The protocol involves a type I hybrid implementation trial design [53], where we pilot test the NP-led iRaPID program. The study is a 2-arm RCT that examines the feasibility and acceptability of the program among people who inject drugs and clinical stakeholders. In the process, we can provide a preliminary estimate of the efficacy of PrEP and MOUD uptake by comparing the iRaPID program against treatment as usual (TAU) among HIV-negative people who inject drugs. We hypothesize that the iRaPID program will be more efficacious than will TAU on PrEP and MOUD uptake and adherence.

In this type I hybrid implementation trial design, we collect process measures to inform future implementation efforts. We will explore potential patient- and provider-level barriers and facilitators of the program regarding its implementation in real-world settings. More specifically, we will assess at both these levels the overall satisfaction, perceived utility, and relevance of each intervention component; determine the relevant needs of the target population (ie, people who inject drugs), thereby delineating intervention characteristics that address those needs; and explore the barriers to implementation of the iRaPID program, such as logistical barriers and time and resource constraints. Finally, changes needed to accommodate same-day coprescription of PrEP and MOUD will be established, along with the resources and structural changes necessary for the successful implementation of the program.

The institutional review board at Yale University approved this protocol (#2000028740) with an institutional reliance agreement with the University of Connecticut. This study is registered at ClinicalTrials.gov (NCT04531670).

This study is being conducted at the New Haven Syringe Service Program (NHSSP) in Connecticut, the first SSP in the United States (established 1986). With steadily high-ranking and rising fatal and nonfatal accidental overdose rates over the past few years, New Haven continues to bear the detrimental impacts of a severe opioid crisis and reflects the nationwide picture of a twin opioid and HIV epidemic, with a high HIV prevalence among people who inject drugs in the city [54,55]. The NHSSP offers services beyond New Haven to exurban and rural communities and integrated medical services through the Community Health Care Van, a 40-foot mobile medical clinic, and minivans that provide personalized services [56-60].

Based on our previous research experience [69-72], we are using several strategies to maximize recruitment and minimize attrition rates. Our recruitment strategies include community-based outreach (eg, through flyers and public advertisements), cross-organizational collaborations, and referrals from harm reduction services such as SSPs and mobile clinics. Moreover, the research team routinely meets with the community-based stakeholders (eg, clinical team members, counselors at the MMP, and staff at the SSPs) to ensure proper screening of participants and the smooth function and operation of all study components.

Strategies to promote retention include rapid enrollment, thorough explanation of study requirements, integration of the research program within community-based clinical and nonclinical settings (eg, SSPs, mobile clinics, addiction treatment centers), close monitoring of participants' clinical status, and accessibility of study staff to patients for questions and problems. Participant locator forms, which include name, address, phone number, and family or friend contact, are collected and updated at each visit. Members of the research staff call or message each participant (according to their previously stated preferred contact method) 1 week and 1 day before the date of their visit. We also issue appointment cards at each visit for subsequent ones. Furthermore, participants are compensated based on the time and effort required to complete the assessments based on the market rate, which has also been an essential retention strategy.

The study will assess the feasibility, acceptability, and preliminary efficacy of the iRaPID intervention using a range of instruments administered at various time points throughout the study. The feasibility and acceptability of the program will be evaluated using both quantitative (in-depth interview) and qualitative (one-to-one interview) mechanisms. Data collected include the following: a quantitative assessment of process indicators, standardized acceptability measures collected through quantitative interviews, and measures of fidelity gauged through implementation checklists. Feasibility will be assessed by quantitative process indicators collected by the research staff, including the number of participants screened, recruited, randomized, retained, and adherent to treatment. Acceptability of the intervention will include a 10-item acceptability rating profile and an intervention fidelity assessment. The acceptability profile [73] will be collected through in-depth quantitative interviews at each follow-up point. We will also examine participants' views on acceptability, areas of perceived usefulness of the program, and their confidence in starting PrEP and MOUD. Ultimately, intervention fidelity will be collected using an implementation checklist specific for each part of the program (ie, baseline visit, safety check, follow-up, and clinical visit on day 30), which NPs will complete, documenting the activities covered in each program domain.

We will also estimate the preliminary efficacy of PrEP and MOUD uptake in this pilot RCT of the iRaPID intervention versus TAU (primary outcome). This will be determined by assessing PrEP and MOUD uptake (ie, current use). For those who initiate PrEP, we will also evaluate the time to PrEP initiation, along with adherence and persistence on PrEP, as part of the secondary outcome. Time to PrEP initiation will be calculated by recording the number of days between the first encounter with the NP or health care provider and the day of initiation of PrEP, validated by the pharmacy PrEP pick-up date. We will measure PrEP adherence using the visual analog scale [74] and confirm with dried blood spot testing [75-77]. Persistence on PrEP will be measured by assessing pharmacy data, including both refill (if refilled within 30 days after exhausting PrEP from previous fill or not) and pick-up information. Given the importance of moderating factors on the effect of efficacy, we will measure individual (eg, sociodemographic, sexually transmitted infection, drug use, depression), social (eg, social support), and structural (eg, stigma, physician distrust) factors at each in-depth interview.

Feasibility will be assessed through the analysis of data collected by the research team, including the number of participants screened and enrolled per month, the proportion of eligible participants who enroll in the study, the treatment-specific proportion of participants completing follow-up visits, rates of adherence to the intervention protocol, and fidelity of implementation measured by the percentage of domains captured by the NPs at each time point. Acceptability analysis will be based on descriptive statistics from the acceptability measures, such as simple means and percentages between treatment arms, and thematic analysis of qualitative data collected in postimplementation focus groups.

Meanwhile, preliminary efficacy analysis will assess the hypothesis that the iRaPID intervention will perform better than TAU over time using a primary outcome (ie, PrEP uptake) and secondary outcomes (ie, time to PrEP initiation, PrEP adherence and persistence). We will first test baseline characteristics for homogeneity between treatment arms using an independent-samples t test or Wilcoxon rank sum test (if unequal variances are assessed) for continuous variables and chi-square tests or Fisher exact tests (if any small cell sizes) for categorical variables. This analysis of baseline characteristics will be used to determine significantly different factors to include in the final model for adjustment. To assess our hypotheses relating to preliminary efficacy, we will use a generalized linear mixed model [78] with random subject effects to account for the correlation in repeated measurements that occur within subjects. Treatment assignment, time, and the interaction between time and treatment assignment, including confounders such as sociodemographic characteristics and prior PrEP or MOUD engagement, will be included as covariates. The proportion of participants that initiate PrEP will be estimated and compared using the linear contrast statement in SAS PROC GLIMMIX (SAS Institute). Similar analyses will be conducted for other outcomes, including MOUD uptake, time to PrEP initiation, optimal adherence to PrEP, and PrEP persistence.

This study aims to test the feasibility and acceptability of the iRaPID program and obtain preliminary estimates of potential effects on HIV prevention outcomes among people who inject drugs. Previous research has shown that pilot studies of 20 to 30 participants per arm are considered adequate to meet proposed study aims similar to this study [79,80]. Our sample size of 50 participants would be ideal for detecting a moderate treatment effect and informing a future RCT. The recruitment of this sample size is feasible based on our formative work.

As previously mentioned, we are using a type I hybrid implementation trial design, where we will pilot test the NP-led iRaPID program while exploring multilevel implementation factors for future refinement and adoption. As such, we will conduct open-ended interviews with iRaPID participants (n=20) and relevant stakeholders (n=10), including recruitment staff, clinical providers, and administrators at the participating clinic.

We will administer a process measure to assess the overall satisfaction and perceived utility of each intervention component regarding organization-level factors (eg, perceived relevance of intervention components and characteristics to target population needs, the usefulness of the intervention to the organization, and barriers to intervention implementation as designed). These questions will elicit feedback about the potential barriers and facilitators to implementing the iRaPID program—as currently designed—regarding issues ranging from specific intervention components to the more general organizational dynamics (eg., time and resource constraints). The process evaluation will provide a nuanced understanding of the intervention effects, barriers, and facilitators to the intervention implementation and refinement needed to maximize implementation success in a real-world setting. Based on this feedback, the iRaPID program will then be adjusted and adapted for future implementation in various clinical settings.

This ongoing trial aims to test an NP-led integrated HIV prevention program for people who inject drugs that combines same-day coprescribing of PrEP and MOUD. This strategy addresses delayed initiation and low linkage to HIV prevention (PrEP) and substance use (MOUD) care in traditional models. We hypothesize that the iRaPID intervention will be feasible and acceptable among people who inject drugs and will prove to be more efficacious than the standard of care for PrEP and MOUD services. We also anticipate that the results and qualitative feedback from participants and stakeholders will inform the refinement of the iRaPID intervention for a future large-scale RCT.

Same-day access to HIV preventive care may be particularly crucial for people who inject drugs with MOUD as they remain a hard-to-reach group and have significantly higher rates of attrition and poor linkage to care. Since HIV acquisition risk persists during delays, timely PrEP and MOUD initiation are critical in at-risk populations. Individuals with streamlined care initiation may also experience enhanced self-efficacy, encouraging continued engagement. Hence, our results could impact local and international PrEP and MOUD scale-up policies and promote engagement in HIV prevention services.

Given the risk of continued HIV outbreaks amidst the ongoing opioid crisis, scaling up PrEP alongside MOUD for people who inject drugs is crucial for HIV prevention. If successful, subsequent stand-alone tailored programs can be developed to support communities where opioid use is high and HIV outbreaks are likely, thereby promoting a transition to integrative care. Considering the limited access to and scale-up of harm-reduction strategies among people who inject drugs and the existing multilevel barriers to PrEP uptake, effective interventions are urgently needed to fill this critical gap. Given the significant growth in the waivered NP workforce, trained nurses are ideally situated to deliver this integrated care model. The iRaPID program represents a paradigm shift in HIV prevention and may be a particularly crucial strategy for people who inject drugs with OUD, as they remain an easy-to-miss subgroup with high rates of loss to follow-up and poor linkage to care.

The pilot trial has several limitations. Our study is restricted to 1 geographical location (Greater New Haven area, CT), potentially limiting the generalizability of our findings to all people who inject drugs across different geographic settings, particularly areas with fewer or absent SSPs. Further, the prescribing privileges of NPs have geographical disparities of their own, as they only have fully independent practice authority in 29 US commonwealths, states, and territories [81], which undermines nationwide program implementation in areas with physician shortages. Additionally, the study relies on self-reported measures of prior drug use, HIV-related risk behaviors, sexual behaviors, and some measures of primary outcomes (eg, adherence to PrEP using the visual analog scale). Impression management might occur to heighten protocol eligibility, which could potentially lead to the overreporting of risk behaviors during screening and subsequent discrepancies between data collected at different time points. Participants in the pilot trial include both out-of-treatment and in-treatment people who inject drugs (ie, those who were on BMT or MMT at the time of enrollment), which can affect treatment and adherence outcomes, especially as participants who were already on BMT or MMT at the time of enrollment did not undergo induction as compared to their out-of-treatment counterparts.

We also encountered many setbacks regarding participant recruitment due to the COVID-19 pandemic and the recurrent surge of cases in the area. Due to the nature of our program mandating in-person laboratory tests and assessments, ensuing research laboratory closures, and programmatic policies and changes that were developed to ensure research staff safety at the workplace (such as shift schedule changes and remote work) negatively affected recruitment efforts.

Although shutdown conditions were lifted, insightful strategies implemented by the Addiction Medicine Program at Yale during the COVID-19 pandemic and grasped by the research and clinical staff for future potential use included establishing safe pick-up and delivery of medication and setting up telehealth access for patients. Comparably, the centralization of PrEP dispensing to clinical settings and the in-person nature of its delivery prompted a recent call in the literature for the integration of telehealth to alleviate patient- and provider-level demands [82]. Recent studies, especially in the context of the COVID-19 pandemic, established the feasibility of PrEP and MOUD delivery among people who inject drugs via telehealth [82,83]. Integrating telehealth services within harm reduction settings (eg, SSPs) could not only boost access and address demands imposed on patients [84-86] but also relieve some of the excess pressures imposed on people who inject drugs specifically, including logistical barriers to in-person care and concerns related to stigma. Future directions in implementing the iRaPID program also include expanding access to newly available HIV prevention tools. Preliminary trials have shown that the new Federal Drug Administration–approved, long-acting injectable cabotegravir (given intramuscularly every 8 weeks) is likely to be superior to daily oral tenofovir disoproxil fumarate-emtricitabine (marketed under the name Truvada) in at-risk cisgender men who have sex with men [87]. With the advent of a new mode of administration for PrEP and its ensuing impact on HIV prevention strategies and adherence rates, the iRaPID program will likely have to be restructured to include a long-acting injectable option for participants.