How Would You Manage HIV Pre-exposure Prophylaxis in This Patient With Medical Comorbidities? : Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

Despite advances in treatment, HIV infection remains an important cause of morbidity and mortality, with more than 30 000 new cases diagnosed in the United States each year. There are several interventions traditionally used to prevent HIV transmission, but these vary in effectiveness and there are challenges to their implementation. In 2014, the Centers for Disease Control and Prevention published initial guidance on the use of antiretroviral pre-exposure prophylaxis (PrEP) to prevent transmission of HIV infection in persons at risk based on multiple studies that showed it to be highly efficacious in various populations. It was updated in 2021 to reflect new drug options. The U.S. Preventive Services Task Force also recently updated its recommendations for PrEP, which strongly support its use in persons at risk. Despite its well-established effectiveness, the implementation of PrEP in clinical practice has been variable, especially among populations underserved by the medical system and marginalized by society. Fewer than one third of persons in the United States who are eligible for PrEP currently receive it. Here, 2 physicians experienced in HIV PrEP debate how best to identify patients who might benefit from PrEP, how to decide what regimen to use, and how to monitor therapy.

Elucidating the Role of Human ALAS2 C-terminal Mutations Resulting in Loss of Function and Disease.

The conserved enzyme aminolevulinic acid synthase (ALAS) initiates heme biosynthesis in certain bacteria and eukaryotes by catalyzing the condensation of glycine and succinyl-CoA to yield aminolevulinic acid. In humans, the ALAS isoform responsible for heme production during red blood cell development is the erythroid-specific ALAS2 isoform. Owing to its essential role in erythropoiesis, changes in human ALAS2 (hALAS2) function can lead to two different blood disorders. X-linked sideroblastic anemia results from loss of ALAS2 function, while X-linked protoporphyria results from gain of ALAS2 function. Interestingly, mutations in the ALAS2 C-terminal extension can be implicated in both diseases. Here, we investigate the molecular basis for enzyme dysfunction mediated by two previously reported C-terminal loss-of-function variants, hALAS2 V562A and M567I. We show that the mutations do not result in gross structural perturbations, but the enzyme stability for V562A is decreased. Additionally, we show that enzyme stability moderately increases with the addition of the pyridoxal 5'-phosphate (PLP) cofactor for both variants. The variants display differential binding to PLP and the individual substrates compared to wild-type hALAS2. Although hALAS2 V562A is a more active enzyme in vitro, it is less efficient concerning succinyl-CoA binding. In contrast, the M567I mutation significantly alters the cooperativity of substrate binding. In combination with previously reported cell-based studies, our work reveals the molecular basis by which hALAS2 C-terminal mutations negatively affect ALA production necessary for proper heme biosynthesis.

Feasibility of paying people who use drugs cash to distribute naloxone within their networks.

INTRODUCTION: Immediate access to naloxone is needed to prevent fatal opioid-related overdoses in the presence of fentanyl analogs saturating the opioid supply. Peer models engage impacted populations who are not accessing naloxone through standard venues, yet compensating peers who utilize syringe service programs with cash stipends to distribute naloxone within networks of people who use drugs is not well described. METHODS: As part of the HEALing Communities Study, syringe service program-based interventions were developed in Holyoke and Gloucester, MA, which paid people who use drugs ("peers") cash to distribute naloxone. Early program outcomes were evaluated for the time each program was funded within the HCS study period. RESULTS: During 22 study-months of observation, peers in two communities distributed 1104 naloxone kits. The total cost of peer compensation for program delivery was $10,510. The rate of peer-distributed naloxone per 100 K population reached 109 kits/mo and 222 kits/mo in the two communities. Participating peers addressed gaps in harm reduction outreach and distributed naloxone and other harm reduction equipment to individuals who were not syringe service program participants, expanding organizational reach. Being compensated with unrestricted cash stipends supported dignity and acknowledged peers' work in overdose prevention. CONCLUSION: The underutilization of compensated peer models is often attributed to funding and organizational barriers. These programs demonstrate that providing cash stipends to peers is feasible and expanded naloxone distribution at two existing syringe service programs. Providing cash stipends for peers who engage in secondary naloxone distribution offers promise in delivering naloxone to people not accessing syringe services.

Structural basis for dysregulation of aminolevulinic acid synthase in human disease.

Heme is a critical biomolecule that is synthesized in vivo by several organisms such as plants, animals, and bacteria. Reflecting the importance of this molecule, defects in heme biosynthesis underlie several blood disorders in humans. Aminolevulinic acid synthase (ALAS) initiates heme biosynthesis in α-proteobacteria and nonplant eukaryotes. Debilitating and painful diseases such as X-linked sideroblastic anemia and X-linked protoporphyria can result from one of more than 91 genetic mutations in the human erythroid-specific enzyme ALAS2. This review will focus on recent structure-based insights into human ALAS2 function in health and how it dysfunctions in disease. We will also discuss how certain genetic mutations potentially result in disease-causing structural perturbations. Furthermore, we use thermodynamic and structural information to hypothesize how the mutations affect the human ALAS2 structure and categorize some of the unique human ALAS2 mutations that do not respond to typical treatments, that have paradoxical in vitro activity, or that are highly intolerable to changes. Finally, we will examine where future structure-based insights into the family of ALA synthases are needed to develop additional enzyme therapeutics.

Opioid Use Disorder.

Opioid use disorder (OUD) is a treatable chronic disorder with episodes of remission and recurrence characterized by loss of control of opioid use, compulsive use, and continued use despite harms. If untreated, OUD is associated with significant morbidity and mortality. Buprenorphine and methadone reduce fatal and nonfatal opioid overdose and infectious complications of OUD and are the first-line treatment options. Physicians have an important role to play in diagnosing OUD and its comorbidities, offering evidence-based treatment, and delivering overdose prevention and other harm reduction services to people who continue to use opioids. Interdisciplinary office-based addiction treatment programs support high-quality OUD care.

Pre-Paid Phone Distribution: A Tool for Improving Healthcare Engagement for People with Substance Use Disorder.

BACKGROUND: The COVID-19 pandemic drove significant disruptions in access to substance use disorder (SUD) treatment and harm reduction services. Healthcare delivery via telemedicine has increasingly become the norm, rendering access to a phone essential for engagement in care. METHODS: Adult patients with SUD who lacked phones (n = 181) received a free, pre-paid phone during encounters with inpatient and outpatient SUD programs. We evaluated changes in healthcare engagement including completed in-person and telemedicine outpatient visits and telephone encounters 30 days before and after phone receipt. We used descriptive statistics, where appropriate, and paired t-tests to assess the change in healthcare engagement measures. RESULTS: Patients were predominantly male (64%) and white (62%) with high rates of homelessness (81%) and opioid use disorder (89%). When comparing 30 days before to 30 days after phone receipt, there was a significant increased change in number of telemedicine visits by 0.3 (95% CL [0.1,0.4], p < 0.001) and telephone encounters by 0.2 (95% CL [0.1,0.3], p = 0.004). There was no statistically significant change in in-person outpatient visits observed. CONCLUSIONS: Pre-paid phone distribution to patients with SUD was associated with an increased healthcare engagement including telemedicine visits and encounters.

Expression of the preadipocyte marker ZFP423 is dysregulated between well-differentiated and dedifferentiated liposarcoma.

BACKGROUND: Well-differentiated and dedifferentiated liposarcomas are rare soft tissue tumors originating in adipose tissue that share genetic abnormalities but have significantly different metastatic potential. Dedifferentiated liposarcoma (DDLPS) is highly aggressive and has an overall 5-year survival rate of 30% as compared to 90% for well-differentiated liposarcoma (WDLPS). This discrepancy may be connected to their potential to form adipocytes, where WDLPS is adipogenic but DDLPS is adipogenic-impaired. Normal adipogenesis requires Zinc Finger Protein 423 (ZFP423), a transcriptional coregulator of Perixosome Proliferator Activated Receptor gamma (PPARG2) mRNA expression that defines committed preadipocytes. Expression of ZFP423 in preadipocytes is promoted by Seven-In-Absentia Homolog 2 (SIAH2)-mediated degradation of Zinc Finger Protein 521 (ZFP521). This study investigated the potential role of ZFP423, SIAH2 and ZFP521 in the adipogenic potential of WDLPS and DDLPS. METHODS: Human WDLPS and DDLPS fresh and paraffin-embedded tissues were used to assess the gene and protein expression of proadipogenic regulators. In parallel, normal adipose tissue stromal cells along with WDLPS and DDLPS cell lines were cultured, genetically modified, and induced to undergo adipogenesis in vitro. RESULTS: Impaired adipogenic potential in DDLPS was associated with reduced ZFP423 protein levels in parallel with reduced PPARG2 expression, potentially involving regulation of ZFP521. SIAH2 protein levels did not define a clear distinction related to adipogenesis in these liposarcomas. However, in primary tumor specimens, SIAH2 mRNA was consistently upregulated in DDLPS compared to WDLPS when assayed by fluorescence in situ hybridization or real-time PCR. CONCLUSIONS: These data provide novel insights into ZFP423 expression in adipogenic regulation between WDLPS and DDLPS adipocytic tumor development. The data also introduces SIAH2 mRNA levels as a possible molecular marker to distinguish between WDLPS and DDLPS.

Effect of police action on low-barrier substance use disorder service utilization.

BACKGROUND: Police action can increase risky substance use patterns by people who use drugs (PWUD), but it is not known how increased police presence affects utilization of low-barrier substance use disorder bridge clinics. Increased police presence may increase or decrease treatment-seeking behavior. We examined the association between Operation Clean Sweep (OCS), a 2-week police action in Boston, MA, and visit volume in BMC's low-barrier buprenorphine bridge clinic. METHODS: In this retrospective cohort, we used segmented regression to investigate whether the increased police presence during OCS was associated with changes in bridge clinic visits. We used General Internal Medicine (GIM) clinic visit volume as a negative control. We examined visits during the 6 weeks prior, 2 weeks during, and 4 weeks after OCS (June 18-September 11, 2019). RESULTS: Bridge clinic visits were 2.8 per provider session before, 2.0 during, and 3.0 after OCS. The mean number of GIM clinic visits per provider session before OCS was 7.0, 6.8 during, and 7.0 after OCS. In adjusted segmented regression models for bridge clinic visits per provider session, there was a nonsignificant level increase (0.643 P = 0.171) and significant decrease in slope (0.100, P = 0.045) during OCS. After OCS completed, there was a significant level increase (1.442, P = 0.003) and slope increase in visits per provider session (0.141, P = 0.007). There was no significant change in GIM clinic volume during the study period. CONCLUSIONS: The increased policing during OCS was associated with a significant decrease in bridge clinic visits. Following the completion of OCS, there was a significant increase in clinic visits, suggesting pent-up demand for medications for opioid use disorder, a life-saving treatment.

Integrating Harm Reduction into Outpatient Opioid Use Disorder Treatment Settings : Harm Reduction in Outpatient Addiction Treatment.

Opioid use disorder (OUD) is increasingly recognized as a chronic, relapsing brain disease whose treatment should be integrated into primary care settings alongside other chronic conditions. However, abstinence from all non-prescribed substance use continues to be prioritized as the only desired goal in many outpatient, primary care-based treatment programs. This presents a barrier to engagement for patients who continue to use substances and who may be at high risk for complications of ongoing substance use such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), superficial and deep tissue infections, and overdose. Harm reduction aims to reduce the negative consequences of substance use and offers an alternative to abstinence as a singular goal. Incorporating harm reduction principles into primary care treatment settings can support programs in engaging patients with ongoing substance use and facilitate the delivery of evidence-based screening and prevention services. The objective of this narrative review is to describe strategies for the integration of evidence-based harm reduction principles and interventions into outpatient, primary care-based OUD treatment settings. We will offer specific tools for providers and programs including strategies to support safer injection practices, assess the risks and benefits of continuing medications for opioid use disorder in the setting of ongoing substance use, promote a non-stigmatizing program culture, and address the needs of special populations with ongoing substance use including adolescents, parents, and families.

"Health Is on the Back Burner:" Multilevel Barriers and Facilitators to Primary Care Among People Who Inject Drugs.

BACKGROUND: The estimated 2.2 million people who inject drugs (PWID) in the USA experience significant gaps in preventive healthcare and a high burden of infectious, psychiatric, and other chronic diseases. Many PWID rely on emergency medical services, which are costly and not designed to deliver preventive services, manage chronic conditions, or address social needs. OBJECTIVE: The objective of this study was to explore barriers and facilitators to primary care utilization from the perspectives of PWID in New England, a region highly affected by the overdose crisis. DESIGN: Participants completed semi-structured qualitative interviews exploring substance use and healthcare utilization patterns. PARTICIPANTS: We recruited 78 PWID through community-based organizations (e.g., syringe service programs) in 16 urban and non-urban communities throughout Massachusetts and Rhode Island. APPROACH: Thematic analysis identified barriers and facilitators to primary care utilization at the individual, interpersonal, and systemic levels. KEY RESULTS: Among 78 PWID, 48 described recent primary care experiences; 33 had positive experiences and 15 described negative experiences involving discrimination or mistrust. Individual-level barriers to primary care utilization included perceived lack of need and competing priorities (e.g., avoiding opioid withdrawal, securing shelter beds). Interpersonal-level barriers included stigma and perceived low quality of care for PWID. Systemic-level barriers included difficulty navigating healthcare systems, inadequate transportation, long wait times, and frequent provider turnover. Participants with positive primary care experiences explained how appointment reminders, flexible hours, addiction medicine-trained providers, case management services, and transportation support facilitated primary care utilization and satisfaction. CONCLUSIONS: Findings regarding the multilevel barriers and facilitators to accessing primary care among PWID identify potential targets for programmatic interventions to improve primary care utilization in this population. Based on these findings, we make recommendations for improving the engagement of PWID in primary care as a means to advance individual and public health outcomes.

It's Time to Expand Chlamydia Treatment for Gay and Bisexual Men.

Expedited partner therapy involves prescribing sexually transmitted infection (STI) treatment for a patient's partner(s) without seeing the partner. It is approved for heterosexual partners of patients with chlamydia in most states. However, the Centers for Disease Control and Prevention recommends against expedited partner therapy in men-who-have-sex-with-men (MSM), citing limited data in this population and concerns that expedited partner therapy could discourage comprehensive STI testing, thereby driving increased HIV transmission. In this piece, we describe the case of a 33-year-old gay man on HIV pre-exposure prophylaxis (PrEP) whose cycle of chlamydia reinfection might have been prevented by expedited partner therapy. His case highlights how new HIV prevention strategies-including PrEP and Treatment as Prevention-challenge the assumption that all MSM with chlamydia are at risk for HIV. Until more data on expedited partner therapy in MSM are available, clinicians should incorporate characteristics of patients' sexual networks in weighing the risks and benefits of expedited partner therapy.

HIV Pre-exposure Prophylaxis and Buprenorphine at a Drug Detoxification Center During the Opioid Epidemic: Opportunities and Challenges.

Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) and buprenorphine decrease HIV acquisition. Between November, 2016 and July, 2017, we surveyed persons (N = 200) at a drug detoxification center to assess their interest in PrEP and in buprenorphine, and to examine factors associated with such interests. Over the previous 6 months, 58% (117/200) injected drugs, 87% (173/200) used opioids, 50% (85/171) had condomless sex. Only 22% (26/117) of persons who injected drugs were aware of PrEP, yet 74% (86/116) and 72% (84/116) were interested in oral or injectable PrEP, respectively. Thirty-eight percent (47/125) of persons not receiving buprenorphine or methadone expressed interest in buprenorphine. After multivariable adjustment, Latinx ethnicity was associated with interest in PrEP (aOR 3.80; 95% CI 1.37-10.53), while male gender (aOR 2.76; 95% CI 1.21-6.34) was associated with interest in buprenorphine. Opportunities exist to implement PrEP and buprenorphine within drug detoxification centers.Clinical trial registration NCT02869776. Clinicaltrials.gov https://clinicaltrials.gov/ct2/show/NCT02869776?term=Sabrina+Assoumou&cond=HIV+HCV&rank=1 .

An integrated videoconferencing intervention for chronic pain and heavy drinking among patients in HIV-care: a proof-of-concept study.

Chronic pain and heavy drinking are common comorbid conditions among people living with HIV/AIDS (PLWHA). An integrated approach to address these co-occurring conditions in a manner that facilitates treatment utilization would represent an important advance in HIV-care. This study examined the acceptability and feasibility of a tailored, videoconferencing intervention to reduce chronic pain and heavy drinking among PLWHA. Participants in HIV-care (n = 8) completed baseline assessments and an in-person intervention session followed by 6 videoconferencing sessions. Acceptability and feasibility were assessed with patient satisfaction ratings and interview responses 8 weeks following baseline along with videoconferencing use during the intervention period. Treatment satisfaction and comprehensibility ratings were high and supported by interview responses indicating the value of the intervention content, treatment alliance, and format. All participants successfully enabled videoconferencing on their own smartphones and completed a median number of 4.5 (out of 6) video-sessions. Changes in heavy drinking and pain provided additional support for the potential utility of this approach. Results suggest that this videoconferencing intervention is an acceptable and feasible method of addressing chronic pain and heavy drinking among PLWHA. Findings provide the basis for future work to examine the efficacy of this approach in a Stage 1b trial.

Stuck in the window with you: HIV exposure prophylaxis in the highest risk people who inject drugs.

The opioid and polysubstance epidemics could drive a surge in new HIV infections among people who inject drugs (PWID). Longstanding strategies to reduce HIV incidence, including syringe service programs, condom distribution, medications for opioid use disorder, and low-barrier HIV testing and treatment have not been adequate to eliminate transmission in this population. Although HIV pre-exposure prophylaxis (PrEP) is an evidence-based intervention that reduces HIV incidence among PWID, uptake in PWID has lagged due to limited PrEP knowledge, discrepancies between perceived and actual HIV risk, stigma, and structural barriers to adherence including homelessness and incarceration. In our efforts to deploy PrEP to PWID in our low-barrier substance use disorder bridge clinic, we have encountered another barrier: the HIV testing window period. We discuss challenges in delivering HIV exposure prophylaxis to the highest risk PWID, our current approach, and the need for more data to guide best practices.

Intranasal Naloxone for Opioid Overdose.

This JAMA Insights describes indications for naloxone use in preventing opioid overdoses and benefits vs barriers to its availability following FDA approval of its availability without a prescription.

Use of an electronic medical record reminder improves HIV screening.

BACKGROUND: More than 1 in 7 patients with human immunodeficiency virus (HIV) infection in the United States are unaware of their serostatus despite recommendations of US agencies that all adults through age 65 be screened for HIV at least once. To facilitate universal screening, an electronic medical record (EMR) reminder was created for our primary care practice. Screening rates before and after implementation were assessed to determine the impact of the reminder on screening rates. METHODS: A retrospective cohort analysis was performed for patients age 18-65 with visits between January 1, 2012-October 30, 2014. EMR databases were examined for HIV testing and selected patient characteristics. We evaluated the probability of HIV screening in unscreened patients before and after the reminder and used a multivariable generalized linear model to test the association between likelihood of HIV testing and specific patient characteristics. RESULTS: Prior to the reminder, the probability of receiving an HIV test for previously unscreened patients was 15.3%. This increased to 30.7% after the reminder (RR 2.02, CI 1.95-2.09, p < 0.0001). The impact was most significant in patients age 45-65. White race, English as primary language, and higher median household income were associated with lower likelihoods of screening both before and after implementation (RR 0.68, CI 0.65-0.72; RR 0.74, CI 0.67-0.82; RR 0.84, CI 0.80-0.88, respectively). CONCLUSIONS: The EMR reminder increased rates of HIV screening twofold in our practice. It was most effective in increasing screening rates in older patients. Patients who were white, English-speaking, and had higher incomes were less likely to be screened for HIV both before and after the reminder.

An opioid overdose curriculum for medical residents: Impact on naloxone prescribing, knowledge, and attitudes.

BACKGROUND: Despite escalating opioid overdose death rates, addiction medicine is underrepresented in residency curricula. Providing naloxone to at-risk patients, relatives, and first responders reduces overdose deaths, but rates of naloxone prescribing remain low. The goal of this study is to examine the impact of a brief curricular intervention for internal medicine residents on naloxone prescribing rates, knowledge, and attitudes. METHODS: Internal medicine residents (N = 160) at an urban, tertiary care medical center received two 1-hour didactic sessions addressing overdose prevention, including intranasal naloxone. The number of naloxone prescriptions generated by residents was compared to faculty, who received no similar intervention, in the 3-month periods before and after the curriculum. Resident knowledge and attitudes, as assessed by pre- and post-intervention surveys, were compared. RESULTS: The resident naloxone prescribing rate increased from 420 to 1270 per 100,000 inpatient discharges (P = .01) and from 0 to 370 per 100,000 ambulatory visits (P < .001) post-intervention. Similar increases were not observed among inpatient faculty, whose prescribing rate decreased from 1150 to 880 per 100,000 discharges (P = .08), or among outpatient faculty, whose rate increased from 30 to 180 per 100,000 ambulatory visits (P < .001) but was lower than the post-intervention resident rate (P = .01). Residents demonstrated high baseline knowledge about naloxone, but just 13% agreed that they were adequately trained to prescribe pre-intervention. Post-intervention, residents were more likely to agree that they were adequately trained to prescribe (Likert mean 2.5 vs. 3.9, P < .001), to agree that treating addiction is rewarding (Likert mean 2.9 vs. 3.3, P = .03), and to attain a perfect score on the knowledge composite (57% vs. 33%, P = .05). CONCLUSIONS: A brief curricular intervention improved resident knowledge and attitudes regarding intranasal naloxone for opioid overdose reversal and significantly increased prescribing rates.

Early Surgical Excision of Necrotic Tissue Following Unintentional Dermal Injection of Extended-Release Buprenorphine.

INTRODUCTION: Extended-release subcutaneous buprenorphine is an increasingly common treatment for opioid use disorder. Serious adverse events are rare and may be poorly understood. This report describes an early surgical intervention to address tissue necrosis resulting from misplaced subcutaneous buprenorphine injection. We review identifying characteristics that distinguish the necrotic reaction from other adverse effects of subcutaneous buprenorphine and offer guidance to continue treatment with subcutaneous buprenorphine. CASE REPORT: A 33-year-old patient returned to clinic within an hour of his buprenorphine injection, reporting pain and skin changes unlike his previous injections. Non blanching erythema consistent with early necrosis was evident, and the patient was referred for surgical removal of his buprenorphine depot. The patient had uncomplicated healing of the surgical site and was provided sublingual buprenorphine before returning to continue treatment with subcutaneous buprenorphine. DISCUSSION: Although skin necrosis is known to be a rare complication of subcutaneous buprenorphine injection, early surgical excision to limit injury has not been described. Signs and symptoms of skin necrosis must be better understood to facilitate early intervention and continued treatment. CONCLUSIONS: This case affirms that a patient may continue treatment with subcutaneous buprenorphine despite suffering skin necrosis and demonstrates the value of early surgical intervention after superficial placement of extended-release buprenorphine.