The American Society of Addiction Medicine Clinical Practice Guideline Development Methodology.

ABSTRACT: The American Society of Addiction Medicine (ASAM) has published clinical practice guidelines (CPGs) since 2015. As ASAM's CPG work continues to develop, it maintains an organizational priority to establish rigorous standards for the trustworthy production of these important documents. In keeping with ASAM's mission to define and promote evidence-based best practices in addiction prevention, treatment, and recovery, ASAM has rigorously updated its CPG methodology to be in line with evolving international standards. The CPG Methodology and Oversight Subcommittee was formed to establish and publish a methodology for the development of ASAM CPGs and to develop an ASAM CPG strategic plan. This article provides a focused overview of the ASAM CPG methodology.

Management of alcohol withdrawal syndrome in patients with alcohol-associated liver disease.

Alcohol-associated liver disease is a common and severe sequela of excessive alcohol use; effective treatment requires attention to both liver disease and underlying alcohol use disorder (AUD). Alcohol withdrawal syndrome (AWS) can be dangerous, is a common barrier to AUD recovery, and may complicate inpatient admissions for liver-related complications. Hepatologists can address these comorbid conditions by learning to accurately stage alcohol-associated liver disease, identify AUD using standardized screening tools (eg, Alcohol Use Disorder Identification Test), and assess risk for and symptoms of AWS. Depending on the severity, alcohol withdrawal often merits admission to a monitored setting, where symptom-triggered administration of benzodiazepines based on standardized scoring protocols is often the most effective approach to management. For patients with severe liver disease, selection of benzodiazepines with less dependence on hepatic metabolism (eg, lorazepam) is advisable. Severe alcohol withdrawal often requires a "front-loaded" approach with higher dosing, as well as intensive monitoring. Distinguishing between alcohol withdrawal delirium and HE is important, though it can be difficult, and can be guided by differentiating clinical characteristics, including time to onset and activity level. There is little data on the use of adjuvant medications, including anticonvulsants, dexmedetomidine, or propofol, in this patient population. Beyond the treatment of AWS, inpatient admission and outpatient hepatology visits offer opportunities to engage in planning for ongoing management of AUD, including initiation of medications for AUD and referral to additional recovery supports. Hepatologists trained to identify AUD, alcohol-associated liver disease, and risk for AWS can proactively address these issues, ensuring that patients' AWS is managed safely and effectively and supporting planning for long-term recovery.

Micro-dosing Intravenous Buprenorphine to Rapidly Transition From Full Opioid Agonists.

For patients with opioid use disorder transitioning from methadone or requiring opioid analgesia, initiating buprenorphine for opioid use disorder can be difficult because of the risk of precipitated withdrawal. Low-dose initiation, also known as micro-dosing, is an alternative to standard initiation. Prior studies relied on nonstandard dosing of tablets or films, patches, or buccal formulations, all of which are unavailable in many hospitals. We report a novel approach to micro-dosing using intravenous buprenorphine. Two patients, one on methadone maintenance and another requiring postoperative opioid analgesia, were transitioned to buprenorphine with concurrent full-agonist opioids and without precipitated withdrawal.

"I'm a Survivor": Perceptions of Chronic Disease and Survivorship Among Individuals in Long-Term Remission from Opioid Use Disorder.

BACKGROUND: While opioid use disorder (OUD) is prevalent, little is known about what patients with OUD in sustained remission think about the chronic disease model of OUD and their perspectives of the cause, course, and ongoing treatment needs of their OUD. OBJECTIVE: To (1) examine patient perceptions of the chronic disease model of addiction and disease identity and (2) use an explanatory model framework to explore how these perceptions inform ongoing treatment needs and help maintain abstinence. DESIGN: Qualitative study of a cross-sectional cohort of patients with OUD in long-term sustained remission currently receiving methadone or buprenorphine. Participants completed a single in-depth, semi-structured individual interview. PARTICIPANTS: Twenty adults were recruited from two opioid treatment programs and two office-based opioid treatment programs in Baltimore, MD. Half of the participants were Black, had a median (IQR) age of 46.5 (43-52) years and the median (IQR) time since the last non-prescribed opioid was 12 (8-15) years. APPROACH: Hybrid deductive-inductive thematic analysis of the transcribed interviews. KEY RESULTS: Some participants described a chronic OUD disease identity where they continue to live with OUD. Participants who maintain an OUD identity describe inherent traits or predetermination of developing OUD. Maintaining a disease identity helps them remain vigilant against returning to drug use. Others described a post-OUD/survivor identity where they no longer felt they had OUD, but the experience remains. Each perspective informed attitudes about continued treatment with methadone or buprenorphine and strategies to remain in remission. CONCLUSIONS: The identity that people with OUD in sustained remission maintain was the lens through which they viewed other aspects of their OUD including cause and ongoing treatment needs. An alternative, post-OUD/survivorship model emerged or was accepted by participants who did not identify as currently having OUD. Understanding patient perspectives of OUD identity might improve patient-centered care and improve outcomes.

Research Needs for Inpatient Management of Severe Alcohol Withdrawal Syndrome: An Official American Thoracic Society Research Statement.

Background: Severe alcohol withdrawal syndrome (SAWS) is highly morbid, costly, and common among hospitalized patients, yet minimal evidence exists to guide inpatient management. Research needs in this field are broad, spanning the translational science spectrum. Goals: This research statement aims to describe what is known about SAWS, identify knowledge gaps, and offer recommendations for research in each domain of the Institute of Medicine T0-T4 continuum to advance the care of hospitalized patients who experience SAWS. Methods: Clinicians and researchers with unique and complementary expertise in basic, clinical, and implementation research related to unhealthy alcohol consumption and alcohol withdrawal were invited to participate in a workshop at the American Thoracic Society 2019 International Conference. The committee was subdivided into four groups on the basis of interest and expertise: T0-T1 (basic science research with translation to humans), T2 (research translating to patients), T3 (research translating to clinical practice), and T4 (research translating to communities). A medical librarian conducted a pragmatic literature search to facilitate this work, and committee members reviewed and supplemented the resulting evidence, identifying key knowledge gaps. Results: The committee identified several investigative opportunities to advance the care of patients with SAWS in each domain of the translational science spectrum. Major themes included 1) the need to investigate non-γ-aminobutyric acid pathways for alcohol withdrawal syndrome treatment; 2) harnessing retrospective and electronic health record data to identify risk factors and create objective severity scoring systems, particularly for acutely ill patients with SAWS; 3) the need for more robust comparative-effectiveness data to identify optimal SAWS treatment strategies; and 4) recommendations to accelerate implementation of effective treatments into practice. Conclusions: The dearth of evidence supporting management decisions for hospitalized patients with SAWS, many of whom require critical care, represents both a call to action and an opportunity for the American Thoracic Society and larger scientific communities to improve care for a vulnerable patient population. This report highlights basic, clinical, and implementation research that diverse experts agree will have the greatest impact on improving care for hospitalized patients with SAWS.

Implementation of a Protocol Using the 5-Item Brief Alcohol Withdrawal Scale for Treatment of Severe Alcohol Withdrawal in Intensive Care Units.

BACKGROUND: There is variation in the treatment of patients with severe alcohol withdrawal and a need for effective protocols. The purpose of this study was to evaluate the implementation of a symptom-triggered benzodiazepine protocol using the 5-item Brief Alcohol Withdrawal Scale (BAWS) for treatment of alcohol withdrawal in intensive care units (ICUs). METHODS: This retrospective study included admissions to ICUs of 2 hospitals over 6 months who had an alcohol withdrawal protocol ordered and experienced severe withdrawal. Records were reviewed to collect demographic data, benzodiazepine exposure, duration of treatment, and withdrawal severity. RESULTS: The protocol was ordered and implemented in 279 admissions; 48 (17.9%) had severe withdrawal defined as a BAWS of 6 or more. The majority of the 48 patients were from the emergency department (79.2%); mean hospital length of stay was 11.2 days and mean ICU stay 6.6 days; 31.3% required mechanical ventilation. A little more than half were treated only with the protocol (53.2%); 25.0% received additional benzodiazepines, 20.8% dexmedetomidine, 10.4% propofol, 25.0% antipsychotics and 2.0% phenobarbital. CONCLUSION: Among ICU patients treated for alcohol withdrawal with a symptom-triggered benzodiazepine protocol using a novel 5-item scale, most did not develop severe withdrawal, and of those who did, approximately half were treated with the protocol alone.

Down the drain: Reconsidering routine urine drug testing during the COVID-19 pandemic.

The COVID-19 pandemic and the move to telemedicine for office-based opioid treatment have made the practice of routine urine drug tests (UDT) obsolete. In this commentary we discuss how COVID-19 has demonstrated the limited usefulness and possible harms of routine UDT. We propose that practitioners should stop using routine UDT and instead use targeted UDT, paired with clinical reasoning, as part of a patient-centered approach to care.

Transition From Methadone to Buprenorphine Using a Short-acting Agonist Bridge in the Inpatient Setting: A Case Study.

: Methadone and buprenorphine are the most common medications for opioid use disorder. Buprenorphine is often the preferred medication because of fewer drug-drug interactions and fewer regulatory barriers. For these reasons, patients often desire to transition from methadone to buprenorphine, but this can be difficult because of the risk of precipitated withdrawal. There are protocols designed to minimize withdrawal; however, these can be time-consuming or infeasible due to formulation and dosage availability of buprenorphine. We describe an inpatient transition from methadone to buprenorphine using a hydromorphone bridge over a 7-day period. This method used commonly available dosages and formulations of buprenorphine. To our knowledge, this is the first time a method has been described that transitions a patient from methadone to buprenorphine using a short-acting opioid agonist bridge and readily available opioid dosages and formulations. This case provides a viable alternative for rapidly transitioning a patient from methadone to buprenorphine that can be used as a template for an alternative method to transitions between these medications.

Evaluation of the Brief Alcohol Withdrawal Scale Protocol at an Academic Medical Center.

OBJECTIVES: The standard of care for treatment of alcohol withdrawal is symptom-triggered dosing of benzodiazepines using a withdrawal scale. Abbreviated scales are desired for clinician efficiency. The objective of this study was to evaluate the use of the 5-item Brief Alcohol Withdrawal Scale (BAWS) protocol. METHODS: This single-center, retrospective, observational, cohort study assessed patients ordered the BAWS protocol between August 1, 2016 and July 31, 2017. Data were collected on benzodiazepine exposure, duration of treatment, withdrawal severity, agitation, over-sedation, and delirium while being treated for alcohol withdrawal. Comparisons were made to analyze predetermined patient subgroups. RESULTS: Seven hundred ninety-nine patients were initiated on the BAWS protocol. Patients received a median (IQR) of 0 (0-4) lorazepam equivalents (LEs) and were on the BAWS protocol for a median (IQR) of 44.9 (22.4-77.2) hours. Of the patients that received benzodiazepines while on the BAWS protocol, a median (IQR) of 4 (2-11) LEs were given. Seventeen (2.1%) patients had severe withdrawal. Days of agitation, over-sedation, and delirium were minimal, with the median (IQR) of 0 (0-0). Few patients received adjunctive medications for symptom management. Intensive care unit (ICU) patients had more severe withdrawal than non-ICU patients, but received the same cumulative benzodiazepine dose. CONCLUSIONS: Most patients on the BAWS protocol received little-to-no benzodiazepines; severe withdrawal, agitation, delirium, or over-sedation were uncommon. This is the first evaluation of the BAWS protocol on a diverse population of hospitalized patients.

Who Leaves Early? Factors Associated With Against Medical Advice Discharge During Alcohol Withdrawal Treatment.

OBJECTIVE: To determine if certain patient, clinical, and disease factors are associated with against medical advice (AMA) discharge among patients admitted for treatment of alcohol withdrawal. METHODS: Data from admissions to a dedicated unit for treatment of substance withdrawal were collected over a 6-month period. Patients with AMA and planned discharge were compared with regard to demographics, clinical data, and substance use disorder disease characteristics. A stepwise logistic regression was used to find the best model. RESULTS: The study population included 655 patient encounters. A total of 93 (14%) discharges were AMA. Bivariate analysis showed patients with AMA discharge were younger (mean age 43 vs 46 years; P < 0.05), more likely to leave on a Tuesday to Thursday, and to have an initial withdrawal score at or above the median (AMA 69% vs planned 56%; P = 0.02). Emergency department (ED) admissions had an AMA discharge rate of 21% compared with 10% of community admissions (P < 0.05). Regression analysis found AMA discharge was significantly associated with admission from the ED (odds ratio [OR] 2.03, confidence interval [CI] 1.27-3.25) and younger age (OR 0.97, CI 0.95-0.99). There was no significant difference in discharge disposition among patients with concurrent opioid use disorder who were on opioid agonist therapy. CONCLUSIONS: AMA discharges occurred in 1 of every 7 admissions. Being admitted from the ED and younger age was associated with AMA discharge. No other patient or clinical factors were found to be associated with AMA discharge.

New and Emerging Illicit Psychoactive Substances.

Several novel psychoactive substances have emerged in recent years. Users are typically young men who use other substances. In the category of stimulants, cathinones ("bath salts") have predominated and can lead to agitation, psychosis, hyperthermia, and death. Synthetic cannabinoids ("spice") are more potent than marijuana and can lead to agitation, psychosis, seizures, and death. There are no rapid tests to identify these substances and general treatment includes benzodiazepines for agitation and supportive therapy. Many Synthetic opioids are potent analogues of fentanyl and carry a high risk of overdose. In addition, there are several designer benzodiazepines that have emerged.

Change in Medical Student Attitudes Toward Patients with Substance Use Disorders After Course Exposure.

OBJECTIVE: Negative physician attitudes toward patients with substance use disorders (SUD) pose a significant barrier to treatment. This study tests the overall and intra-individual change in attitudes of second year medical students after exposure to a 15 hour SUD course. METHODS: Two cohorts of second year medical students (2014 and 2015) responded to an anonymous 13-item previously published survey exploring personal views regarding patients with SUD using a four-point Likert scale. Students were surveyed one day before and up to one month after course completion. Survey items were grouped into the following categories: treatment optimism/confidence in intervention, moralism, and stereotyping. The Wilcoxon nonparametric signed-rank test (α=0.05) was used to compare the pre- and post- survey responses. RESULTS: In 2014 and 2015 respectively, 118 and 120 students participated in the SUD course with pre- and post-response rates of 89.0% and 75.4% in 2014 and 95.8% and 97.5% in 2015. Of the 13 survey questions, paired responses to eight questions showed a statistically significant positive change in attitudes with a medium (d = 0.5) to large effect size (d = 0.8). Items focused on treatment optimism and confidence in treatment intervention reflected a positive attitude change, as did items associated with stereotyping and moralism. CONCLUSIONS: These results support the hypothesis that exposure to a course on SUD was associated with positive change in medical students' attitudes toward patients with SUD.

Impact of a Mandated Change in Buprenorphine Formulation.

OBJECTIVE: This study examines the impact of an insurance-mandated change in formulation of buprenorphine/naloxone (BNX) for patients with opioid use disorder treated in a primary care clinic. METHODS: A retrospective cohort study was conducted to determine the proportion of patients who were switched back to the previous BNX formulation and rates of aberrant urine drug tests for the 3 months before and 3 months after a mandated change in BNX from the sublingual film to the rapidly dissolving tablet (BNX-RDT). Aberrant urine drug tests were defined as the presence of cocaine, nonprescribed opioids/benzodiazepines, or the absence of buprenorphine. RESULTS: In all, 186 patients were included in the analysis. At 3 months after the change, 36.0% of patients remained on BNX-RDT at equivalent dose, 9.1% were prescribed a higher dose of BNX-RDT, 52.7% were switched back to their previous formulation after a trial of BNX-RDT, and 2.2% dropped out of care. There was no significant change in the rates of aberrant urine drug tests pre and postchange (36.6% vs 33.7%; P = 0.27) or in any individual component of urine drug testing. Age, sex, and starting dose were not associated with remaining on BNX-RDT at equivalent dose, compared with increasing dose or changing formulation. CONCLUSIONS: Most patients were dissatisfied with the change in formulation and requested a return to the previous formulation. This change did not appear to impact drug use; however, the flexibility that permitted patients to switch back to their previous BNX formulation likely attenuated the policy's impact.

Development and implementation of an alcohol withdrawal protocol using a 5-item scale, the Brief Alcohol Withdrawal Scale (BAWS).

BACKGROUND: The standard of care for management of alcohol withdrawal is symptom-triggered treatment using the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar). Many items of this 10-question scale rely on subjective assessments of withdrawal symptoms, making it time-consuming and cumbersome to use. Therefore, there is interest in shorter and more objective methods to assess alcohol withdrawal symptoms. METHODS: A 6-item withdrawal scale developed at another institution was piloted. Based on comparison with the CIWA-Ar, this was adapted into a 5-item scale named the Brief Alcohol Withdrawal Scale (BAWS). The BAWS was compared with the CIWA-Ar and a withdrawal protocol utilizing the BAWS was developed. The new protocol was implemented on an inpatient unit dedicated to treating substance withdrawal. Data was collected on the first 3 months of implementation and compared with the 3 months prior to that. RESULTS: A BAWS score of 3 or more predicted CIWA-Ar score ≥8 with a sensitivity of 85.3% and specificity of 65.8%. The demographics of the patients in the 2 time periods were similar: the mean age was 45.9; 70.6% were male; 30.9% received concurrent treatment for opioid withdrawal; and 14.2% were receiving methadone maintenance. During the BAWS phase, patients received significantly less diazepam (mean dose 81.4 vs. 60.3 mg, P < .001). There was no significant difference in length of stay. No patients experienced a seizure, delirium, or required transfer to a higher level of care during any of the 664 admissions in either phase. CONCLUSIONS: This simple protocol utilizing a 5-item withdrawal scale performed well in this setting. Its use in other settings, particularly with patients with concurrent medical illnesses or more severe withdrawal, needs to be explored further.

AST: A Simplified 3-item Tool for Managing Alcohol Withdrawal.

AIMS: This study compared the Glasgow Modified Alcohol Withdrawal Scale (GMAWS) and a newly devised 3-item "Anxiety Sweats Tremor" Scale (AST) to the Revised Clinical Institute Withdrawal Assessment Scale (CIWA-Ar)-the standard of care for symptom-triggered management of alcohol withdrawal syndrome. METHODS: Our study took place over 2 separate 1-week observational periods, and included 332 serial evaluations from 85 unique patients. All study participants were treated per hospital protocol based on CIWA-Ar, with supplemental scoring initially by GMAWS and later by AST in tandem. Internal consistency, interitem correlation, and operational characteristics were explored. RESULTS: Median CIWA-Ar score across both phases was 6 (range 0-13), with a median GMAWS score of 2 (range 0-5) and an AST score of 3 (range 0-7). The internal consistency of CIWA-Ar and GMAWS were both poor, with Cronbach alpha scores of 0.46 (n = 156) and 0.41 (n = 156), respectively. The internal consistency of the AST scale was significantly better, with a Cronbach alpha of 0.68 (n = 176). AST identified individuals with CIWA-Ar ≥8 with an area under the receiver-operating characteristic curve of 0.83 (95% confidence interval 0.77-0.89), compared with 0.81 (95% confidence interval 0.74-0.88) for GMAWS. An AST score of ≥3 (out of a possible 9) predicted CIWA-Ar ≥8, with a sensitivity of 93% and a specificity of 63%, whereas the GMAWS had a sensitivity and specificity of 100% and 12%, respectively, based on previously defined cut-offs. CONCLUSIONS: A simple 3-item scale demonstrated good internal consistency and reliably identified individuals experiencing significant alcohol withdrawal. This scale needs to be tested in other settings and among patients with a broader spectrum of withdrawal severity.

Criminal Charges Prior to and After Enrollment in Opioid Agonist Treatment: A Comparison of Methadone Maintenance and Office-based Buprenorphine.

BACKGROUND: Entry into methadone maintenance is associated with a reduction in criminal activity; less is known about the effects of office-based buprenorphine. OBJECTIVE: To compare criminal charges before and after enrollment in methadone maintenance or office-based buprenorphine. METHODS: Subjects were opioid-dependent adults who initiated either methadone maintenance (n = 252) or office-based buprenorphine (n = 252) between 2003 and 2007. Medical records were reviewed to gather demographic data and a state-maintained web-based database to collect data on criminal charges. Overall charges and drug charges in the 2 years prior to and after treatment enrollment were compared. Multivariable analysis was used to examine risk factors for charges after treatment enrollment. RESULTS: In the 2 years after enrolling in treatment, subjects receiving methadone had a significant decline in the proportion of subjects with any charges (49.6% vs. 32.5%, p < .001) or drug charges (25.0% vs. 17.5%, p = .015), as well as the mean number of cases (0.97 vs. 0.63, p = .002) and drug cases (0.38 vs. 0.23, p = .008), while those who initiated buprenorphine did not have significant changes in any of these measures. On multivariable analysis, the strongest predictor of criminal charges in the 2 years after treatment enrollment was prior charges (adjusted odds ratio 3.35, 95% confidence interval, 2.24-5.01). CONCLUSIONS: Enrollment in office-based buprenorphine treatment did not appear to have the same beneficial effect on subsequent criminal charges as methadone maintenance. If this observation is replicated in other settings, it may have implications for matching individuals to these treatment options.

The Effect of a Payer-Mandated Decrease in Buprenorphine Dose on Aberrant Drug Tests and Treatment Retention Among Patients with Opioid Dependence.

BACKGROUND: The optimal dose for office-based buprenorphine therapy is not known. This study reports on the effect of a change in payer policy, in which the insurer of a subset of patients in an office-based practice imposed a maximum sublingual buprenorphine dose of 16 mg/day, thereby forcing those patients on higher daily doses to decrease their dose. This situation created conditions for a natural experiment, in which treatment outcomes for patients experiencing this dose decrease could be compared to patients with other insurance who were not challenged with a dose decrease. METHODS: Subjects were 297 patients with opioid use disorder in a primary care practice who were prescribed buprenorphine continuously for at least 3 months. Medical records were retrospectively reviewed for urine drug test results and treatment retention. Rates of aberrant urine drug tests were calculated in the period before the dose decrease and compared to rate after it with patients serving as their own controls. Comparison groups were formed from patients with the same insurance on buprenorphine doses of 16 mg/day or lower, patients with different insurance on 16 mg/day or lower, and patients with different insurance on greater than 16 mg/day. Rates of aberrant drug tests and treatment retention of patients on 16 mg/day or less of buprenorphine were compared to that of patients on higher daily doses. RESULTS: The rate of aberrant urine drug tests among patients who experienced a dose decrease rose from 27.5% to 34.2% (p=0.043). No comparison group showed any significant change in aberrant drug test rates. Moreover, all groups who were prescribed buprenorphine doses greater than 16 mg/day displayed lower rates of aberrant urine drug tests than groups prescribed lower doses. Retention in treatment was also highest among those prescribed greater than 16 mg/day (100% vs. 86.8%, 90.1%, and 84.4% p=0.010). DISCUSSION: An imposed buprenorphine dose decrease was associated with an increase in aberrant drug tests. Patients in a control group with higher buprenorphine doses had greater retention in treatment. These findings suggest that buprenorphine doses greater than 16 mg/day are more effective for some patients and that dose limits at this level or lower are harmful.

Impact of hepatitis C status on 20-year mortality of patients with substance use disorders.

BACKGROUND: The magnitude of the effect of hepatitis C viral infection on survival is still not fully understood. The objective of this study was to determine whether the presence of hepatitis C viral antibodies in 1991 was associated with increased mortality 20 years later within a cohort of patients with substance use disorders. Secondary objectives were to determine other factors that were associated with increased mortality in the cohort. METHODS: A subset of a 1991 study cohort of patients who had presented for detoxification was reexamined 20 years later. The Social Security Death Index was queried to identify which of the original patients had died. Attributes of survivors and non-survivors were compared, with special attention to their hepatitis C status in 1991. The original study and this analysis were conducted in the chemical detoxification unit at Johns Hopkins Bayview (previously Francis Scott Key Hospital), an academic urban hospital. All participants met the criteria for alcohol or opioid dependence at the time of admission in 1991. The primary study outcome was 20-year mortality after initial admission in 1991, with a planned analysis of hepatitis C status. RESULTS: Twenty years after admission, 362 patients survived and 82 had died. Of the 284 patients who were hepatitis C positive, 228 survived (80 %). Of the 160 patients who were hepatitis C negative, 134 survived (84 %). This absolute risk increase of 4 % was not statistically significant (p = 0.37). Factors associated with increased mortality included male sex, white race, older age, and reported use of alcohol, cocaine, and illicit methadone. Binary logistic regression including hepatitis C status and these other variables yielded an adjusted odds ratio of 0.87 (95 % CI 0.49-1.55); (p = 0.64) for hepatitis C positive 20-year survival. CONCLUSIONS: Hepatitis C positivity was not associated with a statistically significant difference in 20-year survival. The effect of the virus on mortality, if present, is small, relative to the effect of substance use disorders alone.