PrEP, or pre-exposure prophylaxis, is an HIV prevention method involving antiretroviral medication taken to block the virus from establishing a permanent infection. The most common regimen requires taking a pill daily to maintain continuous protective drug levels. For individuals who do not require continuous protection, “PrEP on Demand,” or event-driven PrEP, is an alternative strategy. This method involves taking the medication only around the time of potential sexual exposure.
The 2-1-1 Dosing Schedule
PrEP on Demand relies on the specific “2-1-1” dosing schedule. This sequence ensures adequate levels of the active drugs, tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), are present in the tissue before HIV exposure. The regimen begins with the “2,” meaning two tablets are taken between 2 and 24 hours before anticipated sexual activity. Taking this initial double dose closer to 24 hours before sex is often recommended for optimal drug concentration.
The next step is the first “1,” taking a single tablet 24 hours after the initial two-pill dose. The final part is the second “1,” where a single tablet is taken another 24 hours later, or 48 hours after the first dose. This post-exposure dosing maintains a high drug concentration to fight off any potential virus.
If sexual activity continues beyond the first day, the user must continue to take one single tablet every 24 hours. Dosing continues until two single tablets have been taken after the last sexual encounter. The 2-1-1 schedule is a minimum four-pill sequence taken over three days for a single sexual event.
Clinical Evidence of Protection
The effectiveness of PrEP on Demand has been confirmed through major international clinical trials. The landmark IPERGAY trial, a randomized, placebo-controlled study, demonstrated a substantial reduction in HIV acquisition risk. When the 2-1-1 protocol was followed correctly, the trial showed an 86% reduction in HIV incidence among men who have sex with men (MSM) compared to the placebo group.
A subsequent open-label study, ANRS Prévenir, supported the strategy’s high protection. This study recorded zero new HIV infections among participants who used the 2-1-1 method correctly. These findings indicate that when the medication is taken as directed, the protective effect is comparable to that of daily PrEP.
The mechanism relies on achieving specific concentrations of the antiretroviral drugs within the rectal tissue before exposure. Pharmacokinetic studies show that the 2-1-1 schedule effectively reaches protective levels in the colorectal tissue, the primary site of HIV entry during receptive anal sex. This rapid tissue saturation explains the strategy’s effectiveness for this specific exposure route.
Clinical trials demonstrate the high efficacy potential of the method, but real-world effectiveness hinges on user adherence to the strict timing. Missing a dose or failing to follow the schedule precisely can lead to insufficient drug levels, compromising the protective barrier.
Key Differences from Daily PrEP
The fundamental difference between PrEP on Demand and the daily regimen is the consistency of drug concentration and the required adherence pattern. Daily PrEP maintains a steady, high level of medication in the bloodstream and tissues at all times, providing continuous protection regardless of when sexual activity occurs. This method is ideal for individuals who engage in frequent or spontaneous sex.
PrEP on Demand requires precise, event-based timing, suitable only for those who can reliably plan sexual activity at least two hours in advance. The adherence challenge shifts from a daily habit to accurately executing a multi-step sequence tied to a specific event. Failure to follow the exact 2-1-1 timing can render the medication ineffective.
The scope of tissue protection is another distinction. The 2-1-1 protocol is primarily effective for preventing HIV transmission via receptive anal sex. Daily PrEP is the only regimen currently recommended to protect against HIV transmission through receptive vaginal sex and injection drug use. This difference exists because the drug takes longer to reach protective levels in vaginal and cervical tissues than in rectal tissue.
Target Users and Contraindications
PrEP on Demand is recommended for cisgender men who have sex with men (MSM) and who can anticipate their sexual encounters. This population benefits most because their risk is intermittent and they can meet the planning requirements of the dosing schedule. It is a viable alternative for those who prefer not to take a pill every day or whose sexual activity is infrequent.
A contraindication for using PrEP on Demand is a pre-existing chronic hepatitis B virus (HBV) infection. The medication (TDF/FTC) is also an effective treatment for HBV, and intermittent dosing can lead to resistance or cause severe liver inflammation when stopped and restarted. Individuals with chronic hepatitis B must use daily PrEP to maintain consistent viral suppression and prevent flares.
The regimen is not recommended for individuals who cannot ensure the two-hour minimum lead time before sex, or for those whose sexual activity is too frequent, such as more than twice a week. For populations at risk through receptive vaginal sex, including cisgender women and transgender men, daily PrEP remains the standard recommendation because the 2-1-1 method does not provide adequate protective drug concentrations in vaginal tissue.