Inpatient Low-dose Transitions From Full Agonist Opioids Including Methadone Onto Long-acting Depot Buprenorphine: Case Series From a Multicenter Clinical Trial.

OBJECTIVES: Persons with opioid use disorder (OUD) suffer disproportionately from morbidity and mortality related to serious addiction-related infections requiring hospitalization. Long-acting buprenorphine (LAB) is an underused medication for OUD that may facilitate linkage to care and treatment retention when administered before hospital discharge. Transition onto buprenorphine in the inpatient setting is often complicated by pain, active infection management, potential surgical interventions, and risk of opioid withdrawal in transition from full agonists to a partial agonist. METHODS: The COMMIT Trial is a randomized controlled trial evaluating LAB administered by infectious disease physicians and hospitalists compared with treatment as usual for persons with OUD hospitalized with infections. We report a case series of participants on full agonist opioids including methadone who were transitioned to sublingual buprenorphine using low-dose ( microdosing ) strategies followed by LAB injection. RESULTS: Seven participants with current opioid use disorder and life-threatening infections, all with significant concurrent pain and many requiring surgical intervention, underwent low-dose transitions starting at buccal buprenorphine doses ranging from 225 µg to 300 µg 3 times a day on the first day. All were well tolerated with average time to LAB injection of 7.5 days (range, 5-10 days). CONCLUSIONS: Inpatient low-dose buprenorphine transition from full agonist opioids including methadone onto LAB is feasible even in those with complex hospitalizations for concurrent infections and/or surgery. This strategy facilitates dosing of LAB before hospital discharge when risk of opioid relapse and overdose are significant.

Dosimetric benefits of daily treatment plan adaptation for prostate cancer stereotactic body radiotherapy.

BACKGROUND: Hypofractionation is increasingly being applied in radiotherapy for prostate cancer, requiring higher accuracy of daily treatment deliveries than in conventional image-guided radiotherapy (IGRT). Different adaptive radiotherapy (ART) strategies were evaluated with regard to dosimetric benefits. METHODS: Treatments plans for 32 patients were retrospectively generated and analyzed according to the PACE-C trial treatment scheme (40 Gy in 5 fractions). Using a previously trained cycle-generative adversarial network algorithm, synthetic CT (sCT) were generated out of five daily cone-beam CT. Dose calculation on sCT was performed for four different adaptation approaches: IGRT without adaptation, adaptation via segment aperture morphing (SAM) and segment weight optimization (ART1) or additional shape optimization (ART2) as well as a full re-optimization (ART3). Dose distributions were evaluated regarding dose-volume parameters and a penalty score. RESULTS: Compared to the IGRT approach, the ART1, ART2 and ART3 approaches substantially reduced the V37Gy(bladder) and V36Gy(rectum) from a mean of 7.4cm3 and 2.0cm3 to (5.9cm3, 6.1cm3, 5.2cm3) as well as to (1.4cm3, 1.4cm3, 1.0cm3), respectively. Plan adaptation required on average 2.6 min for the ART1 approach and yielded doses to the rectum being insignificantly different from the ART2 approach. Based on an accumulation over the total patient collective, a penalty score revealed dosimetric violations reduced by 79.2%, 75.7% and 93.2% through adaptation. CONCLUSION: Treatment plan adaptation was demonstrated to adequately restore relevant dose criteria on a daily basis. While for SAM adaptation approaches dosimetric benefits were realized through ensuring sufficient target coverage, a full re-optimization mainly improved OAR sparing which helps to guide the decision of when to apply which adaptation strategy.

Design and methods of a multi-site randomized controlled trial of an integrated care model of long-acting injectable buprenorphine with infectious disease treatment among persons hospitalized with infections and opioid use disorder.

BACKGROUND: Hospitalization with co-occurring opioid use disorder (OUD) and infections presents a critical time to intervene to improve outcomes for these intertwined epidemics that are typically managed separately. A surge in life-threatening infectious diseases associated with injection drug use, including bacterial and fungal infections, HIV, and HCV accounts for substantial healthcare utilization, morbidity, and mortality. Infectious Disease (ID) specialists manage severe infections that require hospitalization and are a logical resource to engage patients in medication treatment for OUD (MOUD). An injectable long-acting monthly formulation of buprenorphine (LAB) has a potential advantage for initiating MOUD within hospital settings and bridging to treatment after discharge. METHODS: A randomized multi-site trial tests a new model of care (ID/LAB) in which OUD and infections are managed by ID specialists and hospitalists using LAB coupled with referrals to community resources for long-term MOUD. A sample of 200 adults admitted to three U.S. hospitals for OUD and infections are randomly assigned 1:1 to ID/LAB or treatment as usual (TAU). The primary outcome measure is the proportion of patients enrolled in effective MOUD at 12 weeks after randomization. Secondary outcomes include relapse to opioid use, adherence to infectious disease treatment, infection morbidity and mortality, and drug overdose. RESULTS: We describe the design, procedures, statistical analysis, and early implementation issues of this randomized trial. CONCLUSIONS: Study findings will provide insight into the feasibility and effectiveness of integrated treatment of OUD and serious infections and have the potential to reduce morbidity and mortality in this vulnerable population.

Impact of Abstinence and of Reducing Illicit Drug Use Without Abstinence on Human Immunodeficiency Virus Viral Load.

BACKGROUND: Substance use is common among people living with human immunodeficiency virus (PLWH) and a barrier to achieving viral suppression. Among PLWH who report illicit drug use, we evaluated associations between HIV viral load (VL) and reduced use of illicit opioids, methamphetamine/crystal, cocaine/crack, and marijuana, regardless of whether or not abstinence was achieved. METHODS: This was a longitudinal cohort study of PLWH from 7 HIV clinics or 4 clinical studies. We used joint longitudinal and survival models to examine the impact of decreasing drug use and of abstinence for each drug on viral suppression. We repeated analyses using linear mixed models to examine associations between change in frequency of drug use and VL. RESULTS: The number of PLWH who were using each drug at baseline ranged from n = 568 (illicit opioids) to n = 4272 (marijuana). Abstinence was associated with higher odds of viral suppression (odds ratio [OR], 1.4-2.2) and lower relative VL (ranging from 21% to 42% by drug) for all 4 drug categories. Reducing frequency of illicit opioid or methamphetamine/crystal use without abstinence was associated with VL suppression (OR, 2.2, 1.6, respectively). Reducing frequency of illicit opioid or methamphetamine/crystal use without abstinence was associated with lower relative VL (47%, 38%, respectively). CONCLUSIONS: Abstinence was associated with viral suppression. In addition, reducing use of illicit opioids or methamphetamine/crystal, even without abstinence, was also associated with viral suppression. Our findings highlight the impact of reducing substance use, even when abstinence is not achieved, and the potential benefits of medications, behavioral interventions, and harm-reduction interventions.

Self-reported antiretroviral therapy adherence and viral load in criminal justice-involved populations.

BACKGROUND: Self-reported antiretroviral therapy (ART) adherence measures that are associated with plasma viral load (VL) are valuable to clinicians and researchers, but are rarely examined among groups vulnerable to dropping out of care. One-seventh of all those living with HIV pass through incarceration annually and criminal-justice (CJ) involved people living with HIV (PLH) are vulnerable to falling out of care. We examined the association of self-reported ART adherence with VL in a criminal-justice sample compared to a routine-care sample. METHODS: Samples: We examined data from a multisite collaboration of studies addressing the continuum of HIV care among CjJ involved persons in the Seek, Test, Treat, and Retain cohort. Data pooled from seven CJ- studies (n = 414) were examined and compared with the routine-care sample from the Centers for AIDS Research Network of Integrated Clinical Systems' seven sites (n = 11,698). MEASURES: In both samples, data on self-reported percent ART doses taken were collected via the visual analogue scale adherence measure. Viral load data were obtained by blood-draw. ANALYSIS: We examined the associations of adherence with VL in both cohorts using mixed effects linear regression of log-VL, and mixed effects logistic regression of binary VL (≥ 200 copies/mL) outcomes. Interactions by CD4 count and self-reported health status were also tested. RESULTS: Among the CJ sample, the coefficient for log-VL was - 0.31 (95% CI = - 0.43, - 0.18; P < 0.01) and that in the routine-care sample was - 0.42 (95% CI = - 0.45, - 0.38; P < 0.01). For the logistic regression of binary detectable VL on 10% increments of adherence we found the coefficient was - 0.26 (95% CI = - 0.37, - 0.14; P < 0.01) and in the routine-care sample it was - 0.38 (95% CI = - 0.41, - 0.35; P < 0.01). There was no significant interaction by CD4 count level in the CJ sample, but there was in the routine-care sample. Conversely, there was a significant interaction by self-reported health status level in the criminal-justice sample, but not in the routine-care sample. CONCLUSIONS: The visual analogue scale is valid and useful to measure ART adherence, supporting treatment for CJ- involved PLH vulnerable to falling out of care. Research should examine adherence and VL in additional populations.

Combination comet/micronucleus assay validation performed by BioReliance under the JaCVAM initiative.

In the international validation study of the in vivo rat alkaline comet assay (comet assay), the Japanese Center for the Validation of Alternative Methods (JaCVAM) provided three coded chemicals to BioReliance, 1,3-dichloropropene, ethionamide and busulfan, to be tested in a combined in vivo comet/micronucleus assay. Induction of DNA damage (comet) in liver, stomach and jejunum (1,3-dichloropropene only) cells, and induction of MNPCEs in bone marrow, were examined in male Sprague-Dawley (Hsd:SD) rats following oral administration of the test chemical for three consecutive days. A dose range finding (DRF) test was performed with each chemical to determine the maximum tolerated dose (MTD). Based on the results of the DRF test; 1,3-dichloropropene was tested at 50, 100 and 200 mg/kg/day; ethionamide was tested at 125, 250 and 500 mg/kg/day, and busulfan was tested at 10, 20 and 40 mg/kg/day. The results indicated that 1,3-dichloropropene induced DNA damage only in liver cells at all three test article doses, while no effects were observed in the stomach and jejunum cells. Additionally, it did not increase MNPCEs in the bone marrow. 1,3-Dichloropropene was concluded to be negative in the MN assay but positive in the comet assay. Ethionamide did not induce DNA damage in liver. However, in stomach, statistically significant decreases (although still within historical range) in % tail DNA at all test article doses compared to the vehicle control were observed. There was no increase in MNPCEs in the bone marrow. Thus, ethionamide was concluded to be negative in the comet/MN combined assay. Busulfan did not induce DNA damage in any of the organs tested (liver and stomach) but it did induce a significant increase in MNPCEs in the bone marrow. Busulfan was concluded to be negative in the comet assay but positive in the MN assay.

Validation of a Brief Measure of Opioid Dependence: The Rapid Opioid Dependence Screen (RODS).

The Rapid Opioid Dependence Screen (RODS) is an 8-item measure of opioid dependence designed for quick, targeted screening in clinical and research settings. Based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition, criteria, the RODS has an average administration of less than 2 minutes and can easily be administered as a stand-alone instrument or as part of a comprehensive interview. This study reports on the initial validation of the RODS among a sample of 97 newly incarcerated, HIV-positive individuals. Using the Mini International Neuropsychiatric Interview as the primary measure of opioid dependence, the RODS showed good-to-strong sensitivity (.97), specificity (.76), positive predictive value (.69), and negative predictive value (.98), while concordance analysis revealed moderate diagnostic agreement (κ = .67). Psychometric properties revealed strong internal consistency (α = .92) and inter-item correlations (.66 to .87).

Rationale, study design and sample characteristics of a randomized controlled trial of directly administered antiretroviral therapy for HIV-infected prisoners transitioning to the community - a potential conduit to improved HIV treatment outcomes.

BACKGROUND: HIV-infected prisoners experience poor HIV treatment outcomes post-release. Directly administered antiretroviral therapy (DAART) is a CDC-designated, evidence-based adherence intervention for drug users, yet untested among released prisoners. METHODS: Sentenced HIV-infected prisoners on antiretroviral therapy (ART) and returning to New Haven or Hartford, Connecticut were recruited and randomized 2:1 to a prospective controlled trial (RCT) of 6 months of DAART versus self-administered therapy (SAT); all subjects received case management services. Subjects meeting DSM-IV criteria for opioid dependence were offered immediate medication-assisted treatment. Trained outreach workers provided DAART once-daily, seven days per week, including behavioral skills training during the last intervention month. Both study groups were assessed for 6 months after the intervention period. Assessments occurred within 90 days pre-release (baseline), day of release, and then monthly for 12 months. Viral load (VL) and CD4 testing was conducted baseline and quarterly; genotypic resistance testing was conducted at baseline, 6 and 12 months. The primary outcome was pre-defined as viral suppression (VL<400 copies/mL) at 6 months. RESULTS: Between 2004 and 2009, 279 participants were screened, of which 202 met eligibility criteria and 154 were ultimately enrolled in the study; 103 subjects were randomized to DAART and 51 to SAT. Subjects were mostly male (81.2%), people of color (87.0%), had an alcohol use disorder (39.7%), had underlying depression (54.2%), were virally suppressed (78.8%) and had a mean CD4=390.7 cells/mL. CONCLUSIONS: Outcomes from this RCT will contribute greatly to HIV treatment outcomes after release from prison, a period associated with adverse HIV and other medical consequences.

Assessment of genotoxicity induced by 7,12-dimethylbenz(a)anthracene or diethylnitrosamine in the Pig-a, micronucleus and Comet assays integrated into 28-day repeat dose studies.

As part of the Stage 3 of the Pig-a international trial, we evaluated 7,12-dimethylbenz(a)anthracene (DMBA) for induction of Pig-a gene mutation using a 28-day repeat dose study design in Sprague-Dawley rats. In the same study, chromosomal damage in peripheral blood and primary DNA damage in liver were also investigated by the micronucleus (MN) assay and the Comet assay, respectively. In agreement with previously published data (Dertinger et al., [2010]: Toxicol Sci 115:401-411), DMBA induced dose-dependent increases of CD59-negative erythrocytes/reticulocytes and micronucleated reticulocytes (MN-RETs). However, there was no significant increase in DNA damage in the liver cells when tested up to 10 mg/kg/day, which appears to be below the maximum tolerated dose. When tested up to 200 mg/kg/day in a follow-up 3 dose study, DMBA was positive in the liver Comet assay. Additionally, we evaluated diethylnitrosamine (DEN), a known mutagen/hepatocarcinogen, for induction of Pig-a mutation, MN and DNA damage in a 28-day study. DEN produced negative results in both the Pig-a mutation assay and the MN assay, but induced dose-dependent increases of DNA damage in the liver and blood Comet assay. In summary, our results demonstrated that the Pig-a mutation assay can be effectively integrated into repeat dose studies and the data are highly reproducible between different laboratories. Also, integration of multiple genotoxicity endpoints into the same study not only provides a comprehensive evaluation of the genotoxic potential of test chemicals, but also reduces the number of animals needed for testing, especially when more than one in vivo genotoxicity tests are required.

Coupling cytotoxicity biomarkers with DNA damage assessment in TK6 human lymphoblast cells.

There is considerable discussion within the scientific community as to the appropriate measures of cytotoxicity to use when deciding on the maximum concentration of a substance to test in vitro for its ability to induce DNA damage using the Comet assay. Conventional cytotoxicity assessment methods, such as trypan blue dye exclusion or relative cell number (cell counts) may not be the most biologically relevant measurement for cytotoxicity in this assay. Thus, we evaluated for decreased levels of adenosine triphosphate (ATP) and activation of Caspase-3/7 as well as relative cell number and trypan blue exclusion in order to understand the correlation among test compound concentration, cytotoxicity and genotoxicity outcomes in the Comet assay. We tested two non-genotoxic and non-cytotoxic compounds (d-glucose and ethanol), two non-genotoxic but cytotoxic compounds (2,4-dichlorophenol and tunicamycin) and four genotoxic and cytotoxic compounds (methyl methanesulfonate, ethyl methanesulfonate, etoposide and 4-nitroquinoline-N-oxide) in TK6 human lymphoblast cells. Our data show that measuring ATP and Caspase-3/7 levels provides more rapid and perhaps more biologically relevant measures of cytotoxicity compared with trypan blue dye exclusion and relative cell number. Furthermore, incorporating these two assays into the Comet assay also provided insight on the cytotoxic mode of action of the chemicals tested. By extrapolation, such assays may also be useful in other in vitro genotoxicity assays.

Pilot study to enhance HIV care using needle exchange-based health services for out-of-treatment injecting drug users.

The introduction of highly active antiretroviral therapy (HAART) has resulted in marked reductions in mortality and acquired immunodeficiency syndrome (AIDS) incidence across all risk groups; however, the proportionate decrease among injecting drug users (IDUs) has been less impressive. Much of the disparity in benefit to IDUs has been a consequence of decreased access to and receipt of potent antiretroviral combinations. Strategies to increase access to and utilization of HAART have included entry into drug treatment and abstinence. Unfortunately, as few as 15%-20% of active drug users in the United States, and in many other countries, are in drug treatment at any one time. We report a pilot project among out-of-drug treatment IDUs infected with human immunodeficiency virus (HIV); HIV therapy was successfully provided to active heroin injectors using the Community Health Care Van (CHCV) at sites of needle exchange. Subjects were willing to initiate, but were not receiving, recommended HIV therapy and were not interested in formal drug treatment. Antiretroviral therapy regimens were selected and linked to heroin injection timing. Weekly visits were scheduled by CHCV staff to assess adverse side effects and encourage adherence. Of the 13 participants, the mean baseline HIV-1 RNA level and CD4 lymphocyte count were 162,369 (log 5.21) copies per milliliter and 265 cells per milliliter, respectively. By 6 months, the proportion whose HIV-1 RNA was below the limits of detection (<400 copies/mL) was 85% (N=11); 77% (N=10) had nondetectable levels by 9 months. By 12 months, 54% (N=7) had a persistently nondetectable viral load, and the net increase in CD4 lymphocyte count was 150 cells per milliliter. As an additional and unintended benefit of this pilot project, 9 (69%) subjects chose to enter drug treatment after achieving a nondetectable viral load. Entry into drug treatment was associated with durability of viral suppression. This small pilot study suggests that health services based on needle exchange may enhance access to HAART among out-of-treatment HIV-infected IDUs. In addition, it demonstrates that this population can benefit from this therapy with the support of a nontraditional, community-based health intervention.