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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.

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.

Despite advances in antiretroviral therapy, chronic immune activation continues to be observed among individuals with well-controlled HIV viral loads, and is associated with non-AIDS defining morbidities among people living with HIV. Alcohol use disorder impacts a significant proportion of individuals living with HIV, and alcohol exposure is known to damage the intestinal epithelium which may increase translocation of pathogens and their molecular products, driving systemic immune activation and dysregulation. The aim of this study was to determine if adults living with HIV with well-controlled viral loads, who also suffer from alcohol use disorder with and without hepatitis C virus co-infection (n=23), exhibit evidence of advanced systemic immune activation, intestinal damage, and microbial translocation, as compared to adults living with HIV who are not exposed to chronic alcohol or other substances of abuse (n=29). The impact of a 1-month intervention to treatment alcohol use disorder was also examined.

Alcohol use disorder was associated with evidence of advanced innate immune activation, alterations in monocyte phenotype including increased expression of Toll-like receptor 4, increased burden of stimulatory ligands for Toll-like receptor 4, and alterations in plasma cytokine signature, most notably elevations in soluble CD40 ligand and transforming growth factor beta. Alcohol-associated immune activation was more pronounced among individuals with hepatitis C virus co-infection.

Conclusions: Although the 1-month intervention to treat alcohol use disorder did not result in significant reductions in the interrogated indicators of immune activation, these findings suggest that chronic alcohol exposure is a major modifiable risk factor for chronic immune activation and dysregulation among people living with HIV.

Related protocols: CTN-0055

Using data from a randomized trial (CTN-0064, “Linkage to Hepatitis C Virus (HCV) Care Among HIV/HCV Co-Infected Substance Users”), researchers evaluated the cost of HCV care facilitation that supports moving along the continuum of care for HIV/HCV co-infected individuals with substance use disorder.

Participants were HIV patients residing in the community, initially recruited from eight US hospital sites. They received HCV care facilitation (n = 51) or treatment as usual (n = 62) for up to six months. Researchers used micro-costing methods to evaluate costs from the healthcare sector and patient perspectives in 2017 USD, conducted sensitivity analyses varying care facilitator caseloads, and examined offsetting savings using participant self-reported healthcare utilization.

The average site start-up cost was $6320 (site range: $4320-$7000), primarily consisting of training. The mean weekly cost per participant was $20 (site range: $4-$30) for care facilitation visits and contacts, $360 (site range: $130- $700) for supervision and client outreach, and $70 (site range: $20-$180) for overhead. In sensitivity analyses applying a weekly caseload of 10 participants per care facilitator (versus 1–6 observed in the trial), the total mean weekly care facilitation cost from the healthcare sector perspective decreased to $110. Weekly participant time and travel costs averaged $7. There were no significant differences in other healthcare service costs between participants in the intervention and control arms.

Conclusions: Weekly HCV care facilitation costs were approximately $450 per participant, but approximately $110 at a real-world setting maximum caseload of 10 participants per week. No healthcare cost offsets were identified during the trial period, although future savings might result from successful HCV treatment.

Related protocols: CTN-0064

This is the primary outcomes article for CTN-0064.

Direct-acting antivirals can cure hepatitis C virus (HCV). Persons with HCV/HIV and living with substance use are disadvantaged in benefiting from advances in HCV treatment.

In this randomized controlled trial, participants with HCV/HIV were randomized between February 2016 and January 2017 to either care facilitation or control. Twelve-month follow-up assessments were completed in January 2018.Care facilitation group participants received motivation and strengths-based case management addressing retrieval of HCV viral load results, engagement in HCV/HIV care, and medication adherence. Control group participants received referral to HCV evaluation and an offer of assistance in making care appointments. Primary outcome was number of steps achieved along a series of 8 clinical steps (eg, receiving HCV results, initiating treatment, sustained virologic response [SVR]) of the HCV/HIV care continuum over 12 months postrandomization.

Three hundred eighty-one individuals were screened and 113 randomized. Median age was 51 years; 58.4% of participants were male and 72.6% were Black/African American. Median HIV-1 viral load was 27 209 copies/mL, with 69% having a detectable viral load. Mean number of steps completed was statistically significantly higher in the intervention group vs controls (2.44 vs 1.68 steps; 2 [1] = 7.36, P = .0067). Men in the intervention group completed a statistically significantly higher number of steps than controls. Eleven participants achieved SVR with no difference by treatment group.

Conclusions: The care facilitation intervention increased progress along the HCV/HIV care continuum, as observed for men and not women. Study findings also highlight continued challenges to achieve individual-patient SVR and population-level HCV elimination.

Related protocols: CTN-0064

Hepatitis C (HCV) and HIV are associated with opioid use disorders (OUD) and injection drug use. Medications for OUD can prevent the spread of HCV and HIV. This study aimed to describe the prevalence of documented OUD, as well as receipt of office-based medication treatment, among primary care patients with HCV or HIV, using data collected from Phase 1 of the PRimary care Opioid Use Disorders (PROUD) Study (CTN-0074), a pragmatic trial testing whether a collaborative care model increases OUD medication treatment in primary care. Electronic health record and insurance data for adults 18 or older with 2 or more visits to primary care during the study were analyzed. The primary outcome was the diagnosis of OUD; the secondary outcome was OUT treatment with buprenorphine or oral/injectable naltrexone. Prevalence of OUD and OUD treatment was calculated across four groups: HCV only, HIV only, HCV and HIV, and neither HCV nor HIV. In addition, adjusted odds ratios (AOR) of OUD treatment associated with HCV and HIV (separately) were estimated, adjusting for age, gender, race/ethnicity, and site.

The sample included 1,368,604 people, of whom 10,042 had HCV, 5,821 HIV, and 422 both. The prevalence of diagnosed OUD varied across groups: 11.9% for those with HCV, 1.6% for those with HIV, 8.8% for those with both, and 0.92% for those with neither. Among those with diagnosed OUD, the prevalence of OUD medication treatment was 20.9%, 16%, 10.8%, and 22.3% for those with HCV, HIV, both, and neither, respectively. HCV was not associated with OUD treatment, whereas patients with HIV had a lower probability of OUD treatment.

Conclusions: Among patients receiving primary care, those diagnosed with HCV and HIV were more likely to have documented OUD than those without, with the highest prevalence (11.9%) occurring among patients with HCV. Receipt of medication treatment for OUD was uniformly low for all patients, including those with HCV and HIV, with only up to 1/5 of patients with OUD receiving buprenorphine or naltrexone. The finding that patients with HIV who had OUD were less likely to received medication treatment for OUD compared to uninfected patients was unexpected and merits further investigation. These results highlight the need for improved access to medications for OUD, particularly from providers caring for patients living with HCV/HIV. Providing effective treatment for OUD is critical for maximizing the health of people living with HIV and HCV, as well as preventing transmission of these diseases.

Related protocols: CTN-0074

Opioid use disorders (OUD) and hepatitis C or B co-infection (HEP) are common among people living with HIV (PLHIV). The impact of OUD on innate and adaptive immunity among PLHIV with and without HEP is unknown.

This study, part of CTN-0055 (CHOICES), investigated the impact of OUD on monocyte and T-cell phenotypes, cytokine responses to lipopolysaccharide (LPS) and phytohemagglutinin (PHA), and plasma inflammatory markers, among PLHIV with and without HEP. It was a cross-sectional study enrolling PLHIV receiving ART with and without OUD. Flow cytometry determined monocyte and T-cell phenotypes; LPS and PHA-induced cytokine production was assessed following LPS and PHA stimulation by multiplex cytokine array; plasma IL-6, soluble CD163, and soluble CD14 were measured by ELISA.

Twenty-two PLHIV with OUD and 37 PLHIV without OUD were included. PLHIV with OUD exhibited higher frequencies of intermediate and neoclassical monocytes when compared with PLHIV without OUD (P=0.0025; P=0.0001, respectively), regardless of HEP co-infection. Soluble CD163 and monocyte cell surface CD163 expression was increased among PLHIV with OUD and HEP, specifically. Regardless of HEP co-infection, PLHIV with OUD exhibited reduced production of IL-10, IL-8, IL-6, IL-1alpha, and TNF-alpha in response to LPS when compared with PLHIV without OUD; PHA-induced production of IL-10, IL-1alpha, IL-1beta, IL-6, and TNF-alpha were also reduced among individual with OUD.

Conclusions: OUD among PLHIV are associated with altered monocyte phenotypes and a dysregulated innate cytokine response. Defining underlying mechanisms of opioid-associated innate immune dysregulation among PLHIV should be prioritized to identify optimal OUD treatment strategies.

Related protocols: CTN-0055

This is the Results Article for CTN-0066-Ot.

Elevated mortality has been observed among individuals with opioid use disorder (OUD) treated in addiction specialty clinics or programs. Information about OUD patients in general healthcare settings is needed in light of the current effort to integrate addiction services into primary healthcare systems. This study examined mortality rates, causes of death, and associated risk factors among patients with OUD in a large general healthcare system. Mortality data were linked with the electronic health records of 1,683 OUD patients cared for in a large university health system from 2006-2014 (UCLA of the former CTN Pacific Region Node).

There were 465 deaths confirmed (27.6% of the study participants), corresponding to a crude mortality rate of 68.7 per 1000 person-years and SMR of 15.9 (95% CI, 14.5-17.4). Drug overdose and disorder (19.4%), cardiovascular diseases (16.9%), cancer (16.3%), and infectious diseases (14.5%, including 12% hepatitis C virus [HCV]) were the leading causes of death. HCV (HR: 2.08, 95% CI, 1.68-2.59) and cannabis use disorder (HR: 1.63, 95% CI, 1.28-2.07) were two clinically important indicators of overall mortality risk. Chronic pain (AHR: 1.92, 95% CI, 1.16-3.19) and tobacco use disorder (AHR: 2.88; 95% CI, 1.80-4.63) were associated with increased risk of cardiovascular death, HCV infection with cancer mortality risk (AHR: 2.51, 95% CI, 1.47-4.28), and alcohol use disorder with liver-related mortality risk (AHR: 5.06, 95% CI, 2.72-9.42).

Conclusions: Patients with OUD in a general healthcare system demonstrated alarmingly high morbidity and mortality, which challenges health care systems to find innovative ways to identify and treat patients with substance use disorder. Given the chronic, relapsing nature of OUD, and high medical and psychiatric comorbidity, continued care encompassing screening, early intervention, support, and monitoring is essential.

Related protocols: CTN-0066-Ot

Opioid use disorder (OUD) is associated with excess mortality, morbidities, and other adverse health and social conditions. OUD is common among individuals with chronic pain conditions, and chronic pain is common among individuals with OUD. The relationship between chronic pain and OUD and the time course of the two is complex and other physical and mental health problems often co-occur with them both as well. The goal of this study was to examine chronic pain among patients with OUD, as well as to examine other substance use disorders, health, mental health, and treatment for health and mental health among patients in medical settings using electronic health records (EHRs).

Using an EHR database from 2006-2015, the study assessed 5307 adult patients with OUD in a large healthcare system (University of California, Los Angeles, CTN Pacific Region Node), separating them into four categories: no chronic pain (No Pain, 35.6%), OUD prior to pain (OUD First, 9.7%), OUD and pain at the same time (Same Time, 14.9%), and pain condition prior to OUD (Pain First, 39.8%).

Most OUD patients (64.4%) had chronic pain conditions, and among them 61.8% had chronic pain before their first OUD diagnosis. Other SUDs occurred more frequently among OUD First patients than among other groups in terms of alcohol (33.4% vs. 25.4% for No Pain, 20.7% for Same Time, and 20.3% for Pain First), cocaine (19% vs 13.8%, 9.4%, 7.1%), and alcohol or drug-induced disorders. OUD First patients also had the highest rates of HIV (4.7%) and hepatitis C virus (28.2%) among the four groups. Pain First patients had the highest rates of mental disorder (81.7%), heart disease (72%), respiratory disease (68.4%), sleep disorder (41.8%), cancer (23.4%), and diabetes (19.3%).

Conclusions: The alarming high rates of chronic pain conditions occurring before OUD and the associated severe mental health and physical health conditions require better models of assessment and coordinated care plans to address these complex medical conditions.

Substance users are at increased risk for HIV and HCV infection. Still, many substance use treatment programs (SUTP) fail to offer HIV/HCV testing. This secondary analysis of data from the National Drug Abuse Treatment Clinical Trials Network study CTN-0032, a multi-site randomized trial of rapid HIV testing, examines self-reported HIV/HCV testing patterns and serostatus of 2473 SUTP patients in 12 community-based sites that had not previously offered on-site testing. Results indicate that most respondents screened for the randomized trial tested more than a year prior to intake for HIV (52%) and HCV (38%). Prevalence rates were 3.6 and 30% for HIV and HCV, respectively. The majority of participants that were HIV (52.2%) and HCV-positive (40.5%) reported having been diagnosed within the last 1-5 years. Multivariable logistic regression showed that members of high-risk groups were more likely to have been tested.

Conclusions: This analysis demonstrates the potential for community-based substance use treatment programs to identify substance users at-risk for HIV and HCV infection. Access to high quality care and service attentive to the unique needs of substance users is vital to realizing optimal results in both HIV and HCV, reducing the incidence of late diagnosis, extending life expectancy, improving health outcomes and overall quality of life, and decreasing the use of costly medical services. Bundled HIV/HCV testing and linkage to care issues are recommended for expanding testing in community-based SUTP settings.

Related protocols: CTN-0032

Since first being identified in 1989, HCV has quickly gained attention as a public health concern due to its intense proliferation and negative consequences associated with chronic infection. In comparison with other blood-borne illnesses, HCV is now far more common than HIV/AIDS; and unlike HBV, HCV lacks available vaccines. Because injection drug use is by far the most significant risk factor for contracting HCV, and continued substance use among infected persons raises the risk for developing complications, as well as spreading the infection, this study sought to better understand the risk factors associated with HCV among patients enrolled into medication-assisted therapy for opioid dependence. Patients (N=1039) were randomized as part of a larger, multisite clinical trial sponsored by the National Drug Abuse Treatment Clinical Trials Network (CTN-0027) assessing liver function in opioid-dependent participants randomized to medication condition (buprenorphine/naloxone or methadone). HCV status was first assessed with an antibody screen; if positive, then current infection was determined with an antigen screen testing for detectable virus. Patients were classified as HCV negative, HCV positive but have cleared the virus, or as having chronic HCV. Logistic regression analysis was used to examine demographic and behavioral correlates of the three groups.

Thirty-four percent of patients were classified with chronic infection and 14% had evidence of prior infection with apparent clearing of the virus. Chronic infection was associated with recent injection drug use and cocaine use. Chronic HCV infection was also associated with being older and Hispanic.

Conclusions: Age, ethnicity, and current drug use increase the likelihood of being chronically infected with HCV. Strategies targeting high risk subgroups can aid in preventing further disease escalation. Further research would benefit from better understanding the role of ethnicity in transmission and/or spontaneous remission. Early intervention and continuous monitoring of IDUs should be the primary focus for addressing this epidemic.

Related protocols: CTN-0027

There are an estimated 3.2 million individuals in the United States who are chronically infected with hepatitis C virus (HCV), of whom only have had an HCV antibody test and less than a quarter have had a confirmatory HCV RNA test. The US Centers for Disease Control and Prevention (CDC) has set a goal to reduce the proportion of HCV-infected individuals unaware of their status from 55% to 33%. This analysis of data from the National Drug Abuse Treatment Clinical Trials Network, study CTN-0032 (HIV Rapid Testing and Counseling), aimed to evaluate the cost-effectiveness of rapid HCV and simultaneous HCV/HIV antibody testing in substance abuse treatment programs. Researcher used a decision analytic model to compare the cost-effectiveness of no HCV testing referral or offer, off-site HCV testing referral, on-site rapid HCV testing offer, and on-site rapid HCV and HIV testing offer. Base case inputs included 11% undetected chronic HCV, 0.4% undetected HIV, 35% HCV co-infection among HIV-infected, 53% linked to HCV care after testing antibody positive, and 67% linked to HIV care. Disease outcomes were estimated from established computer simulation models of HCV (HEP-CE) and HIV (CEPAC). Measurements included lifetime costs (2011 US dollars) and quality-adjusted life years (QALYs) discounted at 3% annually and incremental cost-effective ratios (ICERs).

On-site rapid HCV testing had an ICER of $18,300/QALY compared with no testing, and was more efficient than (dominated) off-site HCV testing referral. On-site rapid HCV and HIV testing had an ICER of $64,500/QALY compared with on-site rapid HCV testing alone. In one and two-way sensitivity analyses, the ICER of on-site rapid HCV and HIV testing remained <$100,000/QALY, except when undetected HIV prevalence was <0.1% or when we assumed frequent HIV testing elsewhere. The ICER remained <$100,000/QALY in approximately 90% of probabilistic sensitivity analyses.

Conclusions: On-site rapid hepatitis C and HIV testing in substance abuse treatment programs is cost-effective at a <$100,000/quality-adjusted life years threshold. On-site rapid HCV and HIV testing in substance abuse treatment programs represents good value as a public health investment. Policymakers should identify ways to improve the capacity of substance abuse treatment programs to implement on-site HCV and HIV testing, bill for these services, and ensure that individuals testing positive for either virus receive further evaluation and treatment.

Related protocols: CTN-0032, CTN-0032-A-1

The prevalence of hepatitis-C-virus (HCV) infections is high among opioid-dependent individuals. Prior research on the simultaneous treatment of both conditions has primarily assessed success as it pertains to HCV. However, it has been noted that favorable substance use therapy outcomes may improve the likelihood of HCV-treatment initiation and success. Therefore, current guidelines for the treatment of HCV among illicit drug users suggest that treatment for addiction be given the highest priority. This study aimed to determine whether opioid-dependent participants in a clinical trial of buprenorphine-treatment tapering regimens, who tested positive for the HCV antibody, experienced significantly different levels of opioid abstinence than those not infected. Data came from the National Drug Abuse Treatment Clinical Trials Network study CTN-0003, which compared two taper schedules for buprenorphine-naloxone (one rapid and one gradual, n=516). Participants with the HCV antibody were significantly less likely to submit opioid-negative urine analyses during and/or immediately following active treatment, indicating a higher rate of opioid use among this group.

Conclusions: Individualized opioid-dependence treatment strategies may be required for opioid-dependent individuals who test positive for the HCV antibody in order to ensure resources for both opioid-dependence and HCV therapies are used efficiently.

This is the Results Article for CTN-0035-Ot.

Illicit drug users have a high prevalence of HCV and represent the majority of newly infected persons in the U.S. Despite the availability of effective HCV treatment, few drug users have been evaluated or treated for HCV. Racial and ethnic minorities have a higher incidence and prevalence of HCV and higher HCV-related mortality. Factors contributing to poor engagement in care are incompletely understood. In this study, National Drug Abuse Treatment Clinical Trials Network protocol CTN-0035-Ot (“Access to HIV and Hepatitis Screening and Care Among Ethnic Minority Drug Users In and Out of Drug Treatment”), fourteen mixed-gender focus groups of either African American or Latino/a drug users (N=95) discussed barriers to HCV testing and treatment. Themes were identified through content analysis of focus group discussions. Many drug users were tested for HCV in settings where they were receiving care. Outside of these settings, most were unaware of voluntary test sites. After testing HCV positive, drug users reported not receiving clear messages regarding the meaning of a positive HCV test, the impact of HCV infection, or appropriate next steps including HCV clinical evaluations. Many drug users perceived treatment as unimportant because they lacked symptoms, healthcare providers minimized the severity of the diagnosis, or providers did not recommend treatment. Mistrust of the motivations of healthcare providers was cited as a barrier to pursuing treatment. Social networks or social interactions were a source of HCV-related information and were influential in shaping drug users perceptions of treatment and its utility.

Conclusions: Drug users perceived a paucity of settings for self-initiated HCV testing and poor provider-patient communication at test sites and during medical encounters. Notably, drug users reported having an unclear understanding about the meaning of a positive HCV test, the health implications of HCV infection, the importance of clinical evaluations and monitoring, and of treatment options for HCV. Efforts to improve the delivery of clinical messages about HCV infection for drug users at test settings and clinical encounters are needed.

Related protocols: CTN-0035-Ot