WHO: What’s the 2+1+1? Update to WHO’s recommendation on oral PrEP


An increasing number of countries are adopting policies endorsing PrEP for HIV prevention. Emerging evidence from clinical research that different dosing strategies can be effective provides an opportunity to offer flexibility, choice and convenience to individuals who can benefit from PrEP and is considered by WHO in updating its guidance to countries. Based on the available evidence published so far, this technical brief updates the current WHO recommendation on oral PrEP to include an option of event-driven dosing for men who have sex with men. Read the brief here

This technical brief aims to:

  • update the dosing considerations for oral pre-exposure prophylaxis (PrEP) containing TDF for men who have sex with men

  • summarize current evidence on the safety and efficacy of event-driven PrEP (ED-PrEP)

  • describe the rationale for offering ED-PrEP as an alternative to daily oral PrEP to men who have sex with men as part of comprehensive HIV prevention and sexual health services

  • discuss considerations for offering ED PrEP to men who have sex with men, including clear messaging on how men who have sex with men can switch from ED-PrEP to daily dosing (and vice-versa).

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Event-driven PrEP (ED-PrEP) for men who have sex with men consists of the use of a double dose (two pills, which serves as the loading dose) of TDF/FTC (or TDF/3TC) between two and 24 hours in advance of sex; then, a third pill 24 hours after the first two pills, and a fourth pill 48 hours after the first two pills (Fig. 1). ED-PrEP has been described as “2+1+1” dosing, a term that can be helpful to communicate this approach as an alternative to daily dosing for men who have sex with men. This 2+1+1 dosing is the only ED-PrEP regimen that has been demonstrated to be effective. Other regimens, involving use of only a single pill before and after sex, or taking PrEP four times per week, have been studied, but their efficacy is not known (14, 23).

The 2+1+1 dosing describes ED-PrEP when an isolated act of sex is involved. If more sex acts take place over the following days, a single PrEP pill can be continued daily for as long as sex continues, with a single daily pill taken for each of two days after the last sex act.

There have been no trials of ED-PrEP among adolescent men who have sex with men, apart from youth over 18 years who participated in the ADAPT/HPTN 067 trial, where it was found that daily dosing had better coverage than non-daily PrEP. Since youth may require more active support for continuation and in understanding how to safely start and stop PrEP, along with how and when to shift back and forth between daily dosing and EDPrEP), some may find a daily oral schedule easier to follow. Module 12 of the WHO PrEP Implementation Tool (24) offers more information on special considerations for provision of oral daily PrEP to adolescents and young adults.

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At this time there is evidence on safety and efficacy/effectiveness for EDPrEP only for men who have sex with men (men exposed through receptive or insertive anal sex with other men) (26–28). There is insufficient evidence for ED-PrEP to be considered as a dosing strategy for women, transgender women and men who have vaginal and/or anal sex with women. PrEP providers should ensure that these populations are offered daily dosing.

The pharmacology of tenofovir, particularly in the female genital tract, suggests that the original ED-PrEP dosing strategy may not confer sufficient protection for women (25, 29, 30). WHO has addressed this specific issue previously, as part of a technical consultation on the pharmacology of PrEP medicines in 2016 (31). Additional research in women is needed to evaluate the safety and efficacy of different ED-PrEP regimens for vaginal exposure to HIV. Investigational regimens for women could include higher loading doses or co-formulation with additional medications (such as integrase inhibitors) that have good ability to penetrate into vaginal tissues.

Transgender women can safely take daily oral PrEP. Recent pharmacology data on the interaction of PrEP and feminizing hormone therapy in transgender women suggests caution with considering ED-PrEP as an additional choice (32, 33). Data presented at the 2018 International AIDS Conference in Amsterdam indicated that in 20 Thai HIV-negative transgender women on feminizing hormones (iFACT study), daily oral PrEP did not alter feminizing hormone levels (33). However, it was observed that plasma levels of tenofovir (TFV) decreased by 13%. This decrease in tenofovir concentration is small and not expected to decrease the effectiveness of daily PrEP dosing in transgender women, but it could affect the efficacy of ED-PrEP.

Similarly, a study in the United States of America observed changes in the TDF/FTC pharmacology in four transgender women receiving ART containing TDF (32). Unlike the Thai study, which examined plasma levels, this study looked at tenofovir rectal concentrations in transgender women on feminizing hormone therapy. Active anabolite tenofovir-diphosphate levels relative to dATP (the natural substrate of HIV-1 reverse transcriptase) were significantly lower in these transgender women than in cisgender women and decreased with increasing concentrations of estrogen from injectable feminizing hormone therapy. This pilot study was very small and the laboratory methods were challenging; more research is needed to confirm the results.

WHO recognizes the urgent need for health care systems to be more inclusive of transgender populations, especially transgender women, across the spectrum of prevention/PrEP research, from pharmacology to implementation science. In addition, public health authorities should prioritize increasing awareness of and access to PrEP for transgender women. Read the full report