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Prevention Research

Vulnerable Periods: Characterizing Patterns of Sexual Risk and Substance Use During Lapses in Adherence to HIV Pre-exposure Prophylaxis Among Men Who Have Sex With Men

Wray, Tyler B. PhD*; Chan, Philip A. MD; Kahler, Christopher W. PhD*; Simpanen, Erik M. BS*; Liu, Tao PhD; Mayer, Kenneth H. MD§

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: March 1, 2019 - Volume 80 - Issue 3 - p 276-283
doi: 10.1097/QAI.0000000000001914



Although HIV incidence has slowly declined in the United States in recent years, men who have sex with men (MSM) continue to account for 70% of new infections.1 Pre-exposure prophylaxis (PrEP) holds promise for achieving a significant, sustained decline in new infections,2 given that it can achieve over 99% efficacy in preventing HIV acquisition with optimal adherence.3–8 Although clinical guidelines currently recommend daily dosing,9 pharmacokinetic analyses of clinical trial data have shown that fewer doses also result in high levels of protection. Efficacy declines, however, to 96% at 4 doses/week and to 76%–81% at 2–3 doses/week.3,10 Studies of community-recruited MSM show that, although HIV infections are substantially reduced, many patients who start PrEP have difficulty adhering to daily dosing.4,10,11 For example, in a nationwide demonstration study of young MSM (ATN 113), only 34% of participants had drug levels consistent with taking ≥4 doses/week after 48 weeks.12 Likewise, over 40% of MSM in the DEMO Project had similarly low drug levels or had dropped out by 48 weeks.11

Less is known about PrEP adherence in real-world settings. Moreover, typical analyses of PrEP adherence may not accurately reflect the true level of protection achieved. This is because PrEP's effectiveness is likely to depend on patients' adherence specifically around the times when they are exposed to HIV rather than on their adherence over broad intervals (eg, months).13 This view, called prevention-effective adherence,13,14 suggests that patients' engagement in risk behavior fluctuates over time and that understanding PrEP's effectiveness requires exploring how adherence overlaps with potential exposures. Although some international studies suggest that adherence may improve specifically around times when patients are at highest risk,15,16 few studies have explored this in the United States. Because self-reported data on PrEP adherence are generally not dependable,17–20 the majority of available US community studies have assessed adherence by analyzing dried blood spot (DBS) samples collected at regular study visits for PrEP metabolites [eg, tenofovir diphosphate (TFV-DP)].21 Collecting even objective adherence data at such broad time intervals, however, has drawbacks. First, although TFV-DP's long half-life provides a stable measure of cumulative dosing over time,21 long gaps between collection intervals may miss periods of suboptimal dosing. Second, requiring frequent study visits to collect DBS samples in-person could also provide an overly optimistic picture of real-world adherence because regular face-to-face contact with health professionals may itself encourage better adherence.22–24

Alcohol and drug use are common among high-risk MSM, as they are among other groups at risk of HIV.25,26 These behaviors could pose a challenge for PrEP care, given strong evidence that alcohol and drug use are associated with poorer adherence to similar drugs used to treat HIV.27–31 However, few studies have explored the influence of alcohol and drug use specifically in the context of PrEP care. Two studies using medication refill data from large health care systems showed that patients with substance use diagnoses had fewer days covered by PrEP.32,33 However, neither alcohol use nor other substance use was associated with PrEP drug levels over time in the iPrEx OLE or DEMO Project.10,11 Although these studies have been helpful in identifying risk factors for poor PrEP outcomes, their reliance on broad assessments of alcohol/drug use may miss time-dependent elevations in use that co-occur with disruptions in adherence. Aggregated surveys assessing typical use over broad intervals may also result in inaccuracy due to recall biases.34,35 Past research shows that self-reported alcohol/drug use is highly correlated with relevant biomarkers when assessments minimize recall intervals and ask respondents to recall exact behaviors that occurred on specific days.36–42 This approach also has the advantage of allowing researchers to assess whether the specific timing of alcohol/drug behaviors co-occurs with other behaviors (eg, PrEP adherence and high-risk sex) on a daily basis.

In this study, we explored the co-occurrence of sexual risk behavior and substance use with lapses in PrEP adherence over 6 months among MSM at a community PrEP clinic.



Forty MSM were recruited by providers and staff at a community PrEP clinic in Providence, Rhode Island,43 from February to November 2017. Eligible participants were (1) 18+ years old, (2) assigned male sex at birth, (3) reported insertive or receptive anal sex with a man in the past 12 months, and (4) had been prescribed PrEP.


Participants who met the eligibility criteria based on their visit intake forms were approached about the study when attending routine PrEP care visits. Interested participants provided informed consent before completing baseline surveys. Participants were then provided with a digital pill bottle and were instructed to fill their medication into the bottle within a day of having their prescription refilled. Participants were also instructed to complete online dairies every 2 weeks over the six-month period. To facilitate this, emails with links to the diaries were automatically sent from the study database on their due dates, with daily reminders sent for 5 days until completed. Surveys not completed after 5 days were considered incomplete. We chose online surveys because they allowed us to collect detailed daily data at intervals that minimize inaccuracies (eg, recall bias34,35) while also limiting interactions with research personnel that could affect adherence. As such, participants attended face-to-face appointments only at routine PrEP clinical visits (about every 90 days).9 Participants were paid up to $200 based on their rate of diary completion and for agreeing to use the pill bottle. All study procedures were approved by the Lifespan and Brown University Institutional Review Boards.


Digital Pill Bottles

Daily PrEP adherence was continuously assessed using AdhereTech's Generation 2 “smart” pill containers (AdhereTech, New York, NY). These devices had several advantages, including: (1) a continuous internet connection through mobile networks for real-time data uploads, (2) long battery life allowing for use over the entire 6-month study period on a single charge, and (3) no setup or maintenance was required of participants.

Online Diaries

Participants were asked to complete an online Timeline Followback (TLFB)44,45 survey on their sexual behavior, alcohol use, and drug use each day in 2-week increments. Using a custom web application,42 participants were asked to indicate the days on which they had oral, anal, or vaginal sex, drank alcohol, or used drugs, and each of these days were marked with a specific icon. Then, participants were asked more details about each of the behaviors that occurred on specific days. For sexual behavior, participants reported the number of partners they had that day (up to 4), characteristics of each partner (eg, gender, sexually exclusive/nonexclusive, whether they asked about HIV status, and if so, what it was), the acts they engaged in with each (eg, oral, insertive anal, receptive anal, and vaginal), and whether a condom was used for each act. For alcohol use, participants were asked about the number of standard drinks consumed that day. For marijuana, stimulant, or party drug use, participants selected the type of drug they used that day (eg, marijuana, powder/crack cocaine, methamphetamine, and ecstasy) from a list of many drugs. Finally, participants were asked whether they pocketed any PrEP doses (ie, removed several pills from the pill bottle to store in a different container for travel, etc.) during the displayed period, and if so, the days on which they successfully took a PrEP pill after pocketing it. For analyses, missed doses from digital pill bottles were replaced with successfully taken doses if participants indicated taking doses on days when they reported pocketing PrEP pills. High-risk condomless anal sex (CAS) events were defined as engaging in insertive or receptive anal sex without using a condom with an unknown HIV status or sexually nonexclusive partner. Hazardous drinking was defined as 15+ drinks in an average week, or at least one occasion of 5+ drinks in a single occasion at least once in the past month.46

Alcohol Use Disorders Identification Test (AUDIT)

Alcohol Use Disorders Identification Test was used to assess alcohol-related problems in the past 12 months.47 Those who scored >8 were classified as high-risk for alcohol-related problems.48

Dried Blood Spots

DBSs were collected from participants during routine PrEP follow-up visits, typically 3 months after baseline. DBSs were analyzed for TFV-DP, a biomarker of cumulative PrEP dosing up to 3 weeks before sampling,10,11,18,21 as well as phosphatidylethanol (PEth), a biomarker of recent alcohol use that has shown high sensitivity in detecting chronic and binge drinking episodes that occur within 1–2 weeks of sampling.49–52 TFV-DP and PEth were used to corroborate data collected using digital pill bottle and online drinking diaries and to explore pairwise associations between adherence and alcohol use.

Analysis Plan

We first matched pill bottle and diary data by study day and calculated summary statistics for key variables. We then calculated Pearson correlations to explore associations between variables collected at single time points (eg, TFV-DP and PEth). PrEP adherence lapses were defined as missing ≥3 consecutive doses to align with an adherence pattern that begins to reduce PrEP's efficacy. To explore whether the rate of high-risk CAS events differed across lapses and nonlapses, we used estimated generalized estimating equations (GEEs) specifying CAS on a given day as the focal outcome, with relevant covariates and whether a given day was part of a lapse versus a nonlapse as a key predictor (model 1). In model 2, we then added a categorical term reflecting daily alcohol use level [no drinking (reference group), versus 1–4 drinks and 5+ drinks] and a 2-way interaction between alcohol use level and lapse day to explore whether CAS co-occurred with alcohol use more often on adherence lapse days versus nonlapse days. In model 3, we added daily marijuana and stimulant drug use in a similar way. To explore whether alcohol, marijuana, or stimulant use co-occurred with lapses, we then estimated similar GEE models with PrEP lapse days versus nonlapse day as a focal outcome. Because the outcomes of all models were binary, we specified binomial distributions and used a logit link function in each case.


Attrition and Response Rates

Table 1 presents the participant demographic characteristics. Six participants (15%) withdrew before submitting their final 6-month survey, and among these participants, the average time to withdrawal was 2.83 months (SD = 0.98). One of these elected to stop PrEP during the study period, and 5 withdrew only from the study for unknown reasons. Those who withdrew did not differ from those retained with respect to any demographic, clinical, or behavioral characteristics. Among all participants, the overall response rate to bimonthly TLFB surveys was 85.6% (SD = 24.5%). Among those who did not withdraw (N = 34), diary response rates were 94.4% (SD = 11.6%). All available data from participants were retained for analysis, whether or not they withdrew, providing a total of 6013 days matched across TLFB and digital pill bottle data. Among those who did not withdraw, the mean number of matched days per participant was 156.9 (SD = 25.4). Adherence data were corrected for pocketed doses on 42 total days (0.6% of all study days).

Demographic and Behavioral Characteristics of the Study Sample (N = 40)

PrEP Adherence

Twenty-one participants (53%) had a lapse of ≥ 3 PrEP doses at some point over the 6-month period, and of these, 11 (52.4%) had only one such lapse, 7 (33.3%) had 2–3, and 3 (14.3%) had 4–8 lapses. The average total length of an adherence lapse that was ≥3 days was 6.0 days (SD = 4.9). A total of 421 study days (7%) were considered part of such a lapse. Sixty-three percent of participants had tenofovir drug levels consistent with near-daily adherence (>1100 fmol/punch10). Only 5 participants had TFV-DP levels of <700 fmol/punch at the time of collection, and as assessed by digital pill bottle, these participants had a significantly lower average overall adherence rate (52.4% versus 88.4%, P <0.001) and greater number of lapses (2.4 versus 1.0, P < 0.05) compared to those with ≥700 fmol/punch. Percent days adherent to PrEP were moderately to highly correlated with TFV-DP levels (fmol/punch), r = 0.42, P < 0.05. The sample's overall adherence rate, as assessed by digital pill bottle, was 83.9% (SD = 18.0%, range = 19.5%–100%).

High-Risk CAS, and Alcohol, Marijuana, and Stimulant Drug Use During PrEP Lapses

Participants reported 630 total anal sex acts, of which 516 (81.9%) were without a condom and 485 (94.0%) involved CAS with nonexclusive or unknown HIV status partners. Sixty percent of participants met criteria for hazardous drinking. However, only 12.4% had evidence of alcohol-related problems (ie, AUDIT > 8). Participants reported a total of 1523 drinking days, 264 (17.3%) of which involved heavy drinking (ie, drinking 5+ drinks in a single day). Participants' PEth values were strongly associated with self-reported drinking over the 7 days before collecting DBS (r = 0.79, P < 0.05), suggesting that TLFB assessments of drinking were valid. Forty-two percent reported using marijuana over 756 study days. Only 15% of participants reported using stimulants or party drugs over only 51 study days, all of which involved cocaine.

The unadjusted rate at which participants reported high-risk CAS events was 6.9 per 100 person-days during periods in which participants had missed ≥3 PrEP doses, versus 8.1 per 100 person-days during more continuously adherent periods (incidence rate ratio = 0.84, P > 0.05, 95% confidence interval: 0.56 to 1.23). In GEE models of CAS events controlling for basic covariates (Table 2), the incidence rate for engaging in high-risk CAS during a lapse was not significantly different from the rate during more continuously adherent periods. In model 2, alcohol use level on a given day was generally positively associated with engaging in high-risk CAS that day, but the 2-way interaction between drinking and lapse day was not significant (See Figures and Fig. 1, Supplemental Digital Content, In model 3, marijuana use also significantly co-occurred with CAS events during continuously adherent periods, but again the 2-way interaction was not significant. However, the 2-way interaction between stimulant drug use and lapse day significantly predicted CAS events, such that the rate of high-risk CAS events occurring during a lapse was 4.5 times higher on days when party drugs were concurrently used than on non–drug use days.

GEE Models Of High-Risk CAS Events and Days in a PrEP Lapse of >3 Doses
Adjusted incidence rate ratios of engaging in high-risk CAS on a given day from estimated GEE models.

Overlap Between Lapses in PrEP Adherence and Alcohol/Drugs

Overall, neither TFV-DP levels (r = 0.22, P > 0.05) nor digital pill bottle data (r = −0.01, P > 0.05) were strongly associated with PEth levels. Similarly, neither TFV-DP levels (r = 0.24, P >0.05) nor digital pill bottle data (r = 0.13, P > 0.05) were strongly associated with metrics of self-reported alcohol use, such as the number of drinks consumed in the 14 days before DBS collection. However, at the person level, an increasingly higher percentage of those with more alcohol involvement had any PrEP lapse of ≥3 days and had a longer maximum length of adherence lapse (Fig. 2). In GEE models of PrEP lapse days (Table 2), adherence lapse days occurred 3.1 times less often on moderate drinking days when compared to nondrinking days, and there was no difference in the rate of lapse days that occurred on binge drinking days versus nondrinking days (Fig. 3). At the person level, there was no difference in the percentage of those who had any lapse or the average maximum lapse length between those who used any marijuana during the study period and those who did not. In the GEE models, lapse days also occurred 3.3 times less often on marijuana use days.

Percent of participants with any lapse in PrEP adherence of ≥3 days (top panel) and the average maximum length of adherence lapses in days (lower panel) by alcohol use involvement, marijuana use, and stimulant/party drug use. “Hazardous” drinker = consuming >14 drinks in a given week or >5 drinks in a single day. “High AUDIT” = score of >8 on the Alcohol Use Disorders Identification Test (AUDIT).
Adjusted incidence rate ratios of days in PrEP adherence lapses of ≥ 3 days from estimated GEE models.

Spearman rank-order correlations showed that TFV-DP values were not related to either the number of stimulant/party drug use days in the 2 weeks before DBS collection (r = −0.11, P > 0.05) or the number of such drug use days reported across the study period (r = 0.23, P > 0.05). However, 83% of those who reported any stimulant or party drug use had a PrEP lapse of ≥3 days at some point during the study and had an average maximum lapse length of 6.0 days, compared with 47.1% and 4.8 days among those who reported no stimulant use. In GEE models, lapse days occurred 4.5 times more often on stimulant drug use days versus days with no such drug use.


In this study of MSM recruited from a community PrEP clinic, we explored lapses in PrEP adherence (ie, periods of consecutive missed doses that may be sufficiently long to reduce efficacy) and their overlap with relevant risk behaviors. Results suggested that even in this older, PrEP-experienced, and highly adherent sample of MSM, adherence lapses of 3 or more days were common (53%), as was having more than one such lapse over a 6-month period (25% overall). Consistent with past studies,10,11 objective markers of PrEP adherence collected at routine follow-up appointments were generally modestly associated with biomarkers and self-reported alcohol use, suggesting that alcohol use might have little association with tenofovir drug levels. However, using digital pill bottles that collected data continuously, our results showed that a higher percentage of those who drank heavily and screened positive for alcohol-related problems had a significant lapse in PrEP adherence and had longer lapses than moderate drinkers without alcohol problems. However, alcohol use (and heavy drinking) did not seem to occur more often specifically during these lapses in adherence. Together, these results suggest that those with heavier patterns of drinking may be at risk of lapses in adherence, possibly due to the instability it creates in their routines, but that drinking on specific days may not necessarily lead to gaps. Marijuana use was not associated with lapses in adherence, either at the person or day level.

Our results suggest that stimulant drugs may play a more consistent role in adherence lapses. Specifically, our finding that lapse days occurred at a substantially higher rate on stimulant drug use days compared with non–drug use days suggest that stimulant drug use may be involved in clinically meaningful lapses in PrEP adherence. These findings contrast with other studies that have shown that the use of similar drugs was not associated with tenofovir drug levels,11,53 but should be interpreted with some caution due to the low rates of drug use in this sample. Together, these results suggest that further research focused on understanding the effects of stimulants and other drugs on PrEP adherence is needed.

Our results also showed that sex events involving potential HIV exposure (ie, engaging in CAS with a nonexclusive or HIV-status unknown partner) did not occur less often during PrEP adherence lapses when compared with periods of more regular adherence. This finding suggests that lapses in PrEP adherence were not likely due to participants taking deliberate pauses at times when they believed they would not be at risk, but rather to problems adhering to PrEP at times when they were still at risk. As such, this may signal the need for interventions that focus on helping MSM adhere to PrEP more consistently and/or identifying triggers for periods of nonadherence. Our results also showed that consistent with a number of past studies,54–56 the rate of engaging in high-risk CAS was significantly higher on heavy drinking days specifically during periods of regular PrEP adherence. Alcohol use did not significantly co-occur with CAS that occurred specifically during adherence lapses, suggesting that alcohol use was unlikely to have played a role in these risk windows. Also, consistent with past studies,54,55 high-risk CAS events generally occurred at a much higher rate on days when participants reported using stimulant drugs. However, our results also showed that CAS was more likely to occur during a lapse when stimulant drug use also occurred than when stimulant drugs were not used. These findings suggest that use of stimulant drugs could play an important role in promoting potential HIV exposures specifically at times when patients may be less protected by PrEP and underscore the need for interventions that focus on episodic drug use.


Two key limitations should be noted. First, although this study design produced highly detailed, daily data on adherence and related behaviors to understand the timing of these events, our overall sample size (N = 40) was small. As a result, data on some key predictors (eg, stimulant/party drug use) were limited, producing sizable standard errors in our models. As such, although the consistent and sizable effects of stimulant use in these models provide strong evidence of their importance, these findings should be interpreted with caution and further research is needed to confirm their magnitude. Second, this sample consisted of a relatively older, well-educated, predominantly white, and largely PrEP-experienced group of MSM. As such, these results offer a relatively conservative picture of PrEP lapses and related risk behaviors. Future research should focus on younger, more diverse, and less PrEP-experienced MSM.

In summary, this study highlights the value of collecting detailed daily data on PrEP adherence and associated risk behaviors over time to help researchers understand clinically meaningful lapses in adherence and how these lapses may affect patients' risk of HIV. Our results showed that lapses of 3 or more consecutive missed doses were common and seemed to be mostly due to problems adhering to PrEP when they were still at risk. Although alcohol use seemed to play little role in producing adherence lapses or promoting risk behaviors that occurred during lapses, stimulant drug use often co-occurred with HIV risk behavior that occurred specifically during PrEP adherence lapses, suggesting that these drugs may facilitate HIV exposure specifically when PrEP is less protective. Future research should focus on understanding the role of adherence lapses, risk behavior, and alcohol/drug use among younger, less PrEP-experienced MSM.


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pre-exposure prophylaxis; medication adherence; sexual and gender minorities; sexual behavior; substance abuse

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