Despite elevated mortality in people with HIV (PWH) using drugs, drug-related deaths are poorly characterized. Among 6764 drug-related deaths, methamphetamine was more common in PWH than others. One in 4 deaths in PWH involved acute infection. Combatting mortality in PWH who use drugs should include stimulant-specific and infection prevention efforts

Appa, Ayesha

Coffin, Phillip

Hessol, Nancy A

Rowe, Christopher

eScholarship - University of California

UCSFUC San Francisco Previously Published WorksTitleBeyond Overdose: Drug-Related Deaths in People With and Without HIV in San Francisco, 2007–2018Permalinkhttps://escholarship.org/uc/item/47q9j9qhJournalOpen Forum Infectious Diseases, 7(12)ISSN2328-8957AuthorsAppa, AyeshaRowe, ChristopherHessol, Nancy Aet al.Publication Date2020-12-01DOI10.1093/ofid/ofaa565 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaB R I E F  R E P O R TOpen Forum Infectious DiseasesBRIEF REPORT • ofid • 1 Received 8 September 2020; editorial decision 10 November 2020; accepted 12 November 2020.Correspondence: Ayesha Appa, MD, University of California, San Francisco, Zuckerberg San Francisco General, Division of HIV, Infectious Diseases & Global Medicine, 995 Potrero Avenue, Building 80, Box 0874, San Francisco, CA 94110 (ayesha.appa@ucsf.edu).Open Forum Infectious Diseases®2020© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comDOI: 10.1093/ofid/ofaa565Beyond Overdose: Drug-Related Deaths in People With and Without HIV in San Francisco, 2007–2018Ayesha Appa,1,  Christopher Rowe,2 Nancy A. Hessol,2,3 and Phillip Coffin21Zuckerberg San Francisco General Division of HIV, ID, and Global Medicine, University of California San Francisco, San Francisco, California, USA, 2San Francisco Department of Public Health, San Francisco, California, USA, and 3Departments of Clinical Pharmacy and of Medicine, University of California San Francisco, San Francisco, California, USADespite elevated mortality in people with HIV (PWH) using drugs, drug-related deaths are poorly characterized. Among 6764 drug-related deaths, methamphetamine was more common in PWH than others. One in 4 deaths in PWH in-volved acute infection. Combatting mortality in PWH who use drugs should include stimulant-specific and infection preven-tion efforts.Keywords. cause of death; drug overdose; HIV infections; infections.Amidst a national crisis related to soaring rates of drug use and overdose, reducing mortality among people with HIV (PWH) in the United States remains a challenge. In San Francisco, PWH who have a history of injecting drugs have nearly double the 3-year mortality compared with all PWH in San Francisco (21% vs 11%) [1]. In the general US population, the incidence rates of drug overdose and invasive bacterial infections related to drug use have risen in the last decade [2]. However, our un-derstanding of causes of death among PWH who use drugs (including alcohol) has been limited, and few studies have in-vestigated specific causes of drug-related death beyond over-dose [3]. We are unaware of investigations designed to compare drug-related causes of death in people with and without HIV. We sought to compare drug-related deaths and associated causes of death in those with and without HIV in order to in-form targeted interventions to reduce mortality among PWH who use drugs.METHODSStudy Design and PopulationThis was a cross-sectional study of decedents who died from drug-related causes (including alcohol) in San Francisco from January 1, 2007, through December 31, 2018. Decedents aged 14 years or older were identified by obtaining all San Francisco drug-related death records from the California Electronic Death Reporting System (CA-EDRS). Demographic data, causes of death, significant conditions contributing to death, and substances involved in death were obtained. These methods, as well as the San Francisco Chief Medical Examiner’s Forensic Laboratory Division tox-icology screening processes, have previously been described [4]. Using a computational search of causes of death and/or significant condition fields for recreational drugs excluding tobacco (eg, alcohol, heroin, fentanyl, methamphetamine, cocaine, and others) (Supplementary Appendix A), a total of 7056 drug-related deaths were identified. After physician re-view (A.A.), 292 decedents were excluded because the death was not due to illicit drugs, yielding a final sample size of 6764 decedents.To identify decedents who had HIV, we next performed a computational search of death certificate fields for the following terms: “HIV,” “human immunodeficiency virus,” “AIDS,” and “acquired immunodeficiency syndrome,” and 223 decedents were identified. To address the possibility that this method of identification led to an underascertainment of deaths among PWH, we compared the number of deaths among people who had HIV noted on the death certificate with that in the San Francisco Department of Public Health HIV surveillance database. Among this database of all individuals diagnosed with HIV in San Francisco, there was a similar number of San Francisco deaths that listed drug overdose as a cause of death among PWH between 2007 and 2018 [1], suggesting that our approach was sufficient.Classification of Drug-Related DeathsAll drug-related deaths were further classified based on their proximal cause of death, and each death could have multiple classifications. After manual review of a random sample of 100 records weighted by death year, the following categories were established for coding deaths: overdose, acute infection, non-infectious medical complication, trauma or violence, or other miscellaneous cause. The cause of death and significant condi-tion fields were computationally searched for a list of terms cor-responding with each category (Supplementary Appendix B). Each decedent record was then manually reviewed by A.A. to applyparastyle “fig//caption/p[1]” parastyle “FigCapt”2 • ofid • BRIEF REPORTensure classification accuracy, and a subset was secondarily re-viewed for internal consistency by P.C.Statistical AnalysisWe performed chi-square and Fisher exact tests to compare dem-ographic characteristics and substances involved in death be-tween decedents with and without HIV. A separate multivariable logistic regression model evaluated the relationship between HIV status of the decedent (independent variable) and each cause of death category described above (overdose, acute infection, a non-infectious medical cause, trauma or violence, or other; dependent variables), adjusting for the following independent variables; de-cedent age, biological sex, and race/ethnicity. All analyses were performed using Stata 16 (College Station, TX, USA).Patient Consent StatementPatient consent was not obtained, as all data were de-identified before use, and this study was deemed exempt by the University of California, San Francisco, Institutional Review Board (IRB #: 19-27119).RESULTSBetween 2007 and 2018 in San Francisco, 6764 individuals died related to drug use, and 223 of these decedents had HIV noted on their death certificate. The median age was younger among PWH than those without HIV (50 vs 53  years, re-spectively) (Table  1). Stimulants, including cocaine, am-phetamine, methamphetamine, and methylphenidate, were involved in 40% (n  =  90) of drug-related deaths among PWH compared with 29% (n = 1919) of those without HIV (P  <  .01). Similarly, methamphetamine-related deaths were more common among PWH than those without HIV (21% vs 13%; P < .01). In contrast, alcohol-related deaths were less common among PWH (26%) than those without HIV (26% vs 46%; P < .01).Table 1.  Characteristics of Drug-Related Deaths in San Francisco Between 2007 and 2018, by HIV StatusDecedents With HIV (n = 223)Decedents Without HIV (n = 6541) P ValueAge, median (IQR), y 50 (45–56) 53 (42–61) .02Male sex 80 (178) 77 (5020) .33Race/ethnicity, % (No.)     White 59 (130) 54 (3518) .19 Black/African American 26 (58) 21 (1379) .08 Hispanic/Latinx 8 (17) 15 (978) <.01 Asian/Pacific Islander 3 (7) 6 (391) .08 Other/unknown 4 (8) 3 (189) .54Drugs involved, % (No.)     Any opioid 26 (58) 26 (1696) .98 Heroin 2 (5) 6 (373) .03 Fentanyl 2 (4) 3 (215) .22 Any stimulanta 40 (90) 29 (1919) <.01 Cocaine/crack 22 (48) 19 (1211) .26 Methamphetamine 21 (46) 13 (878) <.01 Alcohol 26 (57) 46 (3029) <.01 Any benzodiazepines 6 (13) 7 (466) .55Proximal cause of drug-related death, % (No.)     Overdose 38 (84) 37 (2444) .93 Acute infection 26 (58) 8 (523) <.01 Noninfectious medical cause of death 37 (83) 38 (2500) .76 Trauma/violence 3 (7) 14 (934) <.01 Other 6 (14) 9 (609) .12Infections listed as cause of death,b % (No.)     Sepsis and septic shock 31 (20/65) 49 (256/523)   Pneumonia 29 (19/65) 41 (213/523)   Endocarditis 8 (5/65) 8 (42/523)   Skin and soft tissue infection 2 (1/65) 7 (36/523)   Bacteremia 3 (2/65) 5 (25/523)   Otherc 49 (32/65) 15 (78/523)  Abbreviation: IQR, interquartile range.aSearch terms included cocaine, amphetamine, methamphetamine, and methylphenidate.bNot mutually exclusive. Specific infections with >5% prevalence in at least 1 category of decedents are listed as separate line items.cOther infections excluded those listed above and included any of the following: necrotizing soft tissue infection, empyema, peritonitis, Clostridium difficile colitis, other abdominal infection, urinary tract infection, meningitis, and other infections listed in Supplementary Appendix B.BRIEF REPORT • ofid • 3Acute infection was more commonly involved in drug-related deaths among PWH than decedents without HIV (26%, n = 58; vs 8%, n  =  523; P  <  .01), while drug-related deaths involving trauma or violence were less common (3%, n  =  7; vs 14%, n = 934; P < .01). Compared with those without HIV, PWH had a >5-fold increased adjusted odds of acute infection involved in drug-related death (adjusted odds ratio, 5.58; 95% CI, 4.02–7.74) (Supplementary Figure 1). The manner of reporting the specific infection that led to death is not standardized on death certifi-cates, but the most commonly described specific infections re-ported as a cause of death included sepsis or septic shock (31% of PWH with an infection-related death vs 49% without HIV with an infection-related death), pneumonia (29% vs 41%), endocar-ditis (8% vs 8%), skin and soft tissue infection (2% vs 7%), and bacteremia (3% vs 5%). The remainder of infections were either <5% prevalent in either category of decedents or nonspecific (ie, listed as “bacterial infection,” “infectious complication of drug use,” etc.) (Table 1; Supplementary Appendix B).DISCUSSIONIn this cross-sectional study of drug-related deaths among per-sons with and without HIV, we observed that stimulants, in par-ticular methamphetamine, were more commonly implicated in drug-related death in PWH and that acute infection contrib-uted more to drug-related death among PWH compared with those without HIV.Methamphetamine and other stimulants are known to cause disproportionately higher morbidity among PWH compared with those without HIV, including potentiated HIV neurotoxicity, HIV viremia, and progression to AIDS [5], although few studies have addressed mortality and quantified the burden of specific drugs involved in death among PWH. Although a mortality-focused study reported that stimulant use was not associated with an in-creased odds of all-cause mortality among PWH [6], our finding that 1 in 5 drug-related deaths among PWH involves metham-phetamine helps establish the importance of stimulant-specific programming in the world of drug-related death prevention, par-ticularly for PWH. Many may consider overdose prevention syn-onymous with opioid overdose prevention, but this work suggests that nascent methamphetamine-focused efforts should be en-couraged. Relatedly, prior work has identified a strong connection between methamphetamine use and sexual risk behaviors leading to HIV transmission [5–9], suggesting that future study should in-clude not only mortality, but also nuanced understanding of pat-terns and motivations to use particular substances among specific epidemiologic groups, as this may also help mitigate harm.In the last decade, over one-quarter of drug-related deaths among PWH in San Francisco involved an acute infection. We have long known that HIV and drug use are associated with in-creased risk of infection for many reasons, both independently and together. For example, multiple studies have demonstrated that PWH have an elevated risk of community-acquired pneu-monia, although PWH who use drugs may have the highest risk of pneumonia [10]. Opioids have been associated with invasive pneumococcal disease, due in part to opioid-induced immuno-suppression [11], and methamphetamine has been associated with impaired cellular immunity [12]. In addition to the mech-anistic likelihood that drugs themselves confer increased risk of infection, drug use has been associated with infection related to nonsterile injection practices, skin picking, etc. Mitigating factors with evidence of clinical benefit include syringe serv-ices [13] and vaccination programs [10], but people who use drugs may be least likely to be successfully vaccinated for many common infections [14]. These findings warrant further in-vestigation into the effectiveness of expanding the depth and breadth of current harm reduction programming, safe con-sumption services (eg, safer injection services and services for noninjection practices), and vaccination efforts.Our study was subject to a number of important limitations. Chief among them is recognizing the subjective nature of med-ical examiner determinations of cause of death and signifi-cant contributing conditions, which may be vulnerable to bias and inconsistent documentation. However, these data remain the most valuable source to understand drug-related deaths. Second, the cross-sectional nature of these data limits our ability to understand or comment on substance use patterns be-fore death. That said, prior work has noted consistency between patterns of drug use before and at death [15].In conclusion, among drug-related deaths in San Francisco from 2007 to 2018, methamphetamine was more commonly implicated in deaths among PWH compared with those without HIV, and over one-quarter of drug-related deaths among PWH involved an acute infection. In addition to opioid overdose prevention, health care providers serving PWH who use drugs should consider incorporating stimulant-specific efforts into drug-related death prevention, as well as enhanced efforts to prevent infection, such as expansion of harm reduction services and vaccination promotion.Supplementary DataSupplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.AcknowledgmentsFinancial support.  This work was supported by the National Institutes of Health grants 5T32AI007641-17, K24DA042720, and R25DA033211. This study was also partially funded through the Centers for Disease Control and Prevention cooperative agreement number NU62PS924536-01-00 to the San Francisco Department of Public Health. The funders had no role in study design, data collection and analysis, decision to publish, or prepara-tion of the manuscript.Potential conflicts of interest. None of the authors have conflicts of in-terest to disclose. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.4 • ofid • BRIEF REPORTReferences1. Department of Public Health | HIV Epidemiology Section. HIV/AIDS Programs & Research. Available at: https://www.sfdph.org/dph/comupg/oprograms/HIVepiSec/HIVepiSecReports.asp. Accessed 30 August 2020.2. McCarthy NL, Baggs J, See I, et al. Bacterial infections associated with substance use disorders, large cohort of United States Hospitals, 2012–2017. Clin Infect Dis. 2020. 3. Bosh K, Crepaz N, Dong X, et al. Opioid overdose deaths among persons with HIV infection, United States, 2011–2015. Available at: https://www.croiconference.org/abstract/opioid-overdose-deaths-among-persons-hiv-infection-united-states-2011–2015/. Accessed 30 August 2020.4. Turner C, Chandrakumar D, Rowe C, et al. Cross-sectional cause of death com-parisons for stimulant and opioid mortality in San Francisco, 2005–2015. Drug Alcohol Depend 2018; 185:305–12.5. Urbina A, Jones K. Crystal methamphetamine, its analogues, and HIV infection: med-ical and psychiatric aspects of a new epidemic. Clin Infect Dis 2004; 38:890–4.6. Carrico  AW, Shoptaw  S, Cox  C, et  al. Stimulant use and progression to AIDS or mortality after the initiation of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2014; 67:508–13.7. Colfax G, Shoptaw S. The methamphetamine epidemic: implications for HIV pre-vention and treatment. Curr HIV/AIDS Rep 2005; 2:194–9.8. Shoptaw S, Reback CJ. Methamphetamine use and infectious disease-related be-haviors in men who have sex with men: implications for interventions. Addiction 2007; 102(Suppl 1):130–5.9. Shoptaw  S, Reback  CJ. Associations between methamphetamine use and HIV among men who have sex with men: a model for guiding public policy. J Urban Health 2006; 83:1151–7.10. Dworkin MS, Ward JW, Hanson DL, et al; Adult and Adolescent Spectrum of HIV Disease Project. Pneumococcal disease among human immunodeficiency virus-infected persons: incidence, risk factors, and impact of vaccination. Clin Infect Dis 2001; 32:794–800.11. Edelman  EJ, Gordon  KS, Crothers  K, et  al. Association of prescribed opioids with increased risk of community-acquired pneumonia among patients with and without HIV. JAMA Intern Med 2019; 179:297–304.12. Potula R, Hawkins BJ, Cenna JM, et al. Methamphetamine causes mitrochondrial oxidative damage in human T lymphocytes leading to functional impairment. J Immunol 2010; 185:2867–76.13. Centers for Disease Control and Prevention. Summary of information on the safety and effectiveness of syringe services programs (SSPs). 2019. Available at: https://www.cdc.gov/ssp/syringe-services-programs-summary.html. Accessed 30 August 2020.14. Chen H, Cantrell CR. Prevalence and factors associated with self-reported vacci-nation rates among US adults at high risk of vaccine-preventable hepatitis. Curr Med Res Opin 2006; 22:2489–96.15. Calcaterra S, Binswanger IA. Psychostimulant-related deaths as reported by a large national database. Subst Abus 2013; 34:10.1080/08897077.2012.726959. 

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