1342 Oral preexposure prophyla xis uptake, adherence, and persistence during periconception periods among women in South Africa Lynn T. Matthewsa, Manjeetha Jaggernathb, Yolandie Krielb, Patricia M. Smitha, Jessica E. Habererc, Jared M. Baetend,e, Craig W. Hendrixf, Norma C. Wareg,h, Pravi Moodleyi, Melendhran Pillayj, Kara Bennettk, John Basslerl, Christina Psarosm, Kathleen E. Hurwitzk, David R. Bangsbergn and Jennifer A. Smitb aDivision of Infect Child Health Rese Health Sciences, D Boston, Massachu Seattle,Washingto Maryland, gDepar Women’s Hospita National Health L RWE, Durham, N Birmingham, Alab Massachusetts, US Correspondence t Tel: +1 (205) 934 Received: 18 Janu DOI:10.1097/QAD ISSN 0269-9370 Cop terms of the Creative share the work provi Objective: We developed the Healthy Families-PrEP intervention to support HIV- prevention during periconception and pregnancy. We evaluated preexposure prophy- laxis (PrEP) use with three objective measures. Design: This single-arm intervention study enrolled women in KwaZulu-Natal, South Africa, who were HIV-uninfected, not pregnant, in a relationship with a partner with HIV or unknown-serostatus, and with pregnancy plans. PrEP was offered as part of a comprehensive HIV prevention intervention. Participants were followed for 12months. Methods: We evaluated periconception PrEP uptake and adherence using quar- terly plasma tenofovir concentrations. We modeled factors associated with PrEP uptake and high plasma tenofovir (past day dosing). Patterns of use were analyzed using electronic pillcap data. Dried blood spots to measure intracel- lular tenofovir product (past 2months dosing) were analyzed for a subset of women. Results: Three hundred thirty women with median age 24 (IQR: 22–27) years enrolled. Partner HIV-serostatus was unknown by 96% (N¼316); 60% (195) initiated PrEP. High plasma tenofovir concentrations were seen in 35, 25, 22, and 20% of samples at 3, 6, 9, and 12months, respectively. Similar adherence was measured by pillcap and dried blood spots. In adjusted models, lower income, alcohol use, and higher HIV stigma were associated with high plasma tenofovir. Eleven HIV-seroconversions were observed (incidence rate: 4.04/100 person-years [95% confidence interval: 2.24– 7.30]). None had detectable plasma tenofovir. ious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA, bMaternal Adolescent and arch Unit (MRU), Department of Obstetrics and Gynaecology, University of the Witwatersrand, Faculty of urban, South Africa, cDepartment of Medicine, Massachusetts General Hospital, Harvard Medical School, setts, dDepartment of Global Health, eDivision of Allergy and Infectious Diseases, University of Washington, n, fDepartment ofMedicine (Clinical Pharmacology), JohnsHopkins University, School ofMedicine, Baltimore, tment of Global Health & Social Medicine, Harvard Medical School, hDepartment of Medicine, Brigham and l, Boston, Massachusetts, iUniversity of KwaZulu-Natal, School of Laboratory Medicine and Medical Sciences, aboratory Service, jDepartment of Virology, National Health Laboratory Service, Durban, South Africa, kTarget orth Carolina, lDepartment of Biostatistics, School of Public Health, University of Alabama at Birmingham, ama, mDepartment of Psychiatry, Behavioural Medicine Program, Massachusetts General Hospital, Boston, A, and nVinh University College of Health Sciences, Hanoi, Vietnam. o Lynn T. Matthews, 1900 University Blvd, THT215E, Birmingham, AL 35294, USA. 8148; e-mail: lynnmatthews@uabmc.edu ary 2024; revised: 1 April 2024; accepted: 8 April 2024. .0000000000003925 yright Q 2024 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and ded it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. mailto:lynnmatthews@uabmc.edu http://dx.doi.org/10.1097/QAD.0000000000003925 Preexposure prophylaxis uptake Matthews et al. 1343 Conclusion: The Healthy Families-PrEP intervention supported women in PrEP use. We observed high interest in periconception PrEP and over one-third adhered to PrEP in the first quarter; one-fifth were adherent over a year. High HIV incidence highlights the importance of strategies to reduce HIV incidence among periconception women. Clinical Trial Number: NCT03194308 Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. AIDS 2024, 38:1342–1354 Keywords: adherence, HIV-Prevention, periconception, perinatal, pre-exposure prophylaxis, South Africa Introduction South Africa is home to nearly 7.5 million people with HIV (PWH); in 2021, an estimated 130 000 women and 10 000 children acquired HIV [1]. In HIV-endemic settings, many women conceive a baby with a partner with HIVor whose serostatus is unknown [2]. For women who cannot rely on partners to test, engage in care, and suppress HIV-RNA through antiretroviral treatment, condomless sex leaves them vulnerable to HIV and thus increases perinatal transmission risks. Daily, oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for preexposure prophylaxis (PrEP) reduces HIV-acquisition risk, is well tolerated for use among pregnant and breastfeeding people, and is recommended by the WHO, U.S. Centers for Disease Control and Prevention, and South Africa Department of Health for pregnant and breastfeeding people vulnerable to HIV infection [3–5]. However, many South Africans, including pregnant and breastfeeding people, struggle with adherence [6,7]. Goals to have a healthy baby and remain HIV-free may motivate HIV prevention during periconception and pregnancy [8]. Informed by these observations and our formative work, we developed and tested the Healthy Families-PrEP (HF-PrEP) intervention to support PrEP use during periconception and pregnancy periods [9]. This manuscript describes PrEP use amongwomen planning for pregnancy in South Africa and participating in the intervention.We aimed to discover whether women could be supported to effectively use oral PrEP as a component of comprehensive HIV-prevention for women intending to conceive a child while potentially exposed to HIV. Materials and methods Study design and population We conducted a single-arm longitudinal study among women without HIV in Durban, South Africa. Participants were planning for pregnancy within the next year with a partner with HIV or of unknown serostatus. Data collection occurred from 13 November 2017 to 21 July 2021. Additional eligibility criteria included female sex; age 18–35 years; not on long-acting contraception; and likely to be fertile [10]. Women with pregnancy or HIV at screening were not eligible. Fieldwork teams recruited women from local healthcare clinics, gathering spots near the research site, and through word-of-mouth promotion. Enrolled participants were offered HIV prevention counseling including TDF/FTC PrEP with quarterly adherence support and followed for 12months. Objective adherence data were collected from plasma, whole blood, and electronic pillcaps [9]. This manuscript is restricted to periconception (the period from enrollment until study exit or incident pregnancy); pregnant women were censored for this analysis at the date of the first positive pregnancy test. Study activities HIV prevention counselling (Healthy Families-PrEP) We developed a counselling intervention, ‘‘Healthy Families-PrEP’’ (HF-PrEP), to support women in achieving reproductive goals while minimizing HIV acquisition, based on South African guidelines and our formative work [11]. Those initiating PrEP participated in quarterly adherence support sessions, adapted from Lifesteps for PrEP [12,13] (Table 1). Preexposure prophylaxis provision and monitoring Dispensing Women could initiate or discontinue PrEP at any time. Participants initiating PrEP were provided with a 30-day supply of PrEP at initiation and a 90-day supply at subsequent visits. Clinical laboratory monitoring Women initiating PrEP completed blood testing to evaluate renal function and hepatitis B status. Women with abnormal renal function [serum creatinine > 89mmol/l and estimated glomerular filtration rate (eGFR) < 60ml/min] or active hepatitis B infection (hepatitis B surface antigen positive) were instructed to stop PrEP per WHO guidelines at that time [14]. 1344 AIDS 2024, Vol 38 No 9 Table 1. Healthy Families-PrEP support intervention. Sessionc Activities 1 Rapport building and introduction Safer conception education a Motivational strategies to prepare for behavior change Develop individualized safer conception plan 2 Review prior session content Safer conception plan review a Revise plan as needed Support to implement plan b 3 Review prior session content Safer conception plan review a Revise plan as needed Support to implement plan b aGuidelines at the time recommend that HIV-uninfected women who want to conceive a child with a partner with HIV should encourage partner testing and serostatus disclosurewithin the partnership, encour- agepartner to initiateART,delay sexwithout condomsuntil heachieves HIV RNA suppression or is on ART for six months, consider contracep- tion to delay pregnancy until safer conception strategies are imple- mented, limit condomless sex to peak fertility, and/or consider sperm washing, donor sperm, and adoption as alternatives. We also coun- selled on the availability and benefits of PrEP for HIV prevention. bMethods employed to support clients to implement plan: education, problem solving, motivational strategies, communication skills. cQuarterly adherence support sessions throughout PrEP use. Com- prehensive counselling was performed by trained study counsellors in a group format, with the option of one-on-one counseling sessions based on participant preference and study site logistics. Participants completed beta-HCG urine testing, indi- vidual HIV counseling and testing (HCT), and syndromic screening for sexually transmitted infections (STIs) at each study visit. Those with pregnancy were eligible to remain in the study and referred for antenatal care. Those with STI symptoms were provided with treatment. Participants who seroconverted were exited from the study and followed to promote linkage to care. HIV- RNA samples were sent for genotyping. Electronic pillcaps Women accessing PrEP were provided a pill bottle with an electronic cap (Medication Electronic Monitoring System (MEMS) [AARDEX, Switzerland]) that recorded when the device was opened as a proxy for pill ingestion. Pillcap data were downloaded at each visit and reviewed with participants. Adherence-related laboratory evaluation Women who initiated PrEP provided blood samples at quarterly visits forwhole blood and plasma.Concentrations of tenofovir metabolites were assayed in all plasma and a subset of DBS samples using methods described elsewhere [15]. The subset of DBS included all HIV seroconversion samples and a random subset of other samples such that 101 participants (52%) of ever PrEP users were included. Questionnaires At enrollment, a questionnaire was administered via face- to-face interview with a research assistant fluent in English and the dominant local language to assess constructs within our conceptual framework for periconception HIV prevention behavior [16]. Con- structs were measured using instruments validated in this setting, described in detail elsewhere [9]. COVID-19 protocol adaptations The South African government implemented a nation- wide lockdown from March 27, 2020, through May 1, 2020. The research protocol was temporarily modified to optimize safety for participants and study staff. In-person visits were limited to essential visits with telephonic data collection for other study activities. Once restrictions were loosened, onsite clinical activities resumed per original protocol specifications. Outcomes The primary outcomes included PrEP uptake defined as the proportion of participants who ever collected a 30 day PrEP supply at least once within 12months of enrollment and PrEP adherence as measured by plasma TFV at the first quarterly follow-up visit following initiation. Plasma TFV concentrations at least 40 ng/ml indicate dosing in the last 24 h (categorized as ‘‘high’’ adherence), between 10 and 40 ng/ml indicate dosing in the prior 3 days (‘‘moderate’’ adherence), and less than 10 ng/ml indicate no dosing in the prior 7 days (‘‘low’’ adherence) [17]. We also evaluated adherence using the proportion of days with a record of pill bottle opening and intraerythrocytic TFV-DP concentrations, reflecting use over the prior two months. Pillcap adherence was assessed during active PrEP follow-up (PrEP initiation through to the earlierof reported PrEP discontinuation or study exit) and capped at one opening per day. We estimated mean monthly adherence over time and the proportion of PrEP initiators with mean monthly adherence at least 80% (‘‘high’’ adherence) [18]. Intraerythrocyte concentrations of TFV-DP were a secondary adherence measure for a subset of women. On the basis of limited data for pregnant or postpartumAfrican women [19–21], we categorized intraerythrocytic con- centrations ofmore than 600 fmol/punch, approximately at least 4 doses per week (‘‘high’’ adherence), 450–600 fmol/ punch as about three doses per week (‘‘moderate’’ adherence), and between 16.6 and less than 450 as less than three doses per week (‘‘low’’ adherence) [19,22]. We selected a slightly lower cut-off for the category of ‘‘high’’ basedon the available datawhile accounting forour inability to adjust for anemia, thrombocytopenia, and BMI [23]. Pillcap data were used to evaluate at least 14-day breaks in PrEP use followed by resumption of daily use (i.e. continuation after an interruption) versus 14-day breaks in PrEP use without resumption (i.e. discontinuation). We chose 14 days to prioritize interruptions beyond common-but-transient gaps in pillcap use including pocket doses (i.e., multiple pills removed for later dosing), weekend breaks, reduced access to PrEP due to COVID- 19 restrictions, and travel [24]. Preexposure prophylaxis uptake Matthews et al. 1345 Drug concentration and pillcap data were censored at the last study visit date after the last pillcap opening. If a client stopped using PrEP in January 2020 and reported this at a follow-up visit in March 2020, they contributed adherence data through March and were subsequently classified as having discontinued PrEP and did not contribute ongoing adherence data. Additional outcomes We assessed HIV incidence (overall and by PrEP initiation status) measured as the time to first HIV-positive test from enrollment. Follow-up for incident cases was censored at themidpoint of the first positive and last negative HIV test result for infected women. Data for women who did not acquire HIV was censored at the time of the last available negative test. For all participants who seroconverted, Sanger Sequenc- ing-based HIV resistance genotyping was completed as described by Manasa et al. [25]. The Stanford University HIV drug resistance database (version 9.0) was used to assess the presence of HIV drug resistance mutations and antiretroviral susceptibilities [26,27]. We defined drug resistance as having any major drug resistance mutation (DRM) to nucleoside reverse transcriptase inhibitor (NRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI), or protease inhibitors. Study clinicians monitored adverse events using NIH DHHS guidelines [28] at all scheduled study visits; adverse events were reviewed by the DSMB at annual meetings. Sample size We proposed to enroll 350 women [9]. Due to the COVID-19 pandemic, enrollment was capped at 330 in March 2020; the last participant enrolled on January 31, 2020. Statistical analysis We describe adherence longitudinally with electronic pillcaps, TFV plasma, and TFV-DP in dried blood spots. However, our models to predict adherence were conducted at 3months given high rates of exit due to seroconversion, pregnancy, losses to follow-up, and less stable and less representative numbers at 6, 9, and 12months. We used modified Poisson regression with generalized estimating equations to assess predictors of PrEP initiation and high adherence (defined as TFV �40 ng/ml) at the first quarterly visit following PrEP initiation. Baseline predictors identified based on our periconception HIV risk conceptual framework [35] included age, education, household income, number of prior pregnancies, number of sexual partners, condom use, tobacco and alcohol use, HIV stigma [16], perceived HIV risk [29], sexual relationship power [30], dyadic trust [31], social support [32], and depression [33]. Multivari- able-adjusted risk ratios were constructed using a change- in-estimate approach [34] in which relative to a fully adjusted model (i.e., all known or hypothesized confounding factors identified by subject matter knowl- edge of the underlying causal structure included), we removed, one by one, each factor and recorded the estimated coefficient for the predictor-outcome associa- tion. If the removal of the factor changed the coefficient by at least 10%, it was retained. Missing data are considered missing at random and complete case analyses are reported. All statistical analyses were conducted using SAS software version 9.4 (SAS Institute, Cary, North Carolina, USA) and R Statistical Software (v4.1.2; R Core Team 2021). Ethics and dissemination The protocol was approved by the Human Research Ethics Committee at the University of the Witwatersrand (Pretoria, South Africa), the Institutional Review Boards of Partners Healthcare (Boston,Massachusetts, USA), and University of Alabama at Birmingham. The protocol is registered with the South African Health Products Regulatory Agency, MCC#20170131) and Clinical- Trials.gov (NCT03194308). Consent was obtained from all participants. Role of the funding source Study funders did not have a role in study design, data collection, analysis, interpretation of data, or writing of this report. Results Screening and enrollment We approached 673 women for screening, of whom 621 completed the screening questionnaire, and 330 met eligibility criteria and enrolled. Figure 1 summarizes reasons for ineligibility. Among 330 enrolled women, four (1%) did not complete safer conception counseling. Thus, this manuscript reports on data collected from 326 fully enrolled participants. At enrollment, median (25th, 75th percentile) age was 24 (22, 27) years with 279 (86%) reporting a high school education or beyond and 145 (45%) reporting no prior pregnancies. Most women (n¼ 287; 88%) reported one sexual partner, and most (n¼ 313; 97%) did not know the HIV-serostatus of their desired pregnancy partner. Most (n¼ 205, 70%) reported that at least one of their sexual partners probably had other partners (Table 2). Overall, 189 (58%) women completed all planned follow- up visits (Fig. 1). The most common reasons for discontinuing periconception follow-up were pregnancy (n¼ 56), loss to follow-up (n¼ 46), relocation outside the catchment area (n¼ 24), and withdrawal of consent (n¼ 16). Figure 2 illustrates that 312 women (96%) 1346 AIDS 2024, Vol 38 No 9 Fig. 1. Consort diagram. Flow of participants during screening, enrollment, and follow-up. completed the 3-month follow-up visit and, therefore, all three primary Healthy Families-PrEP counseling sessions (Table 1). Eleven women acquired HIV during follow-up. Preexposure prophylaxis initiation A total of 195 (60%) women initiated PrEP with most (n¼ 162; 83%) starting within 2months of enrollment; 97% initiated within 6months of enrollment. In multivar- iable-adjusted models, participants with higher income, greater educational attainment, and higher HIV risk perception were less likely to initiate PrEP during follow- up (Table 3) (Supplemental File 2 provides unadjusted associations, http://links.lww.com/QAD/D217). Preexposure prophylaxis adherence and persistence Figure 2 highlights summary use at 3, 6, and 9monthswith all three adherence measures.We found that 86–92% took at least some PrEP by pillcap, 23–36% by plasma TFV, http://links.lww.com/QAD/D217 Preexposure prophylaxis uptake Matthews et al. 1347 Table 2. Baseline characteristics, overall and by ever-initiated PrEP. Overall (N¼326) Did not initiate PrEP (N¼131) Initiated PrEP (N¼195) Individual characteristics Age, years Median (IQR) 24 (22, 27) 24 (22, 26) 24 (22, 27) Education Grade 7 (Standard 5) - Grade 11 (Standard 9) 47 (14.4%) 14 (10.7%) 33 (16.9%) Grade 12 (Standard 10) and postgrade 12 279 (85.6%) 117 (89.3%) 162 (83.1%) Income, monthly ($USD) < $116 75 (31.6%) 22 (23.4%) 53 (37.1%) $116–$232 81 (34.2%) 39 (41.5%) 42 (29.4%) > $232 81 (34.2%) 33 (35.1%) 48 (33.6%) Missing 89 37 52 Total pregnancies 0 or 1 266 (81.6%) 112 (85.5%) 154 (79.0%) 2þ 60 (18.4%) 19 (14.5%) 41 (21.0%) Currently using tobacco products Yes 28 (8.6%) 12 (9.2%) 16 (8.3%) No 296 (91.4%) 119 (90.8%) 177 (91.7%) Missing 2 0 2 Frequency of alcohol use in the past year Never 154 (47.7%) 61 (47.3%) 93 (47.9%) Any Amount 169 (52.3%) 68 (52.7%) 101 (52.1%) Missing 3 2 1 Partnership characteristics Partner HIV Status Primary partner’s HIV status is known by participant 11 (3.4%) 3 (2.3%) 8 (4.1%) Primary partner’s HIV status is unknown by participant 313 (96.6%) 127 (97.7%) 186 (95.9%) Missing 2 1 1 Sexual partners, past 3 months 0 or 1 288 (88.6%) 119 (90.8%) 169 (87.1%) 2þ 37 (11.4%) 12 (9.2%) 25 (12.9%) Missing 1 0 1 Pregnancy partner (main or other) has other partners Definitely/Probably does not 90 (30.5%) 41 (33.3%) 49 (28.5%) Definitely/Probably does 205 (69.5%) 82 (66.7%) 123 (71.5%) Missing 31 8 23 Depression Score a � 1.75 303 (94.1%) 120 (92.3%) 183 (95.3%) > 1.75 19 (5.9%) 10 (7.7%) 9 (4.7%) Missing 4 1 3 Parenthood motivation: Social control b Median (IQR) 7 (6, 8) 7 (5, 8) 7 (6, 8) Missing 8 2 6 HIV Stigma Score c Median (IQR) 2 (0, 6) 2 (0, 7) 2 (0, 5) Missing 15 8 7 Perceived HIV Risk d Median (IQR) 20 (18, 22) 20 (19, 22) 20 (18, 22) Missing 17 7 10 Sexual Relationship Power Scale e Median (IQR) 3 (2, 3) 3 (2, 3) 3 (2, 3) Missing 43 18 25 Dyadic Trust Score f Median (IQR) 29 (26, 34) 30 (26, 34) 29 (25, 34) Missing 3 1 2 Social support g Median (IQR) 4 (4, 4) 4 (4, 4) 4 (4, 4) Missing 1 0 1 PrEP Optimism h Median (IQR) 5 (5, 6) 5 (5, 6) 6 (5, 7) Missing 5 2 3 aDepression: Depression was measured using 10 items questions from the Hopkins Symptoms Checklist [33]. Items were scored on a 4-point Likert scale [ranging from (1) ‘‘Not at all’’ through (0) ‘‘Extremely’’]. An average score of 1.75 and above was classified as having depression. bSocial Control: (a) ‘‘My environment (others, family) expect it of me’’; (b) ’’Others around me have children’’; (c) "I want to have a baby to avoid being an outsider’’. cHIV stigma: HIV stigma (attributed stigma, perception howmost people feel) was assessed using 17 items from the HIV Stigma Scale [65,66] with the response profile (1) Agree or (0) Disagree. A score was obtained by summing over the 17 items with higher scores indicating higher attributed stigma about HIV. 1348 AIDS 2024, Vol 38 No 9 dPerceived HIV risk: Perceived HIV risk was measured using the Perceived Risk of HIV scale developed by Napper et al. [29]. Participants responded to the seven-item questions with Likert scale responses: (1) ‘‘What is your gut feeling about how likely you are to get infectedwith HIV?’’ [responses range from (1) Extremely unlikely to (4) Extremely likely], (2) ‘‘I worry about getting infected with HIV’’ [responses range from (1) Never to (4) All the time], (3) ‘‘ Picturingmyself getting HIV is something I find’’[responses range from (1) very hard‘‘ to (4) ‘‘Very easy to do’’], (4) ‘‘Getting HIV is something I am. . ..’’ [responses range from ‘Not concerned about’ to ‘Extremely concerned about’], (5) ‘‘I am sure I will not get infected with HIV.’’ [responses range from (1) ‘‘Strongly agree’’ to (4) ‘‘Strongly disagree’’], (6) ‘‘I feel I am unlikely to get infected with HIV.’’ [responses range from (0) ‘‘Strongly agree’’ through (5) ‘‘Strongly disagree’’], (7) ‘‘I feel vulnerable to HIV infection.’’ [responses range from (5) ‘‘Strongly agree’’ through (0) ‘‘Strongly disagree’’]. Items were summed with higher scores indicating higher perceived HIV risk. eSexual relationship power: Sexual relationship powerwasmeasured using the Sexual relationship Power Scale [67], which includes 23questions and two subscales: relationship control [15 questions with response options ranging from (5) ‘‘Strongly agree’’ through (0) ‘‘Strongly disagree’’] and decision-making dominance subscale [eight questions with response options ‘‘Your partner,’’ ‘‘Both of you equally,’’ or ‘‘You’’]. Items were summed and overall scorewas derived. A higher score indicatemore power in relationship in the area of relationship control anddecision-making dominance. fDyadic trust: Dyadic trust was measured using the Dyadic Trust Scale [31], which includes eight-item questions with a 5-point Likert scale response options [ranging from (4) Agree through (0) Disagree]. An average score was derived with a higher score indicating higher trust. gSocial support: Social support wasmeasured using 10 items from the Duke-UNC Functional Social Support Questionnaire [32]. Items were scored on a 4-point Likert scale [ranging from (1) As much as I would like through (4) Never]. An overall score was derived with higher scores indicating higher social support. hPrEP optimism: PrEP optimism was assessed based on three-item questions adapted from the Partners PrEP adherence sub-Study [68]: (1) ‘‘PrEP reduces risk of getting HIV,’’ (2) ‘‘PrEPmakes it easier to relax about sex without condoms,’’ and (3) ‘‘PrEPmakesmeworry less.’’ Responses to each item questions were given scores of 0 (for ‘‘strongly disagree’’), 1 (for ‘‘disagree’’), 2 (for ‘‘agree’’), 3 (for ‘‘strongly agree’’), and summedwith higher scores indicating greater PrEP optimism. Table 2. Continued. and 49–67% by TFV-DP at 3, 6, 9, and 12months of follow-up. In addition, 27–43% were highly adherent taking at least 80% of doses by pillcap, 20–35% with high plasma tenofovir, and 18–25% with high TFV-DP. Adherence waned over time by all measures. Fig. 2. Periconception PrEP use over 12months by electronic pillc quarter), plasma TFV (past day use), intraerythrocytic TFV-DP (p Among 180 women who initiated PrEP and had pillcap data, median duration of persistent PrEP use was 219 days (range: 1–545). Serial short gaps in use were common; the median proportion of time on PrEP for PrEP users was 63% (IQR 43%, 83%). Seventy-eight (43%) women ap (proportion of days pillcap opened summarized over prior ast 8weeks use). Preexposure prophylaxis uptake Matthews et al. 1349 Table 3. Multivariable-adjusted risk ratios and 95% confidence intervals for (a) initiation of PrEP during follow-up and (b) plasma TFV (>40ng/ml) at 3 months following PrEP initiation. Outcome: Ever initiated PrEP during follow-up a Outcome: Plasma TFV>40 ng/ml at 3 months b Covariate aRR (95% CI) P aRR (95% CI) P Age (years) 1.01 (0.97–1.04) 0.74 1.03 (0.96–1.10) 0.46 Education Grade 7 (Standard 5) - Grade 11 (Standard 9) REF – REF – Grade 12 (Standard 10) and postgrade 12 0.74 (0.58–0.94) 0.02 1.77 (0.68–4.65) 0.24 Income, monthly ($USD) 0.01 c 0.04 c < $116 REF REF $116–$232 0.66 (0.50–0.86) 0.74 (0.37–1.46) > $232 0.78 (0.62–0.99) 0.44 (0.20–0.98) Total pregnancies 0 or 1 REF – REF – 2þ 1.18 (0.93–1.50) 0.18 0.91 (0.35–2.37) 0.85 Currently using tobacco products d No REF – Yes 0.79 (0.49–1.28) 0.34 Frequency of alcohol use in the past year Never REF – REF – Any amount 0.97 (0.81–1.18) 0.78 2.18 (1.20–3.99) 0.01 Sexual partners, past 3 months 0 or 1 REF – REF – 2þ 1.24 (0.96–1.60) 0.10 0.59 (0.17–2.04) 0.40 Pregnancy partner (main or other) has other partners Definitely/Probably is not REF – REF – Definitely/Probably is 1.05 (0.84–1.32) 0.66 0.79 (0.39–1.60) 0.52 Depression Score d � 1.75 REF – > 1.75 0.71 (0.32–1.60) 0.41 Parenthood motivation: Social control 0.99 (0.92–1.07) 0.86 1.10 (0.92–1.31) 0.30 HIV Stigma Score 1.00 (0.97–1.02) 0.83 1.16 (1.07–1.26) <0.01 Perceived HIV Risk 0.97 (0.94–0.99) 0.046 1.06 (0.96–1.18) 0.23 Sexual Relationship Power Scale 1.04 (0.77–1.41) 0.79 0.87 (0.35–2.15) 0.76 Dyadic Trust Score 1.00 (0.98–1.02) 0.69 1.00 (0.93–1.07) 0.94 Social support 0.89 (0.53–1.48) 0.65 3.29 (0.45–24.18) 0.24 PrEP Optimism 1.00 (0.93–1.07) 0.97 1.12 (0.93–1.35) 0.23 See supplemental file 3, http://links.lww.com/QAD/D218 for each minimally adjusted model of factors associated with initiating PrEP. See supplemental file 4, http://links.lww.com/QAD/D219 for fully adjustedmultivariable analysis of factors associatedwith ever-PrEP use and 3-month plasma >40ng/ml. aPrEP initiation analyses conducted among n¼326 participants who completed all enrollment activities. bPlasma TFV analyses conducted among n¼134 PrEP initiators who provided a sample at the 3-month follow-up visit. cP-value computed based on a chi-square distribution with 2 degrees of freedom. dMultivariable-adjusted analyses for tobacco use and depression score were not conducted due to insufficient sample size. P-values <0.05 are in bold. had at least one adherence interruption of 14 days or more (Fig. 3); median time to first 14-day interruption was 77 (IQR 31–127) days with median time to restart was 22 (IQR 17–40) days. Median time to PrEP discontinuation without restarting was 200 (IQR 85–326) days (Fig. 4). Inmultivariable-adjustedmodels, womenwith lower income, any alcohol use, and higher levels of attributed community HIV stigma were more likely to have high plasma TFV concentration (Table 3) (Supplemental File 2 provides unadjusted associations, http://links.lww.com/QAD/D217). HIV incidence Eleven incident infections occurred among 315 partici- pants with a repeat HIV test result, contributing 272 years of follow-up. HIV incidence was 4.04 per 100 person- year [95% confidence interval (95% CI) 2.24–7.30]. Five of these seroconversions occurred among 122 participants who did not initiate PrEP with 108 years of follow-up for an HIV incidence of 4.62 (95% CI: 1.92–11.10). The remaining six seroconversions occurred among 193 women who initiated PrEP with 164 years of follow- up with an HIV incidence of 3.66 (95% CI: 1.64–8.15). Four of the six had undetected plasma TFV at the visit where theywere diagnosed withHIV. The remaining two had undetected plasma TFVat the visit prior to diagnosis with HIV. Three women who had TFV-DP tested had concentrations below limits of detection. Two additional women had either undetected of a low concentration (21.3 fmol/punch) at a visit prior to HIV-seroconversion. Among the six women who initiated PrEP and seroconverted, three had NNRTI resistance mutations (V106M, K103N, E138A), all unrelated to exposure study product (TDF/FTC). http://links.lww.com/QAD/D217 http://links.lww.com/QAD/D218 http://links.lww.com/QAD/D219 1350 AIDS 2024, Vol 38 No 9 Fig. 3. Proportion ofNU180 periconception participants who started PrEP and used the electronic pillcap who had adherence gaps of 1 through >–14days. Adverse events We observed 60 adverse events (among 44 participants) of which 23 events (among 20 participants) were considered serious. None of the serious adverse events were deemed to be related to study procedures, including PrEP use Fig. 4. Time toPrEPdiscontinuation (black) and95%CI (grey),wher in treatment without resumption (based on pillcap data) among N (See Supplemental file 1 for all adverse events, http:// links.lww.com/QAD/D216). No clients were advised to stop PrEP due to renal dysfunction. One unvaccinated person with HBV at baseline stopped PrEP shortly after initiation. ePrEPdiscontinuation is definedas thefirst 14-day interruption U180 periconception participants who initiated PrEP. http://links.lww.com/QAD/D216 http://links.lww.com/QAD/D216 Preexposure prophylaxis uptake Matthews et al. 1351 Discussion We conducted a longitudinal study offering an HIV prevention intervention, Healthy Families-PrEP, to women planning for pregnancy in an urban South African setting with one of the highest HIV prevalence rates in the world. The majority of participants did not know their partner’s status, suspected he had other partners, and were engaging in condomless sex with goals to have a child. The HF-PrEP intervention supported high PrEP uptake (60%) and high adherence over 3months for 20–43% of participants (depending on the adherence measure used). By pillcap, most women had gaps in their PrEP use with a median time to discontinuation of 199 days. We observed high HIV incidence and the findings suggest the importance and value of programming to promote HIV prevention for women planning for pregnancy. PrEP interest is high, and many women need additional adherence support and/or alternative prevention strategies. Our findings of high adherence compared to many other demonstration projects among cisgender women suggest the value of PrEP care for this population. In a recent analysis of more than 6000 cisgender women accessing TDF/FTCPrEP in demonstration projects, including 78% African women, only 17% were highly adherent to PrEP by intracellular tenofovir concentrations [6]. Others also observed goals to have a healthy baby and remainHIV-free can motivate HIV prevention. In a U.S. study conducted among women without HIV planning pregnancy with menwithHIV, 87% took at least four PrEP doses perweek, by intracellular TFV-DP [35]. In Kenya, a periconception HIV prevention study among HIV-serodifferent couples observed that 81%of partnerswithoutHIV tookmore than 80% of PrEP doses [36]. We implemented an intervention similar to that used in the current study in Uganda and observedTFV-DPconcentrations corresponding to at least four doses among 41% of women at 6-month follow-up [37]. These data highlight the importance of integrating HIV prevention counseling, including PrEP, into precon- ception care to reduce HIV incidence among women and infants. In addition, as more products are approved, choice of delivery method (vaginal ring, injectable, oral) may support uptake and adherence [38]. Novel longer-acting PrEP drugs such as the dapivirine (DPV) vaginal ring and injectable cabotegravir are efficacious [39–41], approved for use in South Africa [42,43], andmay serve as important PrEP options for women who struggle with daily oral medications. Indeed, emerging data suggest that PrEP choice may promote use [44,45]. Understanding safety profiles and securing approval for use in women planning for and with pregnancy will be important [46–49]. The intervention supported about a third of women to use daily oral PrEP well enough to be protected from HIV based on pharmacokinetic estimates [18–21]. On the basis of real-world PrEP use, more women had some protection by taking more than two doses per week [6]. ALthough HF-PrEP worked for many women, it did not help all participants to successfully use PrEP. We observed an association of poorer adherence associated with lower perceived community HIV stigma. Women perceiving higher community levels of stigma may have experienced increased motivations to use PrEP and avoid HIV. We also observed higher adherence with alcohol use and lower income; generally, in the literature, womenwith competing demands (e.g., lower income, alcohol use [50,51]) struggle with adherence. Perhaps in this context, women faced other challenges that encouraged them to engage in their HIV prevention strategy; this positive association with alcohol use was also observed among pregnant women accessing PrEP in Cape Town [52] and men accessing PrEP in rural KwaZulu-Natal [53], suggesting that alcohol use should not be a contra-indication to PrEP care. In a nested qualitative substudy, women in our cohort described challenges getting to study visits (including for refills), succeeded when they were able to disclose PrEP use to a supporter, and made decisions about PrEP use based on sexual activity [24]. Additional intervention content could add PrEP modality choice, community delivery options, leverage problem solving to support PrEP use disclosure, and adapt to provide women with the counseling they need when they need it [54]. Interpretation of our data varies by the adherence measure used and degree to which a given adherence threshold correlates with PrEP effectiveness. Differences observed across the three PrEP adherence measures in this cohort highlight the value of incorporating multiple measures and expose gaps in our understandings of tenofovir pharmacokinetics for cis-gender women. High adherence by electronic device waned whereas the proportion with high concentrations by plasma and whole blood measures were relatively stable, suggesting that motivations to use the pillcap due to social desirability bias may have been present and waned over time [55]. However, our limited understandings of how to interpret pharmacokinetics for cis-gender black women may also underestimate adherence [56]. We rely on the pillcap data to evaluate stops and starts, which are common and important to understanding PrEP use. On the basis of our paired pillcap and drug concentration data, the pillcaps may be insensitive for capturing gaps. Importantly, we observed high HIV incidence in this population of women planning for pregnancy. HIV acquisition during pregnancy and breastfeeding contrib- utes to about one-third of childhood HIV incidence [57]. In this study, the first to our knowledge to measure periconception HIV acquisition risk longitudinally in an HIV-endemic setting, we observed an HIV incidence of 4.04 per 100 person-years (95% CI: 2.24–7.30), highlighting the importance of developing effective prevention programs for this population. This finding highlights the importance of offering PrEP to women 1352 AIDS 2024, Vol 38 No 9 independent of whether their partner has been diagnosed and disclosed serostatus. One-third of men with HIV (MWH) in South Africa do not know their serostatus [58], and less than half of women are aware of their partner’s serostatus [59,60]. Interventions to promote knowledge of partner serostatus remain important, but should not undermine opportunities to provide PrEP to women who may not know their partner’s serostatus but live in an HIV- endemic area or otherwise feel vulnerable to HIV [48]. Educating men about HIV-prevention options for their pregnancy partners may also support uptake [61]. Reassuringly, genotyping of the virus among those with seroconversion revealed mutations that are not associated with exposure to NRTIs (e.g., tenofovir, emtricitabine) and thus are likely to represent transmitted resistance [62]. This project was conducted prior to approval of TDF/ FTC as PrEP for women planning for or with pregnancy in South Africa, thus subject to regulations for investigational drug. Accordingly, we collected detailed information on adverse events. We observed a reassuring safety profile consistent with many PrEP studies [63,64]. Strengths of this study include incorporation of multiple adherence measures over time among a rarely studied population of women vulnerable to acquiring HIV. Limitations include that this was a research study, thus adherence may have been higher than among the general population. The project was conducted when TDF/FTC was not recommended for people planning for pregnancy in South Africa, which may have compromised use. Conclusion Our findings support the importance of HIV prevention for women planning for pregnancy in HIV endemic settings. Female-controlled prevention strategies are critical, and oral PrEP is an important component of safer conception care which women choose to use. Our adapted intervention helped support about a quarter of women to use PrEP well with closer to 50% using PrEP well enough to secure some protection. Acknowledgements Lynn T. Matthews – involved in all aspects. Manjeetha Jaggernath – protocol development, data collection, data cleaning, analysis interpretation. Yolandie Kriel – protocol development, data collection, data cleaning, analysis interpretation, manuscript writing. Patricia Smith – data collection, management, writing. Jessica E. Haberer – protocol development, adherence measurement interpretation. Jared Baeten, Craig Hendrix – protocol development. Norma C. Ware – protocol development (qualitative). Pravi Moodley, Melendhran Pillay – data generation, analysis, writing. Kara Bennett, John Bassler – analysis. Christina Psaros – protocol development, adherence counseling support. Kathleen Wirth Hurwitz – protocol development, analysis. David R. Bangsberg – protocol development. Jennifer A. Smit – all aspects. The authors would like to thank our participants, the National Institutes of Mental Health and Gilead Sciences for their support of operations, and all other team members who made this project possible. The data that supports the findings of this study are available in the supplementary material of this article. This work was supported by the National Institutes of Mental Health [www.nimh.nih.gov; Awards: NIMHK23MH095655 and NIMHR01MH108412; PI: LTM]. Gilead Sciences (www.gilead.com) provided Truvada (TDF/FTC) as PrEP and supported operations. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Conflicts of interest Dr Matthews received operational support from Gilead Sciences. Dr Haberer has been a consultant for Merck and owns stock in Natera. Dr Hurwitz and Ms. Bennett are employed by and own equity in Target RWE, which has received fees from Amgen, Baxter International, Gilead Sciences, Janssen Research & Development (Janssen R&D), and Merck outside the submitted work. Dr Baeten is an employee of Gilead Sciences, outside of the present work. Dr Hendrix has received research funding from Gilead Sciences and Merck and is founder and a nonfiduciary manager of Prionde Biopharma, LLC, outside of the present work. There are no conflicts of interest for the remaining authors. http://www.nimh.nih.gov/ http://www.gilead.com/ Preexposure prophylaxis uptake Matthews et al. 1353 References 1. UNAIDS. Country fact sheets: South Africa (2021) 2022 [cited 8 September 2022]. https://www.unaids.org/en/regionscountries/ countries/southafrica. 2. Matthews LT, CrankshawT, Giddy J, Kaida A, Smit JA,WareNC, Bangsberg DR. 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Am J Prev Med 1998; 15:120–127. https://medapps.sahpra.org.za:6006/Home/Details/?id=CfDJ8FLSLpTxgZVDhf4P0SUeWK3vjHjDpecnLPQ6rLPO5XqUxXhE5_-ttoUGRA0pmuDDeIpQUroMcWOoKhJi3odxJZUuEVquwC48tz41hJr9gNbp9-FRdouu8EJH7meBj9_i4w https://medapps.sahpra.org.za:6006/Home/Details/?id=CfDJ8FLSLpTxgZVDhf4P0SUeWK3vjHjDpecnLPQ6rLPO5XqUxXhE5_-ttoUGRA0pmuDDeIpQUroMcWOoKhJi3odxJZUuEVquwC48tz41hJr9gNbp9-FRdouu8EJH7meBj9_i4w https://medapps.sahpra.org.za:6006/Home/Details/?id=CfDJ8FLSLpTxgZVDhf4P0SUeWK3vjHjDpecnLPQ6rLPO5XqUxXhE5_-ttoUGRA0pmuDDeIpQUroMcWOoKhJi3odxJZUuEVquwC48tz41hJr9gNbp9-FRdouu8EJH7meBj9_i4w https://medapps.sahpra.org.za:6006/Home/Details/?id=CfDJ8FLSLpTxgZVDhf4P0SUeWK3vjHjDpecnLPQ6rLPO5XqUxXhE5_-ttoUGRA0pmuDDeIpQUroMcWOoKhJi3odxJZUuEVquwC48tz41hJr9gNbp9-FRdouu8EJH7meBj9_i4w https://medapps.sahpra.org.za:6006/Home/Details/?id=CfDJ8FLSLpTxgZVDhf4P0SUeWK3vjHjDpecnLPQ6rLPO5XqUxXhE5_-ttoUGRA0pmuDDeIpQUroMcWOoKhJi3odxJZUuEVquwC48tz41hJr9gNbp9-FRdouu8EJH7meBj9_i4w https://medapps.sahpra.org.za:6006/Home/Details/?id=CfDJ8FLSLpTxgZVDhf4P0SUeWK3Ye0hD3mKRiDXA19ELzWaM-ygCw9MJVmr5w-BNw6UIm5brorVQSz6dD-cKHgCLMU9yMHKa1v8Ttr_NZI1SFhR-ISPQ3lnNfh1CjtXbKxcAdw https://medapps.sahpra.org.za:6006/Home/Details/?id=CfDJ8FLSLpTxgZVDhf4P0SUeWK3Ye0hD3mKRiDXA19ELzWaM-ygCw9MJVmr5w-BNw6UIm5brorVQSz6dD-cKHgCLMU9yMHKa1v8Ttr_NZI1SFhR-ISPQ3lnNfh1CjtXbKxcAdw https://medapps.sahpra.org.za:6006/Home/Details/?id=CfDJ8FLSLpTxgZVDhf4P0SUeWK3Ye0hD3mKRiDXA19ELzWaM-ygCw9MJVmr5w-BNw6UIm5brorVQSz6dD-cKHgCLMU9yMHKa1v8Ttr_NZI1SFhR-ISPQ3lnNfh1CjtXbKxcAdw https://medapps.sahpra.org.za:6006/Home/Details/?id=CfDJ8FLSLpTxgZVDhf4P0SUeWK3Ye0hD3mKRiDXA19ELzWaM-ygCw9MJVmr5w-BNw6UIm5brorVQSz6dD-cKHgCLMU9yMHKa1v8Ttr_NZI1SFhR-ISPQ3lnNfh1CjtXbKxcAdw https://medapps.sahpra.org.za:6006/Home/Details/?id=CfDJ8FLSLpTxgZVDhf4P0SUeWK3Ye0hD3mKRiDXA19ELzWaM-ygCw9MJVmr5w-BNw6UIm5brorVQSz6dD-cKHgCLMU9yMHKa1v8Ttr_NZI1SFhR-ISPQ3lnNfh1CjtXbKxcAdw https://medapps.sahpra.org.za:6006/Home/Details/?id=CfDJ8FLSLpTxgZVDhf4P0SUeWK3Ye0hD3mKRiDXA19ELzWaM-ygCw9MJVmr5w-BNw6UIm5brorVQSz6dD-cKHgCLMU9yMHKa1v8Ttr_NZI1SFhR-ISPQ3lnNfh1CjtXbKxcAdw https://clinicalinfo.hiv.gov/en/guidelines/perinatal/whats-new?view=full https://clinicalinfo.hiv.gov/en/guidelines/perinatal/whats-new?view=full Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA Temporal changes in the relative frequency of K103N variants in plasma�RNA