---
title: "Modeling the potential benefits of on-demand PrEP (2-1-1) for cisgender women in South Africa"
id: "plos-one-6-estimated-benefits-of-providing-on-demand-pre-exposure-prophylaxis-options-for"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-6-estimated-benefits-of-providing-on-demand-pre-exposure-prophylaxis-options-for"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094"
published_at: "2026-08-27T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Modeling the potential benefits of on-demand PrEP (2-1-1) for cisgender women in South Africa
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-6-estimated-benefits-of-providing-on-demand-pre-exposure-prophylaxis-options-for
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094)
- **Published At:** 2026-08-27T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The study used data from the HPTN 067 Cape Town site to simulate PrEP use among cisgender women and estimate effectiveness of different non-daily oral PrEP strategies compared with daily TDF/FTC. - Investigators created a synthetic cohort with observed sex-act frequency and pill-taking behaviors to model four regimens for six months each: **daily PrEP**, time-driven (twice-weekly plus post-sex dose), event-driven (pre- and post-sex doses), and **2-1-1 PrEP** (2 pills before sex, then 1 pill on each of the two days after). - Effectiveness estimates were derived using published adherence–efficacy relationships and the number of pills taken around sex acts; adherence to 2-1-1 was inferred from observed event-driven adherence patterns because 2-1-1 was not directly tested in HPTN 067. - Median estimated effectiveness: 86% for **daily PrEP**, 47% for time-driven, 42% for event-driven, and 57% for **2-1-1 PrEP** in the simulated cohort. - Women with low adherence to daily PrEP (<2.8 pills/week; ~8% of cohort) derived the largest relative benefit from switching to on-demand 2-1-1: effectiveness rose modestly (from 41% to 44%) while weekly pill-taking decreased (from 2.2 to 1.4 pills/week). - At the population level the overall effectiveness did not change when that low-adherence subgroup switched to on-demand PrEP, and selecting 2-1-1 PrEP based on sex-act frequency offered no advantage in the model. - Authors conclude that offering **on-demand PrEP** could be a feasible, easy-to-implement additional option where daily oral PrEP exists, potentially improving acceptability and reducing pill burden for women with low daily adherence. - Data and code sources are available: HPTN 067 dataset and GitHub repository for analysis; funding and competing interest statements were reported in the source.
## Clinical Analysis & Structured Key Points
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Stansfield , Roles Conceptualization, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing * E-mail: sstansfi@fredhutch.org Affiliation Vaccine & Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0003-3251-8501 ](https://orcid.org/0000-0003-3251-8501 "ORCID Registry") ⨯ * Mia Moore, Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing Affiliation Vaccine & Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America ⨯ * Marie-Claude Boily, Roles Writing – review & editing Affiliation School of Public Health, Imperial College London, London, United Kingdom [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0003-3919-006X ](https://orcid.org/0000-0003-3919-006X "ORCID Registry") ⨯ * James P. Hughes, Roles Data curation, Formal analysis, Writing – review & editing Affiliations Vaccine & Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America, Department of Biostatistics, University of Washington, Seattle, Washington, United States of America ⨯ * Deborah Donnell, Roles Data curation, Formal analysis, Funding acquisition, Writing – review & editing Affiliations Vaccine & Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America, Department of Global Health, University of Washington, Seattle, Washington, United States of America [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0002-0587-7480 ](https://orcid.org/0000-0002-0587-7480 "ORCID Registry") ⨯ * Linda-Gail Bekker, Roles Writing – review & editing Affiliation The Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa ⨯ * Dobromir T. Dimitrov Roles Conceptualization, Funding acquisition, Writing – original draft, Writing – review & editing Affiliations Vaccine & Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America, Department of Applied Mathematics, University of Washington, Seattle, Washington, United States of America ⨯ # Estimated benefits of providing on-demand pre-exposure prophylaxis options for cisgender women in South Africa: A modeling study * Sarah E. Stansfield, * Mia Moore, * Marie-Claude Boily, * James P. Hughes, * Deborah Donnell, * Linda-Gail Bekker, * Dobromir T. Dimitrov ![PLOS](https://journals.plos.org/resource/img/logo-plos-full-color.svg) x * Published: August 27, 2026 * * [Article](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094) * [Authors](https://journals.plos.org/plosone/article/authors?id=10.1371/journal.pone.0357094) * [Metrics](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0357094) * [Comments](https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0357094) * [Media Coverage](http://plos.altmetric.com/details/doi/10.1371/journal.pone.0357094) * [Abstract](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#abstract0) * [1. Introduction](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#sec005) * [2. Methods](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#sec006) * [Results](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#sec011) * [Discussion](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#sec016) * [Conclusion](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#sec017) * [Supporting information](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#sec018) * [References](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#references) * [Reader Comments](https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0357094) * [Figures](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094) ![Accessible Data Icon](https://journals.plos.org/resource/img/accessible_data.svg)Accessible Data [ See the data ![Link Icon](https://journals.plos.org/resource/img/data_link_icon.svg) ](https://github.com/FredHutch/HPTN_067_Cape_Town) This article includes the Accessible Data icon, an experimental feature to encourage data sharing and reuse. [Find out how research articles qualify for this feature.](https://theplosblog.plos.org/2023/07/accessible-data/) ## Abstract ### Introduction On-demand oral tenofovir disoproxil fumarate–emtricitabine (TDF/FTC) pre-exposure prophylaxis (PrEP) has been shown to be effective at preventing HIV acquisition among cisgender men and transgender women but is not recommended for cisgender women. On-demand PrEP may improve PrEP uptake, effective use, and persistence in cisgender women. We utilized published oral PrEP adherence-efficacy curves and data from HPTN 067 study to estimate effectiveness of different non-daily PrEP options when used by cisgender women and investigate which sub-groups may benefit most from on-demand PrEP. ### Methods We created a synthetic cohort of PrEP users with data on sex act frequency and pill taking from the HPTN 067 Cape Town site. We simulated PrEP use with three PrEP regimens tested in HPTN 067: daily, time-driven (2 pills/week+1 pill after sex), and event-driven (1 pill before+1 pill after sex) PrEP, and hypothesized 2-1-1 PrEP (2 pills before+1 pill each of the two days after sex) for six months each. We estimated PrEP effectiveness based on the number of pills taken around sex acts. Adherence to 2-1-1 PrEP, which was not tested in the HPTN 067, was informed by observed adherence to event-driven PrEP. Assignment to 2-1-1 PrEP based on daily PrEP adherence and sex act frequency was also analyzed. ### Results We estimated median effectiveness of 86% for daily, 47% for time-driven, 42% for event-driven, and 57% for 2-1-1 PrEP. PrEP users with low adherence to daily PrEP (less than 2.8 pills per week) benefited most from on-demand PrEP. In this subgroup, comprising 8% of the cohort, PrEP effectiveness increased from 41% to 44% when switching from daily to 2-1-1 PrEP while pill taking decreased from 2.2 to 1.4 pills per week; population-level effectiveness was unchanged when this subgroup switched to on-demand PrEP. We found no advantage in assigning 2-1-1 PrEP by sex act frequency. ### Conclusions Our model suggests that on-demand PrEP could benefit women with low daily PrEP adherence by decreasing the number of days when pills need to be taken and modestly increasing effectiveness compared to a daily regimen. This would be a valuable and easy-to-implement additional option in places where daily oral PrEP is already available. ## Figures ![Fig 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0357094.g002) ![Table 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0357094.t001) ![Table 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0357094.t002) ![Fig 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0357094.g001) ![Fig 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0357094.g002) ![Table 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0357094.t001) ![Table 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0357094.t002) ![Fig 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0357094.g001) **Citation:** Stansfield SE, Moore M, Boily M-C, Hughes JP, Donnell D, Bekker L-G, et al. (2026) Estimated benefits of providing on-demand pre-exposure prophylaxis options for cisgender women in South Africa: A modeling study. PLoS One 21(8): e0357094. https://doi.org/10.1371/journal.pone.0357094 **Editor:** Max von Kleist, Robert Koch Institut, GERMANY **Received:** June 4, 2026; **Accepted:** August 7, 2026; **Published:** August 27, 2026 **Copyright:** © 2026 Stansfield et al. This is an open access article distributed under the terms of the [Creative Commons Attribution License](http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. **Data Availability:** The data for the HPTN 067 study on which this analysis is based is available at . The code is available at . **Funding:** Funding for SES, MM, MCB, DTD was provided by the National Institute of Health (NIH) National Institute of Allergy and Infectious Disease (NIAID), grant number UM1 068617. SES, MM and DTD were also supported by National Institute of Health (NIH) National Institute of Allergy and Infectious Disease (NIAID) R01 AI179417. The funders did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. **Competing interests:** The authors have no conflicts of interest to declare. ## 1. Introduction Multiple types of pre-exposure prophylaxis (PrEP) have shown efficacy in preventing HIV acquisition among cisgender women in randomized-controlled trials including daily oral pills (oral tenofovir disoproxil fumarate/emtricitabine, TDF/FTC), topical (vaginal rings), and long-acting injectable (cabotegravir, CAB-LA, and lenacapavir, LEN) regimens [[1](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref001)–[5](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref005)]. These options should empower more women to find HIV prevention that suits their needs and preferences. Within the oral PrEP options, both daily PrEP and 2-1-1 PrEP (2 pills before and 1 pill each of the following two days after sex) have demonstrated efficacy for cisgender men who have sex with men (MSM) and transgender women (TGW) [[6](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref006)], but only daily PrEP is currently recommended for cisgender women [[7](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref007)]. While daily PrEP is very effective for women when adherent, safety factors such as intimate partner violence and time factors such as childcare and domestic labor act as barriers to high adherence [[8](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref008),[9](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref009)]. Stigma, misinformation, and delayed clinic uptake of PrEP also create serious challenges to successful daily PrEP use [[10](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref010)–[12](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref012)]. In addition to adherence challenges, cisgender women also appear to have less dosing forgiveness than MSM/TGW [[13](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref013)], potentially due to differences in drug distribution to rectal versus vaginal tissue [[14](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref014)], though this has been recently called into question [[15](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref015)]. For MSM, PrEP coverage levels have been associated with efficacy based on an adherence-efficacy curve that had been previously established with data from the iPrEX study [[16](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref016)]. Until recently there was no equivalent dose-efficacy curve for cisgender women. Quantifiable levels of plasma tenofovir, as a marker of short-term adherence, had been established as a correlate of protection, confirming that daily oral PrEP should be effective for women if taken as prescribed [[17](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref017)]. In the last two years, several independent studies utilized the increasing amount of data from controlled usage of oral PrEP to propose adherence-efficacy curves for women [[18](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref018)–[21](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref021)]. These analyses generally supported the prevailing opinion that oral PrEP is less forgiving for doses missed by women [[13](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref013)] and provoked a debate on the feasibility of offering different on-demand PrEP regimens to cisgender women [[22](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref022)]. This is critical, as one recent systematic review of Sub-Saharan African women’s PrEP preferences found that adherence to daily oral PrEP was a barrier to many women and that some women were very interested in on-demand PrEP products, especially women who could accurately predict sex acts [[23](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref023)]. Adolescents in Uganda reported preferences for on-demand oral PrEP if they had less frequent sex acts [[24](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref024)] and young people in South Africa, Uganda, and Zimbabwe preferred on-demand oral PrEP for reasons such as stigma, pill fatigue, and adherence challenges [[25](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref025)]. The HPTN 067 study tested additional non-daily options among cisgender women in Cape Town, South Africa (enrolled from 2011–2012) and among MSM in Harlem, New York, USA, and Bangkok, Thailand (enrolled from 2012–2014) [[26](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref026),[27](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref027)]. Daily PrEP was compared to time-driven PrEP (one pill twice per week with a post-sex dose 0–2 hours after sex) and event-driven PrEP (1 pill 24–48 hours before and 1 pill 0–2 hours after sex). All PrEP regimens used TDF/FTC. Detailed PrEP adherence and sexual behavioral data was collected with electronic monitoring of pill bottles opening and weekly interviews on pill taking and sexual activity and with pharmacokinetic monitoring [[26](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref026),[27](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref027)]. Women in the HPTN 067 Cape Town site had unusually high adherence to daily PrEP compared to other trials in cisgender women [[28](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref028)], with 75% of sex acts reported covered by PrEP and drug detected in 68% of samples where sex had been reported in the previous week [[26](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref026)]. Adherence to the non-daily PrEP regimens was lower than to daily PrEP, with 56% and 52% of sex acts reported covered and drug detected in 58% and 41% of samples where sex had been reported in the previous week in the time- and event-driven arms, respectively. In this study, we use mathematical modeling to estimate sexual activity and pill taking with daily, time-driven, event-driven, and 2-1-1 PrEP and evaluated the overall PrEP effectiveness in a simulated cohort resembling HPTN 067 Cape Town participants. A key feature of our modeling framework is the ability to predict adherence to multiple oral PrEP regimens based on actual trial data. We studied associations between the probability of taking regularly scheduled pills and pills around expected sex acts, sexual behavior, and ability to predict sex acts to estimate how individuals would respond to different assigned PrEP regimens. We explored a “person-centered care” scenario in which either daily or 2-1-1 PrEP was offered to individuals based on adherence to daily PrEP, aiming to identify prevention strategies with the highest effectiveness. This work is an extension of a previously published analysis evaluating a similar person-centered approach when daily and on-demand PrEP options were provided to MSM in the US and Thailand [[29](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref029)]. The ideal PrEP option for an individual may depend on factors including sexual behavior patterns, likelihood of high adherence, and personal preference. A quantitative framework, relating these factors and personal effectiveness can potentially aid providers in suggesting person-centered optimal options as efficacy alone is often not the deciding factor impacting individual choice of regimen [[30](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357094#pone.0357094.ref030)]. ## 2. Methods We used a
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