Nurse Practitioner–Led Integrated Rapid Access to HIV Prevention for People Who Inject Drugs (iRaPID): Protocol for a Pilot Randomized Controlled Trial

Background The ongoing volatile opioid epidemic remains a significant public health concern, alongside continued outbreaks of HIV and hepatitis C virus among people who inject drugs. The limited access to and scale-up of medications for opioid use disorder (MOUD) among people who inject drugs, coupled with multilevel barriers to pre-exposure prophylaxis (PrEP) uptake, makes it imperative to integrate evidence-based risk reduction and HIV prevention strategies in innovative ways. To address this need, we developed an integrated rapid access to HIV prevention program for people who inject drugs (iRaPID) that incorporates same-day PrEP and MOUD for this population. Objective The primary objective of this pilot study is to assess the feasibility and acceptability of the program and evaluate its preliminary efficacy on PrEP and MOUD uptake for a future randomized controlled trial (RCT). We also aim to explore information on the implementation of the program in a real-world setting using a type I hybrid implementation trial design. Methods Using a type I hybrid implementation trial design, we are pilot testing the nurse practitioner–led iRaPID program while exploring information on its implementation in a real-world setting. Specifically, we will assess the feasibility and acceptability of the iRaPID program and evaluate its preliminary efficacy on PrEP and MOUD uptake in a pilot RCT. The enrolled 50 people who inject drugs will be randomized (1:1) to either iRaPID or treatment as usual (TAU). Behavioral assessments will occur at baseline, and at 1, 3, and 6 months. Additionally, we will conduct a process evaluation of the delivery and implementation of the iRaPID program to collect information for future implementation. Results Recruitment began in July 2021 and was completed in August 2022. Data collection is planned through February 2023. The Institutional Review Boards at Yale University and the University of Connecticut approved this study (2000028740). Conclusions This prospective pilot study will test a nurse practitioner–led, integrated HIV prevention program that incorporates same-day PrEP and MOUD for people who inject drugs. This low-threshold protocol delivers integrated prevention via one-stop shopping under the direction of nurse practitioners. iRaPID seeks to overcome barriers to delayed PrEP and MOUD initiation, which is crucial for people who inject drugs who have had minimal access to evidence-based prevention. Trial Registration ClinicalTrials.gov NCT04531670; https://clinicaltrials.gov/ct2/show/NCT04531670 International Registered Report Identifier (IRRID) DERR1-10.2196/42585

1 R21 DA051934-01A1 3 PPAH SHRESTHA, R new differentiated care model of combined, same-day PrEP/OAT for PWID is well-suited to start with APNs. We, therefore, propose to develop and pilot test this model within an implementation science framework. The specific aims are to: 1) Aim 1: examine feasibility and acceptability among PWID and clinical stakeholders for an adapted APN-delivered, rapid HIV prevention program for PWID (iRaPID) that integrates same-day PrEP and OAT; and 2) Aim 2: estimate the preliminary efficacy of PrEP and OAT uptake in a pilot randomized controlled trial of the iRaPID vs. treatment as usual strategy in PWID without HIV. Together, these aims will address a wide gap in HIV prevention by addressing multilevel barriers to dispensing same-day combination prevention. Elements learned from a successful sameday PrEP/OAT model for PWID can guide future scale-up models that incorporate both APNs and physicians in urban and non-urban settings where resources are limited.

PUBLIC HEALTH RELEVANCE:
The opioid epidemic in the United States, especially the rise in injection drug use, necessitates the need for novel strategies to reduce the risk of HIV infection in people who inject drugs (PWID). The proposed research aims to jump-start the HIV prevention cascade by developing and pilot-testing a nurse-delivered, integrated rapid access to HIV prevention program for PWID (iRaPID) program that incorporates same-day access to pre-exposure prophylaxis (PrEP) and opiate agonist therapy (OAT). Findings will inform the development of innovative and tailored primary HIV prevention strategy to address co-occurring sexual and drug risk behaviors and to enhance the HIV prevention gap in PWID amid the ongoing opioid crisis.

CRITIQUE 1
Significance: 2 Investigator(s): 2 Innovation: 2 Approach: 4 Environment: 2 Overall Impact: This proposed study is to assess feasibility, acceptability and preliminary efficacy of an adapted APN-delivered, rapid HIV prevention program called iRaPID that integrates same-day PrEP and opioid agonist therapy (OAT) among people who inject drugs (PWID). The project has novel components, like the rapid PrEP + OAT starts at the same time to decrease attrition from screening to initiation among PWID and the use of advanced practice nurses for PrEP and OAT delivery to expand beyond physician prescription and delivery. The team is very well organized with support from Gilead to provide PrEP, if needed, and strong community collaborations ensuring the project will be feasible with high potential for success. This resubmission was responsive to the prior review but concerns around feasibility of this project in the given time frame remain high. There are some components of the proposal that could have been provided in more detail like the PrEP eligibility and plans for retention, which are very important in PrEP delivery and would be of considerable importance for this underserved population. Despite some remaining limitations, the project is innovative, high risk/reward, and meets a significant gap in the rollout of PrEP, which has almost entirely passed over people who inject drugs and could highly benefit from this important HIV prevention tool. Due to these reasons, enthusiasm for this proposal is high.

Strengths
• The scale up of PrEP among PWID is highly inadequate, despite the urgent need, and this proposal seeks to provide an immediate attempt to address this large gap in the PrEP scale up efforts. • Rapid PrEP delivery with OAT has the ancillary and potentially crucial benefit of preventing attrition in PrEP as PWID may be have increased motivation to maintain OUD treatment.

Weaknesses
• It is not clear that acceptability data are needed with PWID as there is evidence of acceptability of OAT and PrEP, and data cited by the team showing attrition from screening to PrEP initiation among PWID.
• Justification for focusing only on APNs seems to be a limiting factor to the impact of this proposal. Inclusion of physicians seems important and necessary given the current state of APN prescribing limitations in some states.
• Justification for OAT and PrEP integration needs more detail. If OAT and PrEP are both a problem, there may be a negative synergy when both are offered.

Strengths
• The team of investigators at Yale has a long and successful record of observational research and intervention research that are needed with PWID and in the existing community collaborations to make this project feasible and likely to be successful.

Weaknesses
• None Noted by Reviewer

Strengths
• Focus on rapid OAT and PrEP among PWID is novel and builds an efficiency that can optimize benefits for community members.

Weaknesses
• None Noted by Reviewer

Strengths
• Availability of PrEP access via the new Set, Ready, PrEP is an important historical improvement that will better facilitate PrEP access.
• Same day starts for PrEP is important and the right approach to increasing PrEP access.
• Strong plan for clinic visit checklist and important to fidelity checks.
• Established partnership with Gilead is important to ensure rapid starts for PWID interested and eligible to take PrEP.
• Seems like an implementation science approach where all participants receive intervention is appropriate given the team's data on attrition b/t screening and initiation of PrEP in prior research • If aim one does not show feasibility and acceptability, then the team will not have evidence to support moving forward • An important component of the formative work will be to measure, with some level of specificity, additional hours of work on APNs given follow up, and lengthier enrollment visit, etc. to determine feasibility. The additional workload may provide the most important barrier to successful implementation.
• NGTs would be more useful at the end of the study given that the intervention will be tested regardless and the approach is new and clinicians and participants may not be able to anticipate challenges they will face in implementation.
• PrEP eligibility screening is unclear. Are all people who do not have contraindications for PrEP eligible?
• Will this research be biased by PrEP study currently underway with PWID?
• Burden of after work hours participation of providers in NGT seems high. Individual interviews would be a better fit.
• The NGT questions seem straight forward and it is not clear that 5 groups are needed to address identifying barriers to PrEP and OAT delivery and integration.
• Methods for retention are not particularly robust. Though prescribing OAT may help, assisting PWID with PrEP persistence, not just initiation, is essential to reaping the benefit of PrEP.
• The extraordinary use of acronyms, including those not spelled out previously (e.g. TAU) makes for a hard read of the proposal. The writing is also a bit challenging to read and could benefit from some additional proofing.

Strengths
• The letters of support demonstrate the strong community buy in of the community-based organizations.
• The Yale University School of Medicine and Community Health Care Van (CHCV) and the New Haven Syringe Services Program (NHSSP) are long standing research community collaborations and a strong setting for the research.

• None Noted by Reviewer
Study Timeline:

Strengths
• The timeline is better articulated lessening concern about the feasibility of the timeline for the qualitative Phase I activities.

Weaknesses
• Phase II activities still seem ambitious. The team will have to recruit and randomize 90 participants into a 6 months intervention in a 2 year total project along with the qualitative phase and training of APNs on this newly developed protocol. • The investigators were responsive to comments from reviewers; however, the response to #3 that the project was ambitious given the time, budget and amount of work proposed to complete, with the reviewer's being asked to believe the project is feasible based on the successes of Co-Investigators' work on prior project and explanation that nominal group process findings are easily retrievable without in-depth analysis. The project remains ambitious but is a good fit for the R21 mechanism.

Budget and Period of Support:
Recommend as Requested: • Biomarker costs not included

CRITIQUE 2
Significance: 5 Investigator(s): 3 1 R21 DA051934-01A1 7 PPAH SHRESTHA, R Innovation: 2 Approach: 4 Environment: 1 Overall Impact: The team proposes to develop and pilot test an intervention (termed iRAPID) for persons who inject drugs (PWID) that is designed to augment PrEP uptake by incorporating same day access to opiate agonist therapy (OAT) and delivered by advanced practice nurses (APNs). The team proposes a highly innovative application with an exceptionally experienced team. However, the focus on PWID who are on OAT for PrEP is not posited to address the population most at risk for HIV incidence (young PWID who are not on OAT), dampening the significance of the study. Additional moderate weaknesses in the approach, including an overly ambitious timeline, lack of integration of the quantitative and qualitative data, and questionable use of the implementation framework to simultaneously evaluate two interventions (OAT, PrEP) also diminish enthusiasm for the overall application.

Strengths
• HIV infections among all PWID continues to increase with the expansion of the opioid epidemic.
• Need to address strategies to increase uptake of both OAT and PrEP.

Weaknesses
• The co-management of HIV risk with PrEP and OAT among PWID with active drug use requires consideration of many factors in addition to access to medication and facilitation of linkage to care.
• Both OAT and PrEP interventions are highly stigmatized and suffer from low adherences on their own. Thus, trying to address both drug use and HIV risk with OAT and PrEP at the same time might compound these issues among PWID.
• More impact on HIV incidence from any intervention is posited for PWID at highest risk for HIV, i.e., those not connected to any services, including OAT and harm reduction services. Focusing on PWID who have already decided to address their drug use with OAT-i.e., those who have already reduced their risk for HIV by reducing the need to share syringes may not have added value to reducing HIV incidence in this population.
• The single age group of PWID with the highest incidence are 13-34 year old (45% of all cases reported by the CDC in 2018. This group is also most likely to be in the early years of their injection drug use and not linked to OAT. The proposed study focuses on all PWID over age 18, which does not address the population most in need of these interventions.

Strengths
• The junior faculty has adequate experience to successfully carry-out this project given the support of seasoned investigators on the team.

Weaknesses
• PI effort allocated to the project (20%) seems low given the extensive tasks associated with his role.

Strengths
• Addressing HIV risk (PrEP) and drug use management (OAT) simultaneously in a single intervention.

Weaknesses
• None Noted by Reviewer

Strengths
• RCT design is likely to produce robust results.

Weaknesses
• The use of a hybrid implementation model may not be appropriate for evaluation of two evidence-based interventions simultaneously (i.e., both OAT and PrEP uptake).
• The integration of the qualitative and quantitative components is not described.
• Literature presented to support safety of PrEP and OAT is inadequate (e.g., reports on safety of PrEP among HBV-infected with no evidence of OAT use, reference # 183) • Timeline for proposed study is highly infeasible-as there is no room for any potential delays of any kind.

Strengths
• Resources and environment at both performance sites is adequate for the completion of the project.

Weaknesses
• None Noted by Reviewer Study Timeline:

Weaknesses
• The sequential (linear) design with a tight timeline raises concern of the impact of potential delays year 1; the activities proposed for the first 6 months alone is ambitious for a full year of a clinical trial.