presented to their first HIV clinic appointment, 18 (18.4%) changed or stopped their first PEP regimen, including 2 who started PEP at the initial visit and had not been prescribed PEP in the ED. Of note, 18 (19.8%) of the 91 individuals given an ART starter pack in the ED had their regimen modified. The most common reasons for regimen changes included adverse effects (39%), clinician discretion based on the clinical situation (50%), and less frequently drug interactions (11%). Nine percent of patients stopped ART after receiving a starter pack in the ED, 2 on their own accord before the physician visit for uncertain reasons, and 6 at the time of the clinic visit after reevaluating the risks and benefits.TABLE 1: Choice of Antiretroviral Therapy Prescribed in EDs for nPEP and Changes at the Initial Clinic AppointmentThe initial regimen most commonly changed was TDF/FTC plus LPV/r, with 28% of those who initiated PEP with this regimen subsequently modifying it. Of these, 91% of the changes were due to gastrointestinal side effects, and 1 due to drug interactions with antipsychotic medications. Among LPV/r-containing regimens that were switched (n = 11), 4 were changed to TDF/FTC plus RAL, 4 opted to stop treatment, 1 switched to TDF/FTC alone, and 2 individuals switched to darunavir- and ritonavir-containing regimens. Twenty-eight percent of LPV/r-containing regimens vs. 10% of TDF/FTC with or without raltegravir were altered or stopped for any reason (P = 0.053). Six of 40 (17%) LPV/r-containing regimens vs. 1 of 51 (2.2%) other regimens were modified because of adverse effects (P = 0.041). No patients initially prescribed TDF/FTC (n = 40) alone or TDF/FTC + RAL (n = 8) stopped their PEP regimen because of adverse effects (P < 0.01 vs. LPV/r-containing regimens). Our study of 98 individuals presenting for nPEP after high-risk HIV exposures found that a substantial proportion of patients started on nPEP changed or stopped their initial regimen, most often because of adverse effects. LPV/r-containing regimens were the most likely to be changed at the first clinic appointment and were significantly more likely than other regimens to be changed or stopped because of side effects. These findings suggest that TDF/FTC and TDF/FTC plus RAL have superior tolerability to LPV/r-containing regimens in the nPEP setting. There are no randomized clinical trial data demonstrating comparative efficacy of different ART regimens for PEP. Definitive studies are unlikely to occur due to the low efficiency of HIV transmission after a single exposure and the rarity of seroconversion after ART. As such, standard regimens are based on animal studies,7 observational cohort studies,1–3 and expert opinion. Considerations when choosing a regimen therefore include tolerability, risk of serious, adverse effects, local prevalence of resistance, and cost. Optimizing adherence to PEP is a priority in the prevention of HIV transmission.1 LPV/r-containing regimens have been widely used, yet a significant proportion of patients were found to experience adverse effects in this and other studies.8,9 A variety of approaches have been used to support adherence to nPEP by improving tolerability. One approach is using 2-medication ART regimens rather than 3-medication ART regimens in cases where there is a low likelihood of resistance to TDF/FTC and the exposure risk for HIV transmission is low.5 This approach is controversial because of the theoretical possibility of reduced efficacy and is not recommended in newer occupational and nonoccupational PEP guidelines.10,11 Three-drug regimens are gaining favor particularly with the improved tolerability of newer medications. However, a randomized controlled trial of an atazanavir-containing regimen showed that it was no more tolerable in the PEP setting than an LPV/r-containing regimen,12 despite evidence to the contrary when used for treatment of HIV-infected patients.13 In our study, raltegravir was used successfully in combination with TDF/FTC, mirroring other settings that have described good tolerability of this regimen14 (I believe the Fenway studies compared TDF/FTC/RAL to historical controls receiving AZT/3TC or AZT/3TC plus a PI, not necessarily LPV/RTV in older cases). Updated oPEP guidelines now include integrase inhibitors as first-line options.10 However, the twice-daily dosing of raltegravir compared with other regimens might limit optimal adherence.14 The improved tolerability and decreased pill burden of newer combination ART regimens make them attractive.15 However, the increased cost and potential for drug interactions of newer single pill regimens may preclude their use in many situations.6 Overall, regimen choice will need to balance the competing goals of optimizing tolerability and adherence and containing costs; the findings in this cohort suggest that a raltegravir-based regimen is less likely to require a change due to intolerance or drug interactions. Our study is limited by modest enrollment and its nonrandomized design. Moreover, 81 patients did not follow-up with the HIV prevention clinic after discharge: unmeasured cost and medication-related adverse effects are possible explanations for this lack of follow-up.6 However, this study provides important information with respect to nPEP regimen changes in a real-world setting. A substantial proportion of patients require changes to their initially prescribed nPEP regimen, most often due to medication-related adverse effects. LPV/r-containing regimens are associated with more frequent regimen changes for adverse effects than other commonly used regimens. Tolerability should be a strong consideration when choosing first-line nPEP regimens to optimize adherence.

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