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. 2024 Nov 22;79(5):1197-1207.
doi: 10.1093/cid/ciae143.

Type 1 Human Immunodeficiency Virus (HIV-1) Incidence, Adherence, and Drug Resistance in Individuals Taking Daily Emtricitabine/Tenofovir Disoproxil Fumarate for HIV-1 Pre-exposure Prophylaxis: Pooled Analysis From 72 Global Studies

Raphael J Landovitz  1 , Li Tao  2 , Juan Yang  2 , Melanie de Boer  2 , Christoph Carter  2 , Moupali Das  2 , Jared M Baeten  2 , Albert Liu  3 , Karen W Hoover  4 , Connie Celum  5 , Beatriz Grinsztejn  6 , Sheldon Morris  7 , Darrell P Wheeler  8 , Kenneth H Mayer  9 , Sarit A Golub  10 , Linda-Gail Bekker  11 , Souleymane Diabaté  12 , Elske Hoornenborg  13 , Janet Myers  3 , Ashley A Leech  14 , Sheena McCormack  15 , Philip A Chan  16 , Michael Sweat  17 , Lynn T Matthews  18 , Robert Grant  19 ; Global F/TDF PrEP Study Team
Collaborators, Affiliations

Type 1 Human Immunodeficiency Virus (HIV-1) Incidence, Adherence, and Drug Resistance in Individuals Taking Daily Emtricitabine/Tenofovir Disoproxil Fumarate for HIV-1 Pre-exposure Prophylaxis: Pooled Analysis From 72 Global Studies

Raphael J Landovitz et al. Clin Infect Dis. .

Abstract

Background: Oral pre-exposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (F/TDF) has high efficacy against HIV-1 acquisition. Seventy-two prospective studies of daily oral F/TDF PrEP were conducted to evaluate HIV-1 incidence, drug resistance, adherence, and bone and renal safety in diverse settings.

Methods: HIV-1 incidence was calculated from incident HIV-1 diagnoses after PrEP initiation and within 60 days of discontinuation. Tenofovir concentrations in dried blood spots (DBS), drug resistance, and bone/renal safety indicators were evaluated in a subset of studies.

Results: Among 17 274 participants, there were 101 cases with new HIV-1 diagnosis (.77 per 100 person-years; 95% confidence interval [CI]: .63-.94). In 78 cases with resistance data, 18 (23%) had M184I or V, 1 (1.3%) had K65R, and 3 (3.8%) had both mutations. In 54 cases with tenofovir concentration data from DBS, 45 (83.3%), 2 (3.7%), 6 (11.1%), and 1 (1.9%) had average adherence of <2, 2-3, 4-6, and ≥7 doses/wk, respectively, and the corresponding incidence was 3.9 (95% CI: 2.9-5.3), .24 (.060-.95), .27 (.12-.60), and .054 (.008-.38) per 100 person-years. Adherence was low in younger participants, Hispanic/Latinx and Black participants, cisgender women, and transgender women. Bone and renal adverse event incidence rates were 0.69 and 11.8 per 100 person-years, respectively, consistent with previous reports.

Conclusions: Leveraging the largest pooled analysis of global PrEP studies to date, we demonstrate that F/TDF is safe and highly effective, even with less than daily dosing, in diverse clinical settings, geographies, populations, and routes of HIV-1 exposure.

Keywords: HIV-1; emtricitabine; pre-exposure prophylaxis; tenofovir disoproxil fumarate.

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Conflict of interest statement

Potential conflicts of interest. L. T., J. Y., M. d. B., C. Carter, M. D., and J. M. B. are employees and stockholders of Gilead Sciences. R. J. L. and K. H. M. serve on Scientific Advisory Boards for Merck & Co, Inc, and Gilead Sciences. S. Morris serves on Scientific Advisory Boards for the Bill & Melinda Gates Foundation. S. McCormack reports grants from EDCTP 2 (grant RIA2016V-1644) and National Institute for Health and Care Research (NIHR) (grant RP-PG-1212-20006) from Imperial College and participation on the board for Magee-Womens Research Institute and Foundation. J. M. B. reports stock in Gilead Sciences, Inc. M. D. reports stock in Gilead Sciences, Inc. R. J. L. received consulting fees from Gilead Sciences, Inc, and Merck & Co, Inc, and support for travel from Merck. C. Carter reports stock in Gilead Sciences, Inc. A. A. L. reports investigator-sponsored research grants from Gilead Sciences, Inc, and ViiV Healthcare and paid honoraria for medical writing from the International AIDS Society US. K.W.H. reports unrestricted research grants from Gilead Sciences, Inc, and Merck, Inc, and was a scientific advisory board member for Gilead Sciences, Inc, and Merck, Inc. C. Celum reports grants to her institution from the National Institutes of Health (NIH) and the Bill & Melinda Gates Foundation; payments from Gilead Sciences, Inc, for expert testimony and attending meetings; and donated F/TDF from Gilead Sciences, Inc. S. M. reports grants from The California HIV/AIDS Research Program; California Institute for Regenerative Medicine; the NIH; Gilead Sciences, Inc; and Merck & Co, Inc; and owns stock in Bristol-Myers Squibb, Pfizer, and Geron; other nonfinancial interests include Aspera Biomedicines. D. P. W. received grants from The HIV Prevention Trials Network and NIH and honoraria and consulting fees from Gilead Sciences, Inc. K. H. M. participated on the advisory board for and received unrestricted research grants from Gilead Sciences, Inc, and Merck & Co, Inc. S. A. G. received donated F/TDF from Gilead Sciences, Inc. L.-G. B. received paid honoraria/advisory fees from Merck & Co, Inc, ViiV Healthcare, Janssen, Sanofi, Cepheid, and Novartis. E. H. received unrestricted research grants from Gilead Sciences, Inc, paid to her institution. S. McCormack is supported by the UK Medical Research Council grant MC_UU_00004/03 and has received grants from The European & Developing Countries Clinical Trials Partnership (RIA2016V-1644), Imperial College London, and the NIHR (RP-PG-1212-20006). P. A. C. reports grants from the NIH, the Centers for Disease Control and Prevention (CDC), and the Substance Abuse and Mental Health Services Administration (SAMHSA) (none funded the present work); he is currently employed by Brown Medicine, The Rhode Island Department of Health, and the Rhode Island Public Health Institute; he has a role in the National Coalition of STD Directors. M. S. received donated F/TDF from Gilead Sciences, Inc. L. T. M. reports grants from Gilead Sciences, Inc, NIH, and Doris Duke Charitable Foundation Clinical Scientist Development Award; she has received speaker’s payment from the American Sexual Health Association (ASHA); she is currently on 2 Data and Safety Monitoring Boards (DSMBs) but has not received payment. R. G. received funding and medical writing support from Gilead Sciences, Inc. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Graphical Abstract
Graphical Abstract
This graphical abstract is also available at Tidbit: https://tidbitapp.io/tidbits/hiv-1-incidence-adherence-and-drug-resistance-in-individuals-taking-daily-emtricitabine-tenofovir-disoproxil-fumarate-for-hiv-1-pre-exposure-prophylaxis-pooled-analysis-from-72-global-studies-f68925cd-0ee2-41f8-bc7b-309248ffb331?utm_campaign=tidbitlinkshare&utm_source=ITP
Figure 1.
Figure 1.
Map showing the 28 countries in which one or more F/TDF PrEP demonstration studies were conducted (dark gray shading): Austria, Belgium, Benin, Botswana, Brazil, Canada, China, Denmark, Germany, Ecuador, France, Ireland, Italy, Kenya, Malawi, Netherlands, New Zealand, Nigeria, Peru, Senegal, South Africa, Spain, Tanzania, Thailand, Uganda, United Kingdom, United States, and Zimbabwe. Abbreviations: F/TDF, emtricitabine/tenofovir disoproxil fumarate; PrEP, pre-exposure prophylaxis.
Figure 2.
Figure 2.
Odds ratios and 95% CIs for adherence of ≥4 versus <4 F/TDF doses per week (≥700 vs <700 fmol of tenofovir-diphosphate per punch in DBSs) in the subset of 6598 participants with DBS specimens available. aIndividuals were categorized as transgender, but no specific gender identity data were available. bIncludes individuals in the United States who identified as non-Hispanic or Latinx Black or African American. Abbreviations: CI, confidence interval; DBS, dried blood spot; F/TDF, emtricitabine/tenofovir disoproxil fumarate; HIV-1, type 1 human immunodeficiency virus; PrEP, pre-exposure prophylaxis.
Figure 3.
Figure 3.
Adherence measured by TFV-DP in DBS. (A) Proportions of participants in each stratum of adherence as measured by intraerythrocytic TFV-DP in DBS samples. (B) Least-squares means by week for individuals diagnosed with HIV-1 and individuals not diagnosed. The trend of TFV-DP concentrations over time was depicted by fitting the data with a locally weighted scatterplot smoothing model. Abbreviations: DBS, dried blood spots; HIV, human immunodeficiency virus; PrEP, pre-exposure prophylaxis; TFV-DP, tenofovir diphosphate.
Figure 4.
Figure 4.
Creatinine and creatinine clearance versus TFV-DP in DBS measured in specimens collected on the same date. TFV-DP and creatinine concentration data at both baseline and at least 1 follow-up visit were available from 4595 individuals and 13 511 follow-up visits, and TFV-DP concentration and creatinine clearance data from 4417 individuals and 12 525 follow-up visits. (A) Creatinine concentration. (B) Percentage change in creatinine concentration versus baseline. (C) Creatinine clearance rate. Abbreviations: DBS, dried blood spots; TFV-DP, tenofovir diphosphate.
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