Selecting and Initiating a 28-Day Course of PEP

Selecting and Initiating a 28-Day Course of PEP

Reviewed and updated: Medical Care Criteria Committee; August 11, 2022

RECOMMENDATIONS
Preferred Regimens [a]
Antiretroviral (ARV) Medications to Avoid for PEP
  • Clinicians should not prescribe the following for PEP: Abacavir (ABC; brand name Ziagen), efavirenz (EFV; brand name Sustiva), indinavir (IDV; brand name Crixivan), maraviroc (MVC; brand name Selzentry), nelfinavir (NFV; brand name Viracept), nevirapine (NVP; brand name Viramune), and zidovudine (ZDV; brand name Retrovir). (A2)
    • ZDV remains a recommended medication for the prevention of perinatal transmission of HIV and for pediatric PEP.

PEP During Pregnancy or Breastfeeding

———
Note:

  1. The recommendation regarding discussion of the small risk of teratogenicity with DTG in the first trimester and the need for birth control while completing the 28-day PEP regimen has been removed. DTG has been shown to be safe throughout pregnancy. See the MCCC’s statement on Use of Dolutegravir in Individuals of Childbearing Capacity for further discussion [Zash, et al. 2022].

Considerations and Caveats

Suspected seroconversion: If acute HIV infection is suspected at any time, immediate consultation with a clinician experienced in managing acute HIV infection is advised (see the NYSDOH AI guideline Diagnosis and Management of Acute HIV). Clinicians can call the Clinical Education Initiative (CEI Line) to speak with an experienced HIV care provider: 866-637-2342 (press “1” for HIV PEP). The CEI Line is available 24/7.

Source confirmed HIV negative: If the source is confirmed to be HIV negative, the exposed individual’s PEP regimen should be discontinued.

Use of a 3-drug PEP regimen: This Committee recommends a 3-drug ARV regimen as the preferred option once the decision has been made to initiate PEP. When the source is known to have HIV, past and current ARV experience, viral load data, and genotypic or phenotypic resistance data (if available) may indicate the use of an alternative PEP regimen. Consult with an experienced HIV care provider.

Drug-drug interactions and adverse effects: Care providers should advise patients not to take divalent cations (aluminum, calcium, magnesium) or iron supplements concurrently with DTG or RAL. Metformin dosing should be limited to 1 g by mouth per day when an individual is taking DTG concurrently.

Care providers should counsel patients about the low risk of gastrointestinal adverse effects with TDF/FTC, such as nausea, abdominal bloating, and vomiting, along with headache. A low risk of neuropsychiatric effects with DTG may also exist. RAL has been rarely associated with rhabdomyolysis [FDA 2013].

RESOURCES: DRUG-DRUG INTERACTIONS INFORMATION

Impaired renal function: Exposed individuals who have impaired renal function may require dose adjustments of ARV medications used for PEP and may require additional monitoring while completing a 28-day course of PEP [DHHS 2022].

Hepatitis B virus infection: Additional monitoring is required for exposed individuals who have HBV infection.

Tenofovir alafenamide (TAF): Recommended and alternative regimens do not include TAF because evidence suggests decreased vaginal, cervical, and rectal tissue concentrations of the active form (tenofovir diphosphate) in healthy volunteers [Cottrell, et al. 2017]. This Committee does not recommend including TAF in PEP regimens until further research is completed.

Adherence and completion requirements: The recommended 28-day treatment duration is based on limited animal data and expert opinion [Tsai, et al. 1998]. Nonetheless, adherence to a full 28-day course of PEP and completion of therapy is important to prevent HIV seroconversion post exposure.

Repeated requests for non-occupational PEP: PEP should not be routinely dismissed solely based on repeated risk behavior or repeat presentation for PEP (see guideline section Risk Reduction).

PEP completion following sexual assault: Limited data exist on the use of antiretroviral therapy (ART) to prevent HIV infection in sexual assault populations. One study demonstrated higher completion rates (66% vs. 42%) among individuals taking TDF/FTC in combination with DTG or RAL, as compared with those taking TDF/FTC plus darunavir (DRV) boosted with ritonavir (RTV) [Kumar, et al. 2017], suggesting these regimens are better tolerated in this population.

SELECTED GOOD PRACTICE REMINDERS
Selecting and Initiating a 28-Day Course of PEP
  • Avoid drug-drug interactions and medication-related adverse events: Before prescribing a 28-day course of PEP, review the patient’s current medications and comorbidities to identify possible drug-drug interactions and to anticipate and prevent medication-related adverse events.
  • Impaired renal function: Review baseline laboratory test results to identify the need to adjust ARV medication dosing for renal insufficiency or choose an alternative regimen. Consult with an experienced HIV care provider or other resources, such as drug package insert(s), to determine dose adjustments for patients with baseline CrCl <50 mL/min.
  • If 28-day PEP is indicated: Ensure the patient understands the need to complete the full 28 days of PEP and explain the adherence requirements.
  • Make sure the patient understands that if a dose of PEP is missed, a “double-up” dose is not necessary. Instead, if dose is missed at a specific time, it can be taken as soon as it is remembered within 24 hours of the scheduled time.
  • If possible, provide the 28-day supply of medications. If the full course of medications cannot be provided, then supply a starter pack, as noted below, and a prescription for the medications required to complete 28 days of PEP.
    • Non-occupational exposures: Provide a 7-day starter pack.
    • Occupational exposures: Provide a 7-day (at least) starter pack.
    • Sexual assault exposures (per New York State law): Provide a 7-day starter pack if the patient is ≥18 years old; provide the full, 28-day course of PEP medications if the patient is <18 years old.
  • Medication access: Ensure the patient’s ability to obtain the medication needed to complete 28 days of PEP.
  • Discuss possible adverse effects of PEP medications. Ensure the patient knows what to do if they experience those effects. If an individual who is completing 28 days of PEP does not have a primary care provider with whom to follow-up, the NYSDOH PrEP/PEP Provider Directory can be used to identify a care provider for a referral.
References

DHHS. Recommendations for the use of antiretroviral drugs during pregnancy and interventions to reduce perinatal HIV transmission in the United States. 2022 Mar 17. https://clinicalinfo.hiv.gov/en/guidelines/perinatal/whats-new-guidelines [accessed 2018 Feb 1]

CDC. Announcement: Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV – United States, 2016. MMWR Morb Mortal Wkly Rep 2016;65(17):458. [PMID: 27149423]

Cottrell ML, Garrett KL, Prince HMA, et al. Single-dose pharmacokinetics of tenofovir alafenamide and its active metabolite in the mucosal tissues. J Antimicrob Chemother 2017;72(6):1731-1740. [PMID: 28369415]

FDA. Isentress (raltegravir) film-coated or chewable tablets, for oral use 2013 Aug. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022145s029lbl.pdf [accessed 2018 Aug 13]

Ford N, Mayer KH. World Health Organization guidelines on postexposure prophylaxis for HIV: Recommendations for a public health approach. Clin Infect Dis 2015;60 Suppl 3:S161-164. [PMID: 25972497]

Günthard HF, Saag MS, Benson CA, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2016 recommendations of the International Antiviral Society-USA Panel. JAMA 2016;316(2):191-210. [PMID: 27404187]

Kuhar DT, Henderson DK, Struble KA, et al. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol 2013;34(9):875-892. [PMID: 23917901]

Kumar T, Sampsel K, Stiell IG. Two, three, and four-drug regimens for HIV post-exposure prophylaxis in a North American sexual assault victim population. Am J Emerg Med 2017. [PMID: 28596030]

Tsai CC, Emau P, Follis KE, et al. Effectiveness of postinoculation (R)-9-(2-phosphonylmethoxypropyl) adenine treatment for prevention of persistent simian immunodeficiency virus SIVmne infection depends critically on timing of initiation and duration of treatment. J Virol 1998;72(5):4265-4273. [PMID: 9557716]

Zash R, Holmes LB, Diseko M, et al. Update on neural tube defects with antiretroviral exposure in the Tsepamo Study, Botswana. AIDS; 2022 Jul 29-Aug 2; Montreal, Canada. https://www.natap.org/2022/IAC/IAC_31.htm

Preferred and Alternative PEP Regimens

Reviewed and updated: Medical Care Criteria Committee; August 11, 2022

Preferred PEP Regimens for Patients Who Weigh ≥40 kg

The medications that comprise the recommended PEP regimens (and substitutions) listed in Table 2: Preferred PEP Regimen for Patients Who Weigh ≥40 kg, below, have favorable adverse effect profiles, fewer potential drug-drug interactions, and expected efficacy similar to older PEP regimens that contained ZDV or PIs. Researchers have reported increased rates of adherence and regimen completion when TDF/FTC or TDF/3TC have been used as components of the PEP regimen [Mayer, et al. 2008; Tosini, et al. 2010]. Observational cohorts and 1 small randomized study reported improved tolerability with TDF/FTC plus RAL [Mulka, et al. 2016; Mayer, et al. 2012; McAllister, et al. 2017]. Additionally, TDF/FTC has been highly successful in recent studies of pre-exposure prophylaxis [Grant, et al. 2010; Baeten, et al. 2012; Thigpen, et al. 2012]. One observational cohort demonstrated high completion rates with TDF/FTC plus DTG [McAllister, et al. 2017].

Unlike PIs, which block HIV replication after integration with cellular DNA, all currently recommended medications (TDF/FTC plus DTG or RAL) act before viral integration with cellular DNA, providing a theoretical advantage in preventing establishment of HIV infection.

KEY POINT
  • ZDV is not recommended for PEP in adults: This Committee no longer recommends the use of ZDV in PEP regimens for adults. ZDV confers no advantage in expected efficacy over TDF, and it has significantly higher rates of treatment-limiting adverse effects. Tolerability is one of the most important factors in completion of the 28-day PEP regimen. ZDV is still recommended for prevention of perinatal HIV transmission.
Table 2: Preferred PEP Regimen for Patients Who Weigh ≥40 kg [a,b]
[Download PDF]
Preferred Regimen Notes
  • Tenofovir disoproxil fumarate 300 mg/ emtricitabine 200 mg (TDF/FTC; Truvada) once per day or
  • TDF 300 mg/lamivudine (TDF/3TC; Cimduo) 300 mg once per day

plus

  • Raltegravir (RAL; Isentress) 400 mg twice per day or
  • RAL HD 1200 mg once per day [c] or
  • Dolutegravir (DTG; Tivicay) 50 mg once per day
  • DTG: 
    • Metformin dosing should be limited to 1 g by mouth per day when an individual is taking DTG concurrently.
    • Magnesium- or aluminum-containing antacids may be taken 2 hours before or 6 hours after DTG; calcium-containing antacids or iron supplements may be taken simultaneously if taken with food.
    • The recommendation regarding discussion of the small risk of teratogenicity with DTG in the first trimester and the need for birth control while completing the 28-day PEP regimen has been removed. DTG has been shown to be safe throughout pregnancy. See the MCCC’s statement on Use of Dolutegravir in Individuals of Childbearing Capacity for further discussion [Zash, et al. 2022].
  • RAL: Magnesium- or aluminum-containing antacids are contraindicated; coadministration of calcium-containing antacids is not recommended with RAL HD.
  • TDF: Requires dose adjustment for CrCl <50 mL/min. Alternatively, another agent can be considered, in which case consultation with an experienced HIV care provider is advised.
  • TDF/FTC and TDF/3TC: Dosing should be adjusted in patients with baseline CrCl <50 mL/min.

Abbreviations: CrCl, creatinine clearance; PEP, post-exposure prophylaxis.

Notes:

  1. All medications are taken by mouth for 28 days.
  2. Available alternative formulations and methods of administration:
    – 3TC: Acceptable to crush or split. Available as an oral solution (10 mg/mL).
    – DTG: Acceptable to crush.
    – FTC: Acceptable to open and dissolve in water. Available as an oral solution (10 mg/mL).
    – RAL: Available as a chewable tablet (25 mg, 100 mg) and oral powder for suspension (100 mg/packet); neither is bioequivalent to the 400 mg adult dose.
    – TDF: Acceptable to dissolve in water. Available as an oral powder only (40 mg/1 g) that can be mixed with soft food.
    – TDF/FTC: Acceptable to crush and dissolve.
  3. RAL HD: May be prescribed for patients who weigh >40 kg; RAL HD should not be prescribed for pregnant individuals.

Alternative PEP Regimens for Patients Who Weigh ≥40 kg

Table 3, below, lists 2 alternative PEP regimens that are acceptable options when a preferred regimen is not available. They are possibly less well tolerated than the preferred regimen of TDF/FTC plus RAL or DTG, but they are significantly better tolerated than regimens containing ZDV or lopinavir/ritonavir (LPV/RTV). Observational studies have demonstrated excellent tolerability and completion rates [Fätkenheuer, et al. 2016; Valin, et al. 2016; Mayer, et al. 2017].

A single-tablet regimen for a patient with adequate kidney function (CrCl >70 mL/min) and no expected drug-drug interactions may be a good option for those who prefer a once-daily, single-tablet PEP regimen. It also allows use of medication assistance programs if a patient has limited medication coverage options.

Drug-drug interactions: The potential for drug-drug interactions in patients receiving PIs or cobicistat (COBI) is increased due to the extensive cytochrome P450 interactions. Clinicians should assess for potential interactions before prescribing a PEP regimen.

Table 3: Alternative PEP Regimens for Patients Who Weigh ≥40 kg [a,b]
[Download PDF]
Alternative Regimens Notes
  • Elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (EVG/COBI/FTC/TDF) as a fixed-dose single tablet once per day (Stribild) [c]

For individuals with CrCl <70 mL/min: Fixed-dose single tablet EVG/COBI/TDF/FTC is contraindicated.
  • TDF 300 mg/FTC 200 mg (Truvada) plus ritonavir (RTV; Norvir) 100 mg plus darunavir (DRV; Prezista) 800 mg once per day [d]
  • Substitutions:
    • For FTC: Lamivudine (3TC; Epivir) 300 mg once per day.
    • For DRV: Atazanavir (ATV; Reyataz) 300 mg once per day or fosamprenavir (FPV; Lexiva) 1400 mg once per day plus RTV 100 mg once per day.

For individuals with baseline CrCl <50 mL/min: Adjust dosing of 3TC/FTC plus TDF.

Abbreviations: CrCl, creatinine clearance; PEP, post-exposure prophylaxis.

Notes:

  1. All medications are taken by mouth for 28 days.
  2. Available alternative formulations and methods of administration:
    – 3TC: Acceptable to crush or split. Available as an oral solution (10 mg/mL).
    – ATV: Acceptable to open capsule and sprinkle contents. Oral dispersible powder (50 mg/packet).
    – DRV: Probably acceptable to crush. Available as an oral suspension (100 mg/mL).
    – DTG: Acceptable to crush.
    – FTC: Acceptable to open and dissolve in water. Available as an oral solution (10 mg/mL).
    – RAL: Available as a chewable tablet (25 mg, 100 mg) and oral powder for suspension (100 mg/packet); neither is bioequivalent to the 400 mg adult dose.
    – RTV: Available as an oral solution (80 mg/mL).
    – TDF: Can be dissolved in water. Available as an oral powder (40 mg/1 g) that can be mixed with soft food only.
    – TDF/FTC: Acceptable to crush and dissolve.
  3. Cobicistat-containing regimens should not be used during pregnancy.
  4. If DRV or ATV are prescribed during pregnancy, dose adjustments are required. See the guideline section PEP During Pregnancy or Breastfeeding or Clinicalinfo.HIV.gov > Table 11. Antiretroviral Drug Use in Pregnant People with HIV: Pharmacokinetic and Toxicity Data in Human Pregnancy and Recommendations for Use in Pregnancy.
KEY POINT
  • Call the Clinical Education Initiative (CEI Line) to speak with an experienced HIV care provider regarding PEP: 866-637-2342 (press “1” for HIV PEP). The CEI Line is available 24/7.

Other alternative PEP regimens: Other alternative PEP regimens may be acceptable in certain situations. Some clinicians continue to favor the use of ZDV in PEP regimens based on the results of a retrospective study supporting the efficacy of the agent [Cardo, et al. 1997] and from long-term experience in occupational PEP. Clinicians who continue to prescribe ZDV should recognize and inform patients that the drug is associated with significant adverse effects and that better tolerated agents are available.

Use of LPV/RTV has greater potential for drug-drug interactions and adverse effects than RAL, DTG, or DRV/r (the preferred alternative boosted PI), with little added efficacy benefit expected. Studies have demonstrated decreasing PI resistance among HIV strains [Paquet, et al. 2011], suggesting there may be a diminishing benefit to choosing LPV/RTV for its activity against resistant HIV strains. DRV/r has excellent activity against many PI-resistant strains and is better tolerated than LPV/RTV.

This Committee recommends a 3-drug regimen because of the greater likelihood of enhanced effectiveness; however, if tolerability is a concern, use of a 2-drug regimen would be preferred to discontinuing the regimen completely. An early case-control study of occupational exposure demonstrated an 81% reduction in seroconversion with the use of ZDV monotherapy alone [Cardo, et al. 1997], suggesting that treatment with any active ARV agent is beneficial in reducing risk. Other studies have investigated 2-drug PEP regimens and found excellent tolerability [Mayer, et al. 2008; Kumar, et al. 2017].

PEP Regimens for Patients Who Weigh <40 kg

Lead authors for material on PEP in children: Aracelis Fernandez, MD, with Lisa-Gaye Robinson, MD, and Ruby Fayorsey, MD, with the Medical Care Criteria Committee; June 2020

No clinical studies are available to determine the best regimens for HIV PEP in children. The recommendations for drug choices and dosages presented here follow current U.S. Department of Health and Human Services recommendations in Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection, which are based on expert opinion. The recommended regimens reflect experience with ARV combinations that effectively suppress viral replication in children with HIV and with combinations that are well tolerated and increase adherence to PEP. The chosen preferred regimens have demonstrated good potency and tolerability.

The alternative PEP regimens for children are also based on expert opinion. They all have demonstrated potent antiviral activity. However, the PI-containing regimens are often more difficult to tolerate, secondary to gastrointestinal adverse effects. To improve adherence, clinicians can and should prescribe preemptive antiemetics for anticipated gastrointestinal adverse effects.

When choosing a PEP regimen, care providers should consider factors that may affect adherence, such as ARV drug intolerance, regimen complexity, expense, and drug availability. 

Table 4: PEP Regimens for Patients 2 to 12 Years Old Who Weigh <40 kg [a]
[Download PDF]

See DHHS for dosing, administration, and additional information about each medication. Each medication name below is linked to a page about that medication.

Preferred: Tenofovir disoproxil fumarate (TDF; Viread) plus emtricitabine (FTC; Emtriva) plus raltegravir (RAL; Isentress). TDF/FTC is available as the fixed-dose combination (Truvada).

  • Substitutions:
    • Lamivudine (3TC; Epivir) may be substituted for FTC.
    • Dolutegravir (DTG; Tivicay) may be substituted for RAL.
  • Alternatives:
KEY POINTS: SEXUAL ASSAULT IN CHILDREN
  • A systematic review of several studies that included ARV medications used as PEP in children exposed to HIV and of antiretroviral therapy (ART) for children with HIV reported a 4.5% rate of discontinuation due to adverse events [Penazzato, et al. 2015].
  • Limited data exist on dosing or safety for some ARV agents, including INSTIs, used in children.
  • Poor palatability of liquid medication preparations and high pill burden of some pediatric dose formulations can also affect adherence to the PEP regimen.
SELECTED GOOD PRACTICE REMINDERS
Selecting and Initiating a 28-Day Course of PEP
  • Avoid drug-drug interactions and medication-related adverse events: Before prescribing a 28-day course of PEP, review the patient’s current medications and comorbidities to identify possible drug-drug interactions and to anticipate and prevent medication-related adverse events.
  • Impaired renal function: Review baseline laboratory test results to identify the need to adjust ARV medication dosing for renal insufficiency or choose an alternative regimen. Consult with an experienced HIV care provider or other resources, such as drug package insert(s), to determine dose adjustments for patients with baseline CrCl <50 mL/min.
  • If 28-day PEP is indicated: Ensure the patient understands the need to complete the full 28 days of PEP and explain the adherence requirements.
  • Make sure the patient understands that if a dose of PEP is missed, a “double-up” dose is not necessary. Instead, if dose is missed at a specific time, it can be taken as soon as it is remembered within 24 hours of the scheduled time.
  • If possible, provide the 28-day supply of medications. If the full course of medications cannot be provided, then supply a starter pack, as noted below, and a prescription for the medications required to complete 28 days of PEP.
    • Non-occupational exposures: Provide a 7-day starter pack.
    • Occupational exposures: Provide a 7-day (at least) starter pack.
    • Sexual assault exposures (per New York State law): Provide a 7-day starter pack if the patient is ≥18 years old; provide the full, 28-day course of PEP medications if the patient is <18 years old.
  • Medication access: Ensure the patient’s ability to obtain the medication needed to complete 28 days of PEP.
  • Discuss possible adverse effects of PEP medications. Ensure the patient knows what to do if they experience those effects. If an individual who is completing 28 days of PEP does not have a primary care provider with whom to follow-up, the NYSDOH PrEP/PEP Provider Directory can be used to identify a care provider for a referral.
References

Baeten J, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012;367(5):399-410. [PMID: 22784037]

Cardo DM, Culver DH, Ciesielski CA, et al. A case-control study of HIV seroconversion in health care workers after percutaneous exposure. Centers for Disease Control and Prevention Needlestick Surveillance Group. N Engl J Med 1997;337(21):1485-1490. [PMID: 9366579]

Fätkenheuer G, Jessen H, Stoehr A, et al. PEPDar: A randomized prospective noninferiority study of ritonavir-boosted darunavir for HIV post-exposure prophylaxis. HIV Med 2016;17(6):453-459. [PMID: 27166295]

Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010;363(27):2587-2599. [PMID: 21091279]

Kumar T, Sampsel K, Stiell IG. Two, three, and four-drug regimens for HIV post-exposure prophylaxis in a North American sexual assault victim population. Am J Emerg Med 2017. [PMID: 28596030]

Mayer KH, Jones D, Oldenburg C, et al. Optimal HIV postexposure prophylaxis regimen completion with single tablet daily elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine compared with more frequent dosing regimens. J Acquir Immune Defic Syndr 2017;75(5):535-539. [PMID: 28696345]

Mayer KH, Mimiaga MJ, Cohen D, et al. Tenofovir DF plus lamivudine or emtricitabine for nonoccupational postexposure prophylaxis (NPEP) in a Boston Community Health Center. J Acquir Immune Defic Syndr 2008;47(4):494-499. [PMID: 18176318]

Mayer KH, Mimiaga MJ, Gelman M, et al. Raltegravir, tenofovir DF, and emtricitabine for postexposure prophylaxis to prevent the sexual transmission of HIV: safety, tolerability, and adherence. J Acquir Immune Defic Syndr 2012;59(4):354-359. [PMID: 22267017]

McAllister J, Towns JM, McNulty A, et al. Dolutegravir with tenofovir disoproxil fumarate-emtricitabine as HIV postexposure prophylaxis in gay and bisexual men. AIDS 2017;31(9):1291-1295. [PMID: 28301425]

Mulka L, Annandale D, Richardson C, et al. Raltegravir-based HIV postexposure prophylaxis (PEP) in a real-life clinical setting: fewer drug-drug interactions (DDIs) with improved adherence and tolerability. Sex Transm Infect 2016;92(2):107. [PMID: 26892929] 

Paquet A, Evans MC, Petropoulos C, et al. Significant reductions in the prevalence of protease inhibitor and 3-class resistance: Recent trends in a large HIV-1 protease/reverse transcriptase database. Abstract H2-800. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy; 2011 Sep 17-20; Chicago, IL. http://www.natap.org/2011/ICAAC/ICAAC_68.htm

Penazzato M, Dominguez K, Cotton M, et al. Choice of antiretroviral drugs for postexposure prophylaxis for children: a systematic review. Clin Infect Dis 2015;60 Suppl 3:S177-181. [PMID: 25972500]

Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med 2012;367(5):423-434. [PMID: 22784038]

Tosini W, Muller P, Prazuck T, et al. Tolerability of HIV postexposure prophylaxis with tenofovir/emtricitabine and lopinavir/ritonavir tablet formulation. AIDS 2010;24(15):2375-2380. [PMID: 20729709]

Valin N, Fonquernie L, Daguenel A, et al. Evaluation of tolerability with the co-formulation elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate for post-HIV exposure prophylaxis. BMC Infect Dis 2016;16(1):718. [PMID: 27894270]

Zash R, Holmes LB, Diseko M, et al. Update on neural tube defects with antiretroviral exposure in the Tsepamo Study, Botswana. AIDS; 2022 Jul 29-Aug 2; Montreal, Canada. https://www.natap.org/2022/IAC/IAC_31.htm

ARV Medications to Avoid for PEP

Reviewed and updated: Medical Care Criteria Committee; August 11, 2022

RECOMMENDATIONS
Antiretroviral (ARV) Medications to Avoid for PEP
  • Clinicians should not prescribe the following for PEP: Abacavir (ABC; brand name Ziagen), efavirenz (EFV; brand name Sustiva), indinavir (IDV; brand name Crixivan), maraviroc (MVC; brand name Selzentry), nelfinavir (NFV; brand name Viracept), nevirapine (NVP; brand name Viramune), and zidovudine (ZDV; brand name Retrovir). (A2)
    • ZDV remains a recommended medication for the prevention of perinatal transmission of HIV and for pediatric PEP.

Newer ARV medications have demonstrated significantly fewer adverse effects than older ARVs. The medications listed in Table 5, below, should be avoided.

Table 5: Antiretroviral Medications to Avoid for Post-Exposure Prophylaxis
[Download PDF]
ARV Class Agent <40 kg ≥40 kg Comments
First-generation protease inhibitors
  • Indinavir (IDV; Crixivan)
  • Nelfinavir (NFV; Viracept)
 Avoid Avoid

Poorly tolerated
First-generation non-nucleoside reverse transcriptase inhibitors
  • Efavirenz (EFV; Sustiva)
  • Nevirapine (NVP; Viramune)
 Avoid Avoid
  • EFV: Potential for neuropsychiatric adverse effects
  • NVP: Associated with fulminant hepatic failure and risk of Stevens-Johnson syndrome [CDC 2001]
Nucleoside reverse transcriptase inhibitors
  • Abacavir (ABC; Ziagen)
  • Didanosine (ddI; Videx)
  • Stavudine (d4T; Zerit)
  • Tenofovir alafenamide (TAF)
  • Zidovudine (ZDV, AZT; Retrovir)
 Avoid d4T, ddI, ABC, TAF Avoid all
  • ABC: Potential for serious, sometimes fatal hypersensitivity reaction
  • d4T, ddI, ZDV: Significant mitochondrial toxicities
  • TAF: Decreased vaginal, cervical, and rectal tissue concentrations of the active moiety of (tenofovir diphosphate) in healthy volunteers [Cottrell, et al. 2017]
CCR5 antagonist

Maraviroc (MVC; Selzentry)

 Avoid Avoid

Only shows activity against R5-tropic virus

Consultation with an experienced HIV care provider is recommended before using any of the medications listed above for PEP, or before using etravirine or doravirine, for which limited data exist.

SELECTED GOOD PRACTICE REMINDERS
Selecting and Initiating a 28-Day Course of PEP
  • Avoid drug-drug interactions and medication-related adverse events: Before prescribing a 28-day course of PEP, review the patient’s current medications and comorbidities to identify possible drug-drug interactions and to anticipate and prevent medication-related adverse events.
  • Impaired renal function: Review baseline laboratory test results to identify the need to adjust ARV medication dosing for renal insufficiency or choose an alternative regimen. Consult with an experienced HIV care provider or other resources, such as drug package insert(s), to determine dose adjustments for patients with baseline CrCl <50 mL/min.
  • If 28-day PEP is indicated: Ensure the patient understands the need to complete the full 28 days of PEP and explain the adherence requirements.
  • Make sure the patient understands that if a dose of PEP is missed, a “double-up” dose is not necessary. Instead, if dose is missed at a specific time, it can be taken as soon as it is remembered within 24 hours of the scheduled time.
  • If possible, provide the 28-day supply of medications. If the full course of medications cannot be provided, then supply a starter pack, as noted below, and a prescription for the medications required to complete 28 days of PEP.
    • Non-occupational exposures: Provide a 7-day starter pack.
    • Occupational exposures: Provide a 7-day (at least) starter pack.
    • Sexual assault exposures (per New York State law): Provide a 7-day starter pack if the patient is ≥18 years old; provide the full, 28-day course of PEP medications if the patient is <18 years old.
  • Medication access: Ensure the patient’s ability to obtain the medication needed to complete 28 days of PEP.
  • Discuss possible adverse effects of PEP medications. Ensure the patient knows what to do if they experience those effects. If an individual who is completing 28 days of PEP does not have a primary care provider with whom to follow-up, the NYSDOH PrEP/PEP Provider Directory can be used to identify a care provider for a referral.
References

CDC. Serious adverse events attributed to nevirapine regimens for postexposure prophylaxis after HIV exposures–worldwide, 1997-2000. MMWR Morb Mortal Wkly Rep 2001;49(51-52):1153-1156. [PMID: 11198946]

Cottrell ML, Garrett KL, Prince HMA, et al. Single-dose pharmacokinetics of tenofovir alafenamide and its active metabolite in the mucosal tissues. J Antimicrob Chemother 2017;72(6):1731-1740. [PMID: 28369415]

PEP During Pregnancy or Breastfeeding

Reviewed and updated: Medical Care Criteria Committee; August 11, 2022

RECOMMENDATIONS
PEP During Pregnancy or Breastfeeding

Use of ARV prophylaxis in pregnancy generally does not increase the risk of birth defects [DHHS 2022]. ARV prophylaxis can prevent HIV transmission during acute infection in pregnancy, when viral loads are extremely high, which is associated with a high risk of infection to the infant [Patterson, et al. 2007]. No severe adverse effects or adverse pregnancy outcomes have been noted among women taking ART for PEP [CDC 2016]. However, no clinical trial data regarding PEP use in pregnant individuals are currently available [CDC 2016], and data are limited on the use of integrase inhibitors during pregnancy [DHHS 2022].

When screening for HIV in pregnant patients, care providers should be aware that detection of early/acute HIV infection requires HIV RNA testing in most instances and should repeat antibody testing as late as the third trimester [Wertz, et al. 2011] when screening for HIV infection in pregnant patients.

KEY POINT
  • In addition to the risk of seroconversion for the exposed individual, the high viral load levels associated with early or acute HIV infection markedly increase the risk of transmission to the fetus or breastfeeding infant.

Current U.S. Department of Health and Human Services guidelines require dose adjustments for DRV and atazanavir (ATV) [DHHS 2022]:

  • DRV (Prezista): 600 mg twice per day plus RTV (Norvir) 100 mg twice per day
  • ATV (Reyataz): 400 mg once per day plus RTV 100 mg once per day in the third trimester

Although birth defects and adverse effects on human fetuses have generally not been associated with the ARV agents that are currently available, exposure of a fetus to ARV agents during pregnancy carries a theoretical risk of embryotoxicity.

ARV medications to avoid as PEP during pregnancy: The ARV medications to be avoided for PEP above also apply to pregnant individuals. Based on animal data, there has been a theoretical concern for teratogenicity of EFV in the first trimester; however, current federal perinatal guidelines do not preclude its use [DHHS 2022; Martinez de Tejada, et al. 2019]. ZDV is still recommended for prevention of perinatal HIV transmission.

PEP during breastfeeding: Initiation of PEP in exposed individuals who are breastfeeding requires careful discussion. Both HIV and ARV medications may be found in breast milk; therefore, breastfeeding should be avoided for 3 months after the exposure to prevent HIV transmission and potential drug toxicities [American Academy of Pediatrics 2013]. Clinicians should discuss the risks and benefits with the patient. The infant’s pediatrician should be informed of any potential exposure to HIV or ARV medications.

SELECTED GOOD PRACTICE REMINDERS
Selecting and Initiating a 28-Day Course of PEP
  • Avoid drug-drug interactions and medication-related adverse events: Before prescribing a 28-day course of PEP, review the patient’s current medications and comorbidities to identify possible drug-drug interactions and to anticipate and prevent medication-related adverse events.
  • Impaired renal function: Review baseline laboratory test results to identify the need to adjust ARV medication dosing for renal insufficiency or choose an alternative regimen. Consult with an experienced HIV care provider or other resources, such as drug package insert(s), to determine dose adjustments for patients with baseline CrCl <50 mL/min.
  • If 28-day PEP is indicated: Ensure the patient understands the need to complete the full 28 days of PEP and explain the adherence requirements.
  • Make sure the patient understands that if a dose of PEP is missed, a “double-up” dose is not necessary. Instead, if dose is missed at a specific time, it can be taken as soon as it is remembered within 24 hours of the scheduled time.
  • If possible, provide the 28-day supply of medications. If the full course of medications cannot be provided, then supply a starter pack, as noted below, and a prescription for the medications required to complete 28 days of PEP.
    • Non-occupational exposures: Provide a 7-day starter pack.
    • Occupational exposures: Provide a 7-day (at least) starter pack.
    • Sexual assault exposures (per New York State law): Provide a 7-day starter pack if the patient is ≥18 years old; provide the full, 28-day course of PEP medications if the patient is <18 years old.
  • Medication access: Ensure the patient’s ability to obtain the medication needed to complete 28 days of PEP.
  • Discuss possible adverse effects of PEP medications. Ensure the patient knows what to do if they experience those effects. If an individual who is completing 28 days of PEP does not have a primary care provider with whom to follow-up, the NYSDOH PrEP/PEP Provider Directory can be used to identify a care provider for a referral.
References

DHHS. Recommendations for the use of antiretroviral drugs during pregnancy and interventions to reduce perinatal HIV transmission in the United States. 2022 Mar 17. https://clinicalinfo.hiv.gov/en/guidelines/perinatal/whats-new-guidelines [accessed 2018 Feb 1]

American Academy of Pediatrics. Infant feeding and transmission of human immunodeficiency virus in the United States. Pediatrics 2013;131(2):391-396. [PMID: 23359577]

CDC. Announcement: Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV – United States, 2016. MMWR Morb Mortal Wkly Rep 2016;65(17):458. [PMID: 27149423]

Martinez de Tejada B, Gayet-Ageron A, Winterfeld U, et al. Birth defects after exposure to efavirenz-based antiretroviral therapy at conception/first trimester of pregnancy: A multicohort analysis. J Acquir Immune Defic Syndr 2019;80(3):316-324. [PMID: 30570524]

Patterson KB, Leone PA, Fiscus SA, et al. Frequent detection of acute HIV infection in pregnant women. AIDS 2007;21(17):2303-2308. [PMID: 18090278]

Wertz J, Cesario J, Sackrison J, et al. Acute HIV infection in pregnancy: The case for third trimester rescreening. Case Rep Infect Dis 2011;2011:340817. [PMID: 22567467]

Adherence and Completion of the 28-Day PEP Regimen

Reviewed and updated: Medical Care Criteria Committee; August 11, 2022

Reported adherence to a 28-day PEP regimen has historically been modest (40%-60%) [Parkin, et al. 2000; Day, et al. 2006; Lunding, et al. 2010]. However, increased rates of adherence have been reported in studies of PEP regimens that include TDF/FTC or TDF/3TC plus a third agent [Mayer, et al. 2008; Tosini, et al. 2010], and some have reported improved tolerability with use of TDF/FTC plus DTG or RAL [Mulka, et al. 2016; Mayer, et al. 2012; McAllister, et al. 2017].

Single-tablet regimens: With the availability of several single-tablet regimens, many clinicians prefer them for PEP to optimize adherence or to use commercial medication assistance programs that may be available to uninsured or under-insured individuals. Several recently published observational prospective cohort studies support this approach:

  • Two recently published studies examined the use of fixed-dose TDF/FTC/elvitegravir (EVG)/COBI (Stribild) as PEP in observational prospective cohorts in France and Boston. In the French cohort, 92% of participants completed 28 days of PEP, and only 3 individuals switched to another regimen due to adverse effects [Valin, et al. 2016]. Lower rates of completion were noted in the Boston group, with 71% completing the 28-day course as prescribed (no missed doses), 15% stopping or modifying their dosing, and 14% lost to follow-up [Mayer, et al. 2017]. Both cohorts reported gastrointestinal adverse effects as the most common adverse events. Neither study documented HIV seroconversions.
  • Results of a 2015 open-label, single-arm study conducted at 2 public sexual health clinics and 2 hospital emergency departments in Australia demonstrated high PEP completion rates (92%) and no HIV seroconversions with fixed-dose single tablet TDF/FTC/rilpivirine (RPV; Complera). Most participants (86%) reported taking all doses with food, and 95% of those who completed the full course endorsed taking the medication with food. The authors acknowledge that they studied TDF/FTC/RPV in a population with a low background of transmitted nucleoside reverse transcriptase inhibitor (NRTI) (4.1%) and non-NRTI (3.1%) resistance and that this combination should be used carefully in populations with higher rates of transmitted resistance [Foster, et al. 2015].

The Centers for Disease Control and Prevention (CDC) and this Committee recommend DTG as a third agent (and alternative to RAL). A recent open-label, single-arm study at 3 sexual health clinics and 2 emergency departments in Australia found completion rates of 90% and no seroconversions with use of DTG plus TDF/FTC as PEP. Adherence was 98%, measured by pill count and consistent with drug levels, and no unexpected adverse events or serious adverse events occurred [McAllister, et al. 2017].

Alternatively, a once-daily PI-based PEP regimen of DRV/r plus 2 NRTIs has demonstrated lower discontinuation rates compared with LPV/r or EFV plus 2 NRTIs, without significant adverse events [Fätkenheuer, et al. 2016]. Together, these study results demonstrate that once-daily PEP regimens with multiple pills can be well tolerated and have high completion rates.

Regimens containing ZDV and LPV/r had lower rates of completion and higher rates of discontinuation due to adverse effects [Ford, et al. 2015; Leal, et al. 2016]. Many agency guidelines switched first-line recommendations to include RAL as a third agent because it had a more favorable adverse effect profile and fewer drug-drug interactions [Mayer, et al. 2012; McAllister, et al. 2014]. However, given the twice-daily dosing of RAL, nearly one-fourth of one cohort on PEP missed the afternoon dose [Mayer, et al. 2012], which suggests that adherence to a RAL-based regimen is challenging.

SELECTED GOOD PRACTICE REMINDERS
Selecting and Initiating a 28-Day Course of PEP
  • Avoid drug-drug interactions and medication-related adverse events: Before prescribing a 28-day course of PEP, review the patient’s current medications and comorbidities to identify possible drug-drug interactions and to anticipate and prevent medication-related adverse events.
  • Impaired renal function: Review baseline laboratory test results to identify the need to adjust ARV medication dosing for renal insufficiency or choose an alternative regimen. Consult with an experienced HIV care provider or other resources, such as drug package insert(s), to determine dose adjustments for patients with baseline CrCl <50 mL/min.
  • If 28-day PEP is indicated: Ensure the patient understands the need to complete the full 28 days of PEP and explain the adherence requirements.
  • Make sure the patient understands that if a dose of PEP is missed, a “double-up” dose is not necessary. Instead, if dose is missed at a specific time, it can be taken as soon as it is remembered within 24 hours of the scheduled time.
  • If possible, provide the 28-day supply of medications. If the full course of medications cannot be provided, then supply a starter pack, as noted below, and a prescription for the medications required to complete 28 days of PEP.
    • Non-occupational exposures: Provide a 7-day starter pack.
    • Occupational exposures: Provide a 7-day (at least) starter pack.
    • Sexual assault exposures (per New York State law): Provide a 7-day starter pack if the patient is ≥18 years old; provide the full, 28-day course of PEP medications if the patient is <18 years old.
  • Medication access: Ensure the patient’s ability to obtain the medication needed to complete 28 days of PEP.
  • Discuss possible adverse effects of PEP medications. Ensure the patient knows what to do if they experience those effects. If an individual who is completing 28 days of PEP does not have a primary care provider with whom to follow-up, the NYSDOH PrEP/PEP Provider Directory can be used to identify a care provider for a referral.
References

Day S, Mears A, Bond K, et al. Post-exposure HIV prophylaxis following sexual exposure: a retrospective audit against recent draft BASHH guidance. Sex Transm Infect 2006;82(3):236-237. [PMID: 16731676]

Fätkenheuer G, Jessen H, Stoehr A, et al. PEPDar: A randomized prospective noninferiority study of ritonavir-boosted darunavir for HIV post-exposure prophylaxis. HIV Med 2016;17(6):453-459. [PMID: 27166295]

Ford N, Shubber Z, Calmy A, et al. Choice of antiretroviral drugs for postexposure prophylaxis for adults and adolescents: a systematic review. Clin Infect Dis 2015;60 Suppl 3:S170-176. [PMID: 25972499]

Foster R, McAllister J, Read TR, et al. Single-tablet emtricitabine-rilpivirine-tenofovir as HIV postexposure prophylaxis in men who have sex with men. Clin Infect Dis 2015;61(8):1336-1341. [PMID: 26123937]

Leal L, León A, Torres B, et al. A randomized clinical trial comparing ritonavir-boosted lopinavir versus raltegravir each with tenofovir plus emtricitabine for post-exposure prophylaxis for HIV infection. J Antimicrob Chemother 2016;71(7):1987-1993. [PMID: 26994089]

Lunding S, Katzenstein TL, Kronborg G, et al. The Danish PEP Registry: experience with the use of postexposure prophylaxis (PEP) following sexual exposure to HIV from 1998 to 2006. Sex Transm Dis 2010;37(1):49-52. [PMID: 19734819]

Mayer KH, Jones D, Oldenburg C, et al. Optimal HIV postexposure prophylaxis regimen completion with single tablet daily elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine compared with more frequent dosing regimens. J Acquir Immune Defic Syndr 2017;75(5):535-539. [PMID: 28696345]

Mayer KH, Mimiaga MJ, Cohen D, et al. Tenofovir DF plus lamivudine or emtricitabine for nonoccupational postexposure prophylaxis (NPEP) in a Boston Community Health Center. J Acquir Immune Defic Syndr 2008;47(4):494-499. [PMID: 18176318]

Mayer KH, Mimiaga MJ, Gelman M, et al. Raltegravir, tenofovir DF, and emtricitabine for postexposure prophylaxis to prevent the sexual transmission of HIV: safety, tolerability, and adherence. J Acquir Immune Defic Syndr 2012;59(4):354-359. [PMID: 22267017]

McAllister J, Read P, McNulty A, et al. Raltegravir-emtricitabine-tenofovir as HIV nonoccupational post-exposure prophylaxis in men who have sex with men: safety, tolerability and adherence. HIV Med 2014;15(1):13-22. [PMID: 24007390]

McAllister J, Towns JM, McNulty A, et al. Dolutegravir with tenofovir disoproxil fumarate-emtricitabine as HIV postexposure prophylaxis in gay and bisexual men. AIDS 2017;31(9):1291-1295. [PMID: 28301425]

Mulka L, Annandale D, Richardson C, et al. Raltegravir-based HIV postexposure prophylaxis (PEP) in a real-life clinical setting: fewer drug-drug interactions (DDIs) with improved adherence and tolerability. Sex Transm Infect 2016;92(2):107. [PMID: 26892929] 

Parkin JM, Murphy M, Anderson J, et al. Tolerability and side-effects of post-exposure prophylaxis for HIV infection. Lancet 2000;355(9205):722-723. [PMID: 10703807]

Tosini W, Muller P, Prazuck T, et al. Tolerability of HIV postexposure prophylaxis with tenofovir/emtricitabine and lopinavir/ritonavir tablet formulation. AIDS 2010;24(15):2375-2380. [PMID: 20729709]

Valin N, Fonquernie L, Daguenel A, et al. Evaluation of tolerability with the co-formulation elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate for post-HIV exposure prophylaxis. BMC Infect Dis 2016;16(1):718. [PMID: 27894270]

Extending PEP Beyond 28 Days

Reviewed and updated: Medical Care Criteria Committee; August 11, 2022

It is rare that PEP is extended beyond the standard 28-day regimen. The only circumstances under which PEP would be extended include the following:

  • The exposed individual has an indeterminate HIV test result at 4 weeks post exposure or is experiencing acute retroviral syndrome at 4 weeks post exposure.
  • The exposed individual is pregnant and there is a high probability of HIV exposure, given the risk of viral rebound in pregnancy.

In these cases, the care provider should consult with an experienced HIV care provider. Otherwise, no data are available to support extending PEP beyond 28 days to prevent HIV infection following an exposure within the previous 28 days.

SELECTED GOOD PRACTICE REMINDERS
Selecting and Initiating a 28-Day Course of PEP
  • Avoid drug-drug interactions and medication-related adverse events: Before prescribing a 28-day course of PEP, review the patient’s current medications and comorbidities to identify possible drug-drug interactions and to anticipate and prevent medication-related adverse events.
  • Impaired renal function: Review baseline laboratory test results to identify the need to adjust ARV medication dosing for renal insufficiency or choose an alternative regimen. Consult with an experienced HIV care provider or other resources, such as drug package insert(s), to determine dose adjustments for patients with baseline CrCl <50 mL/min.
  • If 28-day PEP is indicated: Ensure the patient understands the need to complete the full 28 days of PEP and explain the adherence requirements.
  • Make sure the patient understands that if a dose of PEP is missed, a “double-up” dose is not necessary. Instead, if dose is missed at a specific time, it can be taken as soon as it is remembered within 24 hours of the scheduled time.
  • If possible, provide the 28-day supply of medications. If the full course of medications cannot be provided, then supply a starter pack, as noted below, and a prescription for the medications required to complete 28 days of PEP.
    • Non-occupational exposures: Provide a 7-day starter pack.
    • Occupational exposures: Provide a 7-day (at least) starter pack.
    • Sexual assault exposures (per New York State law): Provide a 7-day starter pack if the patient is ≥18 years old; provide the full, 28-day course of PEP medications if the patient is <18 years old.
  • Medication access: Ensure the patient’s ability to obtain the medication needed to complete 28 days of PEP.
  • Discuss possible adverse effects of PEP medications. Ensure the patient knows what to do if they experience those effects. If an individual who is completing 28 days of PEP does not have a primary care provider with whom to follow-up, the NYSDOH PrEP/PEP Provider Directory can be used to identify a care provider for a referral.