What’s the 411 on PrEP 2-1-1? On-demand PrEP for preventing HIV

On-demand pre-exposure prophylaxis (PrEP) is a PrEP dosing schedule that involves taking pills only on days before and after having sex, as opposed to taking PrEP every day. On-demand PrEP provides another option that may better suit some people’s circumstances or preferences. However, this dosing schedule can be confusing compared with daily dosing, and it is not a suitable option for everyone. This article will explain how on-demand PrEP works and who it might be a good option for. It will prepare service providers to help clients to consider which type of PrEP might be best for them and to support people who choose to take on-demand PrEP.

Note: In this resource we refer to transgender (trans) and cisgender (cis) people. Trans people have a gender identity and/or gender expression that is different from the sex they were assigned at birth, and cis people identify with the sex they were assigned at birth. 

What is on-demand PrEP and how is it taken?

On-demand PrEP, sometimes called PrEP 2-1-1 or event-driven PrEP, is an alternative dosing schedule to taking PrEP daily.^1,2 With this approach, a person takes PrEP pills only on days before and after having sex.

On-demand PrEP involves taking the PrEP drugs emtricitabine and tenofovir disoproxil fumarate (brand name Truvada). This is the type of PrEP that is recommended to be taken on an on-demand schedule.¹ 

The name PrEP 2-1-1 comes from the dosing schedule, which involves taking:

• 2 pills between 2 and 24 hours before sex 
• 1 pill 24 hours after the first dose
• 1 pill another 24 hours later

If a person continues to have sex, they should continue to take a pill every 24 hours until two days after the last time they have sex. 

When a person anticipates having sex again, but it’s been less than a week since their last dose, they can take just one pill as their starting dose between two and 24 hours before they will have sex. If it has been more than a week since their last dose, they should take a starting dose of two pills.^1,2

Besides taking pills, it is recommended that people using on-demand PrEP visit a healthcare provider every three months for testing for sexually transmitted infections (STIs) and monitoring for side effects.¹ This recommendation also applies to people taking PrEP daily.

Who is on-demand PrEP recommended for and how effective is it for those groups?

Canadian draft* guidelines recommend that on-demand PrEP can be used by cis men and trans women who may be at risk for HIV through sex.¹ 

Gay, bisexual and other men who have sex with men (gbMSM)

Canadian draft* guidelines¹ recommend on-demand PrEP for cis gbMSM. The vast majority of participants in on-demand PrEP research studies have been cis gbMSM. Studies show that on-demand PrEP is very effective in this population. The first study to look at on-demand PrEP in high-resource countries was a randomized controlled trial called ANRS IPERGAY, where 400 gbMSM in France and Canada were randomly assigned to take on-demand PrEP or placebo.² In that study, two people taking on-demand PrEP acquired HIV, compared with 14 in the placebo group (an 86% risk reduction). Importantly, both people in the PrEP group who acquired HIV had not taken PrEP as prescribed, highlighting the critical importance of adherence for PrEP effectiveness. 

Since then, several studies focusing primarily on gbMSM^3–6 have shown that on-demand PrEP is as effective as daily PrEP when adhered to. The largest of these was an open-label observational study called ANRS Prévenir,³ which included 3,056 participants who could choose between daily or on-demand PrEP. About half chose each option, and many participants switched between the two at some time over the study period. There were three infections in participants using daily PrEP and three infections in those using on-demand PrEP. Notably, all infections occurred in people who had stopped taking PrEP weeks or months before their diagnosis, underscoring the importance of adherence. 

Trans women

A limited number of trans women have been included in studies of on-demand PrEP.^3,5–8 On the basis of the available data, Canadian draft* guidelines¹ recommend on-demand PrEP as an option for trans women who may be at risk of HIV from sex with cis men. 

However, many trans women take gender-affirming feminizing hormones, which may modestly decrease PrEP drug levels in the body.^9,10 This is not a concern for people taking daily PrEP, as drug levels remain high enough to be protective even when feminizing hormones are used. For people taking on-demand PrEP, the effectiveness might be reduced because of potentially lower drug levels. This issue should be discussed with trans women who are considering on-demand PrEP while taking feminizing hormones. It is also important to reassure trans women that PrEP drugs do not interfere with the effectiveness of hormone therapies.⁹ 

Cis heterosexual men

Although no studies about on-demand PrEP have included men who exclusively have sex with women, Canadian draft* guidelines¹ recommend that cis heterosexual men can consider this approach. On the basis of studies of gbMSM (including bisexual men), the guidelines infer that there is no biological reason why on-demand PrEP would not be effective for cis heterosexual men. 

Who is on-demand PrEP not recommended for?

Canadian draft* guidelines¹ do not recommend on-demand PrEP for cis women or trans men. They also do not recommend it for people who may be at risk for HIV through sharing injection drug use equipment. This is because there is no research on the 2-1-1 dosing schedule in any of these groups. There is some debate about whether on-demand PrEP could work for cis women and trans men who have vaginal or frontal sex;^11,12 however, research is needed to determine this.

People of all genders who may be at risk for HIV through sex can consider taking daily PrEP or long-acting injectable PrEP. Only daily PrEP is recommended for people who share injection drug use equipment.

Why do we need another option when we know daily PrEP works?

Additional options can increase the overall uptake of PrEP by making PrEP more accessible and appealing to a broader audience. On-demand PrEP is one alternative to daily PrEP. A study among gbMSM in Toronto found that as more PrEP options were presented, interest in using any form of PrEP increased, with on-demand PrEP being the most preferred choice.¹³ This suggests that on-demand PrEP can help expand the number of people benefiting from PrEP. 

What do we know about use and awareness of on-demand PrEP?

We don’t know how many people take on-demand PrEP in Canada.¹⁴ However, studies suggest that many opt to use it when given a choice. In observational studies comparing daily and on-demand PrEP, the proportion of participants choosing on-demand PrEP varied widely, from less than 25%⁸ to over 75%.^5,15 While many are interested in on-demand PrEP, awareness of how to take it correctly is lacking, both among gbMSM^14,16 and among healthcare providers.¹⁴ 

What should someone consider when deciding if on-demand PrEP is a good option for them?

When deciding whether to use on-demand PrEP, a person should consider several factors, including how often they have sex, whether they can predict when they’ll have sex, their ability to follow the 2-1-1 dosing schedule, and their personal preference and circumstances. 

Having sex infrequently is a common reason for choosing on-demand PrEP.^17,18 For people who have sex frequently, the on-demand dosing schedule can be confusing, as it requires tracking how many days have passed since their last sexual encounter or last dose. Also, if someone has sex more than once per week, they might end up taking PrEP on most days anyway, making daily PrEP a more practical choice. 

The ability to follow the on-demand schedule is also important. Some find the 2-1-1 dosing schedule challenging because of confusion over the timing, difficulty remembering to take pills, or an inability to predict when they will have sex.^14,16–18 For those who find this difficult, daily PrEP or injectable PrEP might be a better option.

Choosing the type of PrEP to use is a personal decision influenced by various factors that can change over time.¹⁴ Besides having sex infrequently, other common reasons for preferring on-demand PrEP include concerns about safety or side effects of daily PrEP, challenges adhering to a daily PrEP regimen and financial considerations.^14,17,18 Since on-demand PrEP uses fewer pills, it can be cheaper than daily PrEP for those paying out of pocket.

Can a person who is taking one type of PrEP switch to a different type?

People can switch between PrEP regimens — and many people do.¹⁴ Someone might switch regimens as their situation changes (e.g., if they are having sex more or less often or as their relationships change). A substantial number of participants in on-demand PrEP studies have switched from taking on-demand PrEP to daily PrEP and vice versa.^3,4,6 A person should speak to their healthcare provider before switching regimens. 

Recommendations for service providers

Helping clients decide whether on-demand PrEP might be a good option 

Service providers can educate clients on the different type(s) of PrEP they may consider, depending on their sex, gender and potential HIV risk —from sex, sharing injection drug use equipment or both.

For people who are eligible to take PrEP on-demand, service providers should explain what on-demand PrEP is, how the 2-1-1 dosing schedule works and what to expect when meeting with a healthcare provider about PrEP (e.g., lab testing) and should clarify any misconceptions. It is important to highlight the differences between the different PrEP options, including the advantages and limitations of each. Service providers can help clients to evaluate if on-demand PrEP might work for them. Important factors to consider include how often they have sex, whether they usually plan sex in advance and whether they can adhere to the on-demand dosing regimen. 

The final decision about which type of PrEP to take should always be made in consultation with a healthcare provider, who can consider additional factors like other medications or medical conditions. 

Service providers should develop a list of local healthcare providers who offer PrEP, including those who specialize in providing care to gbMSM and/or trans people, if available. This could include establishing referral pathways with these providers.

Educating and supporting clients who choose to take on-demand PrEP

For people who decide to use on-demand PrEP, service providers should thoroughly explain the dosing schedule and be available to answer questions. It’s important to stress the need to follow the regimen precisely and not miss any doses. Providers should stress that for the maximum protection, this approach should be used for every sexual encounter where there is a possibility of HIV transmission. 

For people who are having trouble remembering to take their pills, service providers can help them develop strategies, such as setting an alarm on their phone, using medication reminder apps or using a pill organizer. 

Some people may need help to understand the dosing schedule. Be prepared to answer questions about this. Let’s look at three scenarios and what a person should do in each.

Scenario 1 – This is the standard on-demand dosing schedule. A person has sex on Thursday only. 

In this scenario, the person takes four pills total, following the 2-1-1 regimen. 

Scenario 2 – A person has sex on Monday and then again on Friday. 

In this scenario, the person follows the 2-1-1 regimen for the first time they have sex in the week. On Friday, they only need to take one pill as a starting dose, since it has been less than seven days since their last dose.

Scenario 3 – A person has sex on Tuesday and Thursday.

In this scenario, the person has sex again before they have completed the 2-1-1 regimen. They simply continue to take one pill a day until two days after the last time they have sex.

* Information in this article reflects recommendations from a draft to the update to the Canadian PrEP guidelines. At the time this article was published, the final guidelines have not yet been published.

References

1. Tan D, Hull M, Yoong D et al. Previewing Canada’s draft guideline for HIV PrEP and PEP. [webinar]. Toronto : CATIE; 2024. Available from: https://www.catie.ca/previewing-canadas-draft-guideline-for-hiv-prep-and-pep
2. Molina JM, Capitant C, Spire B et al. On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. New England Journal of Medicine. 2015 Dec 3;373(23):2237-46.
3. Molina JM, Ghosn J, Assoumou L et al. Daily and on-demand HIV pre-exposure prophylaxis with emtricitabine and tenofovir disoproxil (ANRS PREVENIR): a prospective observational cohort study. The Lancet HIV. 2022 Aug 1;9(8):e554-62.
4. Wang H, Wang Z, Huang X et al. Association of HIV preexposure prophylaxis use with HIV incidence among men who have sex with men in China: a nonrandomized controlled trial. JAMA Network Open. 2022 Feb 1;5(2):e2148782.
5. Noret M, Balavoine S, Pintado C et al. Daily or on-demand oral tenofovir disoproxil fumarate/emtricitabine for HIV pre-exposure prophylaxis: experience from a hospital-based clinic in France. AIDS. 2018 Sep 24;32(15):2161-9.
6. van den Elshout MA, Wijstma ES, Boyd A et al. Sexual behaviour and incidence of sexually transmitted infections among men who have sex with men (MSM) using daily and event-driven pre-exposure prophylaxis (PrEP): four-year follow-up of the Amsterdam PrEP (AMPrEP) demonstration project cohort. Plos Medicine. 2024 May 8;21(5):e1004328.
7. Molina JM, Charreau I, Spire B et al. Efficacy, safety, and effect on sexual behaviour of on-demand pre-exposure prophylaxis for HIV in men who have sex with men: an observational cohort study. The Lancet HIV. 2017 Sep 1;4(9):e402-10.
8. Vuylsteke B, Reyniers T, De Baetselier I et al. Daily and event‐driven pre‐exposure prophylaxis for men who have sex with men in Belgium: results of a prospective cohort measuring adherence, sexual behaviour and STI incidence. African Journal of Reproduction and Gynaecological Endoscopy. 2019 Oct 1;22(10).
9. Senneker T. Drug–drug interactions between gender‐affirming hormone therapy and antiretrovirals for treatment/prevention of HIV. British Journal of Clinical Pharmacology. 2024 Jun 12.
10. Tanaudommongkon A, Chaturvedula A, Hendrix CW et al. Population pharmacokinetics of tenofovir, emtricitabine and intracellular metabolites in transgender women. British Journal of Clinical Pharmacology. 2022;88(8):3674-82.
11. Cottrell ML, Yang KH, Prince HM et al. A translational pharmacology approach to predicting outcomes of preexposure prophylaxis against HIV in men and women using tenofovir disoproxil fumarate with or without emtricitabine. Journal of Infectious Siseases. 2016 Jul 1;214(1):55-64.
12. Stewart J. Challenging the dogma of event-driven PrEP [abstract]. Conference on Retroviruses and Opportunistic Infections, Denver, Colorado, March 3–6, 2024. Abstract 50. Available from: https://www.croiconference.org/abstract/challenging-the-dogma-of-event-driven-prep/
13. Tan DH, Rana J, Tengra Z et al. Preferences regarding emerging HIV prevention technologies among Toronto men who have sex with men: a discrete choice experiment. Scientific Reports. 2021 Nov 15;11(1):22252.
14. Daroya E, Wells A, Gaspar M et al. Navigating patterns of oral PrEP use: a qualitative longitudinal study of gay, bisexual, and queer men's dynamic practices of pausing, on-demand, and stopping PrEP in Canada. SSM-Qualitative Research in Health. 2024 Jun 1;5:100446.
15. Ambrožič J, Adamič P, Tomažič J. Slovenia‘s national HIV PrEP programme: evaluation of real-world implementation. International Journal of STD & AIDS. 2024 Jun 1:09564624241233792.
16. Chan C, Fraser D, Grulich AE et al. Increased awareness of event-driven PrEP and knowledge of how to use it: results from a cross-sectional survey of gay and bisexual men in Australia. Sexual Health. 2022 Aug 3;19(6):501-8.
17. Zimmermann HM, Eekman SW, Achterbergh RC et al. Motives for choosing, switching and stopping daily or event‐driven pre‐exposure prophylaxis–a qualitative analysis. African Journal of Reproduction and Gynaecological Endoscopy. 2019 Oct 1;22(10):325389.
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Externally reviewed by: Patrick O’Bryne & Trish Harris

About the author(s)

Mallory Harrigan is CATIE's knowledge specialist, HIV testing. She has a master’s degree in community psychology from Wilfrid Laurier University.