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# I. LIST OF TABLES AND FIGURES

# II. ABBREVIATIONS AND ACRONYMS
3TC lamivudine

# IV. SUMMARY
The purpose of these guidelines is to provide health care providers in the United States with updated guidelines to the 2005 U.S. Department of Health and Human Services nonoccupational postexposure prophylaxis (nPEP) recommendations 1 on the use of antiretroviral nPEP and other aspects of case management for persons with isolated exposure outside health care settings to blood, genital secretions, or other potentially infectious body fluids that might contain human immunodeficiency virus (HIV). The use of occupational PEP (oPEP) for case management for persons with possible HIV exposures occurring in health care settings are not addressed in this guideline; updated oPEP guidelines have been published separately. 2

# IV-A. What Is New in This Update
This update incorporates additional evidence regarding use of nonoccupational postexposure prophylaxis (nPEP) from animal studies, human observational studies, and consideration of new antiretroviral medications that were approved since the 2005 guidelines, some of which have improved tolerability. New features are inclusion of guidelines for the use of rapid antigen/antibody (Ag/Ab) combination HIV tests, for revised preferred and alternative 3-drug antiretroviral nPEP regimens, an updated schedule of laboratory evaluations of source and exposed persons, updated antimicrobial regimens for prophylaxis of sexually transmitted infections and hepatitis, and a suggested procedure for transitioning patients between nPEP and HIV preexposure prophylaxis (PrEP), as appropriate. a See Figure 1.

# IV-B. Summary of Guidelines
b Numbers in brackets refers readers to the section in these guidelines that provides the basis for the recommendation.
- nPEP is recommended when the source of the body fluids is known to be HIV-positive and the reported exposure presents a substantial risk for transmission. 
- nPEP is not recommended when the reported exposure presents no substantial risk of HIV transmission. 
- nPEP is not recommended when care is sought > 72 hours after potential exposure.
- A case-by-case determination about the nPEP is recommended when the HIV infection status of the source of the body fluids is unknown and the reported exposure presents a substantial risk for transmission if the source did have HIV infection.  a Ritonavir is used in clinical practice as a pharmacokinetic enhancer to increase the trough concentration and prolong the half-life of darunavir and other protease inhibitors; it was not considered an additional drug when enumerating drugs in a regimen.

# V. INTRODUCTION
The most effective methods for preventing human immunodeficiency virus (HIV) infection are those that protect against exposure. Antiretroviral therapy cannot replace behaviors that help avoid HIV exposure (e.g., sexual abstinence, sex only in a mutually monogamous relationship with an HIV-uninfected partner, consistent and correct condom use, abstinence from injection drug use, and consistent use of sterile equipment by those unable to cease injection drug use). Provision of antiretroviral medication after isolated sexual, injection drug use, or other nonoccupational HIV exposure, known as nonoccupational postexposure prophylaxis (nPEP), is less effective at preventing HIV infection than avoiding exposure.
In 2005, the U.S. Department of Health and Human Services (DHHS) released its first recommendations for nPEP use to reduce the risk for HIV infection after nonoccupational exposures to blood, genital secretions, and other body fluids that might contain HIV. 1 In 2012, updated guidelines on the use of occupational PEP (oPEP) for case management for persons with possible HIV exposures occurring in health care settings were published and are not addressed in this guideline. 2 Other organizations, including health departments, professional medical societies, and medical institutions, have developed guidelines, recommendations, and protocols for nPEP delivered to adults and children.  This document updates the 2005 DHHS nPEP recommendations in response to new information regarding clinical experience for delivering nPEP, including using newer antiretroviral regimens and their side-effect profiles and cost-effectiveness of nPEP to prevent HIV infection for different exposure types. We describe in more detail the goals for the new guidelines, funding source of the guidelines, persons involved in guidelines development, definition of competing interest for persons involved in guidelines development and procedures for managing competing interest (Appendix 1A).
CDC scientists selected nPEP subject matter experts from the Food and Drug Administration (FDA), the National Institutes of Health (NIH), hospitals, clinics, health departments, and professional medical societies to participate as panelists to discuss recent developments in nPEP practice by CDC teleconferences in December 2011, and April 2012 (Appendix 1B). Any potential conflicts of interests reported by persons involved in developing the guidelines and the determination made for each of those potential conflicts are listed in Appendix 1C.
A working group of CDC HIV prevention scientists and other CDC scientists with expertise pertinent to the nPEP guidelines conducted nPEP-related systematic literature reviews. Appendix 2 summarizes the methods used to conduct that review, including databases queried, topics addressed, search terms, search dates, and any limitations placed on the searches (i.e., language, country, population, and study type). All studies identified through the literature search were reviewed and included in the body of evidence. Appendix 3 includes a summary of the key observational and case studies among humans that comprise the main body of evidence.
These nPEP guidelines are not applicable for occupational exposures to HIV; however, we attempted to standardize the selection of preferred drugs for nPEP and occupational postexposure prophylaxis (oPEP). 2 These guidelines also do not apply to continuous daily oral antiretroviral prophylaxis that is initiated before potential exposures to HIV as a means of reducing the risk for HIV infection among persons at high risk for its sexual acquisition (preexposure prophylaxis or PrEP 11 ).
Among the limitations of these guidelines is that they are based on a historical case-control study related to occupational PEP among hospital workers, observational and case studies examining nPEP's effectiveness among humans, animal studies related to PEP's efficacy among primates, and expert opinion on clinical practice among humans related to nPEP. Because of concerns about the ethics and feasibility of conducting large-scale prospective randomized placebo-controlled nPEP clinical trials, no such studies have been conducted. Additionally, although nPEP failures were rare in the observational studies we reviewed, those studies often have inadequate follow-up testing rates for HIV infection; therefore, nPEP failures might be underestimated. Because these guidelines represent an update of previous guidelines about a now established clinical practice, we elected not to use a formal grading scheme to indicate the strength of supporting evidence.

# VI. EVIDENCE REVIEW VI-A. Possible Effectiveness of nPEP
No randomized, placebo-controlled clinical trial of nPEP has been conducted. However, data relevant to nPEP guidelines are available from animal transmission models, perinatal clinical trials, observational studies of health care workers receiving prophylaxis after occupational exposures, and observational and case studies of nPEP use. Although the working group mainly systematically reviewed studies conducted after 2005 through July 2015, we also include findings from seminal studies published before 2005 that help define key aspects of nPEP guidelines. Newer data reviewed in this document continue to support the assertion that nPEP initiated soon after exposure and continued for 28 days with sufficient medication adherence can reduce the risk for acquiring HIV infection after nonoccupational exposures.

# V1-A1. oPEP Studies
A case-control study demonstrating an 81% (95% confidence interval  = 48%-94%) reduction in the odds of HIV transmission among health care workers with percutaneous exposure to HIV who received zidovudine (ZDV) prophylaxis was the first to describe the efficacy of oPEP. 12 Because of the ethical and operational challenges, no randomized controlled trials have been conducted to test the efficacy of nPEP directly. In the absence of a randomized controlled trial for nPEP, this case-control study reports the strongest evidence of benefit of antiretroviral prophylaxis initiated after HIV exposure among humans.

# V1-A2. Observational and Case Studies of nPEP
The following is a synopsis of domestic and international observational studies and case reports that have been published since the 2005 U.S. nPEP guidelines were issued. In the majority of studies, failure of nPEP, defined as HIV seroconversion despite taking nPEP as recommended, was typically confirmed by a seronegative HIV enzyme-linked immunosorbent assay (ELISA) at baseline visit, followed by a positive ELISA and Western blot or indirect fluorescent antibody (IFA) during a follow-up visit.

# VI-A2a. Men Who Have Sex with Men
Based on 1 case report 13 and 6 studies  reporting results exclusively or separately among men who have sex with men (MSM), 49 seroconversions were reported after nPEP use. The case report from Italy described an nPEP failure in an MSM despite self-reported 100% adherence to his 3-drug medication regimen consisting of ZDV, lamivudine (3TC), and indinavir (IDV) and denial of ongoing HIV risk transmission behaviors after completing nPEP; concomitant hepatitis C virus (HCV) seroconversion was also diagnosed. 13 In the 6 studies, 48 of 1,535 (31.3 seroconverions/1,000 persons) MSM participants became HIV infected despite nPEP use. At least 40 of the 48 seroconversions likely resulted from ongoing risk behavior after completing nPEP. Thirty-five of these 40 seroconversions occurred  180 days subsequent to nPEP initiation and are unlikely to constitute nPEP failures. 16,18 The remaining 8 seroconverters among 1,535 MSM participants (5.2 seroconverions/1,000 persons) may be classified as potential nPEP failures. This included 1 recipient with an indeterminate HIV test result and isolation of an M184 mutation resistant virus on the last day of his 28-day regimen despite initiating nPEP  48 hours after exposure, 20 indicating that seroconversion was occurring during the 28-day period of nPEP administration. Another 4 patients seroconverted at 91 days, 133 days, 160 days, and 168 days after nPEP initiation, including 3 who reported completing the 28-day regimen; however, there was no description of the presence or lack of ongoing sexual risk behaviors after nPEP completion. 18 Among the remaining 3 men who seroconverted after taking nPEP, taking nPEP was not associated with any suggestion of change in seroconversion risk, although no information was reported regarding the nPEP regimen prescribed, adherence to nPEP, delay in nPEP initiation or timing of HIV-positive results. 15 In a 2-year prospective study in Brazil, investigators provided 200 seronegative MSM at high risk with education regarding nPEP and a 4-day starter pack with instructions to initiate its use for a suspected eligible exposure. 16 A follow-up 24-day pack (to complete a 28-day course) was provided only for those men with eligible exposures. Sixty-eight of 200 MSM initiated nPEP. Adherence to nPEP medications was estimated on the basis of questions at the 28-day visit and remaining pill counts. The entire 28-day nPEP regimen was completed by 89% of men with eligible exposures including 1 participant who seroconverted. Ten of 11 seroconversions occurred among men who did not initiate nPEP. 16 VI-A2b. Sexual Assault VI-A2bi. General Population (all ages). Globally, 3 systematic reviews  and 1 prospective cohort study 23 spanning childhood through adulthood reported wide-ranging proportions of participants being eligible for nPEP (range, 6%-94%), being offered nPEP (range, 5%-94%), accepting nPEP (range, 4%-100%), or completing nPEP (range, 9%-65%). Among the 3 systematic reviews, none reported HIV screening results or the number of nPEP failures.  VI-A2bii. Adults and Adolescents. Although nPEP use for sexual assault survivors has been widely encouraged both in the United States and elsewhere,  documented cases of HIV infection resulting from sexual assault of women or men rarely have been published. 25,28,29 Of 5 individual retrospective studies of nPEP limited to adult and/or adolescent sexual assault survivors that the working group reviewed, 3 reported no seroconversions at baseline or at follow-up among those sexual assault survivors who completed nPEP,  and 2 did not report any information about HIV screening results or the number of nPEP failures. 33,34 VI-A2biii. Children and Adolescents. Studies of nPEP also have focused on children or adolescents evaluated for sexual assault. In a pooled analysis based on 10 studies of 8,336 children or adolescents evaluated for sexual assault or abuse, at least 1,362 were determined to be nPEP eligible. Twenty-four of the remaining 6,974 (3.4 seroconversions/1,000 persons) children or adolescents who were not eligible for nPEP were found to be HIV infected at baseline testing.  Among 672 children or adolescents reported to have been offered nPEP, 472 were known to have initiated nPEP, and 126 were reported to have completed a 28-day nPEP course. No new HIV infections were documented among these 472 (0.0 seroconversions/1,000 persons) children/adolescents in the pooled analysis who initiated nPEP. New HIV infections might have been underestimated as return rates for children or adolescents attending at least 1 follow-up visit during which an HIV test might have been conducted after initiating nPEP ranged from 10% 40 to 76%. 44

# VI-A2c. Mixed or Other Populations
VI-A2ci. Mixed populations. Eighteen studies, including 9 international studies  and 9 domestic studies  examined multiple routes of HIV risk exposure among adults, adolescents, and children with sexual and nonsexual exposures, including consensual sexual relations, sexual assault, injection drug use, and needlestick exposures.
Fifteen of the 19 studies reported both the number of participants who completed 28 days of nPEP and the number of participants who HIV seroconverted after initiating nPEP. 62,63 In these 15 studies, 2,209 participants completed 28 days of nPEP, of whom, at least 19 individuals HIV seroconverted, 52,54,56,62,63 but only seroconversion 47 (8.6/1,000) was attributed to nPEP failure. This seroconversion occurred 6 weeks after nPEP initiation in a sexually assaulted female who presented  4 hours after assault and completed nPEP. 47 She had a positive HIV RNA polymerase chain reaction (PCR) test but no confirmatory HIV ELISA test documented during the 5-6 week follow-up HIV testing period after initiating nPEP. Among the other 18 seroconversions that occurred during follow-up HIV testing among participants who completed 28 days of nPEP, 5 occurred 6 months after nPEP completion and were likely associated with ongoing sexual risk behavior after nPEP completion. 45,54 One seroconversion occurred after a participant reported poor adherence to nPEP, ongoing sexual risk behavior, and multiple nPEP courses after the initial course of nPEP, however, the timing of seroconversion was not clearly specified. 63 One seroconversion occurred in an MSM presenting with acute retroviral syndrome 3 weeks after condomless anal sex with an anonymous partner and no receipt of nPEP. 48 One seroconversion occurred in a woman during the 6-month follow-up period after completing nPEP and it was attributed to ongoing sharing of injection drug use equipment. 48 One seroconversion occurred in a patient who started nPEP > 72 hours after a high-risk exposure. 46 Additional seroconversions occurred at various time periods after initiation of nPEP without detailed information about ongoing sexual exposure or adherence to nPEP (2 and 5 months  62 ; 3 and 6 months  52 ; 5 months  62 ; and 12 months ). 62 Among 3 participants who seroconverted while taking or shortly after taking ZDV-containing nPEP regimens, there was a lack of information about ongoing sexual exposure or detailed information about strict adherence to the full 28-day nPEP regimen. 56 However, only 33.8%-42.1% of all patients who were administered ZDV-containing nPEP regimens in this study completed their regimens as prescribed. 56 In the remaining 4 of 19 studies, 2 studies did not report rates of HIVseroconversion 59,60 and 2 studies did not report rates of completion of the 28-day nPEP regimen, 45,61 including a study that reported 7 seroconversions that occurred at unspecified time periods during the 6 months after nPEP initiation among 649 users of nPEP. 61 Of all nPEP clients in this study, 18.5% had previously used nPEP between 1 and 5 times. 61 In 3 domestic studies, participants who were administered tenofovir (TDF)-containing nPEP regimens were substantially more likely than historical control subjects in studies consisting of ZDV-containing regimens to complete their prophylaxis as prescribed and less likely to experience common side effects. 49,56,57,60 In two studies, the highest completion rates were observed for the TDF-3TC (87.5%) and TDF-emtricitabine (FTC) (72.7%) arms followed by the TDF-FTC-raltegravir (RAL) (57%) and ZDV-3TC-3rd drug arms (the 3rd drug was mainly a protease inhibitor ) (38.8 %). 57 In addition to the 57% of patients who completed all 3 drugs of the TDF-FTC-RAL arm, 27% of patients took their TDF-FTC and first RAL dose daily, but sometimes missed the second dose of RAL. 57 In another study, the completion rates were highest in the TDF-FTC-ritonavir (RTV)-boosted lopinavir (LPV/r) arm (88.3%) compared with the TDF-3TC-RTV-boosted atazanavir (ATV/r) arm (79%), ZDV-3TC-LPV/r arm (77.5%), or ZDV-3TC-nelfinavir (NFV) arm (65.5%). 49 In the last domestic study, TDF-containing compared with ZDV-containing regimens were associated with significantly higher completion rates in the bivariate analysis (OR 2.80 ) but not in the multivariate analysis (OR 1.96 ). 60 VI-A2cii. Other Populations. Data for 438 persons with unintentional nonoccupational needlestick or other sharps exposures described in 7 published reports were reviewed, including data for 417 children and 21 adults.  Childhood and adolescent exposures were characterized as community-acquired exposures occurring in public outdoor places (e.g., playgrounds, parks, or beaches) or by reaching into needle disposal boxes at home or in a hospital. Adult exposures were often similar to occupational exposures occurring while handling needles or disposing of needles in a sharps container. In all cases, the HIV status of the source person was unknown except in 1 report 64 involving multiple percutaneous exposures with lancets among 21 children while playing with discarded needles in a playground. Some of the lancets had been used multiple times to stick different children. One of the children stuck with a lancet was known to be HIV infected before the incident, not receiving antiretroviral therapy, and documented to have an HIV-1 plasma viral load of 5,250,000 copies/mL; the other 20 children were considered potentially exposed to HIV. 64 Additionally, in 1 of the studies, 2 children were hepatitis B surface antigen (HBsAg)-positive at baseline before starting prophylaxis. 66 Among 155 children offered nPEP, 149 accepted and initiated nPEP, and 93 completed their 28-day nPEP course.  Antiretroviral prophylaxis with either ZDV and 3TC or ZDV, 3TC plus a PI (IDV, NFV, LPV/r) or a nonnucleoside reverse transcriptase inhibitor (NNRTI) (nevirapine ) was used for those 149 children or adults accepting and initiating nPEP. No seroconversions for HIV, hepatitis B virus (HBV), or HCV were reported among those receiving or not receiving nPEP.  In the case report of a 12-year old girl in Saudi Arabia with sickle-cell disease who was inadvertently transfused with a large volume of packed red blood cells, the use of a 13-week, 4-drug nPEP regimen of TDF, FTC, ritonavir-boosted darunavir (DRV/r) (later changed to LPV) and RAL resulted in loss of presence of detectable HIV-1 antibodies. 71 No HIV-1 DNA or plasma HIV-1 RNA was detected by PCR testing during the 8-month follow-up period.

# VI-A3. Postnatal Prophylaxis of Infants Born to HIV-infected Mothers
Data regarding the efficacy of infant PEP to prevent mother-to-child HIV transmission provides only limited, indirect information about the efficacy of antiretroviral medications for nPEP. Postpartum antiretroviral prophylaxis is designed to prevent infection after contact of mucosal surfaces (ocular, oral, rectal, or urethral) or broken skin in the infant with maternal blood or other fluids that are present at time of labor and delivery, especially during vaginal births. Trials in which the infant was provided postpartum prophylaxis but the mother received neither prepartum or intrapartum antiretroviral prophylaxis provide the most relevant indirect data regarding nPEP after exposure to a source who did not have suppressed viral load secondary to antiretroviral therapy. Although a combination of prophylaxis during the prenatal, intrapartum, and postpartum periods offers the most effective reduction of perinatal transmission, postpartum prophylaxis alone also offers reduction.  A randomized open-label clinical trial of antiretrovirals provided to infants born to breastfeeding HIV-infected women demonstrated an overall reduction in postnatal HIV infection at 14 weeks (the end of the period of prophylaxis) by approximately 70% (95% CI unreported). The trial compared a control group receiving a shortarm postnatal prophylaxis regimen and 2 comparison groups, each receiving different extended-arm postnatal prophylaxis regimens. 76 The control group received the short-arm regimen consisting of single-dose NVP plus 1-week ZDV and the 2 comparison groups received the control regimen and either 1) extended daily NVP for 14 weeks or 2) extended daily NVP and ZDV for 14 weeks. The corresponding HIV infection rates at 14 weeks were 8.5% in the control group, and 2.6% and 2.5% in the 2 extended arms comparison groups, respectively.
An observational study documented a potential effect of ZDV prophylaxis initially started postnatally compared with the prepartum and intrapartum periods. A review of 939 medical records of HIV-exposed infants in New York State indicated that the later the prophylaxis was started after the prepartum period, the higher the likelihood of perinatal transmission and that a benefit existed to postnatal prophylaxis alone (without maternal intrapartum or prepartum medication). Perinatal prophylaxis started during the prepartum, intrapartum, early postpartum ( 48 hours after birth), and late postpartum (3 days-42 days) periods resulted in corresponding transmission rates of 6.1%, 10.0%, 9.3%, and 18.4%, respectively. 77 A perinatal transmission rate of 31.6% was observed when no perinatal prophylaxis was provided; the study included data from patients who had pregnancies early in the epidemic when HIV perinatal prophylaxis was first being implemented, and it was uncertain whether using intrapartum and/or postnatal prophylaxis alone was beneficial among mothers without prenatal care.

# VI-A4. Animal Studies
Macaque models have been used to assess potential PEP efficacy. These studies examined artificial exposures to simian immunodeficiency virus (SIV) which varied by modes of exposure, virus innocula, and drug regimens. The parameters imposed by those animal studies might not reflect human viral exposures and drug exposures, and those differences should be considered when interpreting their findings. Nevertheless, macaque models have provided important proof-of-concept data regarding PEP efficacy. More recent animal studies have tested the effectiveness of newer antiretrovirals and alternate routes of PEP administration. Subcutaneous tenofovir was reported to block SIV infection after intravenous challenge among long-tailed macaques if initiated  24 hours after exposure and continued for 28 days. 78 All 10 macaques initiated on PEP at 4 or 24 hours post inoculation were documented to be SIV-uninfected at 36-56 weeks post inoculation compared with all 10 macaques that failed to receive any prophylaxis and became SIV infected within 20-36 weeks postinoculation. In a study of 24 macaques, TDF was less effective if initiated 48 or 72 hours post-exposure or if continued for only 3 or 10 days. 79 In contrast, all 11 macaques became SIV infected in a study involving 3 control macaques receiving no prophylaxis and 8 macaques receiving a combination of ZDV, 3TC, and IDV administered orally through nasogastric catheter after intravenous virus inoculation at 4 or 72 hours post-SIV inoculation. 80 High virus innocula and drug exposures that are lower than those achieved among humans as a result of inadequate interspecies adjustment of drug dosing might have contributed to the lack of protection reported for that study. However, a macaque study designed to model nPEP for vaginal HIV exposure demonstrated that a combination of ZDV, 3TC and a high dose of IDV protected 4 of 6 animals from vaginal SIV infection when initiated  4 hours after vaginal exposure and continued for 28 days, whereas 6 of 6 animals in the control group receiving a placebo became SIV infected. 81 In another study, after 20 vaginal simian/human immunodeficiency virus infection (SHIV) challenges and a 10-week follow-up period, 5 of 6 macaques were protected when treated with topically applied gel containing 1% RAL 3 hours after each virus exposure compared with none of four macaques treated with placebo gel. 82 Likewise, macaques administered subcutaneous TDF for 28 days, beginning 12 hours (4 animals) or 36 hours (4 animals) after vaginal HIV-2 exposure, were protected from infection. Three of 4 animals treated 72 hours after exposure were also protected. 83 Three of 4 untreated animals in the control group became infected with HIV-2. Overall, data from these macaque studies demonstrate that PEP might be effective among humans if initiated  72 hours and continued daily for 28 days. In a systematic review and meta-analysis of 25 nonhuman primate studies, including rhesus macaques in10 studies and cynomolgus monkeys in 5 studies, use of PEP was associated with an 89% lower risk of seroconversion compared with nonhuman primates who did not use PEP. Also, use of tenofovir compared with other drugs was associated with lower seroconversion. 84

# VI-B. Possible Risks Associated with nPEP
Concerns regarding potential risks associated with nPEP as a clinical HIV prevention intervention include the occurrence of serious adverse effects from the short-term use of antiretroviral medications by otherwise healthy persons without HIV infection, and potential selection for drug-resistant strains of virus among those who become HIV infected despite nPEP use (particularly if medication adherence is inconsistent during the 28-day course or if the source transmits resistant virus). An additional concern is that persons engaging in consensual sex or nonsterile injection drug use may rely solely on PEP instead of adopting more long-term risk-reduction behaviors such as safer sexual and drug-injecting behaviors.

# VI-B1. Antiretroviral Side Effects and Toxicity
In a meta-analysis 20 of 24 nPEP-related studies, including 23 cohort studies and 1 randomized clinical trial (behavioral intervention to improve nPEP adherence), of 2,166 sexually assaulted persons, clinicians prescribed 2-drug regimens, 36,38,40,42, 3-drug regimens, 23,31,58,89-92 2-and 3-drug regimens, 30,32,50,93,94 or an unknown number of drugs. 46, ZDV was a part of all the regimens and all 2-drug regimens contained ZDV and 3TC, except 1 study in which ZDV and zalcitabine were prescribed. 88 Antiretrovirals provided as a part of 3-drug regimens included ZDV, 3TC, NFV, IDV, LPV/r, NVP, efavirenz (EFV), or co-formulated FTC/TDF with coformulated LPV/r. Nausea, vomiting, diarrhea, and fatigue were the most commonly reported side effects. 20 Serious side effects have been reported occasionally (e.g., nephrolithiasis and hepatitis) in the literature.  Rarely, severe hepatotoxicity has been observed among patients administered NVP-containing regimens for both oPEP and nPEP, including a female health care worker who required a liver transplantation after taking oPEP 101 ; therefore, CDC advises against use of NVP forPEP. 1,99 Also, since January 2001, product labeling for NVP states that using it as part of a PEP regimen is contraindicated. 102 A retrospective study in western Kenya involved 296 patients who were eligible for and initiated nPEP, including 104 who completed a 28-day course of nPEP; patients received either stavudine (d4T), 3TC and NVP or ZDV, 3TC, and LPV/r. 47 Neither the proportion of patients reporting side effects (14%  and 21% ) nor antiretroviral therapy completion rates differed substantially between the 2 arms. The most commonly reported side effects included epigastric pain, skin rash, and nausea among patients receiving NVP-containing regimens and diarrhea, dizziness, and epigastric pain among those receiving LPV/rcontaining regimens. However, 1 hepatitis-related death of a sexual assault survivor taking a NVP-containing regimen prompted investigators to change to a new PEP regimen containing ZDV, 3TC, and LPV/r. Inclusion of NVP and d4T were initially included in nPEP regimens because of availability and cost but were discontinued in 2005 as a result of adverse events and toxicities among healthy patients. This change was also influenced by a black box warning in the drug labeling for NVP describing increased toxicity among patients on NVP with higher CD4 T lymphocyte (CD4) cell counts.
Commonly used medications in the observational studies of nPEP published after 2005 included ZDV, 3TC, LPV/r, TDF, FTC, and RAL. The majority of regimens involved using 3 drugs (range, 2-4 drugs) with a daily 2-pill burden (range, 1-3 pills). The side-effect profile that included fatigue, nausea, headache, diarrhea, and other gastrointestinal complaints was similar across studies of MSM having mainly consensual sex and studies of sexual assault survivors, including mainly women, children, and a limited proportion of men. 20,23,31,44,103 Two trials, including a total of 602 participants, compared TDF-versus ZDV-containing nPEP regimens; both reported better medication tolerability among participants taking TDF-containing regimens. 49,56 Another study reported fewer side effects among 100 adult participants prescribed a 3-drug nPEP regimen that included RAL, TDF, and TDF compared to historical controls using a 3-drug PEP regimen including ZDV, 3TC, and a RTVboosted PI. 57 In an open-label, nonrandomized, prospective cohort study comparing RAL-FTC-TDF in 86 MSM and FTC-TDF in 34 MSM, 92% and 91% of participants completed 28 days of treatment, respectively, with mean adherences of 89% and 90%, respectively. 17 Use of RAL rather than a PI was associated with the avoidance of 8 prescribed drug, and 37 potential illicit drug, interactions. However, in the RAL arm, 8 recipients (9%) developed mild myalgias, and 4 recipients developed grade 4 elevations in creatinine kinase. Both the myalgias and creatinine kinase elevations improved to grade 2 or less by week 4 without RAL discontinuation. Among 100 MSM in an open-label, single-arm study at 2 public health clinics and 2 hospital EDs in urban areas in Australia, a once daily 28-day nPEP single-pill combination regimen of FTC-rilpivirine (RPV)-TDF was well tolerated with 98.5% adherence by self-report and 92% completion of the 28-day regimen. 19 However, within 1 week of completing nPEP, 1 patient developed acute abdominal pain, vomiting, and grade 4 laboratory evidence of acute pancreatitis (lipase 872 IU/L). The pancreatitis resolved  21 days without need for hospitalization. 19 In a 2-arm open label randomized multicenter clinical trial in EDs in 6 urban hospitals in Barcelona, Spain, comparing ZDV/3TC + LPV/r with ZDV/3TC + atazanavir (ATV), 64% of nPEP recipients in both arms completed the 28-day course and 92% of patients reported taking > 90% of scheduled doses (without difference between arms). 53 Adverse events were reported in 46% of patients overall (49%, LPV/r arm; 43%, ATV arm). Gastrointestinal problems were more common in the LPV/r arm.
A pooled series of case reports revealed that 142 (67%; range, 0%-99%) of 213 children and adolescents who initiated nPEP and who had 1 follow-up visit, reported adverse effects and 139 of 465 (30%; range, 0%-64.7%) children and adolescents who initiated nPEP, completed their course of nPEP. 32, Most commonly reported nPEP regimens included ZDV + 3TC or ZDV + 3TC + (NFV or IDV or LPV/r). Most common adverse events among the 213 participants included nausea (n = 83; 39%), fatigue (n = 58; 27%), vomiting (n = 38; 18%), headache (n = 26; 12%), diarrhea (n = 25; 12%), and abdominal pain (n = 15; 7%).

# V1-B2. Selection of Resistant Virus
In instances where nPEP fails to prevent infection, selection of resistant virus by the antiretroviral drugs is theoretically possible. However, because of the paucity of resistance testing in documented nPEP failures, the likelihood of resistance occurring is unknown.
A case report from Brazil documented a 3TC-resistance mutation on day 28 of therapy in a man treated with ZDV and 3TC who subsequently underwent HIV seroconversion. 16 Although the patient was noted to have taken nPEP, detailed information regarding adherence was unreported. Because the source-person could not be tested, whether the mutation was present at the time of transmission or whether it emerged during nPEP use is unknown.
Rationale for the concern regarding acquiring resistant virus from the exposure that leads to nPEP prescription includes data from an international meta-analysis of 287 published studies of transmitted HIV-1 drug resistance among 50,870 individuals during March 1, 2000-December 31, 2013, including 27 studies and 9,283 individuals from North America. 104 The study-level estimate of transmitted drug resistance in North America was 11.5% (resistance to any antiretroviral drug class), 5.8% (resistance to NRTIs), 4.5% (resistance to NNRTIs, and 3.0% (resistance to PIs).

# VI-B3. Effects of nPEP on Risk Behaviors
The majority of studies examining the association between use and availability of nPEP and sexual risk behaviors during or after its use have been conducted in developed countries, primarily among MSM; no studies related to risk compensation were conducted among persons with injection-related risk factors. 14,16, The majority of these studies did not report increases in high-risk sexual behaviors after receipt of nPEP 14,16,106,110,111 and participants sometimes reported a decrease in sexual risk-taking behavior. 16,106 However, in 3 studies, nPEP users were more likely than persons who did not use nPEP to report having multiple partners and engaging in condomless receptive or insertive anal sex with HIV-infected partners or partners with unknown serostatus after completing nPEP. 14,108,110 In 2 of these studies, nPEP users were also more likely to subsequently become HIV infected than patients who did not use nPEP. 108,110 During 2000-2009 in the Amsterdam Cohort Study, MSM who were prescribed nPEP, compared with a reference cohort of MSM, had an incidence of HIV infection approximately 4 times as high (6.4 versus 1.6/100 person-years). 108 During 2001-2007, MSM in a community cohort study in Sydney, Australia reported continued, but not increased, high-risk sexual behaviors among nPEP users; more specifically, no change in sexual behavior was reported at 6 months after 154 incident nPEP uses and after 18 months for 89 incident nPEP uses. Among those MSM who received nPEP, the hazard ratio of subsequent HIV infection was 2.67 (95% CI = 1.40, 5.08). 110 The authors did not attribute this elevated risk for HIV seroconversion among users of nPEP to nPEP failure but rather to a documented higher prevalence of condomless anal intercourse (CAI) with HIV-infected partners among users of nPEP, compared with persons who did not use nPEP. In summary, users of nPEP, compared with participants who did not use nPEP had a continued higher prevalence of ongoing CAI with HIV-infected persons resulting in a greater likelihood of HIV seroconversion during all periods, especially after completing nPEP. In another study, repeated courses of nPEP were unassociated with risk for subsequent HIV infection. 45 In a study of 99 patients who attended a clinic in Toronto to be evaluated for nPEP during January 1, 2013-September 30, 2014, 31 (31%) met CDC criteria for PrEP initiation. PrEP candidacy in this study was associated with sexual exposure to HIV, prior nPEP use, and lack of drug insurance. Those studies 14,108,110,112 demonstrate that certain nPEP users with ongoing high-risk sexual behaviors might need additional behavioral and biomedical prevention interventions, including PrEP, instead of nPEP. 11,113 One U.S.-based study among 89 MSM that examined risk behavior during the 28-day course of nPEP reported that among participants, 21% reported having insertive or receptive CAI, and 43% reported engaging with  1 partner known to be HIV-positive or of unknown serostatus (i.e., a high-risk partner). 105 Ninety-four percent of participants reporting having high-risk partners also reported having insertive or receptive anal intercourse. Of participants with high-risk partners and who practiced insertive or receptive anal intercourse, 26% reported CAI with their high-risk partner while receiving nPEP. The strongest predictor of CAI during nPEP in that study was HIV engagement, defined as receiving services from an HIV-related organization, donating money to or volunteering for an HIV-related cause, or reading HIV-related magazines and online sites. A nearly 5-fold chance of reporting condomless sex with a high-risk partner during nPEP was associated with each standard deviation increase in HIV engagement (OR 4.7 ). Investigators hypothesized that persons who are more involved with HIV-related services or organizations might be more informed about the effectiveness of nPEP and more likely to perceive themselves to be at less risk for HIV transmission while receiving nPEP and therefore more likely to have CAI. 105 Awareness of nPEP availability, defined as general knowledge of availability of nPEP as a tool for preventing HIV infection after a potential HIV exposure 107 or nPEP use more than once in 5 years, 103 was associated with condomless sex among MSM. 103,107 Additionally, a longitudinal study of MSM in the Netherlands reported no associations existed between any nPEP-related beliefs (e.g., perceiving less HIV or acquired immunodeficiency syndrome (AIDS) threat, given the availability of nPEP, or perceiving high effectiveness of nPEP in preventing HIV) and the incidence of sexually transmitted infections (STIs) or new HIV infection. 109

# VI-C. Antiretroviral Use During Pregnancy
No trials have been conducted to evaluate use or the maternal or fetal health effects of short-term (i.e., 28-day) antiretroviral use as nPEP among pregnant women without HIV infection. However, clinical trials have been conducted and extensive observational data exist regarding use of specific antiretrovirals during pregnancy among HIV-infected women both when initiated as treatment for health benefits to the women and when initiated to reduce mother-to-child HIV transmission. Although duration of antiretroviral use during pregnancy has varied in these trials, it often spans months of pregnancy. Only ZDV is specifically approved for use in pregnancy, but as a result of data from clinical trials, other antiretroviral drugs have been reported to have shortterm safety for pregnant women and their fetuses, and therefore can be considered for nPEP in women who are or who might become pregnant. See Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States for information regarding use of specific antiretrovirals during pregnancy. 114 Additionally, results from ongoing surveillance of major teratogenic effects related to antiretroviral use during pregnancy are described in the Antiretroviral Pregnancy Registry International Interim Report every 6 months. 115 Certain antiretrovirals have been associated with severe side effects, toxicity, potential for teratogenicity, or other untoward effects among pregnant and non-pregnant women with HIV infection 114 and therefore are not recommended for nPEP use (see section VII-F2b. Pregnant Women and Women of Childbearing Potential for a list of antiretroviral medications that should not be used for nPEP in pregnant women). These include EFV, NVP, and d4T plus didanosine (DDI). 114 Using IDV without RTV-boosting demonstrated altered drug metabolism during pregnancy. 116,117 No severe side effects, toxicity, or adverse pregnancy outcomes have been reported to occur among HIV-uninfected women taking antiretrovirals for oPEP or nPEP.
Reports are conflicting regarding whether an association exists of substantial malformations with use of EFV during the first trimester among humans. Studies using cynomolgus monkeys reported a potential association between neurologic congenital malformations and first-trimester use of EFV. 118 Although case reports exist of neurologic defects among infants of women receiving EFV, 119,120 no elevated risk for overall congenital malformations associated with first-trimester EFV exposure have been reported in either prospectively reported pregnancies from the Antiretroviral Pregnancy Registry 115 or from a meta-analysis of 23 studies with birth outcomes from 2,026 live births among women receiving EFV during the first trimester. 121 HIV-infected pregnant women receiving combination antiretroviral regimens that included NVP have been reported to suffer severe hepatic adverse events, including death. However, whether pregnancy increases the risk for hepatotoxic events associated with NVP therapy is unknown. Use of NVP in HIV-infected women (regardless of pregnancy status) with high CD4 counts > 250 cells/mm^3 102 or elevated transaminase levels at baseline 122 has been associated with potentially life-threatening rash and hepatotoxicity. NVP use in 3 HIVinfected women with CD4 counts < 100 cells/mm^3 at baseline has been associated with death among those also taking anti-tuberculosis therapy. 122 Among antiretroviral medication combinations no longer recommended, regimens containing d4T with DDI have been associated with severe maternal lactic acidosis among pregnant HIV-infected women, 123,124 including severe necrotic pancreatic and hepatic steatosis and necrotic cellulitis of the abdominal wall in 1 woman, 123 1 fetal demise (normal for gestational age) at 38 weeks gestation, 124 and 1 postnatal death at age 2 weeks in a 1,000 gram infant with trisomy 18. 123 Additionally, using IDV without RTV-boosting during pregnancy results in substantially lower antepartum exposures of IDV, compared with use of RTV-boosted IDV. 116,117

# VI-D. Behavioral Intervention to Support Risk Reduction During nPEP Use
Study findings from 2 randomized control trials underscore the importance of combining nPEP with behavioral interventions 125 to support continuing risk reduction. In a randomized controlled counseling intervention trial among nPEP recipients at a single U.S. site, investigators compared behavioral effects among those who received 2 (standard) versus 5 (enhanced) risk-reduction counseling sessions. Both interventions were based on social cognitive theory, motivational interviewing, and coping effectiveness. Compared with baseline, a reduction occurred at 12 months in the reported number of condomless sex acts for both intervention arms. The group reporting  4 condomless sex acts during the previous 6 months at baseline benefitted more from the 2session intervention, while persons reporting  5 condomless sex acts during the previous 6 months at baseline revealed a greater reduction of condomless sex acts after receiving the 5-session intervention. 126 These findings demonstrate that more counseling sessions might be necessary for persons reporting higher levels of sexual risk behavior when initiating nPEP. In another randomized control trial, MSM who received contingency management, a substance abuse intervention providing voucher-based incentives for stimulant-use abstinence, had greater nPEP completion rates, greater reductions in stimulant use, and fewer acts of condomless anal intercourse compared with control participants who received incentives that were not contingent on their substance abstinence. 127

# VI-E. Adherence to nPEP Regimens and Follow-up Visits
Difficulties in adherence have been noted in both maintaining adherence to daily doses of antiretroviral medication for 28 days among the majority of populations and adherence to follow-up clinical visits for HIV testing and other care. Such adherence difficulties appear particularly severe in studies of nPEP for sexually assaulted persons. Methods for measuring completion of nPEP medication regimen differed across studies, and loss to follow-up was a major hindrance to assessing medication adherence for the majority of studies.
In a systematic review and meta-analysis of 34 nPEP studies not including sexual assault and 26 nPEP studies including only sexual assault, nPEP completion rates were lowest among persons who experienced sexual assault (40.2% ) and highest among persons who had other nonoccupational exposures (65.6% ). 128 In a separate meta-analysis of 24 nPEP-related studies, including 23 cohort studies and 1 randomized behavioral intervention to improve nPEP adherence, of 2,166 sexually assaulted persons receiving nPEP and pooled across the 24 studies, 40.3% (95% CI = 32.5%-48.1%; range, 11.8%-73.9%) adhered to a 28-day course of nPEP, and 41.2% (95% CI = 31.1%-51.4%; range, 2.9%-79.7%) did not return to pick up their prescribed medication or did not return for follow-up appointments. 20 Medication adherence was measured in 24 studies by using varying methodology, including pill count, volume of syrup remaining, self-report, counts of number of pharmacy visits, recall of number of doses taken by notation on a calendar, number of prescriptions filled, and number of weekly clinic appointments kept. Reported medication adherence was lower in developed countries (n=15 studies, 5 countries) 23,36,38,46,50,58,94,97 compared with developing countries (n=8 studies, three countries) 40,42,93,95,96 (33.3% versus 53.2%, respectively; P=0.007), possibly due to higher awareness of HIV transmission risk in countries with a high HIV prevalence. 20 Eight of the 24 (33%) studies 30,32,46,97 provided nPEP medications at time of initiation of prophylaxis as starter packs including 4-7 days of medication, and 1 study provided either a starter pack of medications or a full 28-day supply of nPEP at initiation. 96 In this latter study, the proportion who adhered to the 28 days of nPEP was 29% for patients initially receiving the starter pack and 71% for patients receiving a full 28-day supply. 96 Although sexually assaulted persons are sometimes at risk for HIV transmission, they often decline nPEP, and many who do take it do not complete the 28-day course. This pattern has been reported in multiple countries and in programs in North America. In Ontario, for example, 798 of 900 eligible sexually assaulted persons were offered nPEP, including 69 and 729 at high or unknown risk for HIV transmission due to the factors associated with their sexual assault, respectively. 23 Forty-six (67%) of 69 persons at high risk for HIV transmission and 301 (41%) of 729 persons with unknown risk accepted and initiated nPEP. Twenty-four percent of patients at high risk and 33% of patients with unknown risk completed the 28-day course. Reasons for discontinuing treatment were documented in 96 cases and included adverse effects (81%), interference with routine (42%), inability to take time away from work or school (22%), and reconsideration of HIV risk (19%).
Of the observational studies of sexually assaulted persons provided nPEP, the majority identified similar challenges. Studies have demonstrated that early discontinuation of medication and a lack of follow-up pose challenges to providing nPEP to sexually assaulted persons. 31,33,47,50 Four international studies examined adherence among both men and women with non-assault sexual and injection drug use risk exposures. 46,48,49,51 Full medication adherence in these studies ranged from 60%-88%; 60% 48 and 79% 51 completed therapy (without specifying how completion was defined) and 67% 48 and 88% 49 completed 28 days or 4 weeks of nPEP. The proportion of MSM who adhered to nPEP medication for 28 days reported in those studies ranged from 42%-91%.
Studies that used a fixed dose combination of ZDV/3TC and LPV/r as primary components in the nPEP drug regimen reported low medication adherence for 28 days (24%-44%). 23,44,47 A study among MSM compared use of a fixed-dose combination regimen containing TDF/FTC with or without RAL (an integrase inhibitor) with ZDV/3TC and a RTV-boosted PI; adherence rates were superior for the TDF-containing regimens (57% -72.7% ) compared with the PI-containing regimen (46%). Although 57% of the TDF/FTC/RAL arm reported taking their medications as directed, an additional 27% took their once daily medication, but sometimes missed their second daily dose of RAL. 57

# VI-F. nPEP Cost-effectiveness
Estimates of cost-effectiveness of nPEP as an HIV prevention method reported in the literature vary by HIV exposure route and estimated prevalence of infection among source persons. A study using data from the San Francisco nPEP program estimated the cost-effectiveness of hypothetical nPEP programs in each of the 96 metropolitan statistical areas in the United States. 129 It included 3 different data sources, including data from clinical care and drug cost data from the San Francisco Department of Public Health nPEP program, 130 estimates of the per-act probability of HIV transmission associated with different modes of sexual and parenteral HIV exposure,  and HIV prevalence data from 96 U.S. metropolitan statistical areas. 134 Investigators estimated the cost-effectiveness of hypothetical nPEP programs as an HIV prevention method in each area compared with no intervention. By defining cost-effective programs as those costing <$60,000/quality-adjusted life year (QALY), that study found nPEP programs were cost-effective across the combined metropolitan statistical areas with a cost utility ratio of $12,567/QALY saved (range, $4,147-$39,101). nPEP was most cost-effective for MSM ($4,907/QALY). It was not cost-effective for needle-sharing persons who inject drugs (PWID) ($97,867/QALY), persons sustaining nonoccupational needlesticks ($159,687/QALY), and receptive female partners ($380,891/QALY) or insertive male partners ($650,792/QALY) in penile-vaginal sex. The hypothetical nPEP program would be cost-saving (cost-utility ratio, <$0) only for men and women presenting with receptive anal intercourse or if nPEP use was limited to clients with known HIV-infected partners. 129 In another study limited to San Francisco, the overall cost-utility ratio for the existing nPEP program was $14,449/QALY saved and for men experiencing receptive anal sex, the nPEP program was cost-saving. 130 Studies in Australia and France reported similar results. For example, in Australia, using a threshold for costeffectiveness of $50,000/QALY, nPEP was cost-effective among persons having CAI with an HIV-infected source ($40,673/QALY). 135 In France, using thresholds for cost-saving and cost-effectiveness of 0/QALY saved and <50,000/QALY saved, respectively, nPEP was cost-saving among men and women who had receptive anal intercourse with an HIV-infected man (-22,141/QALY saved ; and -22,031/QALY saved ) and cost-saving among PWID having shared needles with an HIV-infected person (-1,141/QALY saved). 136 Additionally, these same French and Australian studies, and a Swiss study, reported that HIV testing to determine the status of the source person (when possible) was determined to reduce costs associated with nPEP programs by avoiding unnecessary prophylaxis. 48,135,136

# VI-G. Attitudes, Policies, and Knowledge About nPEP Use Among Health Care Providers and Candidates for nPEP
Since 1997, certain health care providers, health policy makers, and scientific investigators of nPEP have recommended wider availability and/or use of nPEP, 24,131, while others have been more cautious about implementing it in the absence of definitive evidence of efficacy or effectiveness. 145,146  Surveys of health care providers and facilities indicate a low level of awareness and capacity to provide nPEP as well as a lack of access for nPEP for those for whom it is recommended need for more widespread dissemination and implementation of guidelines and protocols for nPEP use and a need for improved access. In a study of 181 patients presenting to the emergency department (ED) who had been sexually assaulted, lack of insurance, older patient age, and acquaintance rape were factors associated with not being offered nPEP. 30 A study evaluating access to nPEP services in 117 health care sites in Los Angeles County through use of Internet searches and telephone surveys, determined that only 14% offered nPEP to clients regardless of insurance status, and an even lower percentage, 8%, offered nPEP to uninsured clients, indicating the need to improve access to such services. 149 A survey in New York State (NYS) reported that among 184 EDs, 88% reported evaluating patients with possible nonoccupational exposures to HIV in accordance with NYS guidelines, however, full implementation of NYS nPEP guidelines was incomplete with 4% neither supplying nor prescribing antiretroviral drugs in the ED and only 22% confirming whether linkage to follow-up care was successful. 150 Screening of STIs, risk-reduction counseling, and education about symptoms of acute HIV seroconversion were not consistently performed according to the NYS guidelines. 150 Additionally, in a survey of 142 HIV health care providers in Miami and the District of Columbia, prescribing nPEP was associated with having patients request nPEP, or having a written nPEP protocol, although most providers reported not having a written nPEP protocol and that patients rarely or never requested nPEP. 151 Lack of prescribing nPEP was associated with believing that nPEP would lead to antiretroviral resistance. 151 More health care providers in the District of Columbia compared with those in Miami, prescribed nPEP (59.7% versus 39.5%, respectively P < 0.048). 152 In a cross-sectional study describing program practices related to HIV testing and nPEP among 174 sexual assault nurse examiner (SANE)/forensic nurse examiner (FNE) programs in the U.S. and Canada, 75% had nPEP policies, 31% provided HIV testing, and 63% offered nPEP routinely or based on patient request. 153 Medication cost was the most important barrier to providing nPEP in these programs.
Awareness, knowledge, and use of nPEP has been described among MSM. 14,15,106,108,110,154 Evidence indicates awareness of nPEP and interest in its use among potential patients. When nPEP studies were established in San Francisco, approximately 400 persons sought treatment during December 1997-March 1999. 106,154 In an HIV prevention trial of 4,295 MSM in 6 U.S. cities during 1999-2003, a total of 2,037 (47%) had heard of nPEP at baseline and 315 (7%) reported using nPEP on 1 occasion. 14 Predictors of nPEP use included having multiple partners, engagement in condomless sex with a known HIV-infected partner or with a partner of unknown HIV status, and use of illicit drugs. Among 1,427 MSM in a community cohort of HIV-negative men in Sydney, Australia, during 2001-2007, knowledge of nPEP increased from 78.5% at baseline to 97.4% by the fifth annual interview, and nPEP use increased from 2.9/100 person-years in 2002 to 7.1/100 person-years in 2007. 110 During 2006-2009, knowledge of nPEP among MSM from urban areas in the Netherlands increased from 46% to 73%. 108 Also, the annual number of PEP prescriptions to MSM in Amsterdam increased 3-fold, from 19 in 2000 to 69 in 2007. 15 In a study of 227 pediatric and adolescent patients aged 9 months-18 years who were evaluated for sexual assault in Atlanta, Georgia, 40% of patients were examined  72 hours after the sexual assault, of whom 81% reported a history of genital or anal trauma. 41 In that study, patients aged 13-18 years and those who reported sexual assault by a stranger were more likely to present to the ED  72 hours after the sexual assault. Health care providers in the hospital's ED where this nPEP study was conducted expressed reluctance to prescribe nPEP to pre-pubertal children. For example, of 87 children and adolescents seen in the ED  72 hours after the assault, 23 had anogenital trauma or bleeding, and 5 were offered nPEP.

# VII. PATIENT MANAGEMENT GUIDELINES VII-A. Initial Evaluation of Persons Seeking Care After Potential Nonoccupational Exposure to HIV
Effective delivery of nPEP after exposures that carry a substantial risk for HIV infection requires prompt evaluation of patients and consideration of biomedical and behavioral interventions to address current and ongoing health risks. The initial evaluation provides the information necessary for determining if nPEP is indicated (Figure 1).

# Figure 1. Algorithm for evaluation and treatment of possible nonoccupational HIV exposures
Procedures at the evaluation visit include determining the HIV infection status of the potentially exposed person and the source person (if available), the timing and characteristics of the exposure for which care is being sought, and the frequency of possible HIV exposures. Additionally, to determine whether other treatment or prophylaxis is indicated, health care providers should assess the likelihood of STIs, infections efficiently transmitted by injection practices or needlesticks (e.g., hepatitis B or hepatitis C virus), and pregnancy for women.

# VII-A1. HIV Status of the Potentially Exposed Person
nPEP is only indicated for potentially exposed persons without HIV infection. Because potentially exposed persons might have acquired HIV infection already and be unaware of it, routine HIV antibody testing should be performed on all persons seeking evaluation for potential nonoccupational HIV exposure. If possible, this should be done with an FDA-approved rapid antibody or Ag/Ab blood test kit with results available within an hour. If HIV blood test results will be unavailable during the initial evaluation visit, a decision whether nPEP is indicated should be made based on the initial assumption that the potentially exposed patient is not infected. If medication of HIV prophylaxis is indicated by the initial evaluation and started, it can be discontinued if the patient is later determined to already have HIV infection.

# VII-A2. Timing and Frequency of Exposure
Available data from animal studies indicate that nPEP is most effective when initiated as soon as possible after HIV exposure; it is unlikely to be effective when instituted > 72 hours after exposure. 83 Therefore, persons should seek nPEP as soon as possible after an exposure that might confer substantial risk and health care providers should evaluate such patients rapidly and initiate nPEP promptly when indicated.
nPEP should be provided only for infrequent exposures. Persons who engage in behaviors that result in frequent, recurrent exposures that would require sequential or near-continuous courses of antiretroviral medications (e.g., HIV-discordant sex partners who inconsistently use condoms or PWID who often share injection equipment) should not be prescribed frequent, repeated courses of nPEP. Instead, health care providers should provide persons with repeated HIV exposure events (or coordinate referrals for) intensive sexual or injection risk-reduction interventions, and consider the prescription of daily oral doses of the fixed-dose combination of TDF and FTC (Truvada, Gilead Sciences, Inc., Foster City, California) for PrEP. 11 However, if the most recent recurring exposure is within the 72 hours prior to an evaluation, nPEP may be indicated with transition of the patient to PrEP after completion of 28 days of nPEP medication.
In the special case of children with evidence of chronic sexual abuse who come to the attention of a health care provider  72 hours after their most recent exposure, nPEP can be considered on a case-by-case basis. In addition, child protective services should be engaged for consideration of removal of the child from exposure to the perpetrator of the sexual abuse.

# VII-A3. HIV Acquisition Risk from the Exposure
In addition to determining when the potential exposure occurred, determining whether nPEP is indicated requires assessing if the reported sexual, injection drug use, or other nonoccupational exposure presents a substantial risk for HIV acquisition. Health care providers should consider 3 main factors in making that determination: (1) whether the exposure source is known to have HIV infection, (2) to which potentially infected body fluid(s) the patient was exposed, and (3) the exposure site or surface.
The highest level of risk is associated with exposure of susceptible tissues to potentially infected body fluid(s) from persons known to have HIV infection, particularly those who are not on antiretroviral treatment. Persons with exposures to potentially infectious fluids from persons of unknown HIV status are at unknown risk for acquiring HIV infection. When the source of exposure is known to be from a group with a high prevalence of HIV infection (e.g., a man who has sex with men or a PWID who shares needles or other injection equipment), the risk for unrecognized HIV infection in the source is increased.
The estimated per-act transmission risk, when exposed to infectious fluid(s) from a person with HIV infection, varies considerably by exposure route (Table 1). 155 The highest estimated per-act risks for HIV transmission are associated with blood transfusion, needle sharing during injection drug use, receptive anal intercourse, and percutaneous needlestick injuries. Insertive anal intercourse, insertive penile-vaginal intercourse, and oral sex represent substantially lower per-act transmission risk. A history should be taken of the specific sexual, injection drug use, or other exposure events that can lead to acquiring HIV infection. Eliciting a complete description of the exposure and information about the HIV status of the partner(s) can substantially lower (e.g., if the patient was exclusively the insertive partner or a condom was used) or increase (e.g., if the partner is known to be HIV-positive) the estimate of risk for HIV transmission resulting from a specific exposure.
Percutaneous injuries from needles discarded in public settings (e.g., parks and buses) sometimes result in requests for nPEP. Although no HIV infections from such injuries have been documented, concern exists that syringes discarded by PWID might pose a substantial risk. However, such injuries typically involve small-bore needles that contain only limited amounts of blood, and the infectiousness of any virus present might be low. 156,157 Saliva that is not contaminated with blood contains HIV in much lower titers and constitutes a negligible exposure risk, 158 but saliva that is contaminated with HIV-infected blood poses a substantial exposure risk. HIV transmission by this route has been reported in  4 cases. 

# VII-A4. HIV Status of the Exposure Source
When the exposure source's HIV status is unknown, that person's availability for HIV testing should be determined. When the source person is available and consents to HIV testing, a clinical evaluation visit should be arranged that includes HIV testing by using a fourth-generation combined Ag/Ab test. The risk for transmission might be especially great if the source person has been infected recently because the viral burden in blood and semen might be particularly high. 163,164 However, ascertaining this in the short time available for the initial nPEP evaluation might not be possible. If the risk associated with the exposure is high, starting nPEP and then making a decision whether to continue nPEP after the source's HIV status is determined is recommended.
If the exposure source is known to have HIV infection at the time of the nPEP evaluation visit and consents, the health care provider should attempt to interview that person or that source person's health care provider to determine the history of antiretroviral use and most recent viral load. That information might help guide the choice of nPEP medications to avoid prescribing antiretroviral medications to which the source-virus is likely to be resistant. If the person with HIV infection is willing, the clinician might consider drawing blood for viral load and resistance testing, the results of which might be useful in modifying the initial nPEP medications if the results can be obtained promptly. 165

# VII-B. Laboratory Testing
Laboratory testing is required to (1) document the HIV infection status of the person presenting for nPEP evaluation (and the exposure source when available and consent has been granted), (2) identify and clinically manage any other conditions potentially resulting from sexual-or injection-related exposure to potentially infected body fluids, (3) identify any conditions that would affect the nPEP medication regimen, and (4) monitor for safety or toxicities related to the regimen prescribed (Table 2).  d If exposed person susceptible to hepatitis C at baseline. e If determined to be infected with syphilis and treated, should undergo serologic syphilis testing 6 months after treatment f Testing for chlamydia and gonorrhea should be performed using nucleic acid amplification tests. For patients diagnosed with a chlamydia or gonorrhea infection, retesting 3 months after treatment is recommended.
- For men reporting insertive vaginal, anal, or oral sex, a urine specimen should be tested for chlamydia and gonorrhea.
- For women reporting receptive vaginal sex, a vaginal (preferred) or endocervical swab or urine specimen should be tested for chlamydia and gonorrhea. - For men and women reporting receptive anal sex, a rectal swab specimen should be tested for chlamydia and gonorrhea.
- For men and women reporting receptive oral sex, an oropharyngeal swab should be tested for gonorrhea.
() g If not provided presumptive treatment at baseline, or if symptomatic at follow-up visit. h If woman of reproductive age, not using effective contraception, and with vaginal exposure to semen. i eCrCl = estimated creatinine clearance calculated by the Cockcroft-Gault formula; eCrClCG =   (serum creatinine x 72) (x 0.85 for females). j At first visit where determined to have HIV infection.

# VII-B1. HIV Testing
All patients initiating nPEP after potential HIV exposure should be tested for the presence of HIV-1 and HIV-2 antigens and antibodies in a blood specimen at baseline (before nPEP initiation), preferably using a rapid test. Patients with baseline rapid tests indicating existing HIV infection should not be started on nPEP. Patients for whom baseline HIV rapid test results indicate no HIV infection or rapid HIV test results are not available should be offered nPEP. There should be no delay in initiation of nPEP while awaiting baseline HIV test results. Repeat HIV testing should occur at 4-6 weeks and 3 months after exposure to determine if HIV infection has occurred. See  regarding information on approved HIV tests. Oral HIV tests are not recommended for use among persons being evaluated for nPEP.
Additionally, persons whose sexual or injection-related exposures results in concurrent acquisition of HCV and HIV infection might have delayed HIV seroconversion. This has been documented among MSM with sexual exposure 13 and health care personnel receiving oPEP for needlestick exposures. 166,167 Therefore, for any person whose HCV antibody test is negative at baseline but positive at 4-6 weeks after the exposure, HIV antibody tests should be conducted at 3 and 6 months to rule out delayed seroconversion (see Table 2).

# VII-B2. Recognizing Acute HIV Infection at Time of HIV Seroconversion
Persons initiating nPEP, if it fails, may experience signs and symptoms of acute HIV infection while on nPEP. At the initial visit, patients should be instructed about the signs and symptoms associated with acute (primary) HIV infection (Table 3), especially fever and rash, 168 and asked to return for evaluation if these occur during the 28 days of prophylaxis or anytime within a month after nPEP concludes. Acute HIV infection is associated with high viral load. However, health care providers should be aware that available assays might yield low viral-load results (e.g., <3,000 copies/ml) among persons without HIV infection (i.e., false-positives). Without confirmatory tests, such false-positive results can lead to misdiagnoses of HIV infection. 171 Transient, low-grade viremia has been observed among persons exposed to HIV who were administered antiretroviral nPEP and did not become infected. In certain cases, this outcome might represent aborted infection rather than false-positive test results, but this can be determined only through further testing.
All patients who have begun taking nPEP and for whom laboratory evidence later confirms acute HIV infection at baseline or whose follow-up antibody testing indicates HIV infection, should be transferred rapidly to the care of an HIV treatment specialist (if nPEP was provided by another type of health care provider). If the patient is taking a 3-drug antiretroviral regimen for nPEP at the time of HIV infection diagnosis, the 3-drug regimen should not be discontinued by the nPEP provider until the patient has been evaluated and a treatment plan initiated by an experienced HIV care provider. 173

# VII-B3. STI Testing
Any sexual exposure that presents a risk for HIV infection might also place a person at risk for acquiring other STIs. 174 For all persons evaluated for nPEP because of exposure during sexual encounters, STI-specific nucleic acid amplification (NAAT) testing is recommended for gonorrhea and chlamydia, 174 by testing first-catch urine or with swabs collected from each mucosal site exposed to potentially infected body fluids (oral, vaginal, cervical, urethral, rectal). 174,175 Additionally, blood tests for syphilis should be conducted for all persons evaluated for nPEP.

# VII-B4. HBV Testing
HBV infection is of specific concern when considering nPEP for 2 reasons. First, multiple medications used for nPEP, including 2 in the preferred regimen (TDF and FTC) are active against HBV infection. For safety reasons, health care providers need to know if a patient has active HBV infection (positive hepatitis B surface antigen ) so that the patient can be closely monitored for reactivation "flare ups" when nPEP is stopped, and treatment for HBV infection is discontinued.

# VII-B5. Pregnancy Testing
nPEP is not contraindicated for pregnant women. Moreover, because pregnancy has been demonstrated to increase susceptibility to sexual HIV acquisition, 178 nPEP can be especially important for women who are pregnant at the time of sexual HIV exposure.
For women of reproductive capacity who have had genital exposure to semen and a negative pregnancy test when evaluated for possible nPEP, current contraception use should be assessed, and if a risk for pregnancy exists, emergency contraception should be discussed with the patient.

# VII-B6. Baseline and Follow-up Testing to Assess Safety of Antiretroviral Use for nPEP
All patients who will be prescribed nPEP should have serum creatinine measured and an estimated creatinine clearance calculated at baseline to guide selection of a safe and appropriate antiretroviral regimen for nPEP. Also, health care providers treating patients with nPEP should monitor liver function, renal function, and hematologic parameters when indicated by the prescribing information for the antiretrovirals prescribed. Drugspecific recommendations are available at the online AIDSInfo Drugs Database at:  or the antiretroviral treatment guidelines. 114,173,179 Unusual or severe toxicities from antiretroviral drugs should be reported to the manufacturer or FDA (, or 1-800-FDA-1088 ).
If nPEP is prescribed to a woman who is pregnant at the time of exposure or becomes pregnant while on nPEP, health care providers should enter the patient's information (anonymously) into the Antiretroviral Pregnancy Registry ().

# VII-C. Recommended Antiretroviral nPEP Regimens
A 28-day course of nPEP is recommended for HIV-uninfected persons who seek care  72 hours after a nonoccupational exposure to blood, genital secretions, or other potentially infected body fluids of persons known to be HIV infected or of unknown HIV status when that exposure represents a substantial risk for HIV acquisition. Since adherence is critical for nPEP efficacy, it is preferable to select regimens that minimize side effects, number of doses per day and the number of pills per dose.
No strong evidence exists, based on randomized clinical trials, that any specific combination of antiretroviral medication is optimal for nPEP use. Although a limited number of studies have evaluated the penetration of antiretroviral medications into genital tract secretions and tissues,  evidence is insufficient for recommending a specific antiretroviral medication as most effective for nPEP for sexual exposures. Therefore, the recommended regimens for nPEP in these guidelines are based on expert opinion from the accumulated experience with antiretroviral combinations that effectively suppress viral replication among HIV-infected persons for the purpose of HIV treatment and mainly observational studies of the medication tolerance and adherence when these same drugs are taken for nPEP.
The recommendation for a 3-drug antiretroviral regimen is based on extrapolation of data demonstrating that the maximal suppression of viral replication occurs among persons with HIV infection when combination antiretroviral therapy with 3 drugs is provided. Also, the likelihood of protection against acquiring resistant virus would be greater with a 3-drug regimen compared with a 2-drug regimen. Recommending a 3-drug regimen for all patients who receive nPEP will increase the likelihood of successful prophylaxis in light of potential exposure to virus with resistance mutation(s) and will provide consistency across PEP guidelines for both nPEP and oPEP. 2 Additionally, if infection occurs despite nPEP, a 3-drug regimen will more likely limit emergence of resistance than a 2-drug regimen.   b Ritonavir is used in clinical practice as a pharmacokinetic enhancer to increase the trough concentration and prolong the half-life of darunavir, lopinavir, and other protease inhibitors. Ritonavir is not counted as a drug directly active against HIV in the above "3drug" regimens. c Gilead Sciences, Inc., Foster City, California. d See also Table 6. e Darunavir only FDA-approved for use among children aged  3 years. f Children should have attained a postnatal age of  28 days and a postmenstrual age (i.e., first day of the mother's last menstrual period to birth plus the time elapsed after birth) of  42 weeks. g AbbVie, Inc., North Chicago, Illinois.  Health care providers might consider using antiretroviral regimens for nPEP other than those listed as preferred or alternative because of patient-specific information (e.g., an HIV-infected exposure source with known drugresistance or contraindications to 1of the antiretrovirals in a preferred regimen). In those cases, health care providers are encouraged to seek consultation with other health care providers knowledgeable in using antiretroviral medications for similar patients (e.g., children, pregnant women, those with comorbid conditions) (Appendix 4).
Providers should be aware that abacavir sulfate (Ziagen, ViiV Healthcare, Brentford, Middlesex, United Kingdom) should not be prescribed in any nPEP regimen. Prompt initiation of nPEP does not allow time for determining if a patient has the HLA-B*5701 allele, the presence of which is strongly associated with a hypersensitivity syndrome that can be fatal. 183 Health care providers and patients who are concerned about potential adherence and toxicity or the additional cost associated with a 3-drug antiretroviral regimen might consider using a 2-drug regimen (i.e., a combination of 2 NRTIs or a combination of a PI and a NNRTI). However, this DHHS guideline recommends a 3-drug regimen in all cases when nPEP is indicated.

# VII-D. Prophylaxis for STIs and Hepatitis
All adults and adolescents with exposures by sexual assault should be provided with prophylaxis routinely for STIs and HBV, 174 as follows:
- For gonorrhea, (male and female adults and adolescents), o ceftriaxone 250 mg intermuscular, single dose; o plus azithromycin, 1 g, orally, single dose;
- For chlamydia (male and female adults and adolescents), o azithromycin, 1 g, orally, single dose o or doxycycline, 100 mg, orally, twice a day for 7 days.
- For trichomonas (female adults and adolescents), o metronidazole, 2 g, orally, single dose o or tinidazole, 2 g, orally, single dose All persons not known to be previously vaccinated against HBV, should receive hepatitis B vaccination (without hepatitis B immune globulin), 174 with the first dose administered during the initial examination. If the exposure source is available for testing and is HBsAg-positive, unvaccinated nPEP patients should receive both hepatitis B vaccine and hepatitis B immune globulin during the initial evaluation. Follow-up vaccine doses should be administered during 1-2 months and at 4-6 months after the first nPEP dose. Previously vaccinated sexually assaulted persons who did not receive postvaccination testing should receive a single vaccine booster dose.
HPV vaccination is recommended for female survivors aged 9-26 years and male survivors aged 9-21 years. For MSM with who have not received HPV vaccine or who have been incompletely vaccinated, vaccine can be administered through age 26 years. The vaccine should be administered to sexual assault survivors at the time of the initial examination, and follow-up dose administered at 1-2 months and 6 months after the first dose. 174 Routine use of STI prophylaxis is not recommended for sexually abused or assaulted children. 174

# VII-E. Considerations for All Patients Treated with Antiretroviral nPEP
The patient prescribed nPEP should be counseled regarding potential associated side effects and adverse events specific to the regimen prescribed. Any side effects or adverse events requiring immediate medical attention should be emphasized.

# VII-E1. Provision of nPEP Starter Packs or a 28-day Supply at Initiation
Patients might be under considerable emotional stress when seeking care after a potential HIV exposure and might not be attentive to, or remember, all the information presented to them before making a decision regarding nPEP. Health care providers should consider giving an initial prescription for 3-7 days of medication (i.e., a starter pack) or an entire 28-day course and scheduling an early follow-up visit. Provision of the entire 28-day nPEP medication supply at the initial visit rather than a starter pack of 3-7 days has been reported to increase likelihood of adherence, especially when patients find returning for multiple follow-up visits difficult. 96,184 Routinely providing starter packs or the entire 28-day course requires that health care providers stock nPEP drugs in their practice setting or have an established agreement with a pharmacy to stock, package and urgently dispense nPEP drugs with required administration instructions. At the patient's second visit, health care providers can discuss the results of baseline HIV blood testing (if rapid tests were not used), provide additional counseling and support, assess medication side effects and adherence, or provide an altered nPEP medication regimen if indicated by side effects or laboratory test results. nPEP starter packs or 28-day supplies might also include such medications as antiemetics to alleviate recognized side effects of the specific medications prescribed, if they occur. Health care providers should counsel patients regarding which side effects might occur (Table 6), how to manage them, and when to contact the provider if they do not resolve. 173

# VII-E2. Expert Consultation
When health care providers are inexperienced with prescribing or managing patients on antiretroviral medications or when information from persons who were the exposure source indicates the possibility of antiretroviral resistance, consultation with infectious disease or other HIV-care specialists, if available immediately, is warranted before prescribing nPEP to determine the correct regimen. Similarly, consulting with specialists with experience using antiretroviral drugs is advisable when considering prescribing nPEP for certain persons-pregnant women (infectious disease specialist or obstetrician), children (pediatrician), or persons with renal dysfunction (infectious disease specialist or nephrologist). However, if such consultation is not available immediately, nPEP should be initiated promptly and, if necessary, revised after consultation is obtained. Expert consultation can be obtained by calling the PEPline at the National Clinician's Consultation Center at 888-448-4911 (additional information is available at /).

# VII-E3. Facilitating Adherence
Observational studies have reported that adherence to nPEP regimens is often inadequate and has been especially so among sexual assault survivors. Medication adherence can be facilitated by (1) prescribing medications with fewer side effects, fewer doses per day, and fewer pills per dose; (2) educating the patient regarding potential side effects of the specific medications prescribed and providing medications to assist if side effects occur (e.g., antiemetics); (3) recommending medication adherence aids (e.g., pill boxes); (4) helping patients incorporate doses into their daily schedules; and (5) providing a flexible and proactive means for patient-health care provider contact during the nPEP period. 185,186 Also, establishing a trusting relationship and maintaining good communication about adherence can help to improve completion of the nPEP course. Adherence to the nPEP medications prescribed to children will depend on the involvement of and support provided to parents and guardians.

# VII-E4. HIV Prevention Counseling
The majority of persons who seek care after a possible HIV exposure do so because of failure to initiate or maintain effective risk-reduction behaviors. Notable exceptions are sexual assault survivors and persons with community-acquired needlestick injuries.
Although nPEP can reduce the risk for HIV infection, it is not always effective. Therefore, patients should practice protective behaviors with sex partners (e.g., consistent condom use) or drug-use partners (e.g., avoidance of shared injection equipment) throughout the nPEP course to avoid transmission to others if they become infected and after nPEP to avoid future HIV exposures.
At follow-up visits, when indicated, health care providers should assess their patients' needs for behavioral intervention, education, and services. This assessment should include frank, nonjudgmental questions about sexual behaviors, alcohol use, and illicit drug use. Health care providers should help patients identify ongoing risk concerns and develop plans for improving their use of protective behaviors. 187 To help patients obtain indicated interventions and services, health care providers should be aware of local resources for high-quality HIV education and ongoing behavioral risk reduction, counseling and support, inpatient and outpatient alcohol and drug-treatment services, family and mental health counseling services, and support programs for HIV-infected persons. Information regarding publicly funded HIV prevention programs can be obtained from state or local health departments.

# VII-E5. Providing PrEP After nPEP Course Completion
Persons who engage in behaviors that result in frequent, recurrent exposures that would require sequential or near-continuous courses of nPEP should be offered PrEP 11 at the conclusion of their 28-day nPEP medication course. Because no evidence exists that prophylactic antiretroviral use delays seroconversion and nPEP is highly effective when taken as prescribed, a gap is unnecessary between ending nPEP and beginning PrEP. Upon documenting HIV-negative status, preferably by using an Ag/Ab test, daily use of the fixed dose combination of TDF (300mg) and FTC (200 mg) can begin immediately for patients for whom PrEP is indicated. Clinicians with questions about prescribing PrEP, are encouraged to call the PrEPline 855-448-7737 at the National Clinician Consultation Center or go to their website (/).

# VII.E6. Providing nPEP in the Context of PrEP
Patients fully adhering to a daily PrEP regimen as recommended by their health care practitioner are not in need of nPEP if they experience a potential HIV exposure while on PrEP. PrEP is highly effective when taken daily or near daily. 11,188 For patients who report that they take their PrEP medication sporadically and those who did not take it within the week before the recent exposure, initiating a 28-day course of nPEP might be indicated. In that instance, all nPEP baseline and follow-up laboratory evaluations should be conducted. After the 28-day nPEP regimen is completed, if confirmed to be HIV uninfected, the daily PrEP regimen can be reinitiated.

# VII-E7. Management of Source Persons with HIV Infection
When persons who were the exposure source are present during the course of evaluating a patient for potential HIV exposure, health care providers should also assess that person's access to relevant medical care, behavioral intervention, and social support services. If needed care cannot be provided directly, health care providers should help HIV-infected source persons obtain care in the community (/).

# VII-F. Additional Considerations

# VII-F1. Reporting and Confidentiality
As with all clinical care, health care providers should handle nPEP evaluations with confidentiality. Confidential reporting of STIs and newly diagnosed HIV infections to health departments should occur as indicated by that jurisdiction's local laws and regulations.
For cases of sexual assault, health care providers should document their findings and assist patients with notifying local authorities. 174 How health care providers should document and report their findings is beyond the scope of these guidelines. Laws in all 50 states strictly limit the evidentiary use of a survivor's previous sexual history, including evidence of previously acquired STIs, to avoid efforts to undermine the credibility of the survivor's testimony. Evidentiary privilege against revealing any aspect of the survivor's examination or medical treatment also is enforced in the majority of most states.
Certain states and localities have special programs that provide reimbursement for medical therapy, including antiretroviral medication after sexual assault, and those areas might have specific reporting requirements. In all states, sexually assaulted persons are eligible for reimbursement of medical expenses through the U.S. Department of Justice Victim's Compensation Program in cases where the sexual assault is reported to the police ().When the sexual abuse of a child is suspected or documented, the clinician should report it in compliance with that jurisdiction's laws and regulations.

# VII-F2. Special Populations

# VII-F2a. Sexually Assaulted Persons
Eighteen percent of a national sample of adult women in the United States reported having ever been raped, and approximately 1 in 10 women (9.4%) has been raped by an intimate partner during her lifetime. 189 Sexual assault also occurs among men. Approximately 1 in 71 men (1.4%) in the United States has been raped at some time in his life. 189 In 1 series from an ED, 5% of reported rapes involved men sexually assaulted by men. 190 Sexual assault typically has multiple characteristics that increase the risk for HIV transmission if the assailant is infected. In 1 prospective study of 1,076 sexually assaulted person, 20% had been attacked by multiple assailants, 39% had been assaulted by strangers, 17% had had anal penetration, and 83% of females had been penetrated vaginally. Genital trauma was documented among 53% of those assaulted, and sperm or semen was detected in 48%. 191 Often, in both stranger and intimate-partner rape, condoms are not used 192,193 and STIs are frequently contracted.  In the largest study 198 examining prevalence of HIV infection among sexual assailants, 1% of men convicted of sexual assault in Rhode Island were HIV infected when they entered prison, compared with 3% of all prisoners and 0.3% of the general male population. Persons provided nPEP after sexual assault or child sexual abuse should be examined and co-managed by professionals specifically trained in assessing and counseling patients and families during these circumstances (e.g., Sexual Assault Nurse Examiner  program staff). Local SANE programs can be located at /. Patients who have been sexually assaulted will benefit from supportive services to improve adherence to nPEP if it is prescribed, and from crisis, advocacy, and counseling services provided by sexual assault crisis centers.

# VII-F2b. Pregnant Women and Women with Childbearing Potential
Information is being collected regarding safe use of antiretroviral drugs for pregnant and breastfeeding women who do not have HIV infection, particularly those whose male partners have HIV infection and who use antiretrovirals as PrEP. 114 Because considerable experience has been gained in recent years in the safe and recommended use of antiretroviral medications during pregnancy and breastfeeding among women with HIV infection-either for the benefit of the HIV-infected woman's health or to prevent transmission to newbornsand because of the lack of similar experience in HIV-uninfected pregnant women, nPEP drug recommendations (Table 5) rely on those used for HIV-infected women during pregnancy and breastfeeding.
Health care providers should be aware that certain medications are contraindicated for use as nPEP among potentially or actually pregnant women as follows (Table 7):
- Efavirenz (EFV) is classified as FDA pregnancy Category D because of its potential teratogenicity when used during the first 5-6 weeks of pregnancy. 199 It should be avoided in nPEP regimens for HIVuninfected women during the first trimester and should not be used for women of childbearing age who might become pregnant during an antiretroviral prophylaxis course. For all women with childbearing potential, pregnancy testing must be done before the EFV initiation, and women should be counseled regarding potential risks to the fetus and the importance of avoiding pregnancy while on an EFVcontaining regimen. 114 - Prolonged use of stavudine (d4T) in combination with didanosine (DDI) for HIV-infected pregnant women has been associated with maternal and fetal morbidity attributed to lactic acidosis; therefore, this combination is not recommended for use in an nPEP regimen during pregnancy. 123,124 - Because using indinavir (IDV) is associated with increased risk for nephrolithiasis among pregnant women and its use without co-administration of a ritonavir as a boosting agent can result in substantially decreased plasma levels of IDV (the active agent) among pregnant women, IDV should not be used as nPEP for pregnant women.
- Severe hepatotoxicity has been observed among patients administered nevirapine (NVP)-containing nPEP regimens (regardless of pregnancy status); therefore, NVP is contraindicated for nPEP, including for pregnant women. 83 If nPEP is prescribed to a woman who is pregnant at the time of exposure or becomes pregnant while on nPEP, health care providers should enter the patient's information (anonymously) into the Antiretroviral Pregnancy Registry ().

# VII-F2c. Incarcerated Persons
Approximately 2 million persons are incarcerated in jails and prisons and can be at risk for HIV infection acquisition during incarceration. Studies have indicated that the risk for becoming infected while incarcerated is probably less than the risk outside a facility  ; nevertheless, correctional facilities should develop protocols for nPEP to help reduce the legal, emotional and medical problems associated with an exposure event for this vulnerable population. As foundation for nPEP provision when it is indicated, correctional facilities should provide HIV education, voluntary HIV testing, systems to assist in identifying potential HIV exposures without repercussion for inmates, and provision of nPEP evaluation and medication. Sexual assaults in particular can put inmates at risk for HIV acquisition and inmates may engage in behaviors that put them at risk for HIV acquisition both prior to being incarcerated and upon reentry into the community. A 15-minute interactive educational program designed to educate inmates about nPEP resulted in a 40% increase in knowledge compared to baseline regardless of inmate-related demographics or HIV-risk characteristics. 203 The federal Bureau of Prisons has published a clinical practice guideline that integrates guidance for nonoccupational and occupational HIV-related exposures. 204 Those guidelines specific to nPEP represent an adaptation of the 2005 CDC nPEP guidelines and outline HIV postexposure management recommendations for the different exposure types. The federal Bureau of Prisons nPEP recommendations can be modified for use in correctional facilities of varying sizes and resources. The Bureau of Prisons guidelines provide practical materials for both correctional health care providers and inmates and include worksheets to assist health care providers in systematically documenting HIV exposures and nPEP therapy management, and sample patient consent forms. They recommend that each correctional facility develop its own postexposure management protocol. The CDC recommends that health care providers should make every effort to use of current CDC guidelines related to selection of nPEP antiretrovirals.

# VII-F2d. PWID
A history of injection drug use should not deter health care providers from prescribing nPEP if the exposure provides an opportunity to reduce the immediate risk for acquisition of HIV infection. A survey of health care providers who treat PWID determined a high degree of willingness to provide nPEP after different types of potential HIV exposure. 202 When evaluating whether exposures are isolated, episodic, or ongoing, health care providers should assess whether persons who continue to engage in injecting or sexual HIV risk behaviors are practicing risk reduction (e.g., not sharing syringes, using a new sterile syringe for each injection, and using condoms with every partner or client). For certain persons, a high-risk exposure might be an exceptional occurrence and merit nPEP despite their ongoing general risk behavior. For other persons, the risk exposures might be frequent enough to merit consideration of PrEP either instead of nPEP or after a 28-day nPEP course.
PWID should be assessed for their interest in substance abuse treatment and their knowledge and use of safe injecting and sexual practices. Patients desiring substance abuse treatment should be referred for such treatment. Persons who continue to inject or who are at risk for relapse to injection drug use should be instructed regarding use of a new sterile syringe for each injection and the importance of avoiding sharing injection equipment. In areas where programs are available, health care providers should refer such patients to sources of sterile injection equipment. When sexual practices can result in ongoing risk for HIV acquisition, referral for sexual risk-reduction interventions is recommended.
None of the preferred or alternative antiretroviral drugs recommended for nPEP in Table 5 have substantial interactions with methadone or buprenorphine. However, other antiretrovirals might decrease or increase methadone levels; therefore, health care providers electing to use antiretrovirals not specifically recommended for nPEP should check for interactions before prescribing to persons on opiate substitution therapy. For example, RTV-boosted DRV can decrease methadone levels marginally (within acceptable clinical range), and careful monitoring for signs and symptoms of withdrawal is advised. 205

# VII-F3. Special Legal and Regulatory Concerns

# VII-F3a. HIV Testing of Exposure Source Patients
When approaching persons who were the exposure source for patients being considered for nPEP, health care providers should be aware of potential legal concerns related to requesting them to undergo HIV testing. During 2011, a total of 33 states had  1 HIV-specific criminal exposure laws. 206 These laws focus explicitly on persons living with HIV. HIV-specific criminal laws criminalize or impose additional penalties on certain behaviors (e.g., sexual activity or needle-sharing without disclosure of HIV-positive status) and sex offenses. In jurisdictions where consent to HIV testing might invoke legal repercussions (see /), the exposure source person should be made aware of possible legal jeopardies. Health care providers can opt instead to make nPEP treatment decisions without HIV testing of the source.

# VII-F3b. Adolescents and Clinical Preventive Care
Health care providers should be aware of local laws and regulations that govern which clinical services adolescent minors can access with or without prior parental consent. In certain jurisdictions, minors of particular ages can access contraceptive services, STI diagnosis and treatment, or HIV testing without parental or guardian consent. In fewer settings, minors can access clinical preventive care (e.g. vaccines, nPEP, or PrEP). 207 To provide and coordinate care when a minor presents for possible nPEP, health care providers should understand their local regulations and institutional policies guiding provision of clinical preventive care to adolescent minors.

# VII-F4. Potential Sources of Financial Assistance for nPEP Medication
Antiretroviral medications are expensive, and certain patients are unable to cover the out-of-pocket costs. When public, privately purchased, or employer-based insurance coverage is unavailable, health care providers can assist patients with obtaining antiretroviral medications through the medication assistance programs of the pharmaceutical companies that manufacture the prescribed medications. Applications are available online that can be faxed to the company or certain companies can be called on an established phone line. Requests for assistance often can be handled urgently so that accessing medication is not delayed. Information for specific medications and manufacturers is available at .

# VIII. CONCLUSION
Accumulated data from human clinical and observational studies, supported by data from animal studies, indicate that using antiretroviral medication initiated as soon as possible 72 hours after sexual, injection drug use, or other substantial nonoccupational HIV exposure and continued for 28 days might reduce the likelihood of HIV acquisition. Because of these findings, DHHS recommends prompt initiation of nPEP with a combination of antiretroviral medications when persons seek care 72 hours after exposure, the source is known to be HIV infected, and the exposure event presents a substantial risk for HIV acquisition by an exposed, uninfected person. When the HIV status of the source is unknown and the patient seeks care 72 hours after exposure, DHHS does not recommend for or against nPEP, but encourages health care providers and patients to weigh the risks and benefits on a case-by-case basis. When the HIV acquisition risk is negligible or when patients seek care > 72 hours after a substantial exposure, nPEP is not recommended. A 3-drug nPEP regimen is recommended for all persons for whom nPEP is indicated. Providing a 28-day nPEP supply or a 3-7 day nPEP starter pack at initiation of nPEP might improve adherence. Providing medications to ameliorate specific side effects for the antiretrovirals prescribed might improve adherence to the nPEP regimen. Figure 2 includes a summary of key nPEP considerations.

# Figure 2. nPEP considerations summary

# Initial nPEP Evaluation

# VIII-A. Plans for Updating These Guidelines
These guidelines are intended to assist U.S. health care providers in reducing the occurrence of new HIV infections through the effective delivery of nPEP to the patients most likely to benefit. As new medications and new information regarding nPEP become available, these guidelines will be revised and published.

# X. APPENDICES
Orleans, Louisiana; and Geoffrey Weinberg, MD, University of Rochester Medical Center, School of Medicine and Dentistry, New York.

# CDC Scientific Support Staff
Beverly Bohannon, RN, MS; and Wayne Hairston II, MPH, MBA, ICF International, Atlanta, Georgia.

# CDC editor
C. Kay Smith, Med Abbreviation: nPEP, nonoccupational postexposure prophylaxis.
kinase at baseline; if myalgia or weakness develops, conduct additional during treatment and clinical examination for proximal muscle weakness. Completion rates were higher for this study compared to those in other studies, including similar nPEP regimens. This may have been due to a high level of support provided by the study team including an experienced nPEP nurse, 24-hour contact with the nurse consultant, text reminders of appointments, proactive recall after missed appointments and frequent adherence education.

# Appendix 1A

# Summary of Methods for nPEP Guidelines Development and Roles of Teams and Consultants

# Topic Comment
The guidelines' goal Provide guidance for medical practitioners regarding nPEP use for persons in the United States.

# nPEP Working Group
The nPEP Working Group is composed of 13 members from the Centers for Disease Control and Prevention (CDC) with expertise in nPEP or other subject areas pertinent to the guidelines (e.g., cost-effectiveness, sexual assault, or nPEP adherence), including certain members who were involved in the writing of the previous version(s) of the CDC nPEP guidelines.

# nPEP Writing Group
The nPEP Writing Group is composed of 12 members from CDC with expertise in nPEP or other subject areas pertinent to the guidelines (e.g., cost-effectiveness, sexual assault, or nPEP adherence, etc.), including 1 member who was involved in the writing of the previous version of CDC's nPEP guidelines.

# nPEP external consultants
External consultants were selected from government, academia, and the health care community by CDC to participate in 2 consultations by telephone conference call regarding nPEP on the basis of the member's area of subject matter expertise. Each consultation was chaired by 1 of the CDC nPEP co-chairs. The list of the external consultants is available in Appendix 2B.

# Competing interests and management of conflicts of interest
All internal CDC staff and external consultants involved in developing the guidelines or who served in the external consultations submitted a written financial disclosure statement reporting any potential conflicts of interest related to questions discussed during the consultations or concerns involved in developing of the nPEP guidelines. A list of these disclosures and their last update is available in Appendix 2C. The nPEP co-chairs reviewed each reported association for potential competing interest and determined the appropriate action, as follows: disqualification from the panel, disqualification/recusal from topic review and discussion; or no disqualification needed. A competing interest is defined as any direct financial interest related to a product addressed in the section of the guideline to which a panel member contributes content. Financial interests include direct receipt by the panel member of payments, gratuities, consultancies, honoraria, employment, grants, support for travel or accommodation, or gifts from an entity having a commercial interest in that product. Financial interest also includes direct compensation for membership on an advisory board, data safety monitoring board, or speakers bureau. Compensation and support that filters through a panel member's university or institution (e.g., grants or research funding) is not considered a competing interest.

# Topic Comment OMB Peer Review and OMB Public Engagement
As recommended by the Office of Management and Budget for scientific documents fitting the classification of Influential Scientific Information, during Oct. 2014-December 2015, the draft nPEP guidelines underwent peer review by independent scientific and technical experts. They were asked to review the scientific and technical evidence that provides the basis for the nPEP guidelines and to provide input on the draft guidelines before they were finalized. Peer reviewers were asked whether any recommendations are based on studies that were inappropriate as supporting evidence or were misinterpreted, whether there are significant oversights, omissions, or inconsistencies that are critical for the intended audience of clinicians, and whether the recommendations for the intended audience of health care providers are justified and appropriate. In addition, the recommendations from the draft nPEP guidelines were presented to the public through 2 public engagement webinars on November 14 and 17, 2014. Based on the responses from both peer review and public engagement, updates were made to the nPEP guidelines prior to their publication. CDC's responses to the comments were also posted on the CDC/ATSDR Peer Review Agenda website at  and the CDC Division of HIV/AIDS Prevention Program Planning Scientific Information Quality-Peer Review Agenda website at .

# Guidelines users
Health care providers

# Developer
The CDC nPEP Working Group

# Funding source
Epidemiology Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, TB Prevention, CDC Recommendation ratings Because none of the evidence is based on randomized clinical trials, but rather observational studies or expert opinion, we have elected not to provide graded recommendations for these guidelines.
Abbreviations: AIDS, acquired immunodeficiency virus; CDC, Centers for Disease Control and Prevention; HIV, human immunodeficiency virus; nPEP, nonoccupational postexposure prophylaxis.

# Appendix 1B nPEP Guidelines Development Teams and Consultants
Appendix 1C    6% took all 28 doses; 14.3% took > 90% of doses; at baseline, higher number of lifetime STDs and recent episodes of unprotected anal intercourse were associated with reductions in medication adherence HIV seroconversions: 1 (participant reported nonadherence to nPEP and multiple subsequent sexual exposures) Conclusion: There was a significant indirect association between sexual risk taking and nPEP adherence. Interventions to reduce sexual risk taking will reduce risk for HIV acquisition and may play a role in improving nPEP adherence. The TDF/FTC + LPV/r regimen proved easy to use, well-tolerated, and had less participants to discontinue medications secondary to adverse effects when compared with historical controls. The authors recommend this regimen as standard of care for HIV nPEP. Among those with  1 side effect, 78% diarrhea, 78% asthenia, 59% nausea and/or vomiting.

# Sexual Assault Studies Including Children and/or Adolescents

# Trade-named Drug Compositions
Combivir, ZDV+3TC; Kaletra, LPV/r (lopinavir + ritonavir); Truvada, TDF + FTC.

# Appendix 4

# Consideration of Other Alternative HIV nPEP Antiretroviral Regimens a
Create a combination regimen alternative to those in