The Case for On-Demand PrEP

ContagionApril 2019
Volume 4
Issue 2

What’s the 411 on 2-1-1?

Although the incidence of HIV is declining, the prevalence of HIV infection and those living with the virus remains an issue. In the United States, approximately 1.1 million people are currently living with HIV/AIDS, and 38,739 new cases of HIV infection were reported in 2017.1,2 A majority of those cases are in men, aged 25 to 45 years, and men who have sex with men (MSM) and are disproportionately prevalent in communities of color, specifically black and African American. Worldwide, there are 1 million new sexually transmitted infections (STIs) daily.3 Sexuality, race, ethnicity, age, sex/gender identity, and geographic location have a direct impact on the risk of HIV acquisition.1,2


Understanding an individual’s risk helps to make the right decision regarding HIV prevention strategies. Pre-exposure prophylaxis (PrEP) therapy includes taking an antiretroviral medication used in conjunction with harm reduction strategies to prevent HIV. PrEP is a vital component of the HIV care continuum that can help drastically reduce the number of new HIV infections.

Data from reported that there were 77,000 HIV prevention users in 2016, which shows that for every 1 person with a new diagnosis, there were 2.5 HIV-negative people using PrEP.4 Unfortunately, those who can benefit most from PrEP care are not accessing therapy because of a variety of obstacles. Lack of provider education is a big barrier to PrEP care, with 1 in 3 primary care physicians and nurses reporting no knowledge of PrEP.5 A national online survey conducted in 2016 captured some of the reasons why one of the groups at highest risk (US MSM) was not accessing PrEP care by reviewing prescription data from community and mail-order pharmacies from September 2015 to August 2016. There were 4698 participants, of whom 85% had not used PrEP and 22% were unaware of PrEP.

A majority of respondents (83%) reported at least 1 instance of condomless anal intercourse in the previous 3 months. The top reasons for not accessing PrEP care included cost (40.2%), concerns about potential adverse effects (31.4%), not knowing how to access PrEP care (30.6%), concerns about effects on insurance coverage (19.5%), and not suspecting a risk (19.3%), among others.6 These data show that PrEP therapy was not reaching a majority of those who could most benefit from care, specifically African Americans and Latinos.6 Of the estimated 500,000 PrEP-eligible African Americans, only 1% are received a prescription, and of the 300,000 PrEP-eligible Latino Americans, 3% received PrEP therapy.6 An alternative to a daily dosing strategy has been endorsed by the International Antiviral Society—USA Panel (IAS-USA) and the European AIDS Clinical Society (EACS) and could address some of these concerns and provide cost effectiveness, less toxicity, and easier access to regimens for individuals at high risk.7,8


Tenofovir disoproxil fumarate and emtricitabine (TDF/FTC; Truvada) is the first and only fixed-dose daily oral medication approved by the US Food and Drug Administration for prevention of HIV transmission.9 TDF/FTC was approved for use in adults as HIV prevention in July 2012, with its indication updated in 2018 to include daily dosing for adolescents ≥35 kg.9 The recommendations for daily PrEP therapy were initially published by the US Centers for Disease Control and Prevention (CDC) in 2014 based on the favorable results of the iPrEx trial including MSM.10 Subsequent updates have included additional at-risk groups (heterosexuals/serodiscordant couples at high risk and people who inject drugs) and recommendations to help guide providers on how to best provide PrEP care. The most recent update to the guidelines by the CDC was in 2017. The success of this regimen based on clinical trial data was strongly correlated to adherence and identification of detectable levels of PrEP in the bloodstream or measurable levels in hair follicles.10


On-demand PrEP, also known as event-driven or pericoital PrEP, is HIV prevention based on planned intercourse and is taken only when needed, ie, if a sexual encounter is with a person of known HIV-positive or unknown status, in order to prevent HIV acquisition in MSM.7 The IAS-USA and EACS guidelines have endorsed this alternative dosing strategy for TDF/FTC for on-demand PrEP based on favorable results from the Intervention Préventive de l’Exposition aux Risques avec et pour les Gays (IPERGAY) trial. This strategy entails taking 2 TDF/FTC pills 2 to 24 hours before sexual intercourse followed by 2 single doses of TDF/FTC 24 and 48 hours after the first drug was taken (2-1-1). This alternative dosing is recommended for HIV prevention only in MSM with infrequent sexual exposures but high-risk sexual behavior.7,8

The IPERGAY trial, conducted in France and Canada, was a randomized, double-blind trial evaluating sexual activity based on oral HIV PrEP care in MSM at high risk. PrEP care was prescribed as 2-1-1 with continued daily dosing if there was additional sex, with a maximum dose of 7 pills per week. Results showed high protection (86%; 95% CI, 40-98) against HIV infection in seronegative MSM at high risk when on-demand PrEP was taken as prescribed (2-1-1). 11 Patients took an average of 15 pills per month. Plasma drug levels were measured in a subset of participants randomized to take TDF/FTC and found that 86% had tenofovir (TFV) levels consistent with having taken the drug during the previous week.10,12

An open-label extension (OLE) study was conducted with the same patients who had participated in the original IPERGAY trial. All patients were offered pericoital PrEP as in the original trial, and there was a significant decrease in observed HIV incidence (97% relative risk reduction; 95% CI, 81-100). The 1 participant who acquired HIV had not taken PrEP therapy in the previous 30 days and was in an ongoing relationship with a HIV-positive partner. Greater than 70% of the participants had detectable plasma drug levels of TFV. The efficacy determination by plasma blood levels of TFV was determined as the following: less than 2 doses per week (44%), 2 to 3 doses per week (84%), 4 to 6 doses per week (100%), and 7 days per week (100%). Frequency of pill use was higher in the OLE, with 18 pills per month compared with 15 pills in the original trial.


There are advantages and disadvantages of on-demand PrEP versus daily PrEP therapy. A few of the most notable advantages are decreased pill burden (fewer doses per month), fewer potential adverse effects as a result of less frequent dosing, and cost savings due to fewer pills consumed over time. The cost savings advantage is one of the most measurable specifically in MSM, who could most benefit from on-demand PrEP.13 A new HIV infection can pose a significant financial burden. Infection can be averted through daily PrEP use, which is cost- efficient, but TDF/FTC 30 days per month for 12 months per year can still be expensive and is often a barrier to its use. This financial burden can be lessened with on-demand PrEP, based on the patient’s behavior and number of encounters. The Table14 shows the cost reduction based on the recommendations of event-driven PrEP and specifically the IPERGAY 2-1-1 regimen.

More data are needed for the CDC to fully endorse on-demand PrEP and add this option to its PrEP guidelines. Although, there are good efficacy data to support its use in specific individuals at high risk (MSM), based on those who may be taking very few doses and at less time prior to the sexual encounter, thus not allowing for adequate concentrations in effected tissues such as the rectum. This regimen has been endorsed by the IAS-USA and the EACS, and 2-1-1 dosing is listed in their guidelines. However, access to this medication and the cost factor could be affected by the availability of a generic equivalent to TDF/FTC in Europe. If on-demand PrEP were used in the United States, it would be considered an off-label use. The data currently support the use in MSM only, and there are no data to support its use in transgender men and cisgender women who engage in vaginal—penile intercourse because concentrations of TDF/FTC do not reach optimal levels in vaginal tissue within the on-demand PrEP timeline. PrEP therapy reaches maximum protection against HIV transmission through receptive anal intercourse after approximately 7 days of daily use compared with up to 20 days for receptive vaginal intercourse or injection drug use.7 On-demand PrEP should not be used in transgender women who are currently receiving gender-affirming care with feminizing hormones such as estrogen because of decreased concentrations of TFV.15,16 The reduction in therapeutic concentrations means that only daily PrEP therapy should be recommended in this special situation for the most protection from HIV acquisition.15

Based on the data, on-demand PrEP should be considered a viable option for MSM who are at high risk, and it is one of many options in the toolbox for HIV prevention. PrEP use with TDF/FTC is only the beginning when it comes to using chemoprophylaxis for HIV prevention, and additional options that take into consideration barriers to PrEP care are on the horizon, including an additional oral medication for PrEP (emtricitabine and tenofovir alafenamide [Descovy]). Data from the phase 3 DISCOVER trial were recently presented at the 2019 Conference on Retroviruses and Opportunistic Infections showing noninferiority to TDF/FTC, with improved safety regarding bone and renal health. There are multiple agents in the pipeline being investigated as prevention options in a variety of dosage forms and alternatives to daily oral therapy.17 Addressing the knowledge gaps regarding HIV prevention options and the barriers to care will help those who are eligible for these life-changing therapies. Based on the data, on-demand PrEP is a reasonable alternative to daily PrEP and is highly effective for MSM with infrequent sexual exposure and planned sexual intercourse.

Madison is an associate professor of Pharmacy Practice with Roseman University of Health Sciences College of Pharmacy. She is currently practicing at Huntridge Family Clinic Foundation in Las Vegas, Nevada. Her clinic focuses on the care of the LGTBQ community.Phoenix is the founder of the Huntridge Family Clinic in Las Vegas, NV, which is the largest LGBTQ-focused medical clinic in Nevada and is a nurse practitionerowned and operated clinic. He is currently the president and chief medical officer for the Huntridge Family Clinic Foundation, which is now the nonprofit parent company for the Huntridge Family Clinic.


  1. US Centers for Disease Control and Prevention. HIV Surveillance Report. Diagnoses of HIV Infection in the United States and Dependent Areas, 2017. CDC website. Published November 2018. Accessed March 3, 2019.
  2. US Centers for Disease Control and Prevention. HIV Surveillance Supplemental Report. Estimated HIV Incidence and Prevalence in the United States, 2010-2016. CDC website. Published February 2019. Accessed March 3, 2019.
  3. World Health Organization. Sexually transmitted infections key facts. WHO website. Published February 28, 2019. Accessed March 3, 2019.
  4. AIDSVu. Deeper Look: PrEP. AIDSVu website. Accessed March 3, 2019.
  5. US Centers for Disease Control and Prevention. Vital Signs. Daily Pill Can Prevent HIV. CDC website. Published November 24, 2015. Accessed March 3. 2019.
  6. Mayer KH, Biello K, Novak DS, Krakower D, Mimiaga MJ. Reasons for not using PrEP in a national on-line sample of US men who have sex with men (MSM) - cost, side effects, access lead reasons for PrEP nonuse by US MSM. Presented at: 9th IAS Conference on HIV Science; July 23-26, 2017; Paris, France. Abstract MOPEC0648.
  7. Saag MS, Benson CA, Gandhi RT, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2018 recommendations of the International Antiviral Society—USA Panel. JAMA. 2018 Jul 24;320(4):379-396. doi: 10.1001/jama.2018.8431.
  8. European AIDS Clinical Society. European AIDS Clinical Society Guidelines. V 9.1. EAC Society website. Published October 2018. Accessed March 13, 2019
  9. Truvada [package insert]. Foster City, CA: Gilead Sciences, Inc; 2018.
  10. US Centers for Disease Control and Prevention. US public health service: preexposure prophylaxis for the prevention of HIV infection in the United States—2017 update: a clinical practice guideline. CDC website. Published March 2018. Accessed March 4, 2019
  11. Sagaon-Teyssier L, Suzan-Monti M, Demoulin B, et al. Uptake of PrEP and condom and sexual risk behavior among MSM during the ANRS IPERGAY trial. AIDS Care. 2016;28 Suppl 1:48-55. doi: 10.1080/09540121.2016.1146653.
  12. Molina JM, Capitant C, Spire B, et al. On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med. 2015 Dec 3;373(23):2237-46. doi: 10.1056/NEJMoa1506273.
  13. Mitchell K, Dimitrov D, Hughes J, et al. In what circumstances could nondaily preexposure prophyalxis for HIV substantially reduce program costs? AIDS. 2018 Mar 27;32(6):809-818. doi: 10.1097/QAD.0000000000001766.
  14. Mitchell K, Dimitrov D, Hughes J, et al. In what circumstances could nondaily preexposure prophyalxis for HIV substantially reduce program costs? Table 2. Estimated cost savings with nondaily PrEP. AIDS. 2018 Mar 27;32(6):809-818. doi: 10.1097/QAD.0000000000001766.
  15. Hiransuthikul A, Himmad K, Kerr S, et al. Drug-drug interactions between the use of feminizing hormone therapy and pre-exposure prophylaxis among transgender women: The iFACT study. Presented at: 22nd International AIDS Conference (AIDS 2018); July 23-27, 2018; Amersterdam, Netherlands. Abstract TUPDX0107LB.
  16. Hendrix C, Shieh E, Marzinke M, et al. TGW on estrogen have significantly lower TFV/FTC concentrations during directly observed dosing when compared to cis men. Presented at HIV Research for Prevention 2018; October 21-25, 2018; Madrid, Spain. Abstract OA23.03.
  17. Riddell J 4th, Amico KR, Mayer KH. HIV Preexposure Prophylaxis: A Review. JAMA. 2018 Mar 27;319(12):1261-1268. doi: 10.1001/jama.2018.1917.
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