Individualizing methadone treatment with split dosing: An underutilized tool.

Methadone's long half-life typically allows for once daily dosing. However, a growing body of evidence and clinical experience shows that some patients may benefit from twice-daily ("split") dosing to produce more stable symptoms and minimize side effects, independent of serum peak-to-trough levels. Concerns regarding split dosing typically center on diversion and poor adherence and must be taken seriously. However, policy changes during COVID-19 demonstrate that the rigidity historically applied to methadone may be unnecessarily stringent. Given clinical advances and policy updates, we believe clinicians should weigh the risks and benefits of this underutilized tool for select patients, as we await the evidence-based recommendations our patients deserve.

HIV Exposure Prophylaxis Delivery in a Low-barrier Substance Use Disorder Bridge Clinic during a Local HIV Outbreak at the Onset of the COVID-19 Pandemic.

OBJECTIVES: People who inject drugs (PWID) may experience high human immunodeficiency virus (HIV) risk and inadequate access to biomedical HIV prevention. Emerging data support integrating HIV post-exposure and pre-exposure prophylaxis (PEP, PrEP) into services already accessed by PWID. We describe PEP/PrEP eligibility and receipt in a low-barrier substance use disorder bridge clinic located in an area experiencing an HIV outbreak among PWID at the onset of the COVID-19 pandemic. METHODS: Retrospective chart review of new patients at a substance use disorder bridge clinic in Boston, MA (January 15, 2020-May 15, 2020) to determine rates of PEP/PrEP eligibility and prescribing. RESULTS: Among 204 unique HIV-negative patients, 85.7% were assessed for injection-related and 23.0% for sexual HIV risk behaviors. Overall, 55/204 (27.0%) met CDC criteria for HIV exposure prophylaxis, including 7/204 (3.4%) for PEP and 48/204 (23.5%) for PrEP. Four of 7 PEP-eligible patients were offered PEP and all 4 were prescribed PEP. Thirty-two of 48 PrEP eligible patients were offered PrEP, and 7/48 (14.6%) were prescribed PrEP. Additionally, 6 PWID were offered PrEP who lacked formal CDC criteria. CONCLUSIONS: Bridge clinics patients have high rates of PEP/PrEP eligibility. The majority of patients with identified eligibility were offered PEP/PrEP, suggesting that upstream interventions that increase HIV risk assessment may support programs in initiating PEP/PrEP care. Additional work is needed to understand why patients declined PEP/PrEP. PrEP offers to PWID who did not meet CDC criteria also suggested provider concern regarding the sensitivity of CDC criteria among PWID. Overall, bridge clinics offer a potential opportunity to increase biomedical HIV prevention service delivery.

Towards an Improved Substance Use Disorder Treatment Landscape in Rhode Island - Barriers, Current Progress, and Next Steps.

Expanding addiction treatment services in Rhode Island has never been more urgent. Today, we face colliding syndemics of COVID-19, preventable drug overdoses, and HIV, with another year of record overdoses. While the treatment of substance use disorder (SUD) is an essential component of general medical care, numerous barriers prevent broader treatment access for patients in Rhode Island. Buprenorphine and methadone therapy have restrictions that are not applied to other areas in medicine, including for more dangerous medications. In this piece, we highlight existing barriers to care, applaud current progress being made in our state, and provide recommendations for next steps to turn the tide of this deadly epidemic. We hope that these proposed changes will help develop a robust treatment landscape for all patients with SUD in Rhode Island.

Characterizing Substance Use Disorders Among Transgender Adults Receiving Care at a Large Urban Safety Net Hospital.

OBJECTIVES: In the midst of the opioid crisis, increasing attention has been given to assessing and addressing substance use disorders (SUDs) among transgender and gender diverse (TGD) populations. As electronic health records begin to more uniformly collect gender identity data, clinicians and public health professionals are better able to examine the prevalence of SUDs and the receipt of SUD treatment services in these populations. METHODS: We utilized cross-sectional electronic health records data from January 2005 to December 2019 from a large safety-net hospital in Massachusetts. A cohort of TGD patients was identified using self-reported gender identity data as well as diagnostic and procedures codes associated with receipt of gender-affirming care (n = 2000). We calculated odds of SUD diagnosis and receipt of medications for SUD among TGD patients. RESULTS: Among a cohort of 2000 TGD patients, 8.8% had a SUD diagnosis. SUD diagnoses were more common among older, Black, and transmasculine patients, as well as those holding public health insurance. SUD diagnoses were less likely among those reporting college-level education. Of those with an opioid use disorder (OUD), 46% were prescribed an FDA-approved medication for OUD. CONCLUSIONS: SUD diagnoses among TGD patients were associated with demographic, socioeconomic, and gender-related factors. We found a modestly lower prevalence of non-tobacco SUD among our cohort of TGD patients than the national average of 7.4%. Despite a relatively better receipt of prescription treatment services than the national average, the low rate of treatment overall represents a missed opportunity to address SUDs in these vulnerable populations.

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.

Individual and partnership factors associated with anticipated versus actual partner notification following STI diagnosis among men who have sex with men and/or with transgender women in Lima, Peru.

OBJECTIVES: A detailed understanding of intentions and practices related to partner notification (PN) following STI diagnosis can improve control strategies. We assessed participant-level and partner-level factors guiding notification behaviour among men who have sex with men and/or with transgender women (MSM-TW) in Lima, Peru, including discordances between anticipated and actual notification. METHODS: Men newly diagnosed with gonorrhoea, chlamydia and/or syphilis between 2012 and 2014 reported recent partners' characteristics, anticipated PN practices, and actual PN outcomes following diagnosis. Generalised estimating equation Poisson regression analyses assessed factors guiding PN outcomes. RESULTS: Participants (n=150) predominantly identified as homosexual (70%) and moderno (versatile sexual role, 55%); 55% of partners (n=402) were casual. Among all sexual partners, 35% were notified of the STI diagnosis, though only 51% of predicted PN occurred and 26% of actual notifications were unanticipated. 47% of participants notified no partners, while 24% notified all partners. PN was more common with stable versus casual (adjusted prevalence ratio (aPR), 95% CI: 0.53, 0.39 to 0.73) or commercial (aPR, 95% CI: 0.38, 0.12 to 1.21) partners, and among participants who perceived PN as normative among their peers (aPR, 95% CI: 1.96, 1.37 to 2.82). A trend towards greater notification following condom-protected intercourse was observed (aPR, 95% CI: 1.33, 0.98 to 1.81). PN frequency did not differ by type of STI diagnosed.Anticipated notification predicted actual notification (aPR, 95% CI: 1.67, 1.19 to 2.33) only imperfectly: 81 (54%) participants' PN practices did not match their anticipated behaviour. Successful notification despite anticipated silence (40 participants, 63 partners) was associated with stable partnerships and a normative perception of PN. Non-notification despite intention (43 participants, 73 partners) frequently occurred among participants reporting exclusively oral sex with the partner or with partners identified as activo (insertive role). CONCLUSIONS: Anticipated notification imperfectly reflects actual PN behaviour. Future interventions to improve PN among MSM-TW in Peru need to acknowledge partnership contexts.

Transgender Women Living with HIV Frequently Take Antiretroviral Therapy and/or Feminizing Hormone Therapy Differently Than Prescribed Due to Drug-Drug Interaction Concerns.

PURPOSE: Both hormone therapy (HT) and antiretroviral therapy (ART) can be lifesaving for transgender women (TW) living with HIV, but each has side effects and potential drug-drug interactions (DDI). We assessed how concerns about HT-ART interactions affect treatment adherence. METHODS: This study used a cross-sectional survey of TW (n = 87) in Los Angeles, CA. RESULTS: Fifty-four percent were living with HIV; 64% used HT. Only 49% of TW living with HIV discussed ART-HT DDI with their provider; 40% reported not taking ART (12%), HT (12%), or both (16%) as directed due to DDI concerns. CONCLUSION: Imperfect HT/ART use and limited provider communication suggests a need for improved HT-ART integration.

The LGBTQI health forum: an innovative interprofessional initiative to support curriculum reform.

Lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI) individuals continue to face barriers to accessing appropriate and comprehensive healthcare. Compounding this problem, healthcare trainees report few training opportunities and low levels of preparedness to care for LGBTQI patients. In 2009, an interprofessional group of students and a faculty advisor at the University of California, San Francisco, developed a novel student-organized LGBTQI Health Forum for medical, dental, pharmacy, nursing, and physical therapy students to deliver LGBTQI health content that was otherwise absent from the formal curriculum. This elective course has evolved based upon participant feedback, emerging educational strategies, and the existing curricula infrastructure at our institution. After eight years of growth, this 10-contact hour weekend elective attracts over 250 participants each year. Plenary sessions deliver foundational terminology and skills to all attendees. Learners then select breakout sessions to attend, allowing for an individualized curriculum based upon specific interests and knowledge gaps. Breakout session topics prioritize traditionally underrepresented aspects of LGBTQI health in professional school curricula. This Forum serves as a model in which to supplement LGBTQI content into existing school curricula and offers an opportunity for interprofessional education. Next steps include conducting a formal evaluation of the curriculum, expanding our performance-based assessments, and potentially implementing a continuing education program for licensed practitioners. With a core group of interprofessional student organizers and a faculty champion, other institutions may view this course architecture as a potential way to offer learners not only LGBTQI content, but other underrepresented subjects into their own educational programs.

Outcome and Impact Evaluation of a Transgender Health Course for Health Profession Students.

PURPOSE: Being transgender is associated with numerous health disparities, and transgender individuals face mistreatment and discrimination in healthcare settings. At the same time, healthcare professionals report inadequate preparation to care for transgender people, and patients often have to teach their own medical providers about transgender care. Our study aimed to evaluate the impact of an elective course for health profession students in transgender health that was implemented to address these gaps in provider knowledge. METHODS: Students participated in a 10-session, lunch-hour elective course during the spring of 2015. To evaluate impact, course participants completed pre-, immediately post-, and 3-month postcourse questionnaires, including a previously validated nine-item transphobia scale, to determine the course's effect on knowledge, attitudes, and beliefs about transgender health. RESULTS: Forty-six students completed the pre- and immediately postelective questionnaire (74% response rate). Compared with pre-elective surveys, immediately postelective scores demonstrated increased knowledge in most domains and reduced transphobia. Specific knowledge domains with improvements included terminology, best practices for collecting gender identity, awareness of the DSM-V gender dysphoria diagnosis, medications used for gender affirmation, and relevant federal policies. A previously validated transphobia scale was found to have good reliability in the current sample. CONCLUSION: This elective course led to positive short-term changes in measures of multiple knowledge domains and reduced measures of transphobia among health profession students. Further study is needed to assess the long-term impact. Our methods and findings, including the demonstration of reliability of a previously validated nine-item transphobia scale, serve as formative data for the future development of theory-based transgender medicine curricula and measures.

Selective protection of zidovudine-induced DNA-damage by the antioxidants WR-1065 and tempol.

The cytokinesis-block micronucleus cytome (CBMN) assay, introduced by Fenech, was used to demonstrate different types of DNA damage in MOLT-3 human lymphoblastoid cells exposed to 10 µM zidovudine (AZT). In addition, we explored the cytoprotective potential of two antioxidants, WR-1065 and Tempol, to decrease AZT-induced genotoxicity. Binucleated cells, arrested by Cytochalasin B (Cyt B), were evaluated for micronuclei (MN), caused by DNA damage or chromosomal loss, and chromatin nucleoplasmic bridges (NPBs), caused by telomere attrition. Additionally, nuclear buds (NBUDs), caused by amplified DNA, and apoptotic and necrotic (A/N) cells were scored. We hypothesized that AZT exposure would increase the frequency of genotoxic end points, and that the antioxidants Tempol and WR-1065 would protect against AZT-induced genotoxicity. MOLT-3 cells were exposed to 0 or 10 µM AZT for a total of 76 hr. After the first 24 hr, 0 or 5 µM WR-1065 and/or 0 or 200 µM Tempol were added for the remainder of the experiment. For the last 28 hr (of 76 hr), Cyt B was added to arrest replication after one cell division, leaving a predominance of binucleated cells. The nuclear division index (NDI) was similar for all treatment groups, indicating that the exposures did not alter cell viability. MOLT-3 cells exposed to AZT alone had significant (P < 0.05) increases in MN and NBs, compared to unexposed cells. Both Tempol and WR-1065 protected against AZT-induced MN formation (P < 0.003 for both), and WR-1065, but not Tempol, reduced the levels of A/N (P = 0.041). In cells exposed to AZT/Tempol there were significantly reduced levels of NBUDs, compared to cells exposed to AZT alone (P = 0.015). Cells exposed to AZT/WR-1065 showed reduced levels of NPBs, compared to cells exposed to AZT alone (P = 0.037). Thus WR-1065 and Tempol protected MOLT-3 cells against specific types of AZT-induced DNA damage.

Long-term AZT exposure alters the metabolic capacity of cultured human lymphoblastoid cells.

The antiretroviral efficacy of 3'-azido-3'-deoxythymidine (AZT) is dependent upon intracellular mono-, di-, and triphosphorylation and incorporation into DNA in place of thymidine. Thymidine kinase 1 (TK-1) catalyzes the first step of this pathway. MOLT-3, human lymphoblastoid cells, were exposed to AZT continuously for 14 passages (P(1)-P(14)) and cultured for an additional 14 passages (P(15)-P(28)) without AZT. Progressive and irreversible depletion of the enzymatically active form of the TK-1 24-kDa monomer with loss of active protein was demonstrated during P(1)-P(5) of AZT exposure. From P(15) to P(28), both the 24- and the 48-kDa forms of TK-1 were undetectable and a tetrameric 96-kDa form was present. AZT-DNA incorporation was observed with values of 150, 133, and 108 molecules of AZT/10(6) nucleotides at the 10 microM plasma-equivalent AZT dose at P(1), P(5), and P(14), respectively. An exposure-related increase in the frequency of micronuclei (MN) was observed in cells exposed to either 10 or 800 microM AZT during P(1)-P(14). Analysis of the cell cycle profile revealed an accumulation of S-phase cells and a decrease in G(1)-phase cells during exposure to 800 microM AZT for 14 passages. When MOLT-3 cells were grown in AZT-free media (P(15)-P(29)), there was a reduction in AZT-DNA incorporation and MN formation; however, TK-1 depletion and the persistence of S-phase delay were unchanged. These data suggest that in addition to known mutagenic mechanisms, cells may become resistant to AZT partially through inactivation of TK-1 and through modulation of cell cycle components.

Centrosomal amplification and aneuploidy induced by the antiretroviral drug AZT in hamster and human cells.

The centrosome directs chromosomal migration by a complex process of tubulin-chromatin binding. In this contribution centrosomal abnormalities, including centrosomal amplification, were explored in Chinese hamster ovary (CHO) and normal human mammary epithelial cells (NHMECs) exposed to the antiretroviral drug zidovudine (3'-azido-3'-deoxythymidine, AZT). Centrosomal amplification/fragmentation was observed in both cell types and kinetochore positive micronuclei were found in AZT-exposed CHO cells in correlation with dose. Normal human mammary epithelial cell (NMHEC) strain M99005, previously identified as a strain that incorporates high levels of AZT into DNA (high incorporator, HI), showed greater centrosomal amplification when compared with a second strain, NHMEC M98040, which did not incorporate AZT into DNA (low incorporator, LI). Additionally, an abnormal tubulin distribution was observed in AZT-exposed HI cells bearing multiple centrosomes. Immunofluorescent staining of human cells with Aurora A, a kinase involved in the maturation of the centrosome, confirmed the induction of centrosomal amplification and revealed multipolar mitotic figures. Flow cytometric studies revealed that cells bearing abnormal numbers of centrosomes and abnormal tubulin distribution had similar S-phase percentages suggesting that cells bearing unbalanced chromosomal segregation could divide. Therefore, AZT induces genomic instability and clastogenicity as well as alterations in proteins involved in centrosomal activation, all of which may contribute to the carcinogenic properties of this compound.