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Awareness about and willingness to use long-acting injectable pre-exposure prophylaxis (LAI-PrEP) among people who use drugs

  • Roman Shrestha
    Correspondence
    Corresponding author at: 135 College Street, Suite 323, New Haven, CT 06510, USA.
    Affiliations
    Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA

    Institute for Collaboration on Health, Intervention, and Policy (InCHIP), University of Connecticut, Storrs, CT, USA
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  • Elizabeth E. DiDomizio
    Affiliations
    Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
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  • Rayne S. Kim
    Affiliations
    Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
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  • Frederick L. Altice
    Affiliations
    Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA

    Institute for Collaboration on Health, Intervention, and Policy (InCHIP), University of Connecticut, Storrs, CT, USA
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  • Jeffrey A. Wickersham
    Affiliations
    Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA

    Institute for Collaboration on Health, Intervention, and Policy (InCHIP), University of Connecticut, Storrs, CT, USA
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  • Michael M. Copenhaver
    Affiliations
    Institute for Collaboration on Health, Intervention, and Policy (InCHIP), University of Connecticut, Storrs, CT, USA

    Department of Allied Health Sciences, University of Connecticut, Storrs, CT, USA
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      Highlights

      • Long-acting injectable PrEP (LAI-PrEP) is currently being studied as an alternative form of oral PrEP for HIV prevention.
      • We examined the awareness and willingness to use LAI-PrEP among people who use drugs (PWUD).
      • While only 25.6% of participants were aware of LAI-PrEP, 73.5% were willing to use it, if made available.
      • Findings indicate the potential relevance of LAI-PrEP as an alternative to oral daily PrEP for HIV prevention in PWUD.

      Abstract

      In the Bangkok Tenofovir Study of oral pre-exposure prophylaxis (PrEP; TDF/FTC), adherence was poor. Long-acting injectable pre-exposure prophylaxis (LAI-PrEP) for HIV prevention may help overcome adherence challenges and is currently being tested in clinical trials, but not in people who use drugs (PWUD), an important key population that remains highly vulnerable to HIV. Since PWUD are not currently included in trials of LAI-PrEP, we sought to examine awareness about LAI-PrEP and factors associated with willingness to use LAI-PrEP in this understudied population. Participants included 234 HIV-negative people with opioid use disorder and self-reported HIV–risk behaviors recruited from Connecticut's largest addiction treatment program. We analyzed data from a standardized assessment using audio computer-assisted self-interview (ACASI) to assess the independent factors associated with willingness to use LAI-PrEP. While only 25.6% of participants were aware of LAI-PrEP (67.1% had heard of oral PrEP), after being given a description of it, 73.5% were willing to use it, if it were available. Participants were most commonly concerned about long-term side effects (76.9%) of LAI-PrEP. Independent correlates of willingness to use LAI-PrEP were female sex (aOR = 2.181, p = 0.018), recent visit to healthcare provider (aOR = 2.9, p = 0.023), high perceived risk of acquiring HIV (aOR = 3.3, p = 0.007), and having previously taken oral PrEP (aOR = 3.284, p = 0.017). Findings suggest that PWUD are highly interested in PrEP, especially in LAI-PrEP formulations. Our results indicate the potential for LAI-PrEP, as an alternative to oral daily PrEP, to be implemented into existing evidence-based HIV-based HIV prevention efforts that target high-risk PWUD.

      Keywords

      1. Introduction

      The HIV epidemic among people who use drugs (PWUD) in the U.S. has been declining, but amid a burgeoning opioid epidemic, communities are now increasingly vulnerable to and experiencing HIV outbreaks (
      • Jones C.M.
      • Christensen A.
      • Gladden R.M.
      Increases in prescription opioid injection abuse among treatment admissions in the United States, 2004–2013.
      ;
      • Mack K.A.
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      Illicit drug use, illicit drug use disorders, and drug overdose deaths in metropolitan and nonmetropolitan areas—United States.
      ;
      • Mars S.G.
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      “Every ‘never’ I ever said came true”: Transitions from opioid pills to heroin injecting.
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      ;
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      ;
      • Van Handel M.M.
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      County-level vulnerability assessment for rapid dissemination of HIV or HCV infections among persons who inject drugs, United States.
      ). Recent HIV outbreaks linked to drug injection have introduced HIV into networks of PWUD and, thus, reversed decades of HIV prevention successes. Pre-exposure prophylaxis (PrEP; TDF/FTC) is one promising approach for preventing HIV infection among at-risk groups and is recommended for high-risk PWUD as part of an integrated HIV prevention package (
      • CDC
      US public health service: Preexposure prophylaxis for the prevention of HIV infection in the United States—2017 update: A clinical practice guideline.
      ;
      • WHO
      Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV.
      ). PrEP for HIV prevention is especially useful when other evidence-based harm reduction programs for PWUD (e.g., syringe services programs, opioid agonist therapies) are either unavailable or poorly scaled-to-need. Oral PrEP, formulated as a single, daily pill, was first FDA-approved in 2012 following studies documenting its HIV prevention efficacy among key populations (e.g., PWUD, men who have sex with men; MSM) (
      • Baeten J.M.
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      Preexposure chemoprophylaxis for HIV prevention in men who have sex with men.
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      Thigpen , M. C., Kebaabetswe , P. M., Paxton , L. A., Smith , D. K., Rose , C. E., Segolodi , T. M., … Brooks , J. T. (2012). Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. New England Journal of Medicine, 367(5), 423–434. doi:doi:https://doi.org/10.1056/NEJMoa1110711.

      ;

      Van Damme , L., Corneli , A., Ahmed , K., Agot , K., Lombaard , J., Kapiga , S., … Taylor , D. (2012). Preexposure prophylaxis for HIV infection among African women. New England Journal of Medicine, 367(5), 411–422. doi:doi:https://doi.org/10.1056/NEJMoa1202614.

      ). Challenges with oral PrEP persist, including slow uptake and suboptimal adherence and persistence, indicating the need for new delivery mechanisms.
      Research is currently evaluating injectable formulations of antiretroviral drugs as candidate agents for use as long-acting injectable PrEP (LAI-PrEP) (

      Taylor, B. S., Tieu, H.-V., Jones, J., & Wilkin, T. J. (2019). CROI 2019: Advances in antiretroviral therapy. Topics in Antiviral Medicine, 27(1), 50–68. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/31137003, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550357/.

      ). LAI-PrEP is an attractive alternative to oral PrEP (

      Haberer, J. E., Bangsberg, D. R., Baeten, J. M., Curran, K., Koechlin, F., Amico, K. R., … Goicochea, P. (2015). Defining success with HIV pre-exposure prophylaxis: A prevention-effective adherence paradigm. AIDS (London, England), 29(11), 1277.

      ), especially among individuals for whom daily medication adherence is challenging. LAI-PrEP would be administered to patients as an intramuscular injection in a clinical setting under professional supervision. Although clinical trials remain in progress, early data suggest injections for LAI-PrEP would be spaced at similar time intervals as LAI-ART, which occur approximately every 8 weeks (
      • Delany-Moretlwe S.
      • Hosseinipour M.
      Evaluating the safety and efficacy of long-acting injectable cabotegravir compared to daily Oral TDF/FTC for pre-exposure prophylaxis in HIV-uninfected women.
      ;
      • Landovitz R.
      Safety and efficacy study of injectable cabotegravir compared to daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), for pre-exposure prophylaxis in HIV-uninfected cisgender men and transgender women who have sex with men.
      ). An appealing alternative, LAI-PrEP may be perceived as a simpler delivery system that can confer a consistent level of protection against HIV, unlike oral PrEP, for which efficacy can modulate greatly based on daily adherence (
      • Harper K.N.
      One step closer to ultra-long-acting PREP?.
      ;
      • Jackson A.
      • McGowan I.
      Long-acting rilpivirine for HIV prevention.
      ). LAI-PrEP may also overcome privacy concerns for people who store their medications in discrete locations or by placing them in inconspicuous containers, like vitamin bottles, to avoid stigmatization. It may also provide support for clinicians who lack confidence that PWUD can adhere to daily oral PrEP. Also, LAI-PrEP may be a more convenient option for PWUD patients, given the challenges of adhering to a daily pill-based regimen due to characteristics common among many PWUD, such as chronic substance use and neurocognitive impairment (
      • Huedo-Medina T.B.
      • Shrestha R.
      • Copenhaver M.
      Modeling a theory-based approach to examine the influence of neurocognitive impairment on HIV risk reduction behaviors among drug users in treatment.
      ;
      • Shrestha R.
      • Copenhaver M.
      The influence of neurocognitive impairment on HIV risk behaviors and intervention outcomes among high-risk substance users: A systematic review.
      ;
      • Vik P.W.
      • Cellucci T.
      • Jarchow A.
      • Hedt J.
      Cognitive impairment in substance abuse.
      ).
      There is a growing literature on the willingness to use oral PrEP (TDF/FTC) in PWUD and MSM (
      • Iniesta C.
      • Álvarez-del Arco D.
      • García-Sousa L.M.
      • Alejos B.
      • Díaz A.
      • Sanz N.
      • del Amo J.
      Awareness, knowledge, use, willingness to use and need of pre-exposure prophylaxis (PrEP) during World Gay Pride 2017.
      ;
      • Ojikutu B.O.
      • Bogart L.M.
      • Mayer K.H.
      • Stopka T.J.
      • Sullivan P.S.
      • Ransome Y.
      Spatial access and willingness to use pre-exposure prophylaxis among black/African American individuals in the United States: Cross-sectional survey.
      ;
      • Patrick R.
      • Forrest D.
      • Cardenas G.
      • Opoku J.
      • Magnus M.
      • Phillips 2nd, G.
      • Kuo I.
      Awareness, willingness, and use of pre-exposure prophylaxis among men who have sex with men in Washington, DC and Miami-Dade county, FL: National HIV behavioral surveillance, 2011 and 2014.
      ;
      • Ransome Y.
      • Bogart L.M.
      • Kawachi I.
      • Kaplan A.
      • Mayer K.H.
      • Ojikutu B.
      Area-level HIV risk and socioeconomic factors associated with willingness to use PrEP among Black people in the U.S. south.
      ;
      • Shrestha R.
      • Karki P.
      • Altice F.L.
      • Huedo-Medina T.B.
      • Meyer J.P.
      • Madden L.
      • Copenhaver M.
      Correlates of willingness to initiate pre-exposure prophylaxis and anticipation of practicing safer drug- and sex-related behaviors among high-risk drug users on methadone treatment.
      ;
      • Shrestha R.
      • Altice F.L.
      • Huedo-Medina T.B.
      • Karki P.
      • Copenhaver M.
      Willingness to use pre-exposure prophylaxis (PrEP): An empirical test of the information-motivation-behavioral skills (IMB) model among high-risk drug users in treatment.
      ). Studies on the preference toward using or willingness to use LAI-PrEP, however, have mostly been focused on MSM (
      • Cheng C.-Y.
      • Quaife M.
      • Eakle R.
      • Cabrera Escobar M.A.
      • Vickerman P.
      • Terris-Prestholt F.
      Determinants of heterosexual men’s demand for long-acting injectable pre-exposure prophylaxis (PrEP) for HIV in urban South Africa.
      ;
      • Kerrigan D.
      • Mantsios A.
      • Grant R.
      • Markowitz M.
      • Defechereux P.
      • La Mar M.
      • Murray M.
      Expanding the menu of HIV prevention options: A qualitative study of experiences with long-acting injectable cabotegravir as PrEP in the context of a phase II trial in the United States.
      ;
      • Meyers K.
      • Wu Y.
      • Qian H.
      • Sandfort T.
      • Huang X.
      • Xu J.
      • Shang H.
      Interest in long-acting injectable PrEP in a cohort of men who have sex with men in China.
      ;
      • Meyers K.
      • Wu Y.
      • Brill A.
      • Sandfort T.
      • Golub S.A.
      To switch or not to switch: Intentions to switch to injectable PrEP among gay and bisexual men with at least twelve months oral PrEP experience.
      ). Two qualitative studies in PWUD, however, showed high acceptability and relevance of LAI-PrEP to alleviate many of the barriers PWUD face in taking daily oral PrEP (
      • Allen S.T.
      • O’Rourke A.
      • White R.H.
      • Smith K.C.
      • Weir B.
      • Lucas G.M.
      • Grieb S.M.
      Barriers and facilitators to PrEP use among people who inject drugs in rural.
      ;
      • Biello K.B.
      • Edeza A.
      • Salhaney P.
      • Biancarelli D.L.
      • Mimiaga M.J.
      • Drainoni M.L.
      • Bazzi A.R.
      A missing perspective: Injectable pre-exposure prophylaxis for people who inject drugs.
      ;
      • Footer K.H.A.
      • Lim S.
      • Rael C.T.
      • Greene G.J.
      • Carballa-Diéguez A.
      • Giguere R.
      • Sherman S.G.
      Exploring new and existing PrEP modalities among female sex workers and women who inject drugs in a U.S. city.
      ). Quantitative studies examining the preferences for LAI-PrEP in PWUD, however, are lacking. Therefore, we sought to better understand awareness about and willingness to use LAI-PrEP as a potential modality for PrEP delivery in opioid-dependent PWUD. If LAI-PrEP proves to be effective and safe and becomes available in the U.S., understanding preferences for, and attitudes toward, its use among diverse at-risk populations will facilitate rapid scale-up and implementation.

      2. Methods

      2.1 Participants

      We recruited 234 individuals between July 2018 and October 2019. Individuals were eligible if they were: a) 18 years or older; b) self-reported HIV-uninfected or HIV status unknown; c) reported drug- (i.e., sharing of injection equipment) or sex-related (i.e., condomless sex) HIV risk in the past 6 months; d) met DSM-V criteria for opioid use disorder; e) on methadone maintenance treatment; and f) able to understand, speak, and read English. All patients were stabilized on methadone to treat opioid dependence.

      2.2 Study setting and procedures

      We recruited participants from Connecticut's largest addiction treatment setting (APT Foundation, Inc.), using clinic-based advertisements and flyers, word-of-mouth, and direct referral from counselors. Trained research assistants conducted all screening, enrollment, and interview activities in a private room. We screened a total of 294 individuals for eligibility, with 234 (79.6%) meeting inclusion criteria. The majority of ineligibility was due to low levels of HIV risk. Following informed consent, all participants completed a 45-min interview using audio computer-assisted self-interview (ACASI). We reimbursed all participants $25 for their time. The Investigational Review Board (IRB) at the University of Connecticut approved the study protocol, and we received approval from the board of APT Foundation, Inc.

      2.3 Measures

      We assessed participants for social and demographic characteristics, including age, sex, sexual orientation, ethnicity, marital status, educational status, employment status, annual income, homelessness, visit to a healthcare provider, and current methadone dose. We used standardized scales to assess depression (scores ≥16 indicative of moderate to severe depression on the 20-item Center for Epidemiological Studies Depression Scale [CES-D;
      • Radloff L.S.
      The CES-D scale: A self-report depression scale for research in the general population.
      ]); alcohol use disorders (AUD), using the validated 3-item Alcohol Use Disorders Identification Test for Consumption (AUDIT-C) (cut-offs ≥4 for men and ≥3 for women suggest the presence of an AUD) (
      • Bush K.
      • Kivlahan D.R.
      • McDonell M.B.
      • Fihn S.D.
      • Bradley K.A.
      The AUDIT alcohol consumption questions (AUDIT-C): An effective brief screening test for problem drinking. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol use disorders identification test.
      ); and an HIV risk assessment, adapted from NIDA's Risk Behavior Assessment (
      • Dowling-Guyer S.
      • Johnson M.E.
      • Fisher D.G.
      • Needle R.
      • Watters J.
      • Andersen M.
      • Tortu S.
      Reliability of drug users’ self-reported HIV risk behaviors and validity of self-reported recent drug use.
      ), to measure several aspects of HIV risk behaviors, including measurement of “any” high-risk behavior (sexual or drug-related) in the past 30 days. We measured perceived risk of acquiring HIV by a single question, “What do you think is your current risk of getting HIV?” with a dichotomized response of “low” or “high”. We assessed participants' satisfaction with previous HIV prevention methods using the question “Are you satisfied with your current method of HIV protection (e.g., condom use, clean needle use, daily oral PrEP use)?” with a dichotomized response of “yes” or “no”.
      We assessed participants' awareness (“Before participating in this survey, have you ever heard of daily oral PrEP for protection against HIV?”) and prior use of daily oral PrEP (“Have you ever used PrEP for protection against HIV?”) after we presented participants with a brief description of daily oral PrEP, administered daily per recommendations for PWUD.
      Following these, we asked participants about their awareness about LAI-PrEP (“Before participating in this survey, have you ever heard about the long-acting injectable PrEP for protection against HIV?”). We assessed their interest in LAI-PrEP after providing a brief description of LAI-PrEP. After reviewing the description, we asked participants to respond to a question “Suppose that LAI-PrEP is effective in preventing HIV when injected once every two months. Would you be interested in taking it?” To better understand the pattern of reasoning and decision making around interest in LAI-PrEP use, we explored participants' perceived concerns related to uptake of LAI-PrEP. We asked participants to indicate their agreement on statements listing concerns related to uptake of LAI-PrEP.

      2.4 Data analysis

      We performed all data analyses using IBM SPSS v. 25. We computed descriptive statistics, including frequencies and percentages for categorical variables, and means and standard deviations for continuous variables. We conducted bivariate logistic regression analyses between each independent covariate and the dependent variable, willingness to use LAI-PrEP. We then included covariates significant at p < .10 in a multivariate logistic regression on willingness to use LAI-PrEP. We evaluated estimates for statistical significance based on 95% confidence intervals using p < .05. We assessed the goodness-of-fit of the final multivariate model using the Hosmer and Lemeshow Test (
      • Hosmer D.W.
      • Hosmer T.
      • Le Cessie S.
      • Lemeshow S.
      A comparison of goodness-of-fit tests for the logistic regression model.
      ).

      3. Results

      3.1 Participant characteristics

      Table 1 shows participant characteristics, stratified by their willingness to use LAI-PrEP. Most participants were in their early 40s, with most (74.4%) meeting screening criteria for moderate to severe depression and 31.2% meeting screening criteria for AUD. Almost half of the participants (44.8%) reported injecting illicit drugs in the past 30 days. Of those who reported injecting in the last 30 days, 18.4% reported sharing injection equipment. Of those who reported engaging in sexual activities (e.g., anal, vaginal, or oral) in the past 30 days (71.4%), 39.3% reported having multiple sex partners, and only 6.0% reported always using condoms with their sexual partners. Almost two-thirds of participants (62.0%) reported being satisfied with their current method of HIV prevention (e.g., condom use, clean needle use, PrEP use) and 25.2% perceived that they were at high risk of acquiring HIV.
      Table 1Characteristics of participants and HIV transmission risk behaviors, stratified by willingness to use LAI-PrEP (Bivariate associations; N = 234).
      VariablesEntire sample

      (N = 234)
      Willingness to use LAI-PrEP
      LAI-PrEP: long-acting injectable PrEP.
      OR
      Odds ratio.
      (95% CI
      Confidence interval.
      )
      p
      Frequency%No

      (n = 62)
      Yes

      (n = 172)
      Characteristics of participants
       Age: Mean (±SD), years
      SD: standard deviation.
      42.7 (±10.2)41.5 (±10.6)43.1 (±10.0)1.016 (0.987, 1.046)0.283
       Sex
        Male11950.940 (17.1)79 (33.8)
        Female11549.122 (9.4)93 (39.7)2.140 (1.174, 3.902)0.013
       Heterosexual sexual orientation
        No4920.912 (5.1)37 (15.8)
        Yes18579.150 (21.4)135 (57.7)0.876 (0.423, 1.803)0.721
       Ethnicity
        Non-White8636.822 (9.4)64 (27.4)
        White14863.240 (17.1)108 (46.2)0.928 (0.507, 1.700)0.809
       Currently married/living with partner
        No18378.246 (19.7)137 (58.5)
        Yes5121.816 (6.8)35 (15.0)0.734 (0.372, 1.449)0.373
       High school graduate
        No6527.816 (6.8)49 (20.9)
        Yes16972.246 (19.7)123 (52.6)0.873 (0.452, 1.686)0.686
       Employed
        No20587.652 (22.2)153 (65.4)
        Yes2912.410 (4.3)19 (8.1)0.646 (0.282, 1.478)0.300
       Income level
        <$10,0006829.118 (7.7)50 (21.4)
        ≥$10,00016670.944 (18.8)122 (54.1)0.998 (0.527, 1.892)0.996
       Homeless
      In the past 12 months.
        No10344.026 (11.1)77 (32.9)
        Yes13156.036 (15.4)95 (40.6)0.891 (0.495, 1.603)0.700
       Visited healthcare provider
      In the past 12 months.
        No2711.512 (5.1)15 (6.4)
        Yes20788.550 (21.4)157 (67.1)2.512 (1.103, 5.721)0.028
       Methadone dose (mg): mean (±SD)
      SD: standard deviation.
      81.9 (±30.5)86.9 (±31.2)80.0 (±30.2)0.992 (0.983, 1.002)0.129
       Moderate to severe depression
        No6025.616 (6.8)44 (18.8)
        Yes17474.446 (19.7)128 (54.7)1.012 (0.521, 1.966)0.972
       Alcohol use disorder
        No16168.845 (19.2)116 (49.6)
        Yes7331.217 (7.3)56 (23.9)1.278 (0.672, 2.430)0.455
      HIV transmission risk behaviors
       Duration of drug use: mean (±SD
      SD: standard deviation.
      ) years
      18.4 (±10.1)18.3 (±10.3)18.4 (±10.1)1.001 (0.973, 1.031)0.926
       Used illicit drug
      In the past 30 days.
        No7431.622 (9.4)52 (22.2)
        Yes16068.440 (17.1)120 (51.3)1.269 (0.687, 2.344)0.446
       Injected any illicit drug
      In the past 30 days.
      n = 160
        No5523.515 (9.4)40 (25.0)
        Yes10544.925 (15.6)80 (80 (50.0)1.200 (0.570, 2.526)0.631
       Shared injection equipment
      In the past 30 days.
      n = 105
        No6226.515 (14.3)47 (44.8)
        Yes4318.410 (9.5)33 (31.4)1.053 (0.422, 2.631)0.912
       Engaged in sexual intercourse
      In the past 30 days.
        No6728.618 (7.7)49 (20.9)
        Yes16771.444 (18.8)123 (52.6)1.027 (0.541, 1.949)0.935
       Multiple sex partner
      In the past 30 days.
      n = 167
        No7532.123 (13.8)52 (31.1)
        Yes9239.321 (12.6)71 (42.5)1.495 (0.749, 2.985)0.254
       Consistent condom use
      In the past 30 days.
      n = 167
        No15365.441 (24.6)112 (67.1)
        Yes146.03 (1.8)11 (6.6)1.342 (0.356, 5.054)0.663
       Engaged in transactional sex
      In the past 30 days.
      n = 167
        No12151.736 (21.6)85 (50.9)
        Yes4619.78 (4.8)38 (22.8)2.012 (0.854, 4.736)0.110
       Sex under the influence of alcohol
      In the past 30 days.
      n = 167
        No9440.229 (17.4)65 (38.9)
        Yes7331.215 (9.0)58 (34.7)1.725 (0.842, 3.533)0.136
       Perceived risk of HIV transmission
        Low17574.854 (23.1)121 (51.7)
        High5925.28 (3.4)51 (21.8)2.845 (1.264, 6.404)0.012
       Satisfied with current method of HIV prevention
        No8938.022 (9.4)67 (28.6)
        Yes14562.040 (17.1)105 (44.9)0.862 (0.471, 1.577)0.630
      PrEP-specific variables
      PrEP: pre-exposure prophylaxis.
       Heard of oral PrEP
        No7732.928 (12.0)49 (20.9)
        Yes15767.134 (14.5)123 (52.6)2.067 (1.135, 3.766)0.018
       Ever used oral PrEP
        No17432.956 (23.9)118 (50.4)
        Yes6025.66 (2.6)54 (23.1)4.271 (1.734, 10.520)0.002
       Heard of LAI-PrEP
      LAI-PrEP: long-acting injectable PrEP.
        No17474.450 (21.4)124 (53.0)
        Yes6025.612 (5.1)48 (20.5)1.613 (0.791, 3.290)0.189
      a SD: standard deviation.
      b In the past 12 months.
      c In the past 30 days.
      d PrEP: pre-exposure prophylaxis.
      e LAI-PrEP: long-acting injectable PrEP.
      f Odds ratio.
      g Confidence interval.
      Among 234 participants (Fig. 1), 67.1% and 25.6% of participants reported having heard of oral PrEP and LAI-PrEP, respectively. Similarly, 25.6% had ever used oral PrEP for protection against HIV. Conversations with a healthcare provider (33.3%) and friends (29.9%) were reported as the top sources of PrEP knowledge. The most frequently reported concern about taking LAI-PrEP was the potential for long-term side effects (76.9%). Participants reported slightly less concern about the possibility that the efficacy of LAI-PrEP may wane (37.6%) or confer incomplete protection against HIV (33.3%), followed by the cost of LAI-PrEP (27.4%), fear or dislike of needles (24.8%), and having to return to the clinic for injection of LAI-PrEP every two months (20.5%).

      3.2 Willingness to use long-acting injectable PrEP

      More than two-thirds of participants (73.5%) reported that they would be willing to use LAI-PrEP to reduce their risk of HIV infection (Fig. 1). While Table 1 shows the results of the bivariate logistic regression of being willing to use LAI-PrEP, Table 2 shows the results of the multivariate logistic regression associated with this outcome. Factors independently correlated with willingness to use LAI-PrEP included female sex (aOR = 2.181, p = 0.018), being engaged in healthcare (aOR = 2.919, p = 0.023), having high perceived risk for HIV transmission (aOR = 3.255, p = 0.007), and having ever used oral PrEP previously (aOR = 3.284, p = 0.017). We found none of the variables to be co-linear with each other.
      Table 2Multivariate logistic regression models of factors associated with willingness to use LAI-PrEP (N = 234).
      VariablesWillingness to use LAI-PrEP
      LAI-PrEP: long-acting injectable PrEP.
      aOR
      aOR: adjusted odds ratio.
      95% CI
      CI: confidence interval.
      p
      Sex
       MaleRef
       Female2.1811.144, 4.1590.018
      Visited healthcare provider (last 12 months)
      In the past 12 months.
       NoRef
       Yes2.9191.156, 7.3700.023
      Perceived risk of HIV transmission
       LowRef
       High3.2551.372, 7.7210.007
      Heard of oral PrEP
      PrEP: pre-exposure prophylaxis.
       NoRef
       Yes1.2020.618, 2.3400.588
      Ever used oral PrEP
       NoRef
       Yes3.2841.242, 8.6840.017
      R2 = 0.180
      Hosmer and Lemeshow test: chi-square = 3.079; p = 0.929.
      a In the past 12 months.
      b PrEP: pre-exposure prophylaxis.
      c LAI-PrEP: long-acting injectable PrEP.
      d aOR: adjusted odds ratio.
      e CI: confidence interval.

      4. Discussion

      To our knowledge, this is the first quantitative survey study to evaluate the willingness to use LAI-PrEP for HIV prevention among PWUD. As the opioid crisis in the U.S. expands and HIV transmission outbreaks continue, the demand for PrEP in PWUD will likely increase. Clinicians, however, have not enthusiastically prescribed PrEP to PWUD, partially due to concerns of low adherence (
      • Calabrese S.
      • Ogburn D.
      • Edelman J.E.
      • Mayer K.
      • Magnus M.
      • Kershaw T.
      • Dovidio J.
      Provider biases against people who inject drugs in the context of PrEP clinical decision-making.
      ;
      • Shrestha R.
      • Altice F.
      • Karki P.
      • Copenhaver M.
      Developing an integrated, brief biobehavioral HIV prevention intervention for high-risk drug users in treatment: The process and outcome of formative research.
      ;
      • Spector A.Y.
      • Remien R.H.
      • Tross S.
      PrEP in substance abuse treatment: A qualitative study of treatment provider perspectives.
      ). Findings here suggest that there is suboptimal awareness of oral PrEP and very low awareness of LAI-PrEP among PWUD. Future studies should further evaluate the acceptability of LAI-PrEP in PWUD, including scale-up in the U.S., if available (K.
      • Biello K.B.
      • Bazzi A.R.
      • Mimiaga M.J.
      • Biancarelli D.L.
      • Edeza A.
      • Salhaney P.
      • Drainoni M.L.
      Perspectives on HIV pre-exposure prophylaxis (PrEP) utilization and related intervention needs among people who inject drugs.
      ;
      • Choopanya K.
      • Martin M.
      • Suntharasamai P.
      • Sangkum U.
      • Mock P.A.
      • Leethochawalit M.
      • Kittimunkong S.
      Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): A randomised, double-blind, placebo-controlled phase 3 trial.
      ).
      Despite that all participants in this sample reported injection and/or sexual risk behaviors, nearly two-thirds (62%) reported being satisfied with their current HIV prevention strategy. Considerable data point to this disconnect between risk-taking and perception (
      • Khawcharoenporn T.
      • Mongkolkaewsub S.
      • Naijitra C.
      • Khonphiern W.
      • Apisarnthanarak A.
      • Phanuphak N.
      HIV risk, risk perception and uptake of HIV testing and counseling among youth men who have sex with men attending a gay sauna.
      ;
      • MacKellar D.A.
      • Valleroy L.A.
      • Secura G.M.
      • Behel S.
      • Bingham T.
      • Celentano D.D.
      • Young Men’s Survey Study G.
      Unrecognized HIV infection, risk behaviors, and perceptions of risk among young men who have sex with men: Opportunities for advancing HIV prevention in the third decade of HIV/AIDS.
      ;
      • MacKellar D.A.
      • Valleroy L.A.
      • Secura G.M.
      • Behel S.
      • Bingham T.
      • Celentano D.D.
      • Young Men’s Survey Study, G
      Perceptions of lifetime risk and actual risk for acquiring HIV among young men who have sex with men.
      ;
      • Maughan-Brown B.
      • Venkataramani A.S.
      Accuracy and determinants of perceived HIV risk among young women in South Africa.
      ;
      • Seekaew P.
      • Pengnonyang S.
      • Jantarapakde J.
      • Meksena R.
      • Sungsing T.
      • Lujintanon S.
      • Phanuphak N.
      Discordance between self-perceived and actual risk of HIV infection among men who have sex with men and transgender women in Thailand: A cross-sectional assessment.
      ). After learning more about LAI-PrEP, a large proportion of PWUD were willing to use it, although they expressed concerns about its efficacy, safety, and cost. This is consistent with findings from qualitative interviews with PWUD in other settings, in which participants reported LAI-PrEP to have numerous adherence and logistical advantages over oral PrEP, which must be taken daily (
      • Allen S.T.
      • O’Rourke A.
      • White R.H.
      • Smith K.C.
      • Weir B.
      • Lucas G.M.
      • Grieb S.M.
      Barriers and facilitators to PrEP use among people who inject drugs in rural.
      ;
      • Biello K.B.
      • Edeza A.
      • Salhaney P.
      • Biancarelli D.L.
      • Mimiaga M.J.
      • Drainoni M.L.
      • Bazzi A.R.
      A missing perspective: Injectable pre-exposure prophylaxis for people who inject drugs.
      ;
      • Footer K.H.A.
      • Lim S.
      • Rael C.T.
      • Greene G.J.
      • Carballa-Diéguez A.
      • Giguere R.
      • Sherman S.G.
      Exploring new and existing PrEP modalities among female sex workers and women who inject drugs in a U.S. city.
      ).
      Not surprisingly, we found that those who had previously used oral PrEP were more likely to be willing to use LAI-PrEP; however, the awareness about PrEP, irrespective of the route, was not associated with the willingness to use LAI-PrEP. This may reflect that PWUD who have taken oral PrEP previously are generally satisfied with the concept of PrEP, or it could indicate that this group had wanted PrEP, but were dissatisfied with it as an oral formulation. This difference also supports findings from qualitative research that found PWUD perceived LAI-PrEP as being easier to adhere to relative to oral PrEP (
      • Allen S.T.
      • O’Rourke A.
      • White R.H.
      • Smith K.C.
      • Weir B.
      • Lucas G.M.
      • Grieb S.M.
      Barriers and facilitators to PrEP use among people who inject drugs in rural.
      ;
      • Biello K.B.
      • Edeza A.
      • Salhaney P.
      • Biancarelli D.L.
      • Mimiaga M.J.
      • Drainoni M.L.
      • Bazzi A.R.
      A missing perspective: Injectable pre-exposure prophylaxis for people who inject drugs.
      ;
      • Footer K.H.A.
      • Lim S.
      • Rael C.T.
      • Greene G.J.
      • Carballa-Diéguez A.
      • Giguere R.
      • Sherman S.G.
      Exploring new and existing PrEP modalities among female sex workers and women who inject drugs in a U.S. city.
      ). Other factors explored in other studies suggest that multilevel barriers to PrEP utilization in PWUD exist, including competing health priorities, stigma, and discrimination by healthcare providers who deem them unsuitable for PrEP and among other PWUD in their social network who perceive them as irresponsible and taking too many risks. Other barriers to PrEP utilization include suboptimal capacity for PrEP delivery for PWUD and interrupted care related to homelessness, transportation difficulties, and criminal justice involvement (
      • Biello K.B.
      • Bazzi A.R.
      • Mimiaga M.J.
      • Biancarelli D.L.
      • Edeza A.
      • Salhaney P.
      • Drainoni M.L.
      Perspectives on HIV pre-exposure prophylaxis (PrEP) utilization and related intervention needs among people who inject drugs.
      ;
      • Shrestha R.
      • Copenhaver M.
      Exploring the use of pre-exposure prophylaxis (PrEP) for HIV prevention among high-risk people who use drugs in treatment.
      ). Therefore, the availability of LAI-PrEP may be an attractive alternative for those interested in PrEP and may provide a new option for HIV prevention.
      It is important to note that female participants were significantly more willing to use LAI-PrEP than males. Females may have perceived injectable formulation, unlike an oral regimen, to provide sustained protection from HIV independent of individual behavior (e.g., daily pill-taking). From a biomedical perspective, this could be a game-changer because females must adhere to much higher levels of PrEP relative to males due to a higher adherence threshold of oral PrEP among females (
      • Cottrell M.L.
      • Yang K.H.
      • Prince H.M.A.
      • Sykes C.
      • White N.
      • Malone S.
      • Kashuba A.D.M.
      A translational pharmacology approach to predicting outcomes of preexposure prophylaxis against HIV in men and women using tenofovir disoproxil fumarate with or without emtricitabine.
      ;
      • Hendrix C.W.
      • Andrade A.
      • Bumpus N.N.
      • Kashuba A.D.
      • Marzinke M.A.
      • Moore A.
      • Patterson K.B.
      Dose frequency ranging pharmacokinetic study of tenofovir-emtricitabine after directly observed dosing in healthy volunteers to establish adherence benchmarks (HPTN 066).
      ;
      • Louissaint N.A.
      • Cao Y.-J.
      • Skipper P.L.
      • Liberman R.G.
      • Tannenbaum S.R.
      • Nimmagadda S.
      • Hendrix C.W.
      Single dose pharmacokinetics of oral tenofovir in plasma, peripheral blood mononuclear cells, colonic tissue, and vaginal tissue.
      ;

      Patterson, K. B., Prince, H. A., Kraft, E., Jenkins, A. J., Shaheen, N. J., Rooney, J. F., … Kashuba, A. D. M. (2011). Penetration of tenofovir and emtricitabine in mucosal tissues: Implications for prevention of HIV-1 transmission. Science Translational Medicine, 3(112), 112re114. doi:https://doi.org/10.1126/scitranslmed.3003174.

      ). Though it merits further exploration, evidence from the contraceptive literature shows several parallels with females' interest in LAI-PrEP. First, females have used long-acting contraception in a variety of formulations for decades, including oral, injectable, and patch. Second, women may find LAI-PrEP more appealing, as it may reduce the stigma that one has multiple sex partners because she takes oral PrEP medications. Previous studies have shown that women who have experienced intimate partner violence, which is frequently reported among female PWUD (
      • Meyer J.P.
      • Springer S.A.
      • Altice F.L.
      Substance abuse, violence, and HIV in women: A literature review of the syndemic.
      ), are more fearful of taking medications due to partner resistance (
      • Braksmajer A.
      • Senn T.E.
      • McMahon J.
      The potential of pre-exposure prophylaxis for women in violent relationships.
      ). Qualitative findings have suggested several pathways through which partner violence may cause short-term lapses in contraception adherence, including stress, being forced to leave the home, or a partner who steals pills (
      • Roberts S.T.
      • Haberer J.
      • Celum C.
      • Mugo N.
      • Ware N.C.
      • Cohen C.R.
      • Partners Pr E.P.S.T.
      Intimate partner violence and adherence to HIV pre-exposure prophylaxis (PrEP) in African women in HIV serodiscordant relationships: A prospective cohort study.
      ). LAI-PrEP may be able to help women to overcome many of the challenges of using oral PrEP, and to improve the PrEP care continuum for women who use drugs—a marginalized, at-risk, and understudied group.
      Future research should investigate whether those who are already engaged in healthcare are more likely to prefer LAI-PrEP. There is a longs history of mistrust between PWUD and clinicians (
      • Altice F.L.
      • Mostashari F.
      • Friedland G.H.
      Trust and the acceptance of and adherence to antiretroviral therapy.
      ;
      • Ostertag S.
      • Wright B.R.E.
      • Broadhead R.S.
      • Altice F.L.
      Trust and other characteristics associated with health care utilization by injection drug users.
      ), and it may be that those who engage in healthcare are most accepting of biomedical prevention, including new options. Notably, we recruited participants in the current study from an addiction treatment program, in which healthcare providers saw the participants regularly for their opioid use disorder. While participants in this study reported a high level of engagement with providers, mostly counselors, future research must focus on how clinicians can create an environment in which potential PrEP users can engage in dialogue with the clinicians. This includes communication around whether LAI-PrEP or oral PrEP is right for them in a given moment, particularly given the potential for healthcare-related stigma and discrimination, as well as medical mistrust that impedes access and uptake (;
      • Biello K.B.
      • Bazzi A.R.
      • Mimiaga M.J.
      • Biancarelli D.L.
      • Edeza A.
      • Salhaney P.
      • Drainoni M.L.
      Perspectives on HIV pre-exposure prophylaxis (PrEP) utilization and related intervention needs among people who inject drugs.
      ;
      • Shrestha R.
      • Copenhaver M.
      Exploring the use of pre-exposure prophylaxis (PrEP) for HIV prevention among high-risk people who use drugs in treatment.
      ). Although most participants in our study did not feel that attending LAI-PrEP appointments every two months would be a challenge, a clinician must navigate some concerns related to LAI-PrEP use (e.g., potential side effects and efficacy) during visits. As a cautionary note, studies of other long-acting treatments for alcohol or opioid use disorder show that PWUD often discontinue treatment after three months (
      • Makarenko J.
      • Pykalo I.
      • Mazhnaya A.
      • Marcus R.
      • Fillipovich S.
      • Dvoriak S.
      • Altice F.L.
      Treating opioid dependence with extended-release naltrexone (XR-NTX) in Ukraine: Feasibility and three-month outcomes.
      ;
      • Makarenko I.
      • Pykalo I.
      • Springer S.A.
      • et al.
      Treating opioid dependence with extended-release naltrexone (XR-NTX) in Ukraine: Feasibility and three-month outcomes.
      ;
      • Springer S.A.
      • Brown S.E.
      • Di Paola A.
      • Altice F.L.
      Correlates of retention on extended-release naltrexone among persons living with HIV infection transitioning to the community from the criminal justice system.
      ).
      It is important to note that individuals who stood to benefit the most from PrEP (i.e., those who perceived themselves to be at high risk for HIV acquisition) tended to be the most willing to use LAI-PrEP. This is consistent with prior studies among MSM (
      • Cheng C.-Y.
      • Quaife M.
      • Eakle R.
      • Cabrera Escobar M.A.
      • Vickerman P.
      • Terris-Prestholt F.
      Determinants of heterosexual men’s demand for long-acting injectable pre-exposure prophylaxis (PrEP) for HIV in urban South Africa.
      ;
      • Meyers K.
      • Wu Y.
      • Qian H.
      • Sandfort T.
      • Huang X.
      • Xu J.
      • Shang H.
      Interest in long-acting injectable PrEP in a cohort of men who have sex with men in China.
      ) as well as for oral PrEP (
      • Shrestha R.
      • Karki P.
      • Altice F.L.
      • Huedo-Medina T.B.
      • Meyer J.P.
      • Madden L.
      • Copenhaver M.
      Correlates of willingness to initiate pre-exposure prophylaxis and anticipation of practicing safer drug- and sex-related behaviors among high-risk drug users on methadone treatment.
      ). Our results suggest that participants are making a rational judgment about their risk levels when considering whether to use PrEP. This may indicate not only a concern about the risk of HIV infection but also a self-management response to their HIV risk behaviors, especially given that almost 40% of our sample reported not being satisfied with their current method(s) of HIV prevention. More research is needed, however, to better understand this finding, to understand participants' perceived and actual HIV risk, and to understand the implications of appropriate PrEP messaging in this subgroup of PWUD.
      When interpreting our findings, readers should consider certain limitations. Our study relied on cross-sectional data, restricting our ability to infer the causal directions underlying the observed associations. The use of self-reported measures may have resulted in participant underreporting of socially undesirable behaviors (e.g., sexual or drug-related risk behaviors) or inconsistent reporting (e.g., mental health) because of stigma or fear of judgment. However, this is unlikely given the high risks that this sample reported and our use of ACASI for data collection. Additionally, we screened the PWUD in this study specifically for substantial risk and all were enrolled in methadone maintenance; therefore, our findings may not be generalizable to PWUD in other settings. Notwithstanding these limitations, our results indicate high acceptability and potential relevance of LAI-PrEP as an alternative to oral daily PrEP for existing evidence-based HIV-based HIV prevention efforts that target high-risk PWUD.

      5. Conclusion

      Long-acting injectable pre-exposure prophylaxis (LAI-PrEP) may be an alternative to the oral form of PrEP currently prescribed to individuals at high-risk for HIV infection. PWUD are an important target population for HIV prevention and could greatly benefit from LAI-PrEP. If LAI-PrEP were found to be efficacious and it were provided for free, it could circumvent uptake and adherence challenges associated with daily oral PrEP, thereby reducing social disparities in HIV transmission in this underserved group. Unfortunately, the ongoing clinical trials to test the efficacy of LAI-PrEP do not target PWUD. The exclusion of this at-risk group from LAI-PrEP-related research and programmatic efforts represents a missed opportunity and indicates a vital avenue for future research.

      Acknowledgments

      The authors thank Brian Sibilio, Pramila Karki, and Julia Sharma for their contributions to this study.

      Source of funding

      This work was supported by grants from the National Institute on Drug Abuse for research (R01 DA032290 to MMC) and for career development (K01 DA051346 to RS; K24 DA017072 to FLA; K02 DA033139 to MMC; K01 DA038529 to JAW).

      Author statement

      Roman Shrestha: Conceptualization, Methodology, Resources, Formal analysis, Writing-Original draft preparation, Writing- Reviewing and Editing, Project administration. Elizabeth E. Didomizio: Conceptualization, Writing- Original draft preparation, Writing- Reviewing and Editing,. Rayne S. Kim: Conceptualization, Writing- Original draft preparation, Writing- Reviewing and Editing. Frederick L. Altice: Conceptualization, Writing- Reviewing and Editing, Supervision. Jeffrey A. Wickersham: Conceptualization, Writing- Reviewing and Editing. Michael M. Copenhaver: Conceptualization, Resources, Writing- Reviewing and Editing, Funding acquisition, Supervision.

      Declarations of competing interest

      None.

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