HIV Postexposure Prophylaxis (PEP), Nonoccupational (nPEP)

Updated: Sep 22, 2021
Author: Brian F Lich, MD, DTM&H, FACP;

HIV Postexposure Prophylaxis, Nonoccupational


Nonoccupational HIV Postexposure Prophylaxis (nPEP) refers to the delivery of antiretroviral therapy (ART) to persons who have experienced a nonoccupational exposure that represents a substantial risk for HIV transmission within the past 72 hours, in order to decrease the risk for HIV acquisition. Exposures constituting a substantial risk for HIV transmission include condomless intercourse (receptive or insertive anal or vaginal) or a percutaneous exposure to blood (or body fluids contaminated with blood) when the source has known HIV or is at high-risk of having HIV (eg, man who has sex with men [MSM], injection drug user, sex worker). ART for patients qualifying for nPEP is given as a 28-day course, 3-drug regimen most commonly containing tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and either raltegravir (RAL) OR dolutegravir (DTG) (with special considerations for the choice of the third agent below). The rationale for nPEP is to decrease the risk for HIV transmission to the exposed patient; however, data pertaining to the exact efficacy of this intervention remains limited to observational and animal data.

Several guidelines and recommendations for prevention, screening, diagnosis, treatment, and management of human immunodeficiency virus (HIV) infection have been issued by the Centers for Disease Control and Prevention (CDC) and other federal government agencies.[1] The CDC’s recommendations for antiretroviral postexposure prophylaxis (PEP) after sexual, injection-drug use, or other nonoccupational HIV exposure in the United States are summarized below.[1]

CDC guidelines for occupational HIV exposures are summarized in HIV Postexposure Prophylaxis, Occupational.

Who Should be Considered for nPEP

Patients presenting to a healthcare setting within 72 hours of an exposure constituting a substantial risk for HIV transmission should be considered for nPEP.  High-risk exposures are defined as exposure to a source patient who has known HIV or is at high-risk for having HIV (eg, man who has sex with men [MSM], injection drug user, sex worker) in the following ways:

  • Condomless anal or vaginal receptive or insertive intercourse
  • Percutaneous exposure to blood (or body fluids contaminated with blood)

A case-by-case determination about nPEP is recommended when the HIV infection status or HIV risk status of the source is unknown, and the reported exposure presents a substantial risk for transmission if the source is HIV-positive.

The risk for HIV transmission through sexual intercourse varies, depending on a multitude of factors including the presence of concomitant STIs, lack of circumcision, and the type of sexual contact. Receptive anal intercourse constitutes the highest risk exposure (1 in 72 risk for infection per act), followed by insertive anal intercourse (1 in 900 risk of infection per act), receptive penile-vaginal intercourse (1 in 1250 risk of infection per act), and insertive penile-vaginal intercourse (1 in 2500 risk of infection per act).[1]   Of note, oral intercourse alone is not considered a high-risk exposure warranting the use of nPEP.

Percutaneous exposure to blood (or body fluids contaminated with blood) often occurs through the sharing of needles during IV drug use and entails a 1 in 150 risk for HIV acquisition per exposure.[1]

In cases of sexual assault, patients should be considered for nPEP in addition to a more extensive evaluation as detailed in HIV Prophylaxis in Sexual Assault and Sexual Assault.

Timing of nPEP

Timing is of paramount importance in initiating nPEP to effectively lower the risk for HIV acquisition. A study involving the use of antiretrovirals (ARVs) in macaques for post-exposure prophylaxis demonstrated 100% efficacy when therapy was delivered within 24 hours, with decreased efficacy when therapy was delayed to 48 hours and 72 hours from exposure.[2]  An additional meta-analysis involving PEP in non-human primates demonstrated a significant association between earlier timing of PEP and reduced seroconversion rates.[3]

Therapy should only be considered when ARVs can be started within 72 hours of exposure. This unfortunately can be a barrier for many physicians attempting to initiate nPEP as cost restraints and insurance approval may delay treatment as detailed further below. Considering the strong correlation between timing and efficacy, therapy should not be delayed while awaiting HIV testing from either the exposed or the source patient.[1]

Recommended Antiretroviral (ARV) Regimens

Considering the importance of rapid administration of effective ART, nPEP regimens are standardized and simplified as detailed here. A more in-depth analysis of potential ARV regimens can be found at Antiretroviral Therapy for HIV Infection.

The preferred regimen for otherwise healthy adults and adolescents qualifying for nPEP is a 28-day 3-drug combination of the following:

  • Tenofovir disoproxil fumarate (TDF) (300mg) with  emtricitabine (FTC) (200mg) once daily  plus
  • Raltegravir (RAL) 400mg twice daily OR dolutegravir (DTG) 50mg daily [avoid DTG in women early in pregnancy or of childbearing potential]

An alternative regimen in otherwise healthy adults and adolescents is as follows:

  • Tenofovir disoproxil fumarate (TDF) (300mg)  with  emtricitabine (FTC) (200mg) once daily  plus
  • Darunavir (DRV) (800mg) and ritonavir (RTV) (100mg) once daily

Of note, the combination of tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) is the recommended combination for all first-line nPEP regimens. The third drug of choice varies depending on unique patient variables, below. Dolutegravir (DTG) has the preferred advantage of being dosed once daily though it should be avoided in women early in pregnancy or women who may become pregnant. With the development of tenofovir alafenamide (TAF) as a newer form of tenofovir with less renal and bone toxicity, it is important to note that data and guidelines do not support the use of this medication for nPEP. Part of the reason for this distinction is that TAF does not achieve as high of mucosal tenofovir levels as compared with TDF, theoretically providing less protection against HIV transmission.[4]  The recommendation regarding the unapproved use of TAF in nPEP remains despite its approval for use in HIV pre-exposure prophylaxis (PrEP).[5]

Unique patient variables to consider when choosing the third agent include:

  • Women of childbearing potential or women who are early in pregnancy:
    • Raltegravir (RAL) 400mg bid is the preferred alternative to DTG as the third ARV agent in women of childbearing potential and women who are early in pregnancy.
    • Dolutegravir (DTG) should be avoided in these patients since DTG has been shown to be associated with neural tube defects in unborn infants during the first 28 days of development. [6]
    • If raltegravir is unavailable, alternatives for the third agent may include a ritonavir boosted-PI (darunavir 800mg daily with ritonavir 100mg daily). Healthcare providers seeking advice can call the National Clinical Consultations Center’s PEPline at (888) 448-4911.
  • Renal dysfunction (GFR< 60):
    • TDF-FTC doses should be adjusted on the basis of the patient's GFR. Further guidance regarding renally adjusted doses can be found at emtricitabine/tenofovir DF.
    • It should be noted that TDF has a risk for renal toxicity; however, this toxicity typically occurs with long-term use and is not felt to be a significant risk during the short term 28-day course used during nPEP.

Other studies have examined potential alternative regimens to the CDC recommendations above in efforts to improve compliance and tolerance with nPEP. One study examined the use of a once-daily, fixed-dose combination pill of Elvitegravir/Cobicistat/Tenofovir Disoproxil Fumarate/Emtricitabine and found that 71 of the 100 study participants completed the 28-day regimen with only minimal and self-limited side effects that did not result in medication discontinuation.[7]  No study participants became HIV infected during the 90-day post-exposure study period.

Healthcare providers considering using antiretroviral regimens for nPEP other than those listed in these guidelines as preferred or alternative are encouraged to consult with those providers who have expertise in antiretroviral medication use for similar patients (eg, children, pregnant women, or patients with comorbid conditions such as impaired renal function).

Laboratory Evaluation and Monitoring

All persons considered for nPEP should undergo HIV testing to determine HIV infection status, preferably with rapid combined Ag/Ab, or antibody blood tests. If rapid HIV blood test results are unavailable and nPEP is otherwise indicated, it should be initiated without delay, and can be discontinued if the source is found to be HIV-negative.

A summary of laboratory evaluation and monitoring for patients undergoing nPEP is as follows[1] :

  • HIV Testing: Preferably with a fourth-generation assay that detects HIV p24 antigen and HIV antibodies
    • Frequency: Time of exposure, 4-6 weeks after exposure, 3 months after exposure, (6 months after exposure if acute hepatitis C infection occurs after exposure)
  • Complete blood count (CBC)with differential 
    • Frequency: Time of exposure
  • Serum liver enzymes (AST, ALT), blood urea nitrogen, creatinine
    • Frequency: Time of exposure, 4-6 weeks after exposure
  • Hepatitis B and C serologies: Hep B surface antibody, Hep B surface antigen, Hep B core antibody, Hep C antibody
    • Frequency: Time of exposure, 6 months after exposure
  • Pregnancy test: for women of reproductive age
    • Frequency: Time of exposure, (4-6 weeks after exposure if sexual exposure)
  • Sexually transmitted infections: gonorrhea, chlamydia, syphilis
    • Frequency: Time of exposure, 4-6 weeks after exposure
  • Source patient: The source patient should be tested for HIV, Hep B, Hep C, and STIs near the time of exposure if available

Any indicated prevention, treatment, or supportive care for other exposure-associated health risks and conditions (eg, bacterial sexually transmitted infections, traumatic injuries, hepatitis B virus and hepatitis C virus infection, or pregnancy) should be provided to all persons evaluated for possible nPEP. Of note, if the exposed patient is found to have chronic HBV infection during their course of nPEP, they should be considered for continuation for their ARV course. This is because TDF and FTC are both active against HBV, and discontinuation of these medications may lead to a flare of the patient's chronic HBV infection.  See the following articles for more details: Hepatitis B, Hepatitis C, Gonorrhea, Chlamydia (Chlamydial Genitourinary Infections), Syphilis.

All persons who report behaviors or situations that place them at risk for frequently recurring HIV exposures (eg, injection drug use, sex without condoms) or who report receipt of ≥1 course of nPEP in the preceding year should receive risk-reduction counseling and intervention services, including consideration of preexposure prophylaxis (PrEP).

Rationale for and Barriers to nPEP

The rationale for nPEP is to decrease the risk for HIV transmission to the exposed patient; however, data pertaining to the exact efficacy of this intervention remains limited to observational and animal studies. A meta-analysis of 25 studies involving nonhuman primates showed that the risk for seroconversion was 89% lower among those given PEP in comparison to those not given PEP.[3]   Additionally, a Brazilian study utilizing zidovudine plus lamivudine as nPEP in high-risk MSM individuals demonstrated 11 seroconversions in the study group over a 2-year period, 10 among non-PEP users and 1 that was a PEP failure.[8]  

Ultimately, the decision to initiate nPEP is multi-factorial and hinges on the risks versus benefits of this intervention.

Compliance with nPEP may be largely influenced by the side effect profile of the ARV regimen. Newer regimens (as detailed above) have evidence for improved tolerance amongst patients. For example, a study of 100 patients prescribed the 3-drug ARV regimen of TDF/FTC+RAL for nPEP showed that 57% of participants completed the regimen as prescribed and an additional 27% took their medicine daily but sometimes missed the second dose of RAL.[9]  This study demonstrated that a large percentage of patients tolerated a 28-day course of nPEP despite side effects that are often self-limited or mild (nausea or vomiting (27%), diarrhea (21%), headache (15%), fatigue (14%), abdominal symptoms (16%), myalgias or arthralgias (8%)).

Despite animal and observational data suggesting a potential benefit of nPEP[2, 3, 8] , several barriers to its use remain. The first barrier to nPEP is lack of awareness by both providers and patients. By simplifying the recommended drug regimens as above, this serves to benefit both groups. Another major barrier to the use of nPEP is lack of access to healthcare and ARV medications. Unfortunately, many patients who may qualify for nPEP may come from a disadvantaged population and/or have no medical insurance, limiting their access to medical providers and affordable medications. Additionally, even for patients with medical insurance, prior authorization requirements may delay the timely distribution of ARVs to patients who qualify for nPEP. These barriers limit the utilization of nPEP, and it therefore is an area requiring significant improvement before it can have a meaningful impact on HIV prevention from a public health standpoint.


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