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Efficacy estimates of oral pre-exposure prophylaxis for HIV prevention in cisgender women with partial adherence

Nature Medicine volume 29, pages 2748–2752 (2023)Cite this article

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Abstract

Pre-exposure prophylaxis (PrEP) with tenofovir (TFV) disoproxil fumarate and emtricitabine administered orally daily is effective in preventing human immunodeficiency virus (HIV) acquisition in both men and women with sufficient adherence; however, the adherence–efficacy relationship in cisgender women has not been well established. We calculated the adherence–efficacy curve for cisgender women by using HIV incidence and plasma TFV concentration data from three trials (FEM-PrEP, VOICE and Partners PrEP). We imputed TFV diphosphate (TFV-DP) concentrations, a measure of long-term adherence, from TFV quantification by using data from the HIV Prevention Trials Network 082 study, which measured both TFV-DP and TFV concentrations. Two, four and seven pills per week reduced HIV incidence by 59.3% (95% credible interval (CrI) 29.9–95.8%), 83.8% (95% CI 51.7–99.8%) and 95.9% (95% CI 72.6–100%), respectively. Our adherence–efficacy curve can be validated and updated by HIV prevention studies that directly measure TFV-DP concentrations. The curve suggests that high adherence confers high protection in cisgender women. However, the lower efficacy with partial adherence highlights the need for new PrEP products and interventions to increase adherence.

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Fig. 1: Flowchart of TDF/FTC efficacy estimation.
Fig. 2: Efficacy of TDF/FTC according to TFV-DP measurements.

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Data availability

The data used in this study are available on GitHub (https://github.com/FredHutch/PrEPCiswomen).

Code availability

Model and calibration code is available on GitHub (https://github.com/FredHutch/PrEPCiswomen).

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Acknowledgements

We are grateful to H. Angier, a scientific writer at the Vaccine and Infectious Disease Division of the Fred Hutchinson Cancer Center, for editing the manuscript. This paper was reviewed and approved by the HIV Prevention Trials Network manuscript review committee. This work was funded by the US National Institutes of Health through the following grants from the National Institute of Allergy and Infectious Diseases and the National Institute on Drug Abuse: UM1AI068613, UM1AI068617 and UM1AI068619. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Mia Moore, Sarah Stansfield, Deborah J. Donnell & Dobromir Dimitrov

  2. HPTN Modelling Centre, Imperial College London, London, UK

    Mia Moore, Sarah Stansfield, Marie-Claude Boily, Kate M. Mitchell & Dobromir Dimitrov

  3. Medical Research Council Centre for Global Infectious Disease Analysis, School of Public Health, Imperial College London, London, UK

    Marie-Claude Boily & Kate M. Mitchell

  4. Anschutz Medical Campus, University of Colorado, Aurora, CO, USA

    Peter L. Anderson

  5. Wits RHI, University of Witwatersrand, Johannesburg, South Africa

    Sinead Delany-Moretlwe

  6. Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa

    Linda-Gail Bekker

  7. College of Health Sciences Clinical Trials Research Centre, University of Zimbabwe, Harare, Zimbabwe

    Nyaradzo M. Mgodi

  8. Departments of Global Health, Medicine and Epidemiology, University of Washington, Seattle, WA, USA

    Connie L. Celum

  9. Department of Applied Mathematics, University of Washington, Seattle, WA, USA

    Dobromir Dimitrov

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Contributions

All authors contributed to the preparation of the manuscript. S.D.-M., L.-G.B., N.M.M. and C.L.C. led the HIV Prevention Trials Network 082 trial. Laboratory testing of tenofovir diphosphate concentrations in dried blood spot samples was supervised by P.L.A. M.M. wrote the R code, ran the calibration and wrote the initial draft of the manuscript. D.J.D. and D.D. supervised the analysis of the project. D.J.D., D.D., M.-C.B., K.M.M. and S.S. provided feedback on methodology.

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Correspondence to Mia Moore.

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Competing interests

P.L.A. has received personal fees from Gilead, ViiV and Merck, as well as research support from Gilead, paid to his institution. L.-G.B. has received honoraria for advisories to Gilead Sciences, Merck (Pty) Ltd, ViiV Healthcare and Janssen; these are not ongoing. K.M.M. has received teaching payments from Pfizer, outside the submitted work. All other authors declare no competing interests.

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Nature Medicine thanks Jeremie Guedj, Robin Schaefer and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Alison Farrell, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Efficacy of TDF/FTC by TFV-DP measurement in model h2.

Reduction in incidence in HIV as a function of tenofovir diphosphate (TFV-DP) levels in dried blood spots measurement according to model h_2. Grey ribbon = IQR, Dashed line = 95% Credible Interval. Colored rectangles represent the IQR of TFV-DP measurements associated with two pills per week (red), four pills per week (blue) and seven pills per week (green) derived from directly observed dosing8.

Extended Data Fig. 2 Efficacy of TDF/FTC by TFV-DP measurement in model h3.

Reduction in incidence in HIV as a function of tenofovir diphosphate (TFV-DP) levels in dried blood spots measurement according to model h3. Grey ribbon = IQR, Dashed line = 95% Credible Interval. Colored rectangles represent the IQR of TFV-DP measurements associated with two pills per week (red), four pills per week (blue) and seven pills per week (green) derived from directly observed dosing8.

Extended Data Fig. 3 Adherence-efficacy model curves.

Assumed functional forms for PrEP efficacy as a function of intraerythrocytic tenofovir diphosphate, testing assumptions that individuals with no quantifiable TFV-DP have the same HIV incidence as individuals concurrently randomized to placebo and that HIV incidence approaches zero with increasing TFV-DP. f1 includes both assumptions. f2 challenges the first assumption by allowing individuals with low PrEP adherence to have lower (or higher) efficacy k2 than those on placebo. f3 challenges the second assumption as efficacy approaches k3.

Extended Data Fig. 4 Imputation of TFV-DP concentration from plasma TFV quantifiability.

Measurements of intraerythrocytic TFV-DP among HPTN 082 participants with quantifiable or unquantifiable plasma TFV using the quantification threshold of each trial (see Extended Data Table 2). Plots are based on a total of N = 1083 samples, which are divided into positive and negative depending on the quantification threshold. For FEMPrEP and partners PrEP, the total is only 1081 because for two samples the quantification threshold could not be evaluated due to missing data. Width = frequency, white dot = median, black rectangle = interquartile range, black line = upper and lower adjacent values.

Extended Data Table 1 Estimates of Efficacy
Full size table
Extended Data Table 2 Data from three randomized placebo-controlled efficacy trials of daily oral PrEP in women
Full size table
Extended Data Table 3 Model Parameters
Full size table

Supplementary information

Supplementary Information

Supplementary Fig. 1 and Table 1.

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Moore, M., Stansfield, S., Donnell, D.J. et al. Efficacy estimates of oral pre-exposure prophylaxis for HIV prevention in cisgender women with partial adherence. Nat Med 29, 2748–2752 (2023). https://doi.org/10.1038/s41591-023-02564-5

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