Increased HIV incidence during Event-Driven PrEP compared to Daily PrEP in the Netherlands
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Background
Clinical trials demonstrated high efficacy of daily and event-driven oral pre-exposure prophylaxis (PrEP) in HIV prevention. Event-driven PrEP involves taking two tablets before and two times one tablet after sexual contact (2-1-1/on-demand). While both are implemented in Dutch clinical practice, evaluating real-world effectiveness requires large-scale data from routine clinical care. This study compared HIV incidence between daily and event-driven PrEP in the Netherlands.
Methods
We used surveillance data from the Dutch national PrEP program (August 1, 2019-December 31, 2025). Individuals ≥16 years with ≥1 follow-up consultation after PrEP initiation were included; PrEP regimen since last visit was recorded at each visit. Person-time was modeled as time-varying based on the regimen reported at each consultation. HIV incidence rates were calculated per 100 person-years and Cox proportional hazards models estimated hazard ratios between regimens for HIV acquisition, adjusted for sociodemographics, sexual behavior, and history of sexually transmissible infections.
Findings
16,469 individuals (15,843 men who have sex with men, 579 transgender and gender diverse persons, 45 women and two men who have sex with women) initiated PrEP and had ≥1 follow-up visit (median follow-up 2·0 years (IQR=0·8-4·0)). Median age was 33 years (IQR=27-44). 49 PrEP users were diagnosed with HIV over 41,092 person-years (IR=0·12/100 py;95%CI=0·09-0·16), of whom 42 event-driven users (IR=0·20/100 py;95%CI=0·15-0·27) and seven daily PrEP users (IR=0·04/100 py;95%CI=0·02-0·07). In multivariable Cox regression, event-driven PrEP use was associated with a higher hazard of HIV acquisition (aHR=7·0;95%CI=3·0-16·4).
Interpretation
Despite overall low HIV incidence, the incidence rate in the Dutch national PrEP program was seven-fold higher during event-driven PrEP use compared to daily, which may be due to lower adherence. These findings denotes that, in real-world settings, improved person-centered counseling is needed for individuals interested in, or using event-driven PrEP. Research should identify domains and preferred methods of support.
Funding
None for this study.
Research in context
Evidence before this study
We searched PubMed on 07 July 2026 without language or date restrictions, using the (Mesh)terms (“HIV”[Mesh] OR hiv OR hiv-1 OR hiv-2 OR hiv infections OR acquired immunodeficiency syndrome OR (human immunodeficiency virus* OR human immunodeficiency virus* OR human immuno-deficiency virus* OR human immune-deficiency virus*)) AND (“Incidence”[Mesh] OR incidence) AND (“Pre-Exposure Prophylaxis”[Mesh] OR “Tenofovir”[Mesh] OR “Emtricitabine”[Mesh] OR (“PrEP” OR “Pre-Exposure Prophylaxis” OR “Preexposure Prophylaxis” OR “HIV Pre-Exposure Prophylaxis” OR “HIV PrEP” OR truvada OR emtricitabine OR tenofovir)) AND (event-driven OR intermittent OR on-demand OR 2-1-1 OR “on demand”). This search yielded 213 publications. Clinical trials and cohort studies demonstrated low HIV incidence across both daily and event-driven oral tenofovir disoproxil / emtricitabine (TDF-FTC) PrEP regimens. Most comparative real-world data originated from implementation and demonstration projects in the early oral PrEP era (2014-2020), with follow-up periods ranging from six months to four years. To date, only the ANRS PREVENIR study (a prospective cohort study across 22 sites in the Paris region) provided more recent data with longer follow-up time (i.e., a seven-year follow-up period up to May 2024). Despite high efficacy and effectiveness in study settings, there is evidence that in real-life some event-driven PrEP users incorrectly use PrEP or have more difficulties adhering to the PrEP regimen in comparison to daily PrEP users, in particular young men who have sex with men. A few studies have found a higher HIV incidence among event-driven oral PrEP users than among daily oral PrEP users, related to lower adherence, but these findings were derived from small-scale cohort studies with a low number of participants and restricted to a limited number of clinical sites rather than a national cohort.
Added value of this study
Using real-world national surveillance data comprising data over six years since nationwide implementation of the Dutch national PrEP programme, we evaluated HIV incidence by PrEP regimen. While the overall HIV incidence was low, we found a seven times higher HIV incidence among individuals who reported having used event-driven oral PrEP compared to those reporting daily oral PrEP use, after adjusting for socio-demographics, sexual health and behavior. To the best of our knowledge, this is the first study reporting a significant difference in HIV incidence between the two oral regimens using national surveillance data over an extended follow-up period.
Implications of all the available evidence
While event-driven oral PrEP has been demonstrated to be as effective as daily use in study settings, most likely related to good adherence, individual and contextual challenges might have led to insufficient adherence resulting in lower effectiveness in a real-world setting. This underscores the need to better understand the real-world challenges relating to event-driven PrEP use and improved person-centered counseling of event-driven PrEP.
