Steven J. Shoptaw, PhD - US grants

DESCRIPTION (provided by applicant): The proposed study will launch a multidisciplinary effort to examine the diffusion of HIV and sexually transmitted diseases (STDs including gonorrhea, chlamydia, and syphilis) in drug users in L.A. County to identify the individual level factors, partner-level factors, and environmental factors that promote the spread of these diseases. L.A. County is the second largest epicenter of AIDS cases in the nation, yet injection drug use (IDU) accounts for only a minority (13%) of cases, while the majority of cases involve MSM (70%). Recent, disproportionate increases of HIV infection for women and people of color in L.A. County imply the virus is moving from relatively contained groups into larger segments. This 5-year study proposes to establish a representative cohort of individuals thought to represent the behavioral "bridges" for these pathogens to enter the larger population: drug using MSM (n=240), drug using MSM/W (n=240) a comparison group of non-drug using MSM/W (n=240), and the male (n=288) and female (n=192) sexual partners of these individuals (total=1,200). Assessments will be collected at baseline, 6- and 12-months after enrollment. Data collected will address these study aims: (1) Measure associations between drug involvement (methamphetamine user, other drug user, non-drug user), IDU status, sexual risk behavior (MSM, MSM/W, WSM), and HIV/STDs; (2) Evaluate the types of sexual partnerships and dynamics of the partnerships of these individuals and how these are associated with HIV/STD transmission; and (3) Apply mathematical models to the data on partnerships to study how the incidence of HIV/STDs reflect the size and interconnectedness of the sexual networks of each of the groups and to determine the impact of sexual network structure in future transmission of HIV in L.A. within and beyond MSM and heterosexual drug using groups. The study will use methods of behavioral epidemiology, ethnography, viral analysis of HIV, and mathematical modeling to yield a comprehensive set of information to predict the spread of HIV and STDs from sexual networks of high HIV prevalence (drug using MSM) to those of low prevalence (heterosexuals). Outcomes from the proposed cohort study of IDU and non-lDU methamphetamine-using MSM and MSM/W and their sexual partners should provide evidence to guide policy and prevention efforts in response to the spread of HIV and STDs.

DESCRIPTION (provided by applicant): This application seeks continued support to replace and to extend the existing Medication Development Unit for Stimulant Abuse (P50 DA 12755). The thematic emphasis that unifies this continuation of the Center is the development of pharmacological treatments for stimulant abuse through comprehensive and efficient methodologies applied by a multidisciplinary team. The P50 project activities aligned with this theme will involve an ever greater linkage of Phase I with Phase II work, an even stronger effort to apply advanced biostatistical methods to isolate effects of missing data and to identify potential medication effects in subgroups, a more concerted effort to develop biomarkers that discriminate meaningful differences in outcomes, and a more focused approach to the evaluation of medications within the context of carefully specified and timed behavioral interventions. This P50 Center continuation proposes a Core for conducting Administrative and Scientific Integration and Phase I and Phase II research projects that will complete the development of four medications for methamphetamine abuse from initial stages of safety/interaction through preliminary efficacy trials. The Specific Aims of this coordinated research activity are: (1) to identify and test novel medications for the treatment of stimulant abuse and dependence; (2) to conduct Phase I and Phase II trials of approved medications and novel compounds with potential for the treatment of stimulant-related disorders, in the context of concurrent behavioral treatments; and (3) to improve the efficiency of conducting medications research by using best practices and by applying cutting-edge biostatistical methods when analyzing trials data, creating a resource available to the field as a center of excellence in the area of clinical trials for stimulant abuse and dependence. The activities of the Core and two research projects in this application are designed to reflect innovation and multidisciplinary effort to maximize the likelihood of finding breakthroughs in the pharmacological treatment of stimulant abuse that can be brought into practice.

The research plan described in ths application will conduct two Phase II randomized, placebo-controlled trials, each of which compares two active medications to a common placebo condition as treatments for methamphetamine abuse. The design innovation allows 4 medications to be tested using a total of 240 participants (120 per trial). The trials involve a 2-week baseline period followed by randomization to 12 weeks of medication. In the first trial, participants will be randomly assigned to receive aripiprazole (10mg qd; n=35), rivastigmine (1.5mg bid; n=35), or placebo (matched in appearance; n=50) as relapse prevention agents. Contingency management will be initiated during baseline and continued through the fourth week of medication to instill significant periods of abstinence. Cognitive behavioral therapy will be provided during the entire trial period to teach skills for avoiding relapse. This project will determine whether any of the tested medications have sufficient efficacy and safety to devote resources for full-scale definitive trials. The Specific Aims of these Phase II trials are: (1) to determine whether an active medication compared to placebo reduces drug use (urine drug screens; self-report) among treatment-seeking participants with methamphetamine abuse or dependence; (2) to determine whether an active medication compared to placebo retains participants in treatment longer than placebo; (3) to determine whether an active medication sompared to placebo reduces craving (VAS) for methamphetamine; (4) to assess the ability of an active medication compared to placebo to reduce somatic complaints (BSI), demonstrate acceptable levels of safety (AE reports), improve emotional functioning (BDI-II, QWB), and improve overall clinical improvement (CGI); and (5) to assess the ability of an active medication compared to placebo to reduce HIV-related transmission behaviors (RAB). This P50 renewal will continue our tradition of refining and extending technological expertise in the conduct of medication development for stimulant abuse and dependence.

DESCRIPTION (provided by applicant): This application seeks to establish a research training program on the topic of addiction medicine in primary care at UCLA. The rationale reflects both the significance of the program and recent developments in the field. First, problem use and abuse of psychoactive substances, which is highly prevalent among primary care patients, is one type of "chronic disease." Primary care physicians frequently manage chronic diseases within the context of the "medical home" and as such, represent an important opportunity to reduce personal, fiscal and social impacts of addiction using medical management of addiction problems in primary care. Secondly, four medications have been brought on market for treating opioid, alcohol and nicotine seven dependence over the past decade. There is a significant gap in the evidence describing how these new and standard addiction medications can be optimally integrated into primary care to improve quality of life and to reduce suffering for those afflicted. The goal of this training program is to provide physician and behavioral trainees with the research, academic training and mentored professional development to transition into independently funded clinical researchers in the emerging area of research on the topic of addiction medicine in primary care. The application brings together 14 faculty clinical research mentors at UCLA whose expertise covers the lifespan and includes family medicine, pediatrics, general internal medicine and geriatrics. The program includes a Program Director who has conducted extensive clinical research on addiction medicine in primary and specialty care settings, an Associate Director with outstanding experience in conducting research on under-represented populations and an Executive Committee that provides guidance and oversight that is comprised of senior faculty mentors and a fellow representative. A plan for providing continual evaluation of trainee progress and mentorship quality is described, complete with procedures for corrective action to address deficiencies in progress, should these arise. An energetic plan for the recruitment of trainees is described, including a plan for recruitment and retention of minority investigators. PUBLIC HEALTH RELEVANCE: This training program for physicians and postdoctoral scholars will prepare the next generation of health care providers in detecting, caring for and treating patients with substance abuse problems. The high prevalence and the significant health and social costs of drug use, abuse and dependence in this country justify the need for substance abuse to be addressed in primary care settings.

DESCRIPTION (provided by applicant): Methamphetamine (MA) dependence causes devastating personal and public health consequences, particularly in the Western and Midwestern United States (SAMHSA Office of Applied Statistics 2005). Behavioral therapies help some persons reduce or eliminate their use of the drug (Lee and Rawson 2008), but there are no medications approved for the treatment of MA abuse (Vocci and Appel 2007). The development of one or more medications to reduce MA abuse when implemented with evidence-based behavioral and counseling interventions would have obvious public health significance. As noted in PA-07-333, Medications Development for the Treatment of Amphetamine and Amphetamine-Like Related Disorders, this application seeks funding to conduct an initial safety interaction trial of ibudilast (a.k.a. AV411), a non-selective phosphodiesterase inhibitor that has activity as an attenuator of CNS glial activation. Recent research suggests that glial cells may be important in modulating the rewarding properties of drugs of abuse including MA (Vijayaraghavan 2009) and that MA-induced glial activation may contribute to MA's neurotoxicity and associated cognitive dysfunction via glial cell secretion of pro-inflamatory cytokines (Narita, Suzuki et al. 2008). Therefore, we propose testing a novel approach to pharmacologic treatment of MA dependence: amelioration of MA-related cognitive dysfunction/degeneration via suppression of MA-induced glial activation. The proposed study is a Phase I clinical trial that will utilize a randomized double-blind, placebo-controlled within-subject crossover design to determine safety and tolerability and subjective and reinforcing effects of MA in 12 non-treatment seeking MA-dependent volunteers treated with ibudilast (20mg BID and 50mg BID) and placebo. The study will address the following Specific Aims: (1) to determine whether ibudilast (20 mg BID or 50 mg BID) alters the cardiovascular response to IV methamphetamine; (2) to determine whether ibudilast (20 mg BID or 50 mg BID) alters the subjective effects of IV methamphetamine; (3) to determine whether ibudilast (50 mg BID) alters the reinforcing effects of IV methamphetamine; and (4) to determine whether ibudilast alters the pharmacokinetics of IV methamphetamine. Exploratory neurocognitive and pharmaco- genetic analyses will also be performed. The team assembled at UCLA and Harbor-UCLA has extensive expertise in efforts to develop pharmacotherapies for MA abuse and/or dependence. Results of this study will provide the safety-interaction data required before a Phase II clinical trial to assess the efficacy of ibudilast for treatment of MA dependence can be performed. PUBLIC HEALTH RELEVANCE: In Los Angeles County, methamphetamine accounts for more admissions to publicly funded treatments than any other substance, including alcohol and so there is a significant public health need for medications that could optimize outcomes of behavioral therapies for dependent individuals seeking abstinence from methamphetamine. This trial will collect data describing the safety of a potential new treatment, ibudilast (a non-selective phosphodiesterase inhibitor), at two doses (20 mg BID and 50 mg BID) in the presence of 30 mg methamphetamine delivered intravenously. These interaction data are necessary before moving forward with trials of ibudilast in outpatient settings.

DESCRIPTION (provided by applicant): Methamphetamine (MA) dependence is a significant source of deleterious consequences to individual and public health including HIV infection, psychological distress, and cardiovascular disease (Cruickshank and Dyer 2009), particularly in the Western United States. Behavioral treatments, including cognitive behavioral therapy (CBT) and contingency management (CM) are available (Lee and Rawson 2008) but are modestly effective. Medications that have efficacy in reducing MA use that could be integrated with behavioral therapies would represent a significant advancement in treatment. Cholinergic mechanisms are important in the neurobiology of stimulant dependence including MA (Hiranita, Nawata et al. 2008; Williams and Adinoff 2008). Varenicline is a 1422 nicotinic receptor partial agonist and 17 nicotinic receptor full agonist that is approved for cigarette smoking cessation (Gonzales, Rennard et al. 2006) and shows promise for treating alcohol dependence (McKee, Harrison et al. 2009). Varenicline may be effective for the treatment of MA dependence due to dopaminergic effects, relief of glutamatergic and cognitive dysfunction, and activation of nicotinic cholinergic systems. Building upon this rationale and preliminary experiences (in a Phase I clinical trial and a pilot Phase II trial), the investigators propose a randomized placebo-controlled, double-blind Phase II clinical trial of varenicline for MA dependence. Similar to smoking cessation treatment, study medication will be titrated to 1 mg BID over one week after which participants will take varenicline (1 mg BID) or placebo during a brief inpatient MA-detoxification period (4 nights) followed by 8 additional weeks of outpatient treatment with CBT. The brief inpatient detoxification is an important design innovation, as it facilitates all subjects to achieve a brief period of abstinence, to resolve initial withdrawal symptoms, and to allow measurement of varenicline efficacy as a MA withdrawal treatment. The subsequent 8-week outpatient treatment period allows the investigators to test varenicline for efficacy in preventing MA relapse during early abstinence. Although smoking cessation treatment is not provided, potential effects of varenicline on cigarette smoking will be assessed.

Combination Prevention is the integration of behavioral and biomedical strategies to address HIV, especially structural approaches\Building on 25 years of knowledge accumulated with efficacious behavioral interventions, structural approaches create access, settings, policies, or community level applications of learned principles to advance prevention, detection, and care^. The CHIPTS Combination Prevention Core (previously, the Intervention Core) has reorganized its mission, partners, and outcome markers to emphasize structural, biomedical, information technology, social media and behavioral innovations. Three major trends demand this realignment. First, HIV prevention, including combination prevention is significantly influenced by the global economic recession. Inadequate resources will force 22 countries to disrupt antiretroviral (ARV) treatments for persons living with HIV. The largest cuts in donor funding have been to the 34 countries carrying 75% of disease burden^ California cut its HIV budget by $82 million in fiscal year 2009-10. Los Angeles County halved its prevention budget, and reduced HIV care by a third. This fiscal environment requires smarter, more cost-effective intervention strategies that can be broadly diffused. Second, domestically, HIV is predominantly a disease of ethnic minority men who have sex with men (MSM). Black MSM are overrepresented among persons living with HIV (PLH) PLH; 18% of LA County cases are African American, while African Americans are only 4.7% of the County's populafion.* Latino (32%) and White, non Latino (47%) MSM are also impacted. Both aging MSM (> 50 years; both HIV+ and HIV-) and younger MSM (< 30 years) have been saturated with HIV prevention messages, yet incidence continues to rise in these groups, highlighting need for innovative delivery modalities and messages. The Core's reorganization responds to these risks among MSM, especially in Los Angeles. Third, HIV services have been vertically integrated in specialty settings; now advocates are lobbying for horizontally integrated systems for comprehensive care delivery. The health priorities that compete with HIV, especially other chronic health conditions, are gaining attention. Domestically, the patient-centered medical home in health care reform will transform HIV care. Our prevention and intervention models must be adapted to respond to these trends. The CHIPTS' Combination Prevention Core will lead innovation in detection, prevention and care in response to these trends. Our interdisciplinary team is a resource for identifying, designing, and implementing structural, combination approaches for HIV prevention systems, be they local, regional, national, or global. The Core has planned a strategic approach to impact HIV burden of disease that includes: adoption of innovations and evidence-based combination interventions by health jurisdictions, networks of providers and communities of HIV care, treatment services, and consumers; implementation of collaborative combination prevention efforts with health departments that can implement and diffuse interventions in large populations; and greater engagement in research among populations identified nationally and globally with the highest need for HIV prevention, care and treatment. The specific aims for the Combination Prevention Core are: 1. Science: Leading research in combination prevention interventions and strategies that integrate medical, technology, social media and behavioral advancements in HIV prevention and care through individual scientist driven research and participation in research networks. 2. Networking: Providing time and resources to link experts in social media, global information system-technology (GIS), on-line communication, point-of-sale diagnostics and community engagement strategies with agencies and communities at risk. We establish networks for HIV prevention research and programs among those facing highest risks for HIV transmission: communities of color, especially MSM and women at heightened sexual risk. 3. Capacity Building: Advancing the capacity of linked coalitions and networks of scientists, domestic and international health departments and ministries, and engaged non-governmental organizations (NGOs) and CBOs to launch innovative, bold, and creative interventions for impacted populations.

SPECIFIC AIMS The overall objective of this Research Core, a key component in the Center for Bridging Research, Innovation, Training and Education Solutions for Minority Health's application, is to reduce morbidities in two populations with life-threatening disparities in Los Angeles: African American women with poorly controlled diabetes mellitus and Korean youth seeking smoking cessation. This Research Core provides strong scientific and community-informed services and support to the two proposed studies in reaching the overall goal of reducing morbidities in these populations that each experience significant health disparities. The research projects proposed in this application present unique and immediate demands for community-informed guidance for establishing the significance of the work in addressing community needs and concerns, for tailoring and adapting evidence-based interventions in the randomized controlled trials, for recruitment and retention strategies and for input in incorporating advancements in social media and web-based health approaches into the study designs. The Research Core meets its objectives by providing the following services: (1) assuring integration of the input and guidance from community partnerships into all aspects of the research efforts, (2) providing consultation on the use of state of the art technology in behavior change health-related research, and (3) coordinating educational, statistical and methodological skill enhancement through working in conjunction with the Research and Education Training and Community Core. In meeting these needs, the Research Core is distinct from the other cores in the Center. Demonstrating synergy, the work of the Research Core is proposed to be completed in a manner that draws strength from the interrelatedness of the proposed projects and incorporates efficiencies by including multiple scientists with complementary areas of high-level expertise and by being able to draw on a history of collaboration with stellar scientists, community partners, public systems of public health and health care and local policymakers.

PROJECT SUMMARY (See instructions): A concerted public health effort since the 1960s has reduced the overall prevalence of cigarette smoking in the United States by approximately 50%, with some states like California having even greater reductions. While these efforts are laudable and have led to reductions in morbidity and mortality for many, the gains have not been equal. In Los Angeles County, where only 10.4% of residents smoke cigarettes, alarmingly high prevalence is observed in select sub-groups that have economic and racial/ethnic disparities. Among Korean-Americans in Los Angeles County, smoking prevalence reaches 40% with reduced but still high rates of smoking among youth. This research project builds upon the commitment of community agencies, students and activists, County policymakers and academics to tailor an evidence-based smoking cessation intervention for use with Korean youth and to develop programming to deliver the intervention using the web and mobile Smartphones. The first phase of this research project involves consultative activities and focus group procedures to adapt and to tailor a 6-week, cognitive behavioral-motivational enhancement (CBME) cessation intervention specifically for Korean-American youth. Using iterative procedures between community and student key informants and technology experts, the adapted intervention will be programmed to be delivered using the web. The second phase of this research project involves conduct of an adequately powered, randomized controlled trial of the experimental intervention delivered on the web (n=120) compared to standard of care (n=120) for Korean-American youth (aged 14-19) seeking smoking cessation. Primary outcome variable is 7-day point prevalence of smoking abstinence verified by biomarkers at end of treatment, 24- and 52-week follow-up visits. We expect to find between 2-3 times increase in smoking cessation rates for the experimental group over the control group, which represents an outstanding morbidity reduction. If effective, the intervention will also provide an effective program for adaptation to young smokers of other ethnicities/races.

PROJECT SUMMARY/ABSTRACT HIV treatment and prevention approaches are evolving in response to advancements in pharmacotherapies. Yet in the United States substance using members of key populations such as men of color who have sex with men (MoCSM) face socio-behavioral barriers that inhibit access and adherence across the HIV Care and Prevention Cascades that produce HIV relevant biological changes. Elucidation of how substance use affects basic, biological, behavioral, and social aspects of HIV is vital to advance HIV prevention and treatment. In response to NIDA RFA-DA-18-011 Cohort Studies of HIV/AIDS and Substance Use (U01), the University of California, Los Angeles (UCLA) seeks to continue the MSM and Substances Cohort at UCLA Linking Infections Noting Effects (MASCULINE or the ?mSTUDY?) established in 2013 and to extend the scientific opportunities it offers for another five years. Our proposed competitive renewal will sustain and dynamically refresh the cohort of substance-using HIV-seropositive (HIV+) and high-risk HIV-seronegative (HIV-) MoCSM by retiring older, non-substance-using members and adding younger substance-users. If renewed, this cohort will continue to add specimens to our well-characterized, extensive biobehavioral repository and to provide a platform for high-impact science. Substance use continues to effect adherence to treatment and prevention regimens thereby sustaining high prevalence networks. Proposed investigators lead the science on studying associations between drug use, behaviors, and infectious disease and will contribute a broad portfolio of interdisciplinary work from immunology and basic science to epidemiology, prevention and treatment. This cohort of MoCSM will characterize: (i) effects of substance use on acquisition of HIV and other sexually transmitted infections (STIs: gonorrhea, Chlamydia, syphilis); (ii) the extent to which substance use in MoCSM facilitates behaviors that transmit HIV compared to non-drug using MoCSM (iii) the effects of substance use and HIV on the mucosal environment; (iv) effect of substance use on HIV disease progression; and interactions between substance use and HIV infection on the inflammatory response. We identify the direct ways stimulants, cannabis and other substance use in combination with specific behaviors can change HIV transmission and progression dynamics in multiple compartments via immune function and the microbiome. The application also proposes to expand an already robust biorepository with specimens available for the broader research community. This cohort will be comprised of 514 MoCSM with repeated data visits. At least half will be active substance users and younger than age 30. With a fully enrolled cohort, the mSTUDY has begun to produce high impact publications and spinoff research projects with newly integrated datasets of large sample sizes. The next cycle will further stimulate basic and biologically innovative science from collaborating investigators, newly established collaborations with other NIDA cohorts, and externally funded scientists and generate high impact future science.

? DESCRIPTION (provided by applicant): Methamphetamine (MA) dependence is a significant health problem in South Africa and the U.S. In South Africa, a shift in policy focus is required away from allocating health resources primarily to HIV/AIDS and TB and toward the financial, social and personal consequences of untreated stimulant addiction. In response to PAR 14-331, this application proposes to build capacity for a new linkage of productive teams of clinical researchers at UCLA and the University of Cape Town to conduct studies on the neurobiological foundation of treatment for stimulant dependence. The research direction is innovative in linking findings from neuroscience with clinical outcomes using contingency management (CM) to identify changes in brain structure and function that emerge during purely behavioral therapy. The knowledge gained may guide development of optimally effective behavioral and/or medication therapies. The application design will correlate MA-abstinence outcomes from an 8-week program of voucher-based incentives using an escalating schedule for 30 treatment-seeking, MA-dependent individuals with scores on tasks of working memory and assessments of neuropsychological and demographic status. At the beginning and end of the CM program, participants will participate in MRI scans while performing a working memory task, and will complete a battery of select neurocognitive and psychological assays to address two specific aims: (1) to determine whether changes in neural function within front striatal circuitry from baseline to end of the 8- week CM program are associated with parallel changes in measures of cognitive control and impulsivity and with MA abstinence outcomes; (2) to determine whether structural changes in front striatal circuitry over the 8-week CM intervention correspond with neurocognitive, psychological and MA abstinence measures. Findings from this study will describe associations between: (1) functional and structural indices of brain areas that support working memory, cognitive control/inhibition; (2) performance on select neurocognitive and psychological assessments; and (3) associations between these with MA abstinence outcomes. Study activities and the neuroscience data generated will provide preliminary data for a larger, adequately powered study that will test ways to optimize behavioral therapies for treating stimulant use disorder.

ABSTRACT The Administrative Core implements the vision and mission of the strategic plan for CHIPTS by coordinating the Center's scientific agenda and fostering multidisciplinary collaboration among its members, affiliates and stakeholders. The Administrative Core helps to unite seasoned researchers from medicine and behavioral science to drive innovation and impact in the design, conduct and evaluation of cutting edge HIV prevention research and policy impacts in key populations who live with HIV/AIDS or are at high-risk, especially those who face problems with access and adherence to combination HIV prevention and treatment. The Administrative Core ensures sound oversight of the high impact science, network, and capacity building activities conducted by CHIPTS scientists domestically and internationally. It supports administrative, operational and dissemination functions of CHIPTS and leads strategic investments in new research areas. Its three specific aims are: (1) SCIENCE: To guide scientific consultation and leadership with CHIPTS scientists; convene CHIPTS scientists to promote collaborative and multidisciplinary work; conduct strategic planning efforts and implement its findings; ensure scientific accountability using a process of continuous quality improvement (CQI) and central management of center resources; (2) NETWORKING: To ensure consistent communication mechanisms and manage CHIPTS' internal and external networking activities, including logistical support across Cores, collaborating institutions and at center-related events; and, (3) CAPACITY BUILDING: To expand and improve CHIPTS' mentoring and teaching activities across all career levels and improve capacity for implementing high impact HIV prevention and treatment developments by training key community partners and stakeholders. The Administrative Core consists of the: (1) Senior Leadership Team (CHIPTS Director Steve Shoptaw, PhD, Co- Director Raphael Landovitz, MD, MSc, and Executive Director Uyen Kao, MPH); (2) CHIPTS Core Committee (which includes the Directors, Co-Directors, and Associate Directors of each Core); (3) Scientific and Community Advisory Boards; and (4) CHIPTS support staff. The Administrative Core also includes the Global HIV Prevention Strategies program, which is led by Thomas Coates, PhD and works across all Cores. The Core's activities are carried out by the Senior Leadership Team in conjunction with Core scientists and staff. Administrative Core services include: provision of scientific leadership, guidance, and support to all Cores; conduct of strategic planning and implementation; promotion of global HIV prevention science and mentorship, convening for Scientific and Community Advisory Boards; management of Center resources; implementation of a continuous quality improvement process; management of CHIPTS' internal and external communication activities, including the CHIPTS website; maintaining community collaborations and coordination of dissemination efforts.

Research Abstracts We propose to develop and evaluate optimal combinations of evidence-based interventions (EBIs) to improve HIV outcomes and reduce methamphetamine use among people with opioid use disorder (OUD) who are in methadone maintenance therapy (MMT) in Vietnam (STAR-OM study). Over the past decade, the expansion of MMT has contributed to stemming both HIV and opioid epidemics. However, rising methamphetamine use threatens these achievements. The twinned epidemics of opioid and methamphetamine use have also been reported in the US and other countries. Building on our pilot work with MMT patients in Hanoi, through collaborative work with local MMT providers and patients, we will refine adapted EBIs to develop an adaptive design that offers an individualized approach to treatment. The adaptive design includes: (1) Two frontline interventions: 6 weeks of CM then 6 weeks of weekly group educational sessions (low intensity CM) and 12 weeks of CM (high intensity CM); (2) One (short-term) tailoring outcome: urine tests negative with meth metabolites in both week 11 and 12 are considered responsive to frontline interventions; (3) Three alternative interventions: those with positive outcomes will move to 12-week maintenance stage and receive two daily SMS reminders plus one weekly self-monitoring assessment message. Non-responders will move to 12-week enhanced treatment stage and are randomized to either Matrix group counseling only or Matrix group counseling plus CM. We will compare effectiveness of two frontline interventions and four adaptive interventions with a Sequential Multiple Assignment Randomization Trial in 200 HIV+ (150 from HCMC; 50 from Hanoi) and 400 HIV- (200 from each city) MMT patients who report moderate- and high-risk meth use on self-screening with tablet-based ASSIST and/or have urine positive with methamphetamine metabolites. In each location, the study will stratify participants by HIV status before randomizing them to one of two frontline interventions. Primary outcomes - including HIV viral suppression, HIV risk behaviors, and meth use (reported and urine tests) - will be assessed at 12, 24 and 48 weeks. We will calculate the incremental cost effectiveness ratio (ICER) comparing cost-effectiveness between two frontline interventions as well as among four adaptive strategies. Finally yet importantly, we also conduct ethnographic observations and in-depth interviews with MMT clinic managers, clinical staff and MMT patients (N=60, 30 per city) to identify structural, provider and patient-level factors that influence adoption and scale-up of the adaptive interventions. Findings from this study with Type I Hybrid design to evaluate EFFECTIVENESS-Implementation will provide valuable evidence to develop treatments in resourced and resourced-constrained settings to confront the twinned epidemics of opioid and methamphetamine use in the context of surging HIV epidemic due to drug abuse.

ABSTRACT The Big South/West Node of the NIDA Clinical Trials Network (CTN) represents an expansion of the Texas Node that has been a part of the CTN since 2005. With this expansion, the node will now be guided by the shared leadership of Madhukar H. Trivedi, MD of University of Texas Southwestern Medical Center (UTSW) Steven Shoptaw, PhD of UCLA, and Jennifer S. Potter, PhD, MPH, of UT Health Science Center at San Antonio (UTHSCSA). This fourth competing renewal application builds on our successful track record of leading CTN trials, being good network partners by providing excellent sites for multi-site studies, high productivity in publishing, and training the next generation of scientists. During the 2015-2020 funding cycle, our team developed and led: the largest pharmacotherapy trial for the treatment of methamphetamine use disorder to date (extended-release naltrexone plus high-dose bupropion; CTN0068 ADAPT-2), an in-depth study of the causes of death in a cohort of people living with HIV/HCV and substance use disorder (CTN0064A1), and an implementation study to develop and deploy universal screening for opioid use disorder and measurement based care using buprenorphine (CTN0090 MBC4OUD). Finally, a study testing transcranial magnetic stimulation (TMS) as a treatment for stimulant use disorder has been approved for development, in collaboration with the Southern Consortium Node (CTN0108). For this renewal application, we capitalize on the experience of the Multiple PIs, who collectively have expertise in the treatment of stimulants, the treatment of and public health response to the opioid crisis, and the treatment and care of HIV. Additional investigators bring content expertise spanning addiction science and clinical care, translational science, dissemination and implementation science, informatics, and trial implementation. The expanded Big South/West Node is named to denote the importance of including geographic regions in the South that have historically not been represented within the CTN (i.e., Arkansas, Oklahoma, Louisiana). This geographical expansion provides greater access to diverse patient populations (e.g., diverse racial and ethnic groups; underinsured; underserved; native [American Indian] and immigrant groups) within diverse settings (e.g., rural, urban). Our existing partnerships with primary care networks, large health care systems, and use of electronic health records (EHR) to positively impact substance use, has been further broadened to include multiple statewide networks and resources in new partner states. Our research agenda includes a focus on the fourth wave of the opioid epidemic, building upon the expertise of our investigators in treating stimulant and opioid use disorders, and the changing needs of the regions we serve. Our team has experience with innovative study designs that target all areas of the translational science continuum, and equip our Node to successfully and significantly improve the care of persons who misuse substances.

ABSTRACT The Big South/West Node of the NIDA Clinical Trials Network (CTN) represents an expansion of the Texas Node that has been a part of the CTN since 2005. With this expansion, the node will now be guided by the shared leadership of Madhukar H. Trivedi, MD of University of Texas Southwestern Medical Center (UTSW) Steven Shoptaw, PhD of UCLA, and Jennifer S. Potter, PhD, MPH, of UT Health Science Center at San Antonio (UTHSCSA). This fourth competing renewal application builds on our successful track record of leading CTN trials, being good network partners by providing excellent sites for multi-site studies, high productivity in publishing, and training the next generation of scientists. During the 2015-2020 funding cycle, our team developed and led: the largest pharmacotherapy trial for the treatment of methamphetamine use disorder to date (extended-release naltrexone plus high-dose bupropion; CTN0068 ADAPT-2), an in-depth study of the causes of death in a cohort of people living with HIV/HCV and substance use disorder (CTN0064A1), and an implementation study to develop and deploy universal screening for opioid use disorder and measurement based care using buprenorphine (CTN0090 MBC4OUD). Finally, a study testing transcranial magnetic stimulation (TMS) as a treatment for stimulant use disorder has been approved for development, in collaboration with the Southern Consortium Node (CTN0108). For this renewal application, we capitalize on the experience of the Multiple PIs, who collectively have expertise in the treatment of stimulants, the treatment of and public health response to the opioid crisis, and the treatment and care of HIV. Additional investigators bring content expertise spanning addiction science and clinical care, translational science, dissemination and implementation science, informatics, and trial implementation. The expanded Big South/West Node is named to denote the importance of including geographic regions in the South that have historically not been represented within the CTN (i.e., Arkansas, Oklahoma, Louisiana). This geographical expansion provides greater access to diverse patient populations (e.g., diverse racial and ethnic groups; underinsured; underserved; native [American Indian] and immigrant groups) within diverse settings (e.g., rural, urban). Our existing partnerships with primary care networks, large health care systems, and use of electronic health records (EHR) to positively impact substance use, has been further broadened to include multiple statewide networks and resources in new partner states. Our research agenda includes a focus on the fourth wave of the opioid epidemic, building upon the expertise of our investigators in treating stimulant and opioid use disorders, and the changing needs of the regions we serve. Our team has experience with innovative study designs that target all areas of the translational science continuum, and equip our Node to successfully and significantly improve the care of persons who misuse substances.

ABSTRACT Our overall goal will be to pilot the development of an Innovative Development of Research Engagement Manual (I-DREM) that maps out sustainable solutions that would benefit the recruitment of Black individuals into substance use disorder (SUD) clinical trials and move the meter towards the goal of making diversity in clinical trials a standard part of the SUD clinical research model. Aim 1: To develop a protocol to increase recruitment and retention of Black participants into SUD trials that maps out concrete steps to aid researchers, from planning stages all the way through trial implementation. Aim 2: To develop training modules for research teams to enhance cultural competency and facilitate recruitment and retention of Black individuals into SUD clinical trials.

Implementation science (IS) plays an increasingly important role in the advancement of HIV research. Inherently multidisciplinary, IS recognizes that healthcare systems often struggle to provide high quality services with limited resources and offers a growing number of evidence-based strategies for incorporating research investments in order to improve healthcare value and public health. Moving substantial investments in HIV research into practice in rapid, rigorous, and relevant ways is critical. The UCLA Rapid, Rigorous, Relevant Implementation Science Hub (UCLA 3R Hub) will provide ISC3I with IS expertise and, in coordination with the other Hubs, meet the demand for effective and efficient ways to translate HIV research into practice. The unique goal of the Hub is to provide leadership and support for rapid, rigorous, and relevant (3R) HIV-related implementation research emphasizing pragmatic study designs and methods that address health equity and produce sustainable solutions. We will reach this goal by accomplishing the following Specific Aims: 1) provide consultation, coaching, and technical assistance to Ending the HIV Epidemic (EHE) grantees, with a focus on cutting-edge 3R content, methods, strategies, models, theories, and frameworks; 2) accelerate HIV research impacts by a) collaborating with ISC3I, the other Implementation Hubs, and IS consortia and centers and b) identifying resources and opportunities for advancing evidence-based interventions through the implementation pipeline; 3) provide and promote a platform for multidisciplinary collaborations in support of developing HIV- related implementation research and supporting the next generation of diverse IS investigators; and 4) conduct a cross-Hub multisite pilot implementation research project. EHE awardees assigned to the UCLA 3R Hub will have access to individualized consultation, coaching, and technical assistance sessions; timely roundtable feedback; IS methods workshops; expert discussion sessions; and access to lectures and resources that will advance the application of IS concepts, theories, frameworks, and methods. Additionally, we will support ISC3I's efforts to advance shared measures and frameworks across the projects and in the online community of practice platform. The UCLA 3R Hub team has a strong history of and urgent commitment to using a health equity lens and engaging and mentoring diverse investigators, including racial/ethnic and sexual/gender minorities. Collectively, these activities and efforts will promote the research priorities of the EHE, thereby enhancing HIV research and its impacts and applications in clinical care and public health more broadly.

Abstract This supplemental application aims to establish a new partnership in the geographic area not yet reached by current EHE efforts. This area consists of two EHE priority counties ? Riverside and San Bernardino, collectively called Inland Empire. More than 14,000 individuals live with HIV in the area, and the proportion of undiagnosed infections remains relatively high (18%) and unchanged. Unrecognized HIV infection is the driving force behind the 23% increase in new HIV diagnoses between 2014-2018, as 80% of these new HIV infections can be traced to undiagnosed or out of care individuals. The HIV epidemic in the Inland Empire disproportionately impacts minority populations, as 79% of these new HIV diagnoses were among non-white individuals. Substance use disorder (SUD) is a significant driver of HIV transmission among Latino population, being the cause of one third of new HIV cases in this group. Latino patients are more likely to use health care in emergencies, which suggests a significant number of Latino patients seeking care in the emergency departments (ED) may have undiagnosed HIV infection and concurrent SUD. Loma Linda University (LLU) ED is the only Level 1 Trauma Center in the Inland Empire. It represents an ideal place to consolidate HIV and SUD services and to screen and refer Latino patients to care. Expanding HIV screening in EDs is one of the critical strategies described under the CDC PS20- 2010, supporting EHE programs in the Inland Empire. This is also a strategic priority identified by the local public health departments. In response, this study will adapt and pilot-test an existing computer-based self-screening intervention to identify Latino ED patients with HIV risk and/or SUD-related HIV risk. This screening will be facilitated by community health workers (CHWs). The CHWs, representing the target patient demographic, will be trained as HIV test counselors. They will provide rapid HIV tests to at-risk patients, required post test counseling, and linkage to appropriate care resources. This proposal will be guided by the Exploration, Preparation, Implementation, and Sustainment (EPIS) model. The study team will conduct an ED assessment during the Exploration phase to determine facilitators and barriers to implementing screening intervention. During the Preparation phase, researchers will adapt the existing screening intervention with the help of a multi- disciplinary group meeting weekly for three months. The implementation partners will train CHWs and prepare the LLU ED for a pilot test of the intervention. The Implementation phase will pilot test the intervention, focusing on its acceptability and potential to reach the at-risk Latino population. The Sustainment phase will explore the feasibility of a more extensive evaluation study and the intention to adopt this screening intervention in the LLU ED. The following implementation outcomes will be assessed: feasibility and acceptability of implementing mHealth HIV/SUD screening in the LLU ED, reach and acceptability of this intervention among patients and clinicians, intention to adopt this intervention. This data will be used to inform a more extensive evaluation study.

PROJECT ABSTRACT: HIV disproportionately affects Latino men who have sex with men (LMSM), especially immigrants. The CDC estimates the lifetime HIV risk is 1 in 5 for LMSM compared to 1 in 11 for White MSM. Pre-Exposure Prophylaxis (PrEP) is an evidence-based intervention highly effective in preventing HIV acquisition, with the potential to reduce the number of new HIV infections among immigrant LMSM. However, implementation of interventions such as PrEP with immigrant LMSM may not reach their full potential due to challenges and barriers in delivery. As such, the development of appropriate and feasible implementation strategies holds the potential to improve PrEP delivery to this population. The goal of this planning project is to work within the ?Exploration and Preparation? phases of the Exploration, Preparation, Implementation, Sustainment (EPIS) implementation framework to develop strategies to address inequities in delivery of PrEP to immigrant LMSM in Los Angeles County (LAC). This project focuses on the Prevent Pillar of the national Ending the HIV Epidemic (EHE) initiative and aligns with LAC's EHE plan to facilitate PrEP scale up efforts and reduce barriers to access and continuation. As a first step in this project, we will use an intersectional framework to examine the interplay between stigmatizing identities (i.e., Latinx ethnicity, gay identity, immigrant status) and structures (lack of access to healthcare, institutionalized homophobia and stigma) to understand the experiences of immigrant LMSM in accessing health care and HIV prevention services such as PrEP. In our second step, we will use community-engaged approach to develop implementation strategies to optimize delivery to and adoption of PrEP among immigrant LMSM. More specifically, we will use a concept mapping methodology to work with a panel of key stakeholders with expertise, knowledge and or experience working with immigrant Latino MSM (i.e., service providers, HIV planning body members, community advocates) to collectively address barriers to PrEP delivery to this population. Through the concept mapping process, the panel will conceptualize and define multiple implementation strategies (e.g., new PrEP support services, provider training, and change in practice/policy) to enhance PrEP delivery to the population. The panel will also The expected outcomes include a conceptual model and compilation of stakeholder- and community-generated implementation strategies to enhance access to and delivery of PrEP to immigrant LMSM in LA County. We will share the findings with our local HIV planning body and community partners for future implementation. rate the relative importance and feasibility of the implementation strategies to improve PrEP delivery.