High Levels of Prevention-Effective Adherence to HIV PrEP: An Analysis of Substudy Data From the EPIC-NSW Trial : JAIDS Journal of Acquired Immune Deficiency Syndromes

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Prevention Research

High Levels of Prevention-Effective Adherence to HIV PrEP: An Analysis of Substudy Data From the EPIC-NSW Trial

Bavinton, Benjamin R. PhDa; Vaccher, Stefanie PhDa; Jin, Fengyi PhDa; Prestage, Garrett P. PhDa; Holt, Martin PhDb; Zablotska-Manos, Iryna B. PhDc,d; Guy, Rebecca PhDa; Amin, Janaki PhDe; Templeton, David J. PhDa,f,g; Yeung, Barbara MPHa; Hammoud, Mohamed A. PhDa; Lewis, David PhDc,d; Baker, David MBBSh; Dharan, Nila MDa; McNulty, Anna M. MBBSi; Grulich, Andrew E. PhDa;  for the Expanded PrEP Implementation in Communities in New South Wales (EPIC-NSW) research group

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes 87(4):p 1040-1047, August 1, 2021. | DOI: 10.1097/QAI.0000000000002691
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Oral HIV preexposure prophylaxis (PrEP) prevents HIV infection in individuals at high risk but relies on good adherence.1–3 For those taking daily PrEP, 4 or more pills per week are needed for adequate PrEP protection for anal intercourse, whereas 6 or more pills per week are needed for receptive vaginal/front hole intercourse in cisgender women and transgender men.2,4 “Event-driven” dosing is also effective for cisgender gay, bisexual, and other men who have sex with men (GBM), which requires taking 2 PrEP pills 2 to 24 hours before a sexual encounter and then 1 pill per day for 2 days after the last sexual encounter.5

To prevent HIV infection, individuals need to take PrEP pills at times or “seasons”6 when they are potentially at risk of HIV, a concept termed “prevention-effective adherence.”7 People may take fewer pills, or cease taking PrEP entirely, at times when they believe that they are at no or low risk. A challenge for accurate measurement of PrEP adherence and concomitant HIV risk is that unless pill taking is assessed alongside sexual behavior, it is unknown whether lower pill numbers reflect poor adherence at times of risk or if fewer pills are being taken during periods of low or no risk. Similarly, without first determining the dosing regimen being used by an individual, measures of adherence cannot ascertain whether a low number of used pills represents poor adherence to daily PrEP or effective use of a nondaily dosing regimen.7,8 Most PrEP adherence studies, whether they use self-reported adherence or objective measures of adherence, such as drug concentrations in biological samples, medication event monitoring system (MEMS) caps, or medication possession ratio (MPR), have not typically compared adherence with sexual behavior in the same period; for example, 2 recent systematic reviews of PrEP adherence studies did not mention timing of sexual behavior in relation to pill taking.9,10 However, it has been noted that measurement of prevention-effective adherence in research and programs is a challenge.11

In the Australian state of New South Wales (NSW), PrEP has been widely available since March 2016 through the large-scale implementation trial, Expanded PrEP Implementation in Communities–New South Wales (EPIC-NSW),12 followed in April 2018 by availability at low cost through Australia's national program for subsidized medicines, whereby PrEP can be prescribed by any doctor and dispensed at community pharmacies. Analysis has demonstrated continuing low HIV incidence in 9596 EPIC-NSW participants who were dispensed PrEP (0.16 per 100 person-years) across the trial period and up to 12 months after.13 Additionally, a PrEP-driven 25% decline in state-wide HIV diagnoses among GBM was reported after EPIC-NSW scale-up.14 HIV incidence among participants with an MPR of 1.0 (ie, no days in which they did not possess PrEP pills) was zero [95% confidence interval (CI) = 0.0 to 0.08 per 100 person-years], and none of the 30 seroconverters identified in the trial appeared to be using daily PrEP at the time of HIV infection.13 Further analysis of MPR during EPIC-NSW found that one-quarter of participants discontinued PrEP and did not recommence it during follow-up.15 Additionally, by the final quarter of the study, mean MPR had dropped to 0.6.15 HIV incidence remained very low, despite the levels of discontinuation increasing and adherence to daily PrEP apparently dropping, suggesting that those who ceased PrEP or appeared to have poor adherence may have stopped PrEP or modified how they took PrEP in line with decreased risk. To explore this, we examined the number of pills taken and sexual activity reported by participants in the same period in the behavioral substudy of EPIC-NSW.


Study Design and Participants

The EPIC-NSW study protocol and primary results have been published.12,14 Briefly, EPIC-NSW was a single-arm, prospective implementation trial of daily, single-dose, oral, coformulated tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) in individuals at high risk of HIV infection in which the primary analyses were to calculate cohort-level HIV incidence and state-wide reductions in new HIV notifications after rapid scale-up of PrEP. EPIC-NSW participants were enrolled at 31 clinical sites between March 2016 and April 2018 and followed up until March 31, 2019. Ethical approval was obtained from St Vincent's Hospital, Sydney. Participants were 18 years or older, lived in NSW or Australian Capital Territory (or visited to attend follow-up visits), had a negative fourth-generation HIV antibody/antigen test within 7 days before commencing PrEP, were at high and ongoing risk of HIV infection, and had an estimated glomerular filtration rate (eGFR) of more than 60 mL/min per 1.73 m2. As the primary at-risk population, the study was targeted toward GBM, although cisgender women and heterosexuals at high risk of infection were also able to enroll. At enrollment, all participants gave written consent to participate in the main study and were offered the opportunity to consent to participate in an optional behavioral substudy. The substudy was designed to measure additional demographics, PrEP use, sexual behavior, and drug use throughout follow-up.


Participants who consented to participate in the behavioral substudy received an email after their baseline EPIC-NSW visit and quarterly thereafter with a link to an online survey hosted on the SurveyGizmo platform. For each survey round, they received up to 2 reminder emails, 7 days apart for each survey. Participants could miss a survey but complete the next. Surveys took approximately 5–10 minutes to complete. There were 7 survey rounds including baseline.


Participants were asked about their sex assigned at birth, current gender identity, and current sexual identity; these data were used to classify participants as gay-identified cisgender men or not, and this determined which sexual behavior questions were asked. Country of birth was categorized into 6 regions: Australia, high-income English-speaking countries (United Kingdom, Ireland, New Zealand, Canada, and United States of America), Europe, Asia, Latin America and the Caribbean, and other. Postcode of residence was classified into 4 groups using a previously published method estimating the proportion of men residing in each Australian postcode who identified as gay16 (“≥20% gay,” “10%–19% gay,” “5%–9% gay,” and “<5% gay”); all postcodes classified as “≥20% gay” were in inner-city suburbs of Sydney, NSW. These data were collected at enrollment as part of the main study.

Quarterly MPR was calculated for each participant from PrEP dispensing logs at each clinic as part of the main study. These were reviewed to determine the date and number of pills dispensed. Each participant's time in the study was divided into 90-day intervals from the date of first dispensing, and for each period, MPR was calculated as the number of pills in the participant's possession divided by the number of days in the period, resulting in an MPR ranging from 0 to 1.

The following data were collected from behavioral substudy surveys. Participants were asked about PrEP use in the previous 3 months and the “last full week” (defined as Monday to Sunday). “Adequate PrEP protection” in the last full week was defined as ≥4 pills for participants assigned male sex at birth and ≥6 pills for participants assigned female sex at birth (including transgender men). Condomless sex (CLS) questions were presented to participants based on their sex assigned at birth, current gender identity, and current sexual identity; gay-identified cisgender men were asked about insertive and receptive condomless anal intercourse in the last full week, whereas other participants were asked about receptive or insertive anal and/or vaginal/front hole CLS in the last full week. If participants reported CLS on any day of the last full week, we termed this a “CLS-week.” Both groups were asked to indicate whether they had CLS in the last full week with HIV-positive men with undetectable viral loads, HIV-positive men with detectable or unknown viral loads, HIV-negative men on PrEP, HIV-negative men not on PrEP (or unknown to be on PrEP), and unknown HIV status men. “Higher risk CLS” was defined as CLS with HIV-positive men with detectable/unknown viral loads or with unknown HIV status men. Although at the time of the study, only daily PrEP was recommended, participants were also asked about the ideal preference for PrEP dosing: “every day” (termed “daily PrEP”), “for periods of time when I feel I am at high risk of getting HIV” (“periodic PrEP”17), “only on specific occasions when I am at high risk of getting HIV” (“event-driven PrEP”5), and “other.”

Statistical Analysis

This analysis aimed (1) to determine the proportion of weeks in which higher-risk CLS occurred but were inadequately protected by PrEP and (2) among weeks in which higher-risk CLS occurred, to determine factors associated with inadequate PrEP protection (defined as weeks in which <4 pills for participants assigned male sex at birth and <6 pills for participants assigned female sex at birth were taken). Participants were included if they completed the baseline survey and at least 1 follow-up behavioral survey. For each follow-up survey completed, only the last full week was examined; participants could complete multiple follow-up surveys (maximum = 6). If participants missed follow-up surveys, these data points were not included in the analysis. The last full week data from each survey were compared with the quarterly MPR of the period that the date of survey completion fell in. We describe the characteristics of the last full weeks by the following: total cumulative number of last full weeks reported by all participants, occurrence of any sex, occurrence of any CLS, occurrence of any higher risk CLS, and adequate or inadequate PrEP protection. Within the higher risk CLS weeks, we examined factors associated with inadequate PrEP protection using bivariate and multivariate generalized estimating equation modeling to control for inter- and intrasubject variability. Variables with P values of <0.1 in bivariate models were included in the multivariate model. We report odds ratios (OR), adjusted ORs (aOR), 95% CIs, and 2-sided P values for these associations. All analyses were conducted with Stata version 14.2 (StataCorp, College Station, TX).


Between March 2016 and April 2018, 9709 participants were enrolled in EPIC-NSW and 9596 were dispensed PrEP. Of those dispensed PrEP, 6429 participants (67.0%) consented to the behavioral survey substudy and completed the baseline survey, and 4401 completed at least 1 follow-up survey and were included in the analysis (45.9% of participants dispensed PrEP, 68.5% of those completing the baseline survey). Overall, the 4401 participants included in this analysis were similar to the full EPIC-NSW cohort and those who completed the baseline survey (Table 1); there was a marginal difference in the proportion born in Australia (61.1% versus 52.7%). The included participants had a slightly higher mean MPR than all participants dispensed PrEP in the parent study (0.85 versus 0.81) and compared with the participants excluded from the analysis (0.77).

TABLE 1. - Characteristics of the Full EPIC-NSW Cohort, Those Who Completed the EPIC-NSW Baseline Survey, and Those Who Completed Baseline and at Least 1 Follow-up Survey*
Full EPIC-NSW Cohort (n = 9596) Completed EPIC-NSW Baseline Survey (n = 6429) Completed Baseline and At least 1 Follow-up Survey (n = 4401)
Male gender identity 9455 (98.5) 6347 (98.7) 4347 (98.8)
Gay sexual identity 8781 (91.5) 5917 (92.0) 4091 (93.0)
Age—median (IQR), yr 34 (28–43) 35 (29–44) 36 (30–46)
Aboriginal or Torres Strait Islander 129 (1.3) 114 (1.8) 72 (1.6)
Region of birth
 Australia 5059 (52.7) 3957 (61.6) 2690 (61.1)
 High-income English-speaking country 1049 (10.9) 862 (13.4) 625 (14.2)
 Europe 370 (3.9) 275 (4.3) 183 (4.2)
 Asia 1240 (12.9) 854 (13.3) 579 (13.2)
 Latin America and Caribbean 374 (3.9) 239 (3.7) 143 (3.3)
 Other 326 (3.4) 242 (3.8) 181 (4.1)
 Not reported 1178 (12.3) 0 (0.0) 0 (0.0)
Postcode of residence
 ≥20% gay 2912 (30.4) 2027 (31.5) 1471 (33.4)
 10%–19% gay 846 (8.8) 623 (9.7) 450 (10.2)
 5%–9% gay 1120 (11.7) 749 (11.7) 511 (11.6)
 <5% gay 4602 (48.0) 3030 (47.1) 1969 (44.7)
 Not reported 116 (1.2) 0 (0.0) 0 (0.0)
Type of recruitment site
 Sexual health centre 4441 (46.3) 2871 (44.7) 1782 (40.5)
 Private GP 4707 (49.1) 3359 (52.3) 2481 (56.4)
 Hospital clinic 448 (4.7) 199 (3.1) 138 (3.1)
 University education 3812 (59.3) 2650 (60.2)
 Took PrEP in 3 months prior to enrollment 851 (13.2) 618 (14.0)
 MPR over follow-up—mean (SD) 0.81 (0.27) 0.83 (0.25) 0.85 (0.22)
 MPR over follow-up—median (IQR) 0.95 (0.69–1.00) 0.96 (0.75–1.00) 0.96 (0.80–1.00)
*Data are n (%) unless otherwise specified.
High-income English-speaking countries included the United Kingdom, Ireland, New Zealand, Canada, and the United States.
This information was collected in the behavioral survey substudy only so was not available for the full EPIC-NSW cohort.

The included participants overwhelmingly identified as male (98.8%) and most identified as gay (93.0%); 334 participants (7.6%) were not cisgender gay men. Median age was 36 years [interquartile range (IQR) = 30 to 46 years). More than half (61.1%) were born in Australia (including 1.6% of the overall sample who were Indigenous Australians), 13.2% were born in Asia, and 14.2% in high-income English-speaking countries. More than half (60.2%) were university educated. Less than half (44.7%) lived in <5% gay postcodes, whereas 33.4% lived in ≥20% gay postcodes. In the 3 months before enrolling in EPIC-NSW, 14.0% had taken PrEP (90 of the 618 participants who had previously taken PrEP had been enrolled in the precursor demonstration trial, PRELUDE18,19). At baseline, 70.2% (n = 3090) preferred daily PrEP, 15.7% (n = 691) periodic PrEP, and 12.0% (n = 530) event-driven PrEP.

Among included participants, the median number of follow-up surveys completed was 2 (range = 1 to 6; IQR = 1 to 4). Most participants (81.9%, n = 3605) reported daily PrEP use in the 3 months before each follow-up survey, whereas 6.7% (n = 296) had at least one 3-month follow-up period of nondaily use, and 11.4% (n = 500) had at least one 3-month period during which they did not take PrEP. During follow-up, 6.9% (n = 302) of participants reported any sex work, 67.9% (n = 2989) any group sex, and 43.7% (n = 1921) any drug use for the purposes of sex. One-quarter of participants (n = 1140, 25.9%) ever used methamphetamines. Over follow-up, 53.9% (n = 2370) of participants consistently preferred daily PrEP as their ideal dosing regimen. Four participants (0.1%) included in this analysis seroconverted (of 30 seroconverters in the parent study13).

Participants provided information on 12,399 “last full weeks.” When examining the quarterly MPR for each participant for the quarter in which they completed the survey (and thus in which the last full week occurred), there was a relationship between quarterly MPR and the number of pills taken in the last full week (Table 2). For example, those who took no pills in the last full week had a median MPR in that quarter of 0.19, compared with a median of 1.00 for those who took ≥7 pills in the last full week.

TABLE 2. - Comparison of Number of Self-Reported Pills Taken in “Last Full Week’ and Quarterly MPR
Self-reported Number of Pills Taken in “Last Full Week” Quarterly MPR From Dispensing Records in the Quarter in Which Survey Was Completed
Mean Quarterly MPR (SD) Median Quarterly MPR (IQR)
0 pills in last full week 0.43 (0.45) 0.19 (0.00–1.00)
1–3 pills in last full week 0.58 (0.39) 0.63 (0.19–1.00)
4–6 pills in last full week 0.82 (0.29) 0.99 (0.77–1.00)
≥7 pills in last full week 0.92 (0.20) 1.00 (0.97–1.00)

Participants reported any sexual activity with male partners in 74.8% (n = 9272) of the 12,399 observed weeks, and they reported CLS with male partners in 60.4% (n = 7485) of weeks (Fig. 1 and Table 3). These CLS weeks were reported by 3417 participants (77.6%). Of the 7485 CLS weeks, ≥7 PrEP pills were taken in 85.3% (n = 6382) of weeks, 4–6 pills were taken in 8.1% (n = 607), 1–3 pills in 0.5% (n = 38), and no pills in 6.1% (n = 458) of weeks, respectively. Overall, 6.6% (n = 497) of the 7495 CLS weeks were inadequately protected by PrEP.

Sexual behaviors reported in “last full week” and PrEP protection.
TABLE 3. - Number of Self-Reported PrEP Pills Taken During the “Last Full Week’ by Sexual Behaviors Reported During That Week
No. of weeks Self-Reported Number of Pills Taken in “Last Full Week’
No Pills 1–3 Pills 4–6 Pills ≥7 Pills
All observed weeks 12,399 1029 (8.3) 87 (0.7) 1038 (8.4) 10,245 (82.6)
Sexual behavior reported during last full week
 No sex during last full week 3127 388 (12.4) 32 (1.0) 292 (9.4) 2415 (77.2)
 Some sex reported in last full week 9272 641 (6.9) 55 (0.6) 746 (8.1) 7830 (84.5)
 No CLS reported in last full week 4914 571 (11.6) 49 (1.0) 431 (8.8) 3863 (78.6)
 CLS reported in last full week 7485 458 (6.1) 38 (0.5) 607 (8.1) 6382 (85.3)
  Weeks with no CLS with HIV-positive men with detectable/unknown viral load or unknown HIV status men 4964 367 (7.4) 26 (0.5) 393 (7.9) 4178 (84.2)
  Weeks with any CLS with HIV-positive men with detectable/unknown viral load or unknown HIV status men 2521 91 (3.6) 12 (0.5) 214 (8.5) 2204 (87.4)
 Weeks with adequate PrEP protection* 2418 0 (0.0) 0 (0.0) 214 (8.9) 2204 (91.1)
 Weeks with inadequate PrEP protection* 103 91 (88.3) 12 (11.7) 0 (0.0) 0 (0.0)
*Adequate PrEP protection defined as ≥4 pills for participants assigned male at birth and ≥6 pills for participants assigned female at birth; “inadequate PrEP protection” defined as <4 pills for participants assigned male at birth and <6 pills for participants assigned female at birth.

One-third (n = 2521, 33.7%) of the CLS weeks involved higher risk sex, that is, with HIV-positive men with detectable/unknown viral load (n = 281 weeks) or unknown HIV status men (n = 2431 weeks); these weeks were reported by 1558 participants. Of the 2521 weeks involving higher risk CLS, participants took ≥7 pills in 87.4% (n = 2204) of weeks, 4–6 pills in 8.5% (n = 214), 1–3 pills in 0.5% (n = 12), and no pills in 3.6% (n = 91). There were 103 weeks when participants did not have adequate PrEP protection and reported higher risk CLS, equating to 4.1% of the higher risk CLS weeks (n = 103/2521), 1.4% of all CLS weeks (n = 103/7485), or 0.8% of all observed weeks (n = 103/12,399). The 103 inadequately protected higher risk CLS weeks were reported by 98 individuals (2.2% of included participants). When examining the 91 weeks in which no pills were taken, 67 (73.6%) were when participants reported taking no PrEP in the previous 3 months.

Among the 2521 higher risk CLS weeks, we examined factors associated with the 103 weeks inadequately protected by PrEP (Table 4). In multivariate analysis, inadequately protected weeks were less likely to be in participants aged 45 years or older, and there was a significant trend for age. They were more likely to be in participants living in a <20% gay postcode, in participants who preferred nondaily PrEP dosing options, and in participants who completed <3 follow-up surveys. Inadequately protected higher risk CLS weeks were not independently associated with sexual and gender identity, university education, country of birth, sexual partner numbers, group sex, sex work, drug use for the purposes of sex, or methamphetamine use.

TABLE 4. - Among all Weeks Involving CLS With HIV-Positive Men With Detectable/Unknown Viral Load or Unknown HIV Status Men (n = 2521), Factors Associated With Inadequate PrEP Protection* (n = 103) Using Generalized Estimating Equations
n/N (%) OR (95% CI) P aOR (95% CI) P
Age group
 Less than 25 yrs 8/112 (7.1) Ref. Ref.
 25–34 yrs 37/713 (5.2) 0.72 (0.32 to 1.59) 0.411 0.70 (0.31 to 1.58) 0.390
 35–44 yrs 29/762 (3.8) 0.54 (0.24 to 1.21) 0.135 0.54 (0.24 to 1.21) 0.132
 45 years or older 29/934 (3.1) 0.44 (0.20 to 0.98) 0.044 0.42 (0.19 to 0.96) 0.040
Sexual and gender identity
 Not gay-identified cisgender man 12/212 (5.7) Ref.
 Gay-identified cisgender man 91/2309 (3.9) 0.65 (0.34 to 1.25) 0.199
 University education 55/1440 (3.8) 0.83 (0.55 to 1.25) 0.365
 Born in Australia 64/1568 (4.1) 1.03 (0.67 to 1.59) 0.899
Postcode of residence
 ≥20% of men identify as gay 23/854 (2.7) Ref. Ref.
 <20% of men identify as gay 80/1667 (4.8) 1.78 (1.10 to 2.88) 0.018 1.74 (1.08 to 2.81) 0.023
 More than 10 sex partners in last 3 mo 29/814 (3.6) 0.83 (0.54 to 1.27) 0.388
 Any group sex in last 3 mo 68 1850 (3.7) 0.72 (0.47 to 1.10) 0.132
 Any sex work in last 3 mo 9/156 (5.8) 1.47 (0.69 to 3.15) 0.317
 Any drug use for the purposes of sex in last 3 mo 47/1013 (4.6) 1.25 (0.82 to 1.89) 0.301
 Any methamphetamine use in last 3 mo 29/612 (4.7) 1.22 (0.78 to 1.91) 0.373
Preference for ideal way to take PrEP
 Daily 58/1789 (3.2) Ref. Ref.
 Periodic (specific periods of high risk) 22/311 (7.1) 2.30 (1.40 to 3.79) 0.001 2.28 (1.38 to 3.77) 0.001
 Event-driven (only around the time of sexual encounters) 19/316 (6.0) 1.92 (1.14 to 3.25) 0.015 2.12 (1.25 to 3.60) 0.005
 Other 4/105 (3.8) 1.21 (0.43 to 3.40) 0.715 1.13 (0.40 to 3.16) 0.816
No. of follow-up surveys completed§
 5 to 6 follow-up surveys 25/1076 (2.3) Ref. Ref.
 3 to 4 follow-up surveys 31/816 (3.8) 1.66 (0.94 to 2.94) 0.082 1.57 (0.89 to 2.75) 0.119
 1 to 2 follow-up surveys 47/629 (7.5) 3.31 (1.99 to 5.51) <0.001 3.06 (1.84 to 5.11) <0.001
*Adequate PrEP protection defined as ≥4 pills for participants assigned male at birth and ≥6 pills for participants assigned female at birth; “inadequate PrEP protection” defined as <4 pills for participants assigned male at birth and <6 pills for participants assigned female at birth.
Numbers and row percentages for each variable and category within nondichotomous variables.
P-trend for age group in bivariate analysis was OR = 0.77, 95% CI = 0.61 to 0.95, P trend = 0.021 and in multivariate analysis was aOR = 0.76, 95% CI = 0.61 to 0.96, P-trend = 0.018.
§P trend for number of follow-up surveys in bivariate analysis was OR = 1.84, 95% CI = 1.42 to 2.38, P-trend <0.001 and in multivariate analysis was aOR = 1.77, 95% CI = 1.36 to 2.30, P-trend <0.001.


In this large-scale PrEP implementation study, we observed prevention-effective adherence in more than 99% of observed follow-up weeks among substudy participants. A small proportion of weeks involving CLS were inadequately protected by PrEP (6.6% of CLS weeks, where inadequate PrEP protection was defined as having taken <4 pills or <6 pills in the last full week in those assigned male or female at birth, respectively), and only 1.4% of all CLS weeks were inadequately protected and involved sexual activity with higher-risk partners (ie, HIV-positive partners with detectable/unknown viral load or unknown HIV status partners). We have shown that measuring both pill taking and sexual behavior during the same period more fully captures the context of adherence. Studies that measure pill taking or drug concentrations only cannot explain apparent mismatches between level of PrEP adherence or persistence and HIV incidence. Our findings help to explain why the long-term analysis of EPIC-NSW participants found very low HIV incidence despite MPR at the end of the study decreasing to 0.6 (thus suggesting PrEP discontinuation or suboptimal adherence).13,15 Thus, although MPR is commonly used to estimate PrEP adherence in research studies,20–22 its limitations must be acknowledged when interpreting HIV outcomes data.

Our data indicated that few participants had suboptimal adherence around times of risk, as opposed to having stopped or paused PrEP. Of the higher risk CLS weeks with inadequate PrEP protection, 88.4% were in participants who took no pills at all in that week. This suggests that among our substudy participants, the main issue was safely stopping and restarting PrEP rather than continued, suboptimal adherence. The small number of seroconversions in EPIC-NSW13 demonstrates that some individuals struggled with maintaining prevention-effective adherence, although it must be acknowledged that poor adherence appears to be less of a systemic problem in Australia than in many other settings internationally.23 There are 2 main issues of concern: individuals may stop or pause PrEP and then be exposed to HIV or they may continue using PrEP with suboptimal adherence.24 Internationally, discontinuation of PrEP has been associated with younger age,25–27 minority ethnic status,27,28 financial barriers,29 and drug use.25,26 However, as many people do appear to stop or pause their PrEP use in line with periods of lower risk,30,31 more research is needed to determine ways to identify patients who are more likely to discontinue PrEP and subsequently engage in risk behavior. This issue has become especially pertinent in the context of the COVID-19 pandemic, during which many GBM ceased taking PrEP while physical distancing restrictions were in effect.32

In our analysis, weeks involving CLS with higher risk partners and having inadequate PrEP protection were more likely in participants with a preference for nondaily PrEP. It is not surprising that individuals with a preference for nondaily PrEP took fewer pills than those who preferred daily dosing. Nonetheless, it is a concern that this association occurred in weeks involving higher risk CLS. Daily PrEP is not suitable for all people engaging in higher risk sex, and these findings underscore the continuing need for new PrEP modalities not reliant on daily pill taking, such as long-acting injectable PrEP or long-acting PrEP implants.33 It is important to note that there had not been any widespread community education about nondaily PrEP options in NSW during this substudy's period of observation. Other research has found relatively low levels of event-driven dosing among PrEP-using GBM in Australia (ranging from 6% among former EPIC-NSW participants in late 2019/early 20208 to 13% in gay community HIV behavioral surveillance in 202034), although 43% of PrEP-experienced men showed interest in using it.8 Event-driven PrEP may help reduce the occurrence of these episodes of higher risk CLS by providing an option more acceptable to people who do not want to take daily PrEP. Community education about event-driven PrEP is a critical priority.

Other factors were also associated with higher risk CLS weeks and having inadequate PrEP protection. As mentioned above, younger age has been associated with discontinuation of PrEP and also poorer adherence,35 including in EPIC-NSW,15 and there is evidence from multiple Australian sources that younger men tend to have lower rates of PrEP uptake.36–38 In our data, older age (ie, 45 years and older) was indeed associated with better prevention-effective adherence, and participants younger than 25 years had the highest proportion of higher risk CLS weeks not adequately protected by PrEP. Living in a suburb with a lower concentration of gay-identified resident men (ie, less than 20% of the men) was associated with inadequate PrEP protection in higher risk CLS weeks. Before PrEP, evidence suggested that living in suburbs with high concentrations of gay men was associated with higher HIV risk.36 However, PrEP uptake and the population-level declines observed in HIV diagnoses have been greatest in these suburbs,14 along with a greater sense of connection to the gay community, higher formal education and employment, more frequent HIV testing, and lower levels of “unprotected” CLS (ie, anal intercourse not protected by condoms, PrEP, or undetectable viral load).36,39,40 Men living outside the traditional “gaybourhoods”16 require targeted PrEP adherence education and support appropriate to their circumstances, the sex they have, and where they live. Consideration should also be given to the support needs of PrEP providers outside of inner-city locations.41

Our analysis had some limitations. Adherence was measured by self-report only and may have been subject to social desirability bias. However, in our data, self-reported adherence in the last full week was related to MPR from the quarter that week fell in, and previous research in NSW has demonstrated a strong correlation between self-reported adherence and direct measurement of tenofovir levels in blood.17 The short recall period of the last full week may have ameliorated problems with longer-term recall. Some weeks may have been misclassified as having inadequate PrEP protection in users of event-driven regimen: if the loading dose occurred in the days immediately before the first day of the last full week, only 1–2 pills may have been reported in the last full week. However, this situation is likely to have been rare given that only 2.6% of last full weeks were in participants reporting event-driven dosing. The EPIC-NSW trial was designed to be as “real-world” as possible, and the surveys were optional; there was incomplete follow-up survey data (although, as the primary unit of analysis was the “last full week,” the goal was not to have an uninterrupted period of follow-up as is the case in most longitudinal cohort analyses).

Additionally, the results highlight the challenging problem of selection bias in the context of an optional survey-based substudy implemented as part of a larger trial (which at the time was the only way to access PrEP in NSW). Participants who completed fewer surveys were more likely to have inadequate PrEP protection in higher risk CLS weeks (Table 4), and they had slightly lower MPR. Based on the number of seroconversions (ie, 4 in the substudy participants versus 30 in the parent study), it is likely that those who could be included in this analysis had lower HIV risk, even considering that there were few differences between those included and the full EPIC-NSW cohort as shown in Table 1. Given that EPIC-NSW and this substudy were primarily in cisgender GBM in Australia, the findings may not be generalizable to other populations or GBM in other countries.


In the context of a large-scale PrEP implementation trial, prevention-effective adherence to PrEP during observed weeks was close to 100% among participants of a large substudy and most substudy participants sustained high levels of protection from PrEP by aligning PrEP use with periods of sexual activity and risk. Although it must be acknowledged that those who volunteered to participate in the substudy may have had different patterns of adherence to those who did not, our findings nonetheless illustrate the additional benefits of measuring pill taking during the period in which sexual events occur. This approach can help explain high levels of PrEP effectiveness even when PrEP discontinuation or periods of suboptimal adherence seem relatively common given that measurement of pill taking without reference to sexual behavior may be likely to overestimate HIV risk.


The authors thank all the study participants, participating clinical sites, pharmacies, and EPIC-NSW research personnel. The authors acknowledge EPIC-NSW research staff Barbara Yeung, Erin Ogilvie, Gesalit Cabrera, Shawn Clackett, Toby Vickers. The authors acknowledge EPIC-NSW site principal investigators Andrew Carr, Anna McNulty, Ben Anderson, Brad Forssman, Catriona Ooi, Christopher Carmody, Daniel Chanisheff, David Baker, David Lewis, David Smith, David Templeton, David Townsend, Debra Allen, Don Smith, Eva Jackson, Emanuel Vlahakis, Gia Han Thai, Hugh MacLeod, Josephine Lusk, Katherine Brown, Kym Collins, Mark Bloch, Nathan Ryder, Nicolas Doong, Phillip Read, Robert Finlayson, Rohan Bopage, Sarah Martin, and Tuck Meng Soo. The authors acknowledge EPIC-NSW site coordinators Adriana Trujillo, Alison Kincaid, Alison Nikitas, Almario Mangaran, Amanpreet Bedi, Andrew Buggie, Anik Ray, Annabelle Caspersz, Brett Hadlow, Brett Sinclair, Ching Tan, Natalie Arvela, Melissa Benson, Damien Brown, David Ninham, Dianne Morris, Elizabeth Griggs, Elizabeth Scally, Karen Chronister, Jennifer Walsh, Jessie Payne, Jodie-Lee Little, Joanne Gough, John McAllister, Katherine Ognenovska, Kim Grant, Kylie Strong, Lesley Williams, Lucy Williamson, Margaret Crowley, Melissa Power, Michael O'Reilly, Michael Williamson, Nerida Grant, Nives Houlihan, Phillip Habel, Phuoc Loc Le, Rasanga Liyanage, Roisin Steward, Ruthy McIver, Sally-Anne Brennan, Shane Hewitt, Sarah Holliday, Shannon Woodward, and Sophie Dinning.


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HIV; preexposure prophylaxis; prevention-effective adherence; men who have sex with men; sexual behavior

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