With the adoption of combination antiretroviral therapy (ART), most HIV-infected individuals in care are on five or more medications and at risk of harm from polypharmacy, a risk that likely increases with number of medications, age, and physiologic frailty. Established harms of polypharmacy include decreased medication adherence and increased serious adverse drug events, including organ system injury, hospitalization, geriatric syndromes (falls, fractures, and cognitive decline) and mortality. The literature on polypharmacy among those with HIV infection is limited, and the literature on polypharmacy among non-HIV patients requires adaptation to the special issues facing those on chronic ART. First, those aging with HIV infection often initiate ART in their 3rd or 4th decade of life and are expected to remain on ART for the rest of their lives. Second, those with HIV may be at higher risk for age-associated comorbid disease, further increasing their risk of polypharmacy. Third, those with HIV may have an enhanced susceptibility to harm from polypharmacy due to decreased organ system reserve, chronic inflammation, and ongoing immune dysfunction. Finally, because ART is life-extending, nonadherence to ART is particularly concerning. After reviewing the relevant literature, we propose an adapted framework with which to address polypharmacy among those on lifelong ART and suggest areas for future work.

Background HIV infected (HIV+) individuals may be more susceptible to alcohol-related harm than uninfected individuals. Methods We analyzed data on HIV+ and uninfected individuals in the Veterans Aging Cohort Study (VACS) with an Alcohol Use Disorders Identification Test-Consumption AUDIT-C score from 2008–2012. We used Cox proportional hazards models to examine the association between alcohol exposure and mortality through July, 2014; and linear regression models to assess the association between alcohol exposure and physiologic injury based on VACS Index Scores. Models were adjusted for age, race/ethnicity, smoking, and Hepatitis C infection. Results The sample included 18,145 HIV+ and 42,228 uninfected individuals. Among HIV+ individuals, 76% had undetectable HIV-1 RNA (<500 copies/ml). The threshold for an association of alcohol use with mortality and physiologic injury differed by HIV status. Among HIV+ individuals, AUDIT-C score ≥4 (hazard ratio [HR] 1.25, 95% CI 1.09–1.44) and ≥30 drinks per month (HR, 1.30, 95% CI 1.14–1.50) were associated with increased risk of mortality. Among uninfected individuals, AUDIT-C score ≥5 (HR, 1.19, 95% CI 1.07–1.32) and ≥70 drinks per month (HR 1.13, 95% CI 1.00–1.28) were associated with increased risk. Similarly, AUDIT-C threshold scores of 5–7 were associated with physiologic injury among HIV+ individuals (beta 0.47, 95% CI 0.22, 0.73) and a score of 8 or more was associated with injury in uninfected (beta 0.29, 95% CI 0.16, 0.42) individuals. Conclusions Despite antiretroviral therapy, HIV+ individuals experienced increased mortality and physiologic injury at lower levels of alcohol use compared with uninfected individuals. Alcohol consumption limits should be lower among HIV+ individuals.

Methadone for opioid use disorder can be dispensed only from US Substance Abuse and Mental Health Services Administration (SAMHSA)-certified opioid treatment programs (OTPs), creating access barriers in rural counties with a shortage of facilities. Canada and Australia allow primary care prescribing and pharmacy dispensing of methadone to expand access. 1 Therefore, we examined drive times to the nearest OTP in urban and rural counties in 5 US states with the highest county rates of opioid-related overdose mortality. 2 In addition, we compared drive times to federally qualified health centers (FQHCs) as potential primary care methadone-prescribing locations and to dialysis centers as treatment locations for a different chronic disease requiring frequent engagement. Methods |The outcome was the minimum drive time in minutes from the county mean center of population to the nearest OTP, FQHC, and dialysis center using the Esri ArcGIS rural drive-time tool (September 2017 version), which simulates automobile movement between 2 points along a national street network based on historical average speeds. 3 From the 2010 US Census, we obtained the coordinates of the county mean center of population for all counties in Indiana, Kentucky, Ohio, Virginia, and West Virginia, excluding counties with geographic changes after the census. We geocoded 2017 OTP, FQHC, and dialysis center street addresses from the SAMHSA OTP Directory

IMPORTANCE Some opioids are known immunosuppressants; however, the association of prescribed opioids with clinically relevant immune-related outcomes is understudied, especially among people living with HIV.OBJECTIVE To assess the association of prescribed opioids with community-acquired pneumonia (CAP) by opioid properties and HIV status. DESIGN, SETTING, AND PARTICIPANTSThis nested case-control study used data from patients in the Veterans Aging Cohort Study (VACS) from January 1, 2000, through December 31, 2012. Participants in VACS included patients living with and without HIV who received care in Veterans Health Administration (VA) medical centers across the United States. Patients with CAP requiring hospitalization (n = 4246) were matched 1:5 with control individuals without CAP (n = 21 146) by age, sex, race/ethnicity, length of observation, and HIV status. Data were analyzed from March 15, 2017, through August 8, 2018.EXPOSURES Prescribed opioid exposure during the 12 months before the index date was characterized by a composite variable based on timing (none, past, or current); low (<20 mg), medium (20-50 mg), or high (>50 mg) median morphine equivalent daily dose; and opioid immunosuppressive properties (yes vs unknown or no). MAIN OUTCOME AND MEASURE CAP requiring hospitalization based on VA and Centers for Medicare & Medicaid data.RESULTS Among the 25 392 VACS participants (98.9% male; mean [SD] age, 55 [10] years), current medium doses of opioids with unknown or no immunosuppressive properties (adjusted odds ratio [AOR], 1.35; 95% CI, 1.13-1.62) and immunosuppressive properties (AOR, 2.07; 95% CI, 1.50-2.86) and current high doses of opioids with unknown or no immunosuppressive properties (AOR, 2.07; 95% CI, 1.50-2.86) and immunosuppressive properties (AOR, 3.18; 95% CI, 2.44-4.14) were associated with the greatest CAP risk compared with no prescribed opioids or any past prescribed opioid with no immunosuppressive (AOR, 1.24; 95% CI, 1.09-1.40) and immunosuppressive properties (AOR, 1.42; 95% CI, 1.21-1.67), especially with current receipt of immunosuppressive opioids. In stratified analyses, CAP risk was consistently greater among people living with HIV with current prescribed opioids, especially when prescribed immunosuppressive opioids (eg, AORs for current immunosuppressive opioids with medium dose, 1.76 [95% CI, 1.20-2.57] vs 2.33 [95% CI, 1.60-3.40]).CONCLUSIONS AND RELEVANCE Prescribed opioids, especially higher-dose and immunosuppressive opioids, are associated with increased CAP risk among persons with and without HIV.

Post-release opioid-related overdose mortality is the leading cause of death among people released from jails or prisons (PRJP). Informed by the proximate determinants framework, this paper presents the Post-Release Opioid-Related Overdose Risk Model. It explores the underlying, intermediate, proximate and biological determinants which contribute to risk of post-release opioid-related overdose mortality. PRJP share the underlying exposure of incarceration and the increased prevalence of several moderators (chronic pain, HIV infection, trauma, race, and suicidality) of the risk of opioid-related overdose. Intermediate determinants following release from the criminal justice system include disruption of social networks, interruptions in medical care, poverty, and stigma which exacerbate underlying, and highly prevalent, substance use and mental health disorders. Subsequent proximate determinants include interruptions in substance use treatment, including access to medications for opioid use disorder, polypharmacy, polydrug use, insufficient naloxone access, and a return to solitary opioid use. This leads to the final biological determinant of reduced respiratory tolerance and finally opioid-related overdose mortality. Mitigating the risk of opioid-related overdose mortality among PRJP will require improved coordination across criminal justice, health, and community organizations to reduce barriers to social services, ensure access to health insurance, and reduce interruptions in care continuity and reduce stigma. Healthcare services and harm reduction strategies, such as safe injection sites, should be tailored to the needs of PRJP. Expanding access to opioid agonist therapy and naloxone around the post-release period could reduce overdose deaths. Programs are also needed to divert individuals with substance use disorder away from the criminal justice system and into treatment and social services, preventing incarceration exposure.

Aims To estimate the influence of non-medical use of prescription opioids (NMUPO) on heroin initiation among U.S. veterans receiving medical care. Design Using a multivariable Cox regression model, we analyzed data from a prospective, multi-site, observational study of HIV-positive and an age/race/site matched control group of HIV-negative veterans in care in the United States. Approximately annual behavioral assessments were conducted and contained self-reported measures of NMUPO and heroin use. Setting Veterans Health Administration (VHA) infectious disease and primary care clinics in Atlanta, Baltimore, New York, Houston, Los Angeles, Pittsburgh, and Washington, DC. Participants A total of 3,396 HIV-infected and uninfected patients enrolled in the Veterans Aging Cohort Study who reported no lifetime NMUPO or heroin use, had no opioid use disorder diagnoses at baseline, and who were followed between 2002 and 2012. Measurements The primary outcome measure was self-reported incident heroin use and the primary exposure of interest was new onset NMUPO. Our final model was adjusted for sociodemographics, pain interference, prior diagnoses of post-traumatic stress disorder and/or depression, and self-reported other substance use. Findings Using a multivariable Cox regression model, we found that NMUPO was positively and independently associated with heroin initiation (adjusted hazard ratio [AHR] = 5.43, 95%CL: 4.01, 7.35). Conclusions New onset non-medical use of prescription opioids (NMUPO) is a strong risk factor for heroin initiation among HIV-infected and uninfected veterans in the United States who reported no previous history of NMUPO or illicit opioid use.

Pre-exposure prophylaxis for HIV (PrEP) is recommended for people who inject drugs (PWID). Despite their central role in disease prevention, willingness to prescribe PrEP to PWID among primary care physicians (PCPs) is largely understudied. We conducted an online survey (April – May 2015) of members of a society for academic general internists regarding PrEP. Among 250 respondents, 74% (n=185) of PCPs reported high willingness to prescribe PrEP to PWID. PCPs were more likely to report high willingness to prescribe PrEP to all other HIV risk groups (p’s<0.03 for all pair comparisons). Compared with PCPs delivering care to more HIV-infected clinic patients, PCPs delivering care to fewer HIV-infected patients were more likely to report low willingness to prescribe PrEP to PWID (Odds Ratio [95% CI]= 6.38 [1.48–27.47]). PCP and practice characteristics were not otherwise associated with low willingness to prescribe PrEP to PWID. Interventions to improve PCPs’ willingness to prescribe PrEP to PWID are needed.

The previously undescribed heterozygous missense mutation E758K was discovered in the human AE1/SLC4A1/band 3 gene in two unrelated patients with well-compensated hereditary spherostomatocytic anemia (HSt). Oocyte surface expression of AE1 E758K, in contrast to that of wild-type AE1, required coexpressed glycophorin A (GPA). The mutant polypeptide exhibited, in parallel, strong GPA dependence of DIDS-sensitive (36)Cl(-) influx, trans-anion-dependent (36)Cl(-) efflux, and Cl(-)/HCO(3)(-) exchange activities at near wild-type levels. AE1 E758K expression was also associated with GPA-dependent increases of DIDS-sensitive pH-independent SO(4)(2-) uptake and oxalate uptake with altered pH dependence. In marked contrast, the bumetanide- and ouabain-insensitive (86)Rb(+) influx associated with AE1 E758K expression was largely GPA-independent in Xenopus oocytes and completely GPA-independent in Ambystoma oocytes. AE1 E758K-associated currents in Xenopus oocytes also exhibited little or no GPA dependence. (86)Rb(+) influx was higher but inward cation current was lower in oocytes expressing AE1 E758K than previously reported in oocytes expressing the AE1 HSt mutants S731P and H734R. The pharmacological inhibition profile of AE1 E758K-associated (36)Cl(-) influx differed from that of AE1 E758K-associated (86)Rb(+) influx, as well as from that of wild-type AE1-mediated Cl(-) transport. Thus AE1 E758K-expressing oocytes displayed GPA-dependent surface polypeptide expression and anion transport, accompanied by substantially GPA-independent, pharmacologically distinct Rb(+) flux and by small, GPA-independent currents. The data strongly suggest that most of the increased cation transport associated with the novel HSt mutant AE1 E758K reflects activation of endogenous oocyte cation permeability pathways, rather than cation translocation through the mutant polypeptide.