Missed opportunity, or cause for concern? Methamphetamine Use is Associated with Greater Interest in Event-Driven PrEP Among Sexual Minority Men

Abstract

INTRODUCTION:

Among the many behaviors associated with increased risk for HIV acquisition, the use of methamphetamine (i.e., Crystal Meth) stands out as a major driver of new HIV infections. Efforts to achieve equity in HIV prevention and care are innately associated with attending to the needs of the community who uses CM, most of whom are people of color. Identifying opportunities to support PrEP candidates who engage in CM use is a key component for a holistic U.S. national HIV prevention plan. Event-driven (ED) PrEP presents a straightforward way to expand PrEP protections and uptake nationally, it is possible that this method would align better with the needs of individuals who use CM.

METHODS:

The following study assessed the association between CM use with awareness and interest in ED PrEP among HIV negative, and those with unknown serostatus cisgender males and transgender people. We performed log-binomial regression analysis to predict awareness (i.e., having heard of ED PrEP), and being interested in ED PrEP.

RESULTS:

We found that participants who recently used CM were less likely to know of ED PrEP (aPR = 0.83, 95% CI 0.69 – 0.99), but more interested in ED PrEP (aPR = 1.12, 95% CI 1.01 – 1.30), after accounting for demographic and HIV-related behaviors.

CONCLUSION:

Opportunities to expand PrEP uptake and improve adherence among individuals who report CM use are essential to significantly impact the HIV epidemic. Continued research on the needs and best practices to work with this community are needed to ensure a successful roll out and implementation of ED PrEP to them.

INTRODUCTION

The annual incidence of HIV in the US has consistently been between 30,000 to 40,000 new cases per year since 2011 (1, 2), despite the wide availability of successful prevention options, like preexposure prophylaxis (PrEP), which has been approved for use since 2012. Oral PrEP has a United States Preventive Services Task Force (USPSTF) grade A recommendation such that it provides near-universal (i.e., 99%) protection with proper adherence (3–6) and it is available in various modalities (i.e., oral formulation since 2012, injectable formulation since 2022, and topical form since 2023) and pharmacological formulations (7–9) ) – though only oral formulation has the grading currently, and topical form is unavailable in the US. Recent estimates suggest that approximately 350,000 PrEP initiations have taken place in the US since 2012 (8); however, this number represents less than one-third of the estimated number of people standing to benefit from PrEP (10) and does not account for improper adherence or PrEP discontinuation.

Racial, sexual, and gender minority communities bear a disproportionate risk of acquiring HIV in the US, men who have sex with men (MSM), for example, account for over 65% of new annual HIV infections (1, 11). Moreover, uptake of PrEP is disproportionally lower among Latinos and Black people (12). Among the many behaviors associated with increased risk for HIV acquisition, the use of methamphetamine (i.e., Crystal Meth) stands out as a major driver of HIV incidence, with one 2020 U.S. national cohort of MSM and trans people who have sex with men reporting over one-third of seroconversions to be among individuals who reported persistent crystal meth use (CM use) (13) (defined as reported use in the 3 months prior to enrollment and continued use during the first year of follow-up). CM use increases sexual libido and reduces inhibitions—meaning it makes people more interested in having sex, often over extended periods of time, with multiple partners, while also reducing inhibitions to take action to protect one’s health (e.g., such as using a condom). CM use has been associated with increased condomless anal sex (CAS) acts, changes in rectal functions, and catalysis of HIV infection by activation of rectal cytokines, that significantly increase the opportunity for HIV infection to take place (14–20). CM can cause irritation and inflammation in the rectal mucosa, which can lead to the breakdown of the mucosal barrier, facilitating the virus entering the bloodstream. Furthermore, the impact of CM in immune cells present in the rectal mucosa may increase the number of CD4 T Cells (i.e., cells targeted by the HIV virus), which can lead to a favorable environment for HIV replication to take place (14–20). The association of CM use with infection of rectal mucosa cells has been proposed as one of the mechanisms for the increased risk of HIV faced by MSM communities (16). Efforts to achieve equity in HIV prevention and care are, therefore, innately associated with attending to the needs of the community who uses CM. Identifying opportunities to support PrEP candidates who engage in CM use is a key component of a comprehensive national HIV prevention plan.

The use of CM has been increasing in the recent past, and that surge has been particularly acute in Black and Brown MSM communities (21–24). Though the reasons for this resurgence are unknown, researchers have associated CM use with sexuality and sexual coping, as a way to deal with other stress (25). The association between PrEP adherence and the use of stimulants (e.g., CM) is complex and intricate. Although there are growing concerns that using stimulants may limit one’s ability to maintain a routine that would allow for daily PrEP compliance (26, 27), there is evidence that PrEP initiation among MSM who used CM has been comparable to their peers who did not use CM (28–36). Nevertheless, empirical studies have pointed to the many challenges MSM who use CM face adhering to the daily PrEP routine (31, 37, 38), increasing the odds of discontinuation or failure. It is possible that individuals can identify their HIV prevention needs and initiate PrEP, but the available options may not support their specific needs (e.g., if daily PrEP is the only option). A 2015 study, for example, found that the odds of repeating post-exposure prophylaxis (PEP) prescriptions were 5-fold in participants who reported CM use (39) – which underscores the need for more options that can be taken sporadically or, at least, in a simpler form. Interventions that are shorter-term and can be safely replicated are a potential avenue for improving uptake and adherence of PrEP in communities using CM. Because of concerns about behavioral inconsistencies and regimen adherence, focusing on supportive interventions and complimentary services may be essential to ensure that interventions will deliver positive results for this community.

In 2021, new clinical guidelines for PrEP were released in the US containing a provision which allows for off-label prescription of event-driven PrEP (ED PrEP) at a medical provider’s discretion (40). ED PrEP (also known as PrEP 2-1-1 and on-demand PrEP) is a method that has been approved and supported by the World Health Organization since 2019 (41), with countries having implemented it successfully (42); current recommendations involve taking two 300 mg TDF/200 mg FTC-formulation PrEP (i.e., Truvada, generic PrEP) doses between 2 to 24 hours prior to sexual activity, and then 1 pill 24 hours later, and another 48 hours later (24 hours after the last pill). ED PrEP presents a straightforward way to expand PrEP protections and uptake nationally, for eligible people, by increasing the number of PrEP options and reaching out populations who may differ from traditional daily PrEP populations (e.g., those who struggle with daily PrEP adherence). It is possible that this method would align better with the needs of individuals who use CM, given it is more sporadic and can be aligned with a pre-planned activity (e.g., use CM), however much remains unknown about ED PrEP implementation efforts in the US and its compatibility with the needs of those who use CM. To this end, the following study, using the screening instrument of a large study targeting individuals who use CM, will assess the association between CM use with awareness and interest in ED PrEP among HIV negative, and those with unknown serostatus cis males and transgender people.

METHODS

About the study

Data used for our study comes from the screening questionnaire of PrEP Readiness Interventions for Supporting Motivation (PRISM), a randomized controlled trial testing the feasibility, acceptability, and preliminary effectiveness of distinct combinations of telehealth motivational interviewing and contingency management in sexual minority men who use stimulants, such as methamphetamine, and that are not engaged in PrEP.

Participants were recruited using geo-located ads on men-seeking-men and queer social networking applications across the United States from May 2021 to December 2022. Those who saw the study’s national ads clicked on the link which took them to a screener consent and screener questionnaire that assessed the following inclusion criteria: 1) being 18 years of age or older; 2) identifying as a cisgender man; 3) reporting anal sex with a man in the past 6 months; 4) reporting using methamphetamine, powder cocaine, or crack-cocaine in the past 3 months; 5) having an HIV-negative or unknown serostatus; 6) meeting the original 2017 CDC criteria for PrEP eligibility (40) ; and 7) not currently being prescribed PrEP. Additionally, participants were asked about Event-driven PrEP (ED PrEP) awareness, interests, and previous experiences. These variables represent the outcomes explored in our current study. Our study used only the screening assessment questionnaire, which was conducted in English. Full details of the study procedures have been described elsewhere (43), participants were not compensated for the screening survey. For the present analysis, we analyzed data from 1,201 screening candidates who reported being HIV-negative or having an unknown serostatus, male assigned at birth and having never used ED PrEP. Participants were informed of the study procedures, and use of data during the consent process, which each participant was required to sign regardless of eligibility to the final study. The overall study was approved by the University of Miami Internal Review Board.

Analytical Variables

Our choice of analytical variables was informed by the limited content of the dataset, and factors that are significant for understanding PrEP uptake and related behaviors in the US, such as demographics and behavioral information. We include demographic, sexual behavior, and practices variables that are associated with increased the risk for HIV acquisition. Additionally, we analyzed awareness, and interest in ED PrEP, which were the main outcome variables of the study.

Demographics, PrEP use and knowledge, and behavioral factors

Participants were categorized by age into four groups (≤24, 25-29, 30-39, ≥40 years) and by ethno-racial identity as white, Black, Latino, or multiracial/other, prioritizing Latino identity over Black race where applicable. Gender identity was grouped into cisgender males and transgender/non-binary (TGNB) people. Participants were also classified based on current PrEP use (on PrEP or not on PrEP) and recent STI diagnosis within the past 6 months (yes/no). Additional behavioral variables included whether participants had engaged in anal sex in the past 6 months (yes/no) and the average number of sex partners reported for the same period.

Substance use was assessed by asking participants if they had used opioids or crystal meth in the past 3 months (yes/no, for each). Engagement in sex work over the past 6 months was also reported (yes/no).

Regarding event-driven PrEP (ED PrEP), participants’ awareness was measured by asking if they had ever heard of ED PrEP, also known as PrEP 2-1-1 or PrEP on demand, and how much they knew about it. Responses ranged from “No, I’ve never heard of it” to “I know a lot about it” and were collapsed into two categories: No/Very Little and Some/A Lot. Interest in ED PrEP was gauged by presenting participants with a detailed explanation of the regimen, “which involves taking 2 PrEP pills 2 to 24 hours before sex, one pill 24 hours later, another pill 24 hours after that, and continuing daily until 2 sex-free days have passed”. No prompt about daily PrEP was provided at any moment. Participants then responded to the statement: “I would be interested in using PrEP 2-1-1,” using a Likert scale. For analysis, responses were collapsed into two categories: Disagree/Neutral and Agree.

Analytical Plan

Our analysis initiated with a bivariate analysis of the data stratified by recent CM use (i.e., in the past 3 months). For categorical variables, we conducted chi-square tests of independence, and for our continuous variable a t-test – we reported the tests estimates and their respective p-value. Though our dataset was limited, we south to include demographic variables associated with PrEP disparities, and behaviors that are associated with PrEP eligibility. For our regression analysis, we built two univariate log-binomial models, one predicting ED PrEP awareness (i.e., has heard of ED PrEP) and one predicting interested in ED PrEP; for both models recent CM use was the exposure variable. Next, we repeated the analysis building two adjusted models, which were controlled for age group, race/ethnicity, gender, PrEP use, positive STI diagnosis, anal sex, opioid use, and sex work. Adjusted models were constructed with the relevant outcome variable and all a priori variables loaded on the model. We set p < .05 as the threshold for statistical significance. All analysis were conducted using SAS 9.4 (44).

RESULTS

Sample Description

In total, our sample was comprised of n = 1201 diverse individuals who reported being HIV-negative or having an unknown serostatus. Table 1 provides a full description of our sample, which was 36% over 40 years old, and about 20% under 30 years old. Most participants (56%) were white, 24% were Latino, 9% were Black and the remaining were another race. Nearly one-tenth of our sample identified as trans or non-binary (9%). Knowledge and interest on ED PrEP were opposed, as our sample had low awareness and high interest - two-thirds (66%) reported having heard nothing or very little of the topic, and two-thirds (66%) reported interest in ED PrEP. Approximately one quarter of the sample were current PrEP users (23%), and nearly all (94%) said they had anal sex in the past 6 month. In total, 16% said they had an STI in the past 6 months, 12% used opioids in the past 3 months, and 25% said they participated in sex work, either paying or receiving payment, drugs or shelter in the past 6 months. Participants reported an average of ten sexual partners in the past 6 months. Over three-quarters of the sample (78%) reported recent crystal meth use.

Table 1.

Demographics, behavioral, sexual practices, and PrEP-related sample description

	CM use in past 3 month
			Yes	%	No	%	Chi-square test	p -value
Sample	1201		892	74.3%	309	25.7%
Age Group							101.26	<.0001
24 or less	77	6.4%	31	3.5%	48	15.5%
25-29	188	15.7%	111	12.4%	89	28.8%
30-39	504	42.0%	278	31.2%	136	44.0%
40+	432	36.0%	372	41.7%	66	21.4%
Race/Ethnicity							20.26	0.0002
White	669	55.7%	517	58.0%	152	49.2%
Black	103	8.6%	64	7.2%	39	12.6%
Latino	288	24.0%	197	22.1%	91	29.4%
Other/Multiracial	132	11.0%	108	12.1%	24	7.8%
Gender							0.56	0.45
Cisgender men	1095	91.2%	816	91.5%	279	90.3%
Trans- and/or non-binary person	104	8.7%	74	8.3%	30	9.7%
PrEP use							35.23	<.0001
on PrEP	272	22.6%	164	18.4%	108	35.0%
Not on PrEP	923	76.9%	722	80.9%	201	65.0%
STI in past 6 months							1.47	0.23
Yes	189	15.7%	147	16.5%	42	13.6%
No	1003	83.5%	738	82.7%	265	85.8%
Anal Sex in past 6 months							7.01	0.008
Yes	1126	93.8%	846	94.8%	280	90.6%
no	75	6.2%	46	5.2%	29	9.4%
Opioid Use in past 3-months							10.91	0.001
Yes	145	12.1%	124	13.9%	21	6.8%
No	1056	87.9%	768	86.1%	288	93.2%
Sex Work in past 6 months							36.76	< .0001
Yes	302	25.1%	264	29.6%	38	12.3%
No	893	74.4%	623	69.8%	270	87.4%
Heard of ED-PrEP							8.75	0.003
No or very little	790	65.8%	608	68.2%	182	58.9%
some or a lot	411	34.2%	284	31.8%	127	41.1%
Interrested in ED-PrEP							8.65	0.003
No or neutral	404	33.6%	279	31.3%	125	40.5%
Yes	797	66.4%	613	68.7%	184	59.5%
Continuous variable	mean	SD	mean	SD	mean	SD	t-test
Average # of partners in past 6 months**	10.6	19.6	11.9	22.2	7.1	10.10	−5.11	<0.0001

bolded numbers indicate statistical significance at alpha = 0.05

Participants who reported recent CM use significantly differed from those who did not use CM in several aspects. Individuals who reported CM use were significantly older with over 40% being over 40 years old, as opposed to 21% of the non-CM use participants (chi-square= 101.26; p-value = <.0001). CM-use was more common among white participants (58% vs 49%), and those who reported other races (12% vs 8%; chi-square= 20.26; p-value = 0.0002). PrEP use was significantly less common in participants reporting recent CM use (81% vs 65% not on PrEP, chi-square= 35.23; p-value = <.0001), though they were significantly more likely to report anal sex in the past 6 month (95% vs 91%, chi-square= 7.01; p-value = 0.008) with more partners on average (12 vs 7 partners, t-test = −5.11; p-value = <0.0001). Additionally, Participants who reported recent CM use were twice as likely to report opioid use in the past 3 months (14% vs 7%, chi-square= 10.91; p-value = 0.001), as well as have participated in sex work in the past 6 months (30% vs 12%, chi-square= 36.76; p-value =< 0.0001). With respect to ED PrEP, a higher percentage of participants who recently used CM were unaware or knew little about PrEP, compared to those who had not recently used CM (68% vs 59%, chi-square= 8.75; p-value =< 0.0031), but a higher percentage of recent CM users were interested in ED PrEP (69% vs 59%, chi-square= 8.65; p-value =< 0.0033).

Our log-binomial regression confirmed that recent CM use was, in fact, a significant predictor of participants awareness and interest in ED PrEP – full results are reported on Table 2. Participants who recently used CM were less likely to know of ED PrEP, after accounting for demographic and HIV-related behaviors than their counterparts (aPR = 0.83, 95% CI 0.69 – 0.99). Conversely, participants who reported recent CM use were 12% more likely to be interested in ED PrEP than those who did not report any CM use, after accounting for demographic and HIV-related behaviors (aPR = 1.12, 95% CI 1.01 – 1.25).

Table 2.

Log-binomial models predicting awareness and interest in ED PrEP among those who reported CM use

	ED PrEP Awareness (i.e., has heard of ED PrEP)						Interested in ED PrEP
Models	Prevalence Ratio	95% CI		aPR	95%CI		PR	95% CI		aPR	95%CI
Meth Use past 3 months (ref = no)	0.77	0.66	0.91	0.83	0.69	0.99	1.15	1.04	1.28	1.12	1.01	1.25
Age Group (ref =30-39)
24 or less				0.76	0.53	1.10				0.98	0.82	1.18
25-29				1.05	0.86	1.29				0.91	0.80	1.04
40+				0.74	0.61	0.90				0.99	0.91	1.08
Race/Ethnicity (Ref= White)
Black				0.87	0.63	1.20				0.98	0.82	1.18
Latino				1.19	1.00	1.42				1.09	0.96	1.25
Other/Multiracial				0.98	0.75	1.28				0.98	0.89	1.08
Gender (ref = Cis)
Trans- and/or non-binary person				1.04	0.79	1.36				1.01	0.88	1.16
PrEP use (ref = On PrEP)
Not on PrEP				0.97	0.80	1.17				1.2	1.07	1.34
STI in past 6 months (ref = no)
Yes				0.94	0.75	1.18				0.87	0.76	0.99
Anal Sex in past 6 months (ref = no)
Yes				1.27	0.88	1.83				1.08	0.9	1.29
Opioid Use in past 3 months (ref = no)
Yes				0.92	0.76	1.12				1.04	0.95	1.14
Sex Work in past 6 months (ref = no)
Yes				0.89	0.68	1.16				0.99	0.88	1.12

DISCUSSION

We surveyed a large sample of HIV-negative and unknown status cis men and trans people at increased risk for HIV acquisition – 75% reported recent CM use, and only 22% were currently taking PrEP– about their knowledge and interest in ED PrEP. We found that participants who reported recent CM use knew less about ED PrEP but displayed greater interest in this PrEP modality than their counterparts. There were clear demographic and behavioral differences between our participants that are worth noting, as we seek to investigate characteristics and behavioral patterns that can elicit interventions to support PrEP choice and use overall. Given the disproportionally high incidence of HIV in individuals who use CM, understanding their preferences for PrEP modalities, like ED PrEP, presents some of the clearest pathways to moving forward and increasing PrEP uptake and use in the US.

Awareness of ED PrEP was lower in participants who reported recent CM use, and our regression analysis indicated that demographic characteristics were also contributing to this effect. Individuals 40 years and older were less likely to be aware of ED PrEP when compared to those between 30 and 39 years old; in contrast Latino participants seemed to have greater awareness than white participants in our adjusted regression analysis. Demographic disparities bring about the importance of ensuring equal access to the information across all the diversity that makes up our communities. This includes ensuring that materials and tools are representative of the community, from the characters depicted in materials to the modes and formats of communication. On the other hand, CM use was associated with greater interest in ED PrEP, and this association was influenced by behavioral variables. Our analysis showed that participants who were not using daily PrEP were more likely to be interested in ED PrEP. Similarly, participants who had a recent STI were less likely to be interested in ED PrEP, which can denote that their behavior is better suited for daily PrEP (45). Indeed, our findings seem to confirm our previous research indicating the importance of a person-centered approach towards PrEP choice (46). Here, participants reviewed a prompt about ED PrEP, judged it against their behavior, and indicated their interest regardless of their demographics. We observed the same outcome when investigating a sexual health clinic sample of PrEP users in 2019 (46).

Although we found an association between interest in ED PrEP and CM use, in practice there are significant concerns best practices for rolling it out to the community, particularly those who use stimulants. First, there is evidence that CM use is detrimental to PrEP adherence (31, 37, 38), which may be the reason why some in our sample were drawn to ED PrEP. However, the same concern is valid when considering the rigid adherence and sequential requirements of ED PrEP (i.e., the 2-1-1 sequence). While there is a natural inclination towards timing the initial dosing (i.e., two pills 2 – 24 hours prior sexual activity) with CM use behavior, the following doses are at risk of being forgotten or skipped during an episode of CM use, which could span several days of continuous use, without sleep. Additionally, we continue to have limited systems to deliver PrEP to those who need it the most. With few limited examples (47), PrEP care still requires attendance of medical appointments, and financial worries (i.e., coverage, patient assistance programs, lab payments) (48), which pose a threat to communities facing marginalization like those who use CM. Funding and technical support are needed to ensure community-based organizations are well equipped to deliver this care. Moreover, expanding options for PrEP initiation to other types of health professionals and community health workers provides another set of opportunities to develop PrEP delivery and care systems.

Limitations

There are several limitations that must be considered when reviewing our findings. Our sample, though large and diverse, is not a representative sample of individuals who use CM, nor all individuals facing increased risk for HIV infection. The cross-sectional design employed in our analysis is representative of a snapshot in time, which may not be representative of the current state of efforts to implement and offer ED PrEP in the US. Our use of a screening dataset containing self-reported data can be associated with social desirability bias, or answering questions in a way the satisfies the current norms. Using self-administered surveys, such as the ones in this study, is one way to mitigate this type of bias (49). Additionally, we were constrained by the limited number of variables and categories that were contained in the screening survey. The use of ED PrEP has only been validated and studied for sexual risk among cisgender MSM engaging in anal sex, and therefore it is possible that people engaging in CM use via intravenous drug use may not be conferred the same degree of protection. In our analysis, we did not have access to the mode of use of each participant, and therefore could not control for eligibility for ED PrEP based on method of CM use. Lastly, there are several variables that are important to consider when researching HIV prevention that were not available for our analysis, such as geographic location, access to health care, and other behavioral variables.

CONCLUSION

Among the many behaviors that increase the risk of acquiring HIV, CM use stands out as one of the major drivers of seroconversions in the US. Opportunities to expand PrEP uptake and improve adherence among individuals who report CM use are essential to significantly impact the HIV epidemic. ED PrEP is a PrEP dosage that has the potential to benefit this community, however they must know about and be able to access it. We found that individuals who reported CM use in our study were more unaware of ED PrEP but showed greater interest in this modality of PrEP – indicating some opportunity to explore implementation strategies. Strategies to better advertise the benefits of this modality, tools to support potential users, and delivery systems that meet individual needs are some of the immediate actions that ensure greater access and uptake of ED PrEP and HIV prevention overall. Continued research on the needs and best practices to work with this community are needed to ensure a successful roll out and implementation of ED PrEP.