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Over the past two decades, the National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) has made major contributions to progress in substance use treatment research. However, contributions to research addressing the considerable medical and mental health comorbidities of substance use, which can impede treatment efficacy and compromise health, have been emphasized less. In this Commentary, we review the contributions of CTN studies focused on medical comorbidities, initially centered on the HIV epidemic in people who use drugs, and subsequently broadening to address hepatitis C and life-threatening bacterial infections; as well as mental health comorbidities, especially post-traumatic stress disorder, attention-deficit/hyperactivity disorder, and suicidality. These studies demonstrate that comorbidities assessments and treatment can be feasibly implemented in substance use treatment programs and, conversely, that substance use assessments and treatments can be feasibly implemented in clinical care sites. We highlight the NIDA CTN Data Share as an invaluable resource for secondary analyses of comorbidities using data from CTN substance use treatment protocols and provide examples of its use. We describe the work of the CTN Comorbidities of Substance Use Special Interest Group (SIG), formerly known as the HIV SIG, as an example of the role that SIGs can play in facilitating CTN research in areas of emerging significance. We emphasize the importance of implementing a “whole person” approach—one that integrates both substance use and comorbidities outcomes. We identify promising opportunities for conducting this research by studying strategies for integrating prevention, screening, linkage, treatment, adherence, and retention support for comorbidities into substance use disorder (SUD) treatment venues; as well as strategies for integrating SUD treatment into primary care venues, hospitals, and other non-SUD clinical settings.

The COVID-19 pandemic exacerbated health challenges among people who use opioids (PWUO) and substance using men who have sex with men (SU-MSM) in Southeastern United States cities. Within the larger NIDA Clinical Trials Network Protocol 0082 PrEP attitudes and opioid use services implementation survey, N=171 PWUO and N=169 SU-MSM answered a COVID-19 vaccine attitudes survey, including measures of vaccine willingness and health beliefs. In mixed-effects linear models for PWUO and SU-MSM, respectively: (1) belief in vaccine protection from illness was positively correlated with vaccine willingness; and (2) sense of being “a guinea pig” was negatively correlated with vaccine willingness. Having previously used a COVID-19 antigen test was positively correlated with vaccine willingness in SU-MSM. This study aims to define vaccine willingness during the COVID-19 pandemic among people who use drugs and proposes the use of the Health Belief Model to conceptualize the correlation between health beliefs and intended behaviors.

Related protocols: CTN-0082

Southern U.S. communities experience high HIV incidence and substance use prevalence, yet low PrEP uptake. In CTN-0082, providers (N=191) completed a survey about willingness to refer/link clients with HIV risk to PrEP. Through in-depth interviews, 12 directors (5 sexually transmitted infection [STI] clinics; 5 syringe services programs [SSPs]; 2 substance use treatment programs [SUTPs]) described multi-level factors that contextualized provider willingness. Providers were more willing to refer/link clients with unspecified HIV risk and men who have sex with men to PrEP vs. other populations. SUTP (vs. SSP) providers were less willing to refer/link clients with unspecified risk and men who use opioids. Older (vs. younger) providers were less willing, and more (vs. less) experienced providers more willing to refer/link to PrEP. Directors described facilitators (e.g., comprehensive health center partnerships) and barriers (e.g., provider stigma toward people who use drugs) to PrEP implementation. Findings highlight the importance of considering multi-level factors in PrEP implementation.

Related protocols: CTN-0082

Men who have sex with men who use substances (SU-MSM) can benefit from pre-exposure prophylaxis (PrEP) for HIV prevention, especially in Southern US cities where HIV incidence is high; however, uptake remains low. Identifying barriers and facilitators is crucial for developing and implementing strategies to enhance uptake. Few studies of PrEP barriers and facilitators have focused on Southern SU-MSM, and most existing studies have not robustly measured such barriers and facilitators. In this study, 225 SU-MSM were recruited from community STI clinics, syringe services programs, or substance use treatment programs in eight Southern cities. Using structural equation modeling, we examined latent variable constructs of barriers and facilitators (i.e., affordability, burden, risk compensation, side effects, and stigma) and their associations with both willingness to take PrEP and length of PrEP use. Greater concern over affordability was robustly associated with more willingness to take PrEP under a variety of conditions. Risk compensation was associated with greater length of PrEP use, suggesting a major motivator to remain on PrEP was the perceived freedom to forego condoms during sex. Findings advance research on measurement of barriers and facilitators of PrEP willingness and uptake and highlight the importance of addressing affordability in PrEP implementation.

Related protocols: CTN-0082

Background: Methamphetamine (MA) use has been linked to engaging in sexual risk behaviors (SRBs) that are associated with HIV/STIs, particularly among men who have sex with men (MSM) and men who have sex with men and women (MSMW; hereafter MSM/W). The objectives of this analysis were to determine whether reduced MA is associated with decreases in SRBs in a sample of MSM/W.

Method: Data came from the ADAPT-2 trial, a randomized, double-blind, two-stage sequential parallel design trial evaluating extended-release injectable naltrexone (NTX) and oral bupropion (BUP) vs. placebo for MA use disorder. In the first 6 weeks of the trial (stage 1), participants were randomized to receive NTX-BUP or placebo. In the second 6 weeks, participants in the placebo group who did not have a treatment response were rerandomized (stage 2). For this secondary analysis, the independent variable was the number of MA-negative urine drug screens (UDS). The dependent variables included three different types of SRBs. Regression models of the independent and dependent variables were adjusted for age, race/ethnicity status, marital status, treatment assignment, and baseline SRBs.

Results: Of the 151 participants, median age was 40 years and majority were non-Hispanic white (52%) and completed more than high school education (82%). Each additional MA-negative UDS was associated with a 7% (adjusted rate ratio (aRR) =0.93; 95% CI, 0.87, 0.99) reduction in total number of sex partners in stage 2 only. Each additional MA-negative UDS was associated with a 13% (aRR =0.87 95%; confidence interval (CI), (0.76, 0.98)) and 9% (aRR =0.91; 95% CI, 0.84, 0.99) reduction in number of condomless sexual encounters in stage 1 and stage 2, respectively. Lastly, each additional MA-negative UDS was associated with a 16% (aRR =0.84; 95% (CI), 0.75, 0.94)) and 27% (aRR =0.73; 95% CI, 0.64, 0.84) reduction in number of sexual encounters when high on MA.

Conclusions: Our analysis showed that reductions in MA use was associated with reductions in several sexual risk behaviors associated with HIV/STI. These findings provide further support for exploring reductions in sexual risk behaviors as a clinical endpoint in future treatment interventions for MA use.

Related protocols: CTN-0068

Background: The opioid epidemic presses on as a significant public health issue in the U.S., with particularly high overdose death rates in the Southeast. Naloxone is the standard of care for reversing opioid overdose; however, many people who use drugs (PWUD) experience barriers to naloxone use. This cross-sectional survey study aims to describe awareness of, experience with, willingness, barriers, and distribution strategies for naloxone among PWUD in the Southeast.

Methods: Data were obtained from a larger implementation survey study (CTN-0082). Descriptive analyses focused on N = 381 people in substance use treatment programs, syringe services programs, and sexually transmitted infection clinics who reported non-prescription opioid use in the past 12 months and completed a naloxone-related questionnaire.

Results: Most PWUD reported using opioids daily (60–62 %). 82 % had previously heard of naloxone, but only 43 % reported having received any type of training to use it. On a 5-point scale, PWUD without prior training (n = 219) reported being very willing to be trained to use naloxone on someone who overdoses (Mdn=5.00, IQR=2.00). Among all PWUD, not knowing where to go for naloxone training was the only barrier to using naloxone that was endorsed with certainty (Mdn=4.00, IQR=2.00). PWUD endorsed three strategies to improve naloxone distribution, including wanting their site to offer naloxone training (Mdn=4.00, IQR=1.00), increased access to naloxone education (Mdn=4.00, IQR=1.00), and connecting people to training programs (Mdn=4.00, IQR=1.00).

Conclusion: This study suggests that improvements are still needed in the saturation of naloxone training and distribution among PWUD, including in settings that provide non-opioid related services.

Related protocols: CTN-0082

This narrative review, which is not directly part of a CTN study but whose primary authors are funded by the CTN and are working on protocols related to this topic, addresses post-2020, specific, complex challenges for use of and adherence to pre-exposure prophylaxis (PrEP) for HIV prevention among out-of-treatment people who use drugs (PWUD) at syringe services programs (SSPs).

The COVID-19 pandemic and its associated changes to the provision of healthcare have significantly impacted HIV prevention, especially for PWUD. Through a synthesis of literature and clinical experience, we (1) characterize the operational changes imposed by the pandemic on SSPs that shaped the current HIV prevention landscape; (2) describe three levels of current challenges for PWUD, including consumer attitudes, non-medical and medical provider attitudes, and structural and scalability barriers; (3) characterize current models for PrEP in SSPs; and (4) offer practical recommendations for HIV prevention in harm reduction programs.

Conclusions: PrEP is a highly effective prevention tool if taken as prescribed. It has been enthusiastically promoted by members of the research, public health and provider communities. Despite its efficacy, PWUD struggle to engage with the PrEP care continuum. We highlight opportunities to advance HIV prevention for PWUD by enhancing tailored, whole-person approaches that may set aside PrEP in favor of other risk reduction routes. For most PWUD who receive services at SSPs, PrEP is a single tool and not realistic until other social and structural determinants of health are addressed.

This is one of the primary outcomes articles for CTN-0082.

In Southern U.S. states with high HIV incidence and low HIV Pre-Exposure Prophylaxis (PrEP) uptake, enhanced efforts to increase interest in and willingness to use PrEP are needed. This implementation survey examined the associations of sociodemographic background, substance use, and sexual risk behaviors with willingness to use daily oral and long-acting injectable (LAI) PrEP among substance using men who have sex with men (SU-MSM). Participants were 225 SU-MSM recruited from sexually transmitted infection (STI) clinics, syringe services programs (SSPs), and substance use treatment programs (SUTPs) in eight Southern U.S. cities. Rates of willingness were high for both daily oral PrEP (78%) and LAI PrEP (66%). In multivariable analyses, distinct factors were associated with willingness towards each. For daily oral PrEP, greater willingness was associated with condomless anal sex, less frequent non-injection opioid use, prior PrEP awareness, and past use of PrEP. For LAI PrEP, greater willingness was associated with Black race, identifying as gay, being single, and higher injection drug use frequency. Lower willingness to use LAI PrEP was associated with higher non-injection opioid use frequency. Findings about willingness to use LAI PrEP, as a relatively newer modality, and greater willingness among Black SU-MSM as a disproportionately HIV-impacted population, are especially important.

Conclusions: These findings argue for the necessity to enhance PrEP promotion efforts that distinguish between oral and LAI PrEP and that are specifically tailored to major SU-MSM subgroups in the Southern U.S.

Related protocols: CTN-0082

This poster reports on an initiative to implement HIV rapid testing in substance abuse treatment programs in the state of South Carolina. A multi-agency collaboration between the Single State Authority, the state Health Department, the regional Addiction Technology Transfer Center (ATTC), and one substance abuse treatment program (Lexington-Richland Alcohol and Drug Abuse Council (LRADAC)), facilitated state-wide implementation. LRADAC, a community-based treatment program, was one of twelve sites that participated in the CTN trial on HIV rapid testing (protocol CTN-0032). Upon completion of the trial, LRADAC implemented a rapid HIV testing and counseling program as a clinical service. South Carolina’s previous efforts to implement on-site rapid HIV testing in 10 pilot agencies had less than optimal success due to the absence of a successful model on which agencies could base their implementation plan. With support from the collaborating agencies, staff developed and presented a 2 1/2 day HIV testing and counseling curriculum at the annual SC School of Alcohol and Drug Studies in 2010. Following the successful completion of the course, participants were fully certified to conduct testing and counseling in their local programs. Course participants had the opportunity to learn the counseling and testing procedures that LRADAC staff found successful in implementing their program. Although challenging, implementing HIV testing program in substance abuse treatment programs is feasible for agencies. The multi-agency collaboration in South Carolina supported the development of an HIV testing and counseling course that was team taught and showcased a successful model on which implementation could be based. Consequently, this effort increased the likelihood that additional substance abuse agencies within the state would move forward with implementation.

Related protocols: CTN-0032

This poster discusses the results of a survey done as part of protocol CTN-0012 (“Characteristics of Screening, Evaluation, and Treatment of HIV/AIDS, Hepatitis C Viral Infections, and Sexually Transmitted Infections in Substance Abuse Treatment Programs”), emphasizing the perspective of state substance abuse and health departments in relationship to the treatment programs within their jurisdiction for three infection groups: HIV/AIDS, Hepatitis C virus, and sexually transmitted infections. State substance abuse and health departments were compared regarding priorities, written guidelines and availability of funding for 8 selected services for the 3 infections (24 comparisons). In addition, clarity of guidelines and availability of funding for the 8 services, as reported by administrators and clinicians at treatment programs offering these services were compared with guidelines and funding as reported by the states. Surveys were received from 48 states and DC (96%) representing 46 substance abuse and 42 health departments. The response rate from treatment program administrators and clinicians was 269 (84%) and 1723 (78%), respectively. There was general agreement between states and the two departments within the states regarding priorities and availability of funding (19 of 24 comparisons). While most states had guidelines for infection-related services, clarity of guidelines as expressed by treatment program administrators and clinicians was less than optimal. For funding, treatment program administrators indicated less availability than the states for all 24 comparisons, 19 of which were statistically significant. While states appear generally to have their priorities, guidelines and funding in place, the mosaic that constitutes the healthcare delivery system may be too complex for the treatment programs to access most efficiently.

Although substance abuse treatment programs are an important point of contact to provide health services to diagnose, treat and prevent transmission of hepatitis B (HBV) and hepatitis C (HCV) viral infection, little is known about the availability of these services in substance abuse programs. This presentation reports on a study that evaluated the prevalence and spectrum of HBV and HCV services offered by drug treatment programs in the U.S. A questionnaire-based survey of drug treatment programs within the National Drug Abuse Treatment Clinical Trials Network was conducted as part of protocol CTN-0012 (“Characteristics of Screening, Evaluation, and Treatment of HIV/AIDS, Hepatitis C Viral Infections, and Sexually Transmitted Infections in Substance Abuse Treatment Programs”). Completed questionnaires were received from 269 (84.3%) of the 319 program administrators. Although 78.7% of programs reported that they offered ongoing hepatitis training for clinical staff, only a minority of programs offered testing for HBsAg (37.7%), HBsAb (36.7%), HBcAb (27.7%), HBV DNA (7.8%), HCV antibodies (52.9%), HCV qualitative (10.1%) or quantitative (8.9%) PCR, and HCV genotyping (11.6%). Hepatitis A and B vaccinations were offered by 68.3% of programs, either on site (19.3%) or via referral (49.1%). Programs having clear guidelines for hepatitis testing were significantly more likely to offer each of the hepatitis tests as compared with those that did not have clear guidelines. Only 28.9% of programs offered HCV treatment either on-site or via referral.

Despite the importance of substance abuse in sustaining the hepatitis epidemics in the U.S., many substance abuse treatment programs do not offer comprehensive HBV, HCV and hepatitis vaccination services. Public health interventions to improve access to hepatitis testing, treatment and prevention for substance abusers are needed.

In addition to the studies underway, CTN participants are planning multi-site clinical trials with emerging results that address HIV/AIDS. The CTN has a HIV/AIDS Special Interest Group (SIG) that meets regularly to discuss study ideas and policy approaches. The SIG provides a supportive place to discuss HIV research related to the CTN, share information with each other about opportunities and developments, promote AIDS ideas and research in the CTN, and link CTN research with the AIDS Research Office of NIDA. The SIG periodically reviews and prioritizes study ideas before they work their way up the organizational hierarchy, and, in the latest CTN Call for Concepts, had developed approximately ten suggestions for HIV-related research studies.

Several studies using the CTN ?platform? have also been fielded with external resources. The term ?platform study? describes extramurally funded research that builds on the CTN infrastructure. Studies can add a dimension to a CTN trial, test an intervention by using the infrastructure of the CTN, focus on CTN programs to understand an issue, include CTN programs in data collection, or provide training or career development in the CTN. Extramurally funded platform studies are addressing such issues as models of care for HIV and hepatitis, integrating medical treatment with addiction treatment, and improving adherence to HIV medications.

Pre-exposure prophylaxis (PrEP) dramatically reduces HIV transmission risk. PrEP is underutilized among men who have sex with men who use substances (SU-MSM) in the Southern U.S., for whom there is limited research and high PrEP need. Using cross-sectional data from the National Institute on Drug Abuse (NIDA) Clinical Trials Network CTN-0082 study, we explored factors associated with PrEP awareness and use among 225 SU-MSM in the Southern U.S. Participants were recruited from community-based sexually transmitted infection clinics, syringe services programs and outpatient substance use treatment programs in eight cities across five Southern states with high HIV incidence. Multinomial logistic regressions examined PrEP awareness and use relative to sociodemographic factors, sexual behaviors and substance use. Results demonstrated overall high awareness, yet limited uptake of PrEP. Younger age, higher education, condomless anal sex and more frequent popper use were associated with greater odds of PrEP awareness. Higher education, condomless anal sex and more frequent popper use were associated with greater odds of PrEP use. Results highlight the need for innovative PrEP outreach to Southern SU-MSM that accounts for age, education and substances used.

This secondary analysis of CTN-0049 and CTN-0064 aimed to determine whether endorsement patterns of psychosocial symptoms revealed distinct subgroups, or latent classes, of people living with HIV who use substances (PLWH-SU), and to assess whether these classes demonstrated differential health outcomes over time. It uses data from 801 PLWH-SU initially enrolled across 11 US hospitals during 2012–2014 (CTN-0049) and followed up in 2017 (CTN-0064). Latent class analysis included 28 psychosocial items. Regression analysis examined class membership as a predictor of viral suppression. Survival analysis examined class as a predictor of all-cause mortality. The selected model identified five unique classes. Individuals in classes characterized by more severe and more numerous psychosocial symptoms at baseline had lower likelihoods of viral suppression and survival.

Conclusions: The study demonstrated the importance of considering patterns of overlapping psychosocial symptoms to identify subgroups of PLWH-SU and reveal their risks for adverse outcomes. Integration of primary, mental health, and substance use care is essential to address the needs of this population.

Related protocols: CTN-0049, CTN-0064

The COVID-19 pandemic strained the U.S. health care system, posing logistical challenges for community-based programs. This study surveyed 11 program directors in sexually transmitted infection (STI) clinics and syringe services programs (SSPs) that served people who use substances and are at risk for HIV in five southeastern U.S. states. The 11 sites were all participants in NIDA Clinical Trials Network (CTN) multisite protocol CTN-0082. Brief survey questions asked about programs’ use of in-person and telehealth services. Results indicated widespread reduction of in-person services and concomitant adoption of telehealth services. In STI clinics, telehealth replaced in-person visits for all but urgent treatment of active symptoms. In SSPs, in-person contact continued or increased from pre-pandemic volumes. In both programs, the most salient telehealth use barrier was limited device or internet access and limited technological ease. Services were sustained through innovative adaptations.

Conclusions: This snapshot of response to the early COVID-19 lockdown phase offers actionable guidance about service preparedness for future public health catastrophes in community-based programs serving vulnerable populations.