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BACKGROUND: Hepatitis C virus (HCV) infection can be cured, and the United States has joined the World Health Organization in calling for HCV elimination by 2030. However, historically low uptake of HCV treatment among people who inject drugs (PWID) threatens HCV elimination and exacerbates social and racial health disparities. OBJECTIVE: To assess whether all-oral HCV treatments were accessed by PWID and reduced liver disease burden and mortality. DESIGN: Community-based, longitudinal cohort study of persons with a history of injection drug use. SETTING: Baltimore, Maryland. PARTICIPANTS: 1323 participants enrolled in the ALIVE (AIDS Linked to the IntraVenous Experience) study from 2006 to 2019 and chronically infected with HCV. MEASUREMENTS: Liver stiffness measures (LSMs) by transient elastography, HCV RNA, and mortality from the National Death Index. RESULTS: Among 1323 persons with evidence of chronic HCV infection at baseline, the median age was 49 years. Most were Black (82%), male (71%), and HIV-negative (66%). The proportion in whom HCV RNA was detected decreased from 100% in 2006 to 48% in 2019. Across 10 350 valid LSMs, cirrhosis was detected in 15% of participants in 2006, 19% in 2015, and 8% in 2019. Undetectable HCV RNA was significantly associated with reduced odds of cirrhosis (adjusted odds ratio, 0.28 [95% CI, 0.17 to 0.45]) and reduced all-cause mortality risk (adjusted hazard ratio, 0.54 [CI, 0.38 to 0.77]). LIMITATION: Noninvasive markers of liver fibrosis have not been validated in persons with sustained virologic response. CONCLUSION: Many community-based PWID in Baltimore are receiving HCV treatment, which is associated with sharp decreases in liver disease and mortality. Additional efforts will be needed to reduce residual barriers to treatment and to eliminate HCV as a public health threat for PWID. PRIMARY FUNDING SOURCE: National Institutes of Health.

Objective: People who inject drugs are a population who are often unengaged with health care services. The objective of this study was to characterize COVID-19 vaccine hesitancy and uptake in a community-based sample of people who inject drugs in Baltimore, Maryland. Methods: The ALIVE study (AIDS Linked to the IntraVenous Experience) in Baltimore is a community-based cohort study of people with a history of injection drug use. From March 2 through June 28, 2021, 346 ALIVE participants completed a survey on substance use, structural determinants of health, and COVID-19 vaccine hesitancy. The exposure of interest was COVID-19 vaccine hesitancy, and the primary outcome was vaccination status as of June 30, 2021. We extracted data on the dates of vaccination from electronic medical records linked to study participants. Results: The median age of the sample was 60 years; most participants were male (66%) and non-Hispanic Black (87%). Most (55%) trusted the COVID-19 vaccine, and 68% had received ≥1 dose. After age standardization, survey participants were more likely than the Maryland general population to be unvaccinated (prevalence ratio = 1.20; 95% CI, 0.97-1.49; P = .10). Participants who somewhat trusted or did not trust the COVID-19 vaccine had 6-fold higher odds of being unvaccinated than participants who trusted the vaccine (odds ratio = 6.30; 95% CI, 3.74-10.60). Conclusion: Uptake of COVID-19 vaccine among people with a history of injection drug use was high. Attitudes and knowledge about vaccination were important predictors of vaccine uptake. Education and outreach efforts could be effective in reducing hesitancy and increasing vaccination in substance-using populations.

Background Understanding the sources of HIV transmission provides a basis for prioritizing HIV prevention resources in specific geographic regions and populations. This study estimated the number, proportion, and rate of HIV transmissions attributable to individuals along the HIV care continuum, within different HIV transmission risk groups in six US cities. Methods We used a dynamic, compartmental HIV transmission model that draws on racial/ethnic- and risk-behavior-specific linkage to HIV care and use of HIV prevention services from local, state and national surveillance sources. We estimated the rate and number of HIV transmissions attributable to individuals in the stage of acute undiagnosed HIV, non-acute undiagnosed HIV, HIV diagnosed but antiretroviral therapy (ART) naive, off ART, and on ART, stratified by HIV transmission group for the 2019 calendar year. Results Individuals with undiagnosed non-acute HIV infection accounted for the highest proportion of total transmissions in every city, ranging from 36.8% [26.7%-44.9%] in New York City to 64.9% [47.0%-71.6%] in Baltimore. Individuals who had discontinued ART contributed to the second highest percentage of total infections in four of six cities. Individuals with acute HIV had the highest transmission rate per 100 person years, ranging from 76.4 [58.9-135.9] in Miami to 160.2 [85.7-302.8] in Baltimore. Conclusion These findings underline the importance of both early diagnosis and improved ART retention for ending the HIV epidemic in the US. Differences in the sources of transmission across cities indicate that localized priority-setting to effectively address diverse microepidemics at different stages of epidemic control is necessary.

Background HIV infection is associated with more rapid progression of some comorbidities. This study assessed the impact of HIV-infection on the presentation and outcome of HCC. Methods HCC patients attending the Mulago National Referral Hospital in Uganda were enrolled into a natural history study of HCC between March 2015 and February 2019. Standardized methods were used to collect clinical, ultrasound and laboratory data at enrolment. HCC cases were confirmed and enrolled based on a combination of clinical, ultrasound, tumor marker and pathology data. Follow-up contact was made at one, three, six, and twelve months post-enrolment to determine vital status. Symptoms and signs at diagnosis and subsequent survival were compared by HIV status. Kaplan Meier curves were used to assess HCC survival. Results Of 441 persons with HCC, 383 (87.0%) died within 12 months following HCC diagnosis. The median (IQR) survival was 42 (20, 106) days. HIV infection was present in 79 (18%) cases. After adjusting for baseline demographic and clinical characteristics, HIV infection was associated with increased mortality but only among those with severe HIV-associated immunosuppression (CD4 count Conclusion Among relatively young Ugandans, HCC is a devastating disease with rapid mortality that is especially rapid among people living with HIV(PLWH). HIV was associated with slightly higher mortality, notably among PLWH with lower CD4 cell counts. As a substantial majority of PLWH diagnosed with HCC were engaged in HIV care, further investigation should determine the effectiveness of incorporating screening and early identification of HCC among high-risk individuals into existing HIV care programs. Concurrent with growing access to curative localized treatment for HCC in sub-Saharan Africa, leveraging HIV care infrastructure affords opportunities for earlier HCC intervention.

Supplementary Table S1 shows Clinical information of US/EU patients analyzed. Supplementary Table S2 is a summary of whole genome cfDNA analyses. Supplementary Table S3 shows clinical information of Hong Kong patients analyzed. Supplementary Table S4 shows the lowest scoring transcription factors in US/EU cohort samples. Supplementary Table S5 lists the plasma volume and cfDNA amounts used in genomic libraries.

Supplementary Figure S1 shows contributions of individual genomic regions to the final trained DELFI surveillance model. Supplementary Figure S2 shows DELFI scores in individuals without cancer by age and sex. Supplementary Figure S3 shows DELFI scores in high-risk individuals without cancer across racial or ethnic groups. Supplementary Figure S4 shows DELFI scores in cirrhotic patients in relation to severity. Supplementary Figure S5 shows DELFI scores in individuals in relation to BMI. Supplementary Figure S6 Shows Performance of alternative DELFI models. Supplementary Figure S7 shows Correlation between rank ordered DELFI. Supplementary Figure S8 shows DELFI scores in patients with HCC were related to tumor characteristics. Supplementary Figure S9 shows DELFI scores in by etiology of underlying liver disease. Supplementary Figure S10 shows the DELFI score in patients with HCC is correlated to AFP levels. Supplementary Figure S11 shows the correlation of fragmentation profiles. Supplementary Figure S12 shows Genome wide fragmentation profiles in the Hong Kong validation cohort Supplementary Figure S13 shows chromosomal copy number in Hong Kong cohort. Supplementary Figure S14 shows the implementation of DELFI in liver cancer screening.

Background: HIV is associated with accelerated decline in lung function and increased risk for chronic obstructive pulmonary disease (COPD). Recently, there has been growing attention toward the impairment in the diffusing capacity of the lungs for carbon monoxide (DLCO), a marker of pulmonary gas exchange, observed among persons living with HIV. Although increased emphysema can contribute to the DLCO impairment observed, other factors may drive this association. Methods: Using cross-sectional data from the Study of HIV in the Etiology of Lung Disease, we studied the association between HIV and DLCO independent of emphysema. We also analyzed the joint influence of HIV and COPD on DLCO impairment. An analysis was conducted among 339 participants (229 with HIV) with lung function and chest CT imaging data. Multivariable regression models were generated with percent predicted DLCO and odds of DLCO impairment as outcomes. Results: After adjusting for confounders, including emphysema severity, HIV was associated with lower DLCO (β −4.02%; P = 0.020) and higher odds of DLCO impairment (odds ratio 1.93; P = 0.017). Even among those without COPD, HIV was independently associated with lower DLCO (β −3.89%; P = 0.049). Compared with HIV-uninfected participants without COPD, those with both HIV and COPD experienced the greatest impairment in DLCO (β −14.81; P < 0.001). Conclusions: HIV is associated with impaired pulmonary gas exchange independent of emphysema severity. Our data also suggest a potentially additive influence between HIV and COPD on DLCO impairment. Further studies should investigate the other factors, including pulmonary vascular disease, which may contribute to DLCO impairment among persons living with HIV.

BACKGROUND: People with HIV (PWH) have a higher hospitalization rate than the general population. The Veterans Aging Cohort Study (VACS) Index at study entry well predicts hospitalization in PWH, but it is unknown if the time-updated parameter improves hospitalization prediction. We assessed the association of parameterizations of the VACS Index 2.0 with the 5-year risk of hospitalization. SETTING: PWH ≥ 30 years old with at least 12 months of antiretroviral therapy (ART) use, and contributing hospitalization data from 2000 to 2016 in North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were included. Three parameterizations of the VACS Index 2.0 were assessed and categorized by quartile: 1) “baseline” measurement at study entry, 2) time-updated measurements, and 3) cumulative scores calculated using the trapezoidal rule. METHODS: Discrete-time proportional hazard models estimated the crude and adjusted associations (and 95% confidence intervals [CI]) of the VACS Index parameterizations and all-cause hospitalizations. The Akaike information criterion (AIC) assessed the model fit with each of the VACS Index parameters. RESULTS: Among 7,289 patients, 1,537 were hospitalized. Time-updated VACS Index fitted hospitalization best with a more distinct dose-response relationship (score

Background Evidence of whether people living with HIV are at elevated risk of adverse COVID-19 outcomes is inconclusive. We aimed to investigate this association using the population-based National COVID Cohort Collaborative (N3C) data in the USA. Methods We included all adult (aged ≥18 years) COVID-19 cases with any health-care encounter from 54 clinical sites in the USA, with data being deposited into the N3C. The outcomes were COVID-19 disease severity, hospitalisation, and mortality. Encounters in the same health-care system beginning on or after January 1, 2018, were also included to provide information about pre-existing health conditions (eg, comorbidities). Logistic regression models were employed to estimate the association of HIV infection and HIV markers (CD4 cell count, viral load) with hospitalisation, mortality, and clinical severity of COVID-19 (multinomial). The models were initially adjusted for demographic characteristics, then subsequently adjusted for smoking, obesity, and a broad range of comorbidities. Interaction terms were added to assess moderation effects by demographic characteristics. Findings In the harmonised N3C data release set from Jan 1, 2020, to May 8, 2021, there were 1 436 622 adult COVID-19 cases, of these, 13 170 individuals had HIV infection. A total of 26 130 COVID-19 related deaths occurred, with 445 among people with HIV. After adjusting for all the covariates, people with HIV had higher odds of COVID-19 death (adjusted odds ratio 1·29, 95% CI 1·16–1·44) and hospitalisation (1·20, 1·15–1·26), but lower odds of mild or moderate COVID-19 (0·61, 0·59–0·64) than people without HIV. Interaction terms revealed that the elevated odds were higher among older age groups, male, Black, African American, Hispanic, or Latinx adults. A lower CD4 cell count (

Liver cancer is a major cause of cancer mortality worldwide. Screening individuals at high risk, including those with cirrhosis and viral hepatitis, provides an avenue for improved survival, but current screening methods are inadequate. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome analyses to evaluate 724 individuals from the United States, the European Union, or Hong Kong with hepatocellular carcinoma (HCC) or who were at average or high-risk for HCC. Using a machine learning model that incorporated multifeature fragmentome data, the sensitivity for detecting cancer was 88% in an average-risk population at 98% specificity and 85% among high-risk individuals at 80% specificity. We validated these results in an independent population. cfDNA fragmentation changes reflected genomic and chromatin changes in liver cancer, including from transcription factor binding sites. These findings provide a biological basis for changes in cfDNA fragmentation in patients with liver cancer and provide an accessible approach for noninvasive cancer detection.Significance:There is a great need for accessible and sensitive screening approaches for HCC worldwide. We have developed an approach for examining genome-wide cfDNA fragmentation features to provide a high-performing and cost-effective approach for liver cancer detection.See related commentary Rolfo and Russo, p. 532.This article is highlighted in the In This Issue feature, p. 517

ImportanceEstimating the medical complexity of people aging with HIV can inform clinical programs and policy to meet future healthcare needs.ObjectiveTo project the prevalence of comorbidities and multimorbidity among people with HIV (PWH) using antiretroviral therapy (ART) in the US through 2030.DesignAgent-based simulation modelSettingHIV clinics in the United States in the recent past (2020) and near future (2030)ParticipantsIn 2020, 674,531 PWH were using ART; 9% were men and 4% women with history of injection drug use; 60% were men who have sex with men (MSM); 8% were heterosexual men and 19% heterosexual women; 44% were non-Hispanic Black/African American (Black); 32% were non-Hispanic White (White); and 23% were Hispanic.Exposure(s)Demographic and HIV acquisition risk subgroupsMain Outcomes and MeasuresProjected prevalence of anxiety, depression, stage ≥3 chronic kidney disease (CKD), dyslipidemia, diabetes, hypertension, cancer, end-stage liver disease (ESLD), myocardial infarction (MI), and multimorbidity (≥2 mental or physical comorbidities, other than HIV).ResultsWe projected 914,738 PWH using ART in the US in 2030. Multimorbidity increased from 58% in 2020 to 63% in 2030. The prevalence of depression and/or anxiety was high and increased from 60% in 2020 to 64% in 2030. Hypertension and dyslipidemia decreased, diabetes and CKD increased, MI increased steeply, but there was little change in cancer and ESLD. Among Black women with history of injection drug use (oldest demographic subgroup in 2030), CKD, anxiety, hypertension, and depression were most prevalent and 93% were multimorbid. Among Black MSM (youngest demographic subgroup in 2030), depression was highly prevalent, followed by hypertension and 48% were multimorbid. Comparatively, 67% of White MSM were multimorbid in 2030 (median age in 2030=59 years) and anxiety, depression, dyslipidemia, CKD, and hypertension were highly prevalent.Conclusion and relevanceThe distribution of multimorbidity will continue to differ by race/ethnicity, gender, and HIV acquisition risk subgroups, and be influenced by age and risk factor distributions that reflect the impact of social disparities of the health on women, people of color, and people who use drugs. HIV clinical care models and funding are urgently required to meet the healthcare needs of people with HIV in the next decade.KEY POINTSQuestionHow will the prevalence of multimorbidity change among people with HIV (PWH) using antiretroviral therapy in the US from 2020 to 2030?FindingsIn this agent-based simulation study using data from the NA-ACCORD and the CDC, multimorbidity (≥2 mental/physical comorbidities other than HIV) will increase from 58% in 2020 to 63% in 2030. The composition of comorbidities among multimorbid PWH vary by race/ethnicity, gender, and HIV acquisition risk group.MeaningHIV clinical programs and policy makers must act now to identify resources and care models to meet the increasingly complex medical needs of PWH over time, particularly mental healthcare needs.

Background and aims Over the past decades, people who inject drugs (PWID) have been impacted by the development of combination antiretroviral therapy (cART) to combat HIV/AIDS, the prescription opioid crisis, and increased use of lethal synthetic opioids. We measured how these dynamics have impacted mortality among PWID in an urban U.S. city. Design Prospective cohort study using data from the AIDS Linked to the Intravenous Experience (ALIVE) SETTING: Baltimore, Maryland, USA from 1988-2018. Participants 5,506 adult PWIDs (median age at baseline 37 years). Measurements Mortality was identified by linkage to National Death Index-Plus (NDI-Plus) and categorized into HIV/infectious disease (HIV/ID) deaths, overdose and violence-related (drug-related) deaths, and chronic-disease deaths. Person-time at risk accrued from baseline, and ended at the earliest of death or study period. All-cause and cause-specific mortality were calculated annually. Fine and Gray method was used to estimate the sub-distribution hazards of cause-specific deaths accounting for competing risks. Findings Among 5,506 participants with 84,011 person-years of follow-up, 43.9% were deceased by 2018. Among all deaths, 30.5% were HIV/ID-deaths, 24.4% drug-related deaths, and 33.3% chronic-disease deaths. Age-standardized all-cause mortality increased from 23 to 45 per 1000-person-years from 1988-1996, declined from 1996 through 2012, then trended upward through 2018. HIV/ID-deaths peaked in 1996 coincident with the availability of cART, then continuously declined. Chronic-disease deaths increased continuously as the cohort aged. Drug-related deaths declined until 2011, but increased over 4-fold by 2018. HIV/HCV infection and active injecting were independently associated with HIV/ID and drug-related deaths. Female and Black participants had higher risk of dying from HIV/ID deaths and a lower risk of dying from drug-related deaths than male and non-Black participants. Conclusions Deaths in Baltimore, Maryland, USA attributable to HIV/ID appear to have declined following the widespread use of combination antiretroviral therapy. Increases in the rates of drug-related deaths in Baltimore were observed prior to and continue in conjunction with national mortality rates associated with the opiate crisis.

OBJECTIVE People with HIV (PWH) experience increased prevalence of obstructive lung disease (OLD), regardless of greater observed smoking behaviors. We investigated whether the effect of incident OLD on mortality differed by HIV and HIV viral suppression among persons who inject drugs (PWID) and report smoking history. DESIGN ALIVE is a longitudinal, observational cohort study of HIV-positive and seronegative PWID. This analysis included participants who had at least one spirometry measure to assess OLD between 2007 and 2016, excluding those who never smoked (5%, n = 62) or had baseline OLD (17%, n = 269). METHODS Incident OLD occurred when the first prebronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) less than 0.70 during follow-up. The effect of incident OLD on all-cause mortality was estimated in PWH and seronegative participants using inverse-probability-of-treatment-weighted marginal structural models controlling for baseline (age, race, sex, calendar year, smoking pack-years) and time-varying (smoking intensity, viral suppression, and calendar time) confounders. RESULTS Among 1204 participants, 269 (22.3%) and 157 (13.0%) experienced incident OLD and death, respectively, over a median of five person-years of follow-up. There was no effect of OLD on mortality among seronegative participants [hazard ratio = 0.84, 95% confidence interval (CI): 0.47-1.48]; however, PWH diagnosed with OLD experienced an increased mortality risk (hazard ratio = 1.71, 95% CI: 1.04-2.80) during follow-up. HIV viral suppression did not confound or modify the effect of OLD on mortality among PWH. CONCLUSION There was an apparent effect of OLD on all-cause mortality irrespective of viral suppression among PWH but not among seronegative persons, after accounting for baseline and time-varying confounders. These results highlight the need for enhanced screening and management of OLD among PWH.

Background: The AGE hIV cohort study is a prospective cohort study evaluating the occurrence of age-related comorbidities in people living with and without HIV. We previously reported a lower forced vital capacity (FVC) in HIV-positive compared with HIV-negative participants in those without heavy smoking exposure at time of enrolment in the AGE hIV cohort study. In this study we evaluate longitudinal changes in spirometry indices in the same AGE hIV cohort accounting for smoking behaviour and other risk factors. Methods: We obtained pre-bronchodilator spirometry measurements in AGE hIV cohort participants during biennial visits over a median of 5·9 years (IQR 5·7–6·0). Adjusted declines in forced expiratory volume in 1 s (FEV 1), FVC, and FEV 1/FVC ratio were modelled using linear mixed-effects models and compared by HIV status and smoking status. To evaluate whether changes in spirometry measurements could be driven by increased levels of chronic inflammation, we assessed associations between rates of FEV 1 and FVC decline and CD4 and CD8 T-cell counts, and plasma concentrations of C-reactive protein (CRP), interleukin 6, soluble CD14, soluble CD163, and intestinal fatty-acid-binding protein in separate models. The study is registered at ClinicalTrials.gov, NCT01466582. Findings: 500 HIV-positive and 481 HIV-negative participants were included with spirometry data from Oct 29, 2010, to Aug 14, 2018. HIV-positive participants were virally suppressed (

Aims The extent to which human immunodeficiency viral (HIV) infection is independently associated with myocardial disease in the era of combination antiretroviral therapy (cART) remains understudied. We assessed differences in cardiovascular magnetic resonance imaging (CMR) metrics among people living with HIV (PLWH) and without HIV (PWOH). Methods and results Among 436 participants (aged 54.7 ± 6.0 years, 29% women) from three cohorts, we acquired CMR cines, late gadolinium enhancement (LGE), and T1 mapping. Multivariable linear regressions were used to evaluate associations between HIV serostatus and CMR metrics. Baseline characteristics were similar by HIV serostatus; 63% were PLWH of whom 88% received cART and 73% were virally suppressed. Median left ventricular ejection fraction was normal and similar by HIV serostatus (73%, PWOH vs. 72%, PLWH, P = 0.43) as were right ventricular function, biventricular volumes, and masses. LGE prevalence was similar (32%, PWOH vs. 36%, PLWH, P = 0.46) with low scar extents (4.1, PWOH vs. 4.9 g, PLWH, P = 0.51) and few ischaemic scars (3%, PWOH vs. 4%, PLWH, P = 0.70). Extracellular volume fraction (ECV) was higher among PLWH (29.2 ± 4.1% vs. 28.3 ± 3.7%, P = 0.04) as was indexed maximum left atrial (LA) volume (LAVI, 29.7 ± 10.3 vs. 27.8 ± 8.7 mL/m2, P = 0.05). After multivariate adjustment, ECV was 0.84% higher among PLWH (P = 0.05) and LAVI was 2.45 mL/m2 larger (P = 0.01). HIV seropositivity and higher ECV contributed to higher LAVI (P Conclusion HIV seropositivity was independently associated with greater diffuse non-ischaemic fibrosis and larger LA volume but no other differences in CMR metrics.

Apolipoprotein L1 (APOL1), an innate immune factor against African trypanosoma brucei, inhibits HIV-1 in vitro. The impact of APOL1 G1-G2 variants on HIV-1-associated opportunistic infections (OIs) is unknown. Here, we report findings from a metaanalysis of four HIV/AIDS prospective cohorts (ALIVE, LSOCA, MACS, and WIHS) including 2066 African American participants. Using a global test combining all four cohorts, carriage of two APOL1 variant alleles is associated with a 50% reduction in odds of OI (combined OR 0.50, 95% CI 0.33-0.76). Subgroup analysis of OI etiological categories (viral, parasitic, fungal and Mycobacterial) suggests the possibility of specific protection from fungal infections (OR 0.54. 95% CI 0.32-0.93; PBonferroni corrected = 0.08). We observe an association of APOL1 variant alleles with host protection against OI in HIV-positive individuals. The study suggests a broader role of APOL1 variant alleles in innate immunity in vivo., An et al. determine the presence of variants of the innate immune factor APOL1 in four cohorts of HIV-positive patients. The study suggests that APOL1 might confer carriers of two variant alleles protection from HIV related opportunistic infections, especially fungal infections.

Background Childhood adversity is associated with the onset of harmful adult substance use and related health problems, but most research on adversity has been conducted in general population samples. This study describes the prevalence of adverse childhood experiences in a cohort of people who have injected drugs and examines the association of these adverse experiences with medical comorbidities in adulthood. Methods Six hundred fifty three adults were recruited from a 30-year cohort study on the health of people who have injected drugs living in and around Baltimore, Maryland (Median age = 47.5, Interquartile Range = 42.3–52.3 years; 67.3% male, 81.1% Black). Adverse childhood experiences were assessed retrospectively in 2018 via self-report interview. Lifetime medical comorbidities were ascertained via self-report of a provider diagnosis. Multinomial logistic regression with generalized estimating equations was used to examine the association between adversity and comorbid conditions, controlling for potential confounders. Results Two hundred twelve participants (32.9%) reported 0–1 adverse childhood experiences, 215 (33.3%) reported 2–4, 145 (22.5%) reported 5–9, and 72 (11.1%) reported ≥10. Neighborhood violence was the most commonly reported adversity (48.5%). Individuals with ≥10 adverse childhood experiences had higher odds for reporting ≥3 comorbidities (Adjusted Odds Ratio = 2.9, 95% CI = 1.2 – 6.8, p = .01). Conclusions Among people who have injected drugs, adverse childhood experiences were common and associated with increased occurrence of self-reported medical comorbidities. Findings highlight the persistent importance of adversity for physical health even in a population where all members have used drugs and there is a high burden of comorbidity.

Aim: To investigate the role of epigenetics in HIV pathophysiology. Materials & methods: We conducted an epigenome-wide association scan on HIV infection status among people who inject drugs in the AIDS Linked to the IntraVenous Experience study with primary (n = 397) and validation samples (n = 390). DNA methylation from blood was measured by the Illumina EPIC BeadChip. We controlled for cell type heterogeneity by HIV status. Results: HIV infection status was associated (p -8) with DNA methylation at 49 CpG sites. Sites were enriched in response to virus, interferon signaling pathway, etc. Among these sites, discovery and validation t-statistics were highly correlated (r = 0.96). Conclusion: In a cohort of people who inject drugs, HIV status was associated with differential DNA methylation at biologically meaningful sites.

Background Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors. Methods To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 male, 1520 female) of European, African, and Hispanic ancestry. We performed autosomal, and X chromosome sex-stratified and combined association analyses in each ancestry group. Results A male-specific region near the adenosine diphosphate–ribosylation factor–like 5B (ARL5B) gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have chronic HCV infection than individuals with the T allele (OR, 0.69; P = 1.98 × 10−07), and this was not seen in females. The ARL5B gene encodes an interferon-stimulated gene that inhibits immune response to double-stranded RNA viruses. We also identified suggestive associations near septin 6 and ribosomal protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared with the A allele (OR, 1.4; P = 2.46 × 10−06). Septin 6 facilitates HCV replication via interaction with the HCV NS5b protein, and ribosomal protein L39 acts as an HCV core interactor. Conclusions These novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development.

The latent reservoir for human immunodeficiency virus type 1 (HIV-1) in CD4+ T cells is a major barrier to cure. HIV-1–infected persons who inject drugs (PWID) often struggle to maintain suppression of viremia and experience nonstructured treatment interruptions (NTIs). The effects of injecting drugs or NTIs on the reservoir are unclear. Using the intact proviral DNA assay, we found no apparent effect of heroin or cocaine use on reservoir size. However, we found significantly larger reservoirs in those with frequent NTIs or a shorter interval from last detectable HIV RNA measurement. These results have important implications for inclusion of PWID in HIV-1 cure studies.

Background Chronic respiratory disease represents an important comorbidity for persons living with HIV (PLWH). HIV itself is associated with greater impairment in lung function. We aimed to determine the association between declining lung function and both quality of life (QOL) and health care utilization for PLWH. Methods Using longitudinal data from the Study of HIV Infection in the Etiology of Lung Disease 2009-2017, we studied the association between changes in lung function and both QOL and acute care events (emergency department visit or hospitalization). The Medical Outcomes Studies-HIV Questionnaire provided QOL domains. Multivariable regression models were performed with generalized estimating equations accounting for 1499 participants, 485 with HIV, contributing 10,825 spirometry visits. Results Among PLWH, decreased FEV1 was associated with worse physical health for those with higher viral load [β: -1.66, 95% confidence interval (CI): -3.11 to -0.39] compared to those with viral suppression (β: -0.58, 95% CI: -1.06 to -0.162), even in those without airflow obstruction. Lower FEV1 was also associated with increased odds of both emergency department (odds ratio: 1.21, 95% CI: 1.09 to 1.34) and inpatient (odds ratio: 1.26, 95% CI: 1.12 to 1.42) hospitalizations for PLWH. Lung function was not associated with increased odds of acute care events for HIV-uninfected participants. Conclusions FEV1 declines represent an independent predictor of QOL and acute care events among PLWH. Although the generalizability of these results may be limited, because of the high-risk population included, findings suggest that care for PLWH should involve monitoring FEV1 over time, especially in those with poor virologic control, with emphasis on the development and implementation of interventions to mitigate lung function decline.

Clearance of acute infection with hepatitis C virus (HCV) is associated with the chr19q13.13 region containing the rs368234815 (TT/ΔG) polymorphism. We fine-mapped this region to detect possible causal variants that may contribute to HCV clearance. First, we performed sequencing of IFNL1-IFNL4 region in 64 individuals sampled according to rs368234815 genotype: TT/clearance (N = 16) and ΔG/persistent (N = 15) (genotype-outcome concordant) or TT/persistent (N = 19) and ΔG/clearance (N = 14) (discordant). 25 SNPs had a difference in counts of alternative allele >5 between clearance and persistence individuals. Then, we evaluated those markers in an association analysis of HCV clearance conditioning on rs368234815 in two groups of European (692 clearance/1 025 persistence) and African ancestry (320 clearance/1 515 persistence) individuals. 10/25 variants were associated (P

Background Current mitigation strategies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rely on the population-wide adoption of nonpharmaceutical interventions (NPIs). Monitoring the adoption of NPIs and their associations with SARS-CoV-2 infection history can provide key information for public health. Methods We sampled 1030 individuals in Maryland from 17–28 June 2020 to capture sociodemographically and geographically resolved information about NPI adoption and access to SARS-CoV-2 testing, and examine associations with self-reported SARS-CoV-2 positivity. Results Overall, 92% reported traveling for essential services and 66% visited friends/family. Use of public transport was reported by 18%. In total, 68% reported strict social distancing indoors and 53% reported strict masking indoors; indoor social distancing was significantly associated with age, and race/ethnicity and income were associated with masking. Overall, 55 participants (5.3%) self-reported ever testing positive for SARS-CoV-2, with strong dose-response relationships between several forms of movement frequency and SARS-CoV-2 positivity. In a multivariable analysis, a history of SARS-CoV-2 infection was negatively associated with strict social distancing (adjusted odds ratio [aOR] for outdoor social distancing, 0.10; 95% confidence interval, .03–.33). Only public transport use (aOR for >7 times vs never, 4.3) and visiting a place of worship (aOR for ≥3 times vs never, 16.0) remained significantly associated with SARS-CoV-2 infection after adjusting for strict social distancing and demographics. Conclusions These results support public health messaging that strict social distancing during most activities can reduce SARS-CoV-2 transmission. Additional considerations are needed for indoor activities with large numbers of persons (places of worship and public transportation), where even NPIs may not be possible or sufficient.

Objective Frailty is a critical aging-related syndrome marked by diminished physiologic reserve and heightened vulnerability to stress, predictive of major adverse clinical outcomes in HIV-infected and uninfected adults. Frailty is a dynamic state, yet little data exist on predictors and consequences of frailty transitions. Design/methods Frailty was assessed semiannually among HIV-infected and uninfected persons with prior injection drug use using the five Fried phenotype domains. An inflammatory index score was constructed from IL-6 and soluble TNF-α receptor-1 data. Markov transition models assessed determinants of frailty transitions. Cox proportional hazards models estimated mortality risk. Results Among 1353 AIDS Linked to the IntraVenous Experience participants with 9559 frailty transition assessments, 33% were HIV-infected. Younger age, higher education, employment, reduced comorbidity, HIV virologic suppression, elevated CD4 nadir (>500 cells/μl) and absence of a prior AIDS diagnosis were significantly associated with both reduced frailty progression and greater frailty recovery. Each SD decrease in inflammatory index score was associated with decreased frailty progression [odds ratio 0.78; 95% confidence interval (CI), 0.65, 0.92] and increased frailty recovery (odds ratio 1.29; 95% CI, 1.08, 1.53). Being frail at one of two consecutive visits was associated with increased mortality, compared with maintenance of a nonfrail state. Being frail at both of two consecutive visits demonstrated the highest mortality risk (hazard ratio 3.23; 95% CI, 2.1, 4.96). Conclusion Sustained, and to a lesser degree, intermittent frail states are associated with increased mortality. HIV virologic suppression with earlier antiretroviral therapy, reduced comorbidity, and reduced inflammation may prevent frailty progression and promote frailty recovery, consequently improving survival for persons aging with HIV and persons with prior injection drug use.

Spontaneous clearance of acute hepatitis C virus (HCV) infection is associated with single nucleotide polymorphisms (SNPs) on the MHC class II. We fine-mapped the MHC region in European (n = 1,600; 594 HCV clearance/1,006 HCV persistence) and African (n = 1,869; 340 HCV clearance/1,529 HCV persistence) ancestry individuals and evaluated HCV peptide binding affinity of classical alleles. In both populations, HLA-DQβ1Leu26 (p valueMeta = 1.24× 10-14) located in pocket 4 was negatively associated with HCV spontaneous clearance and HLA-DQβ1Pro55 (p valueMeta = 8.23× 10-11) located in the peptide binding region was positively associated, independently of HLA-DQβ1Leu26. These two amino acids are not in linkage disequilibrium (r2 < 0.1) and explain the SNPs and classical allele associations represented by rs2647011, rs9274711, HLA-DQB1∗03:01, and HLA-DRB1∗01:01. Additionally, HCV persistence classical alleles tagged by HLA-DQβ1Leu26 had fewer HCV binding epitopes and lower predicted binding affinities compared to clearance alleles (geometric mean of combined IC50 nM of persistence versus clearance; 2,321nM versus 761.7nM, p value = 1.35× 10-38). In summary, MHC class II fine-mapping revealed key amino acids in HLA-DQβ1 explaining allelic and SNP associations with HCV outcomes. This mechanistic advance in understanding of natural recovery and immunogenetics of HCV might set the stage for much needed enhancement and design of vaccine to promote spontaneous clearance of HCV infection.

In 2020, the first year of the COVID-19 pandemic, overdose deaths increased. However, no studies have characterized changes in mortality during the pandemic in a well-characterized cohort of people who use drugs in active follow-up at the time of pandemic onset.We compared all-cause and cause-specific mortality in the first year of the pandemic (Mar-Dec 2020) to the five years preceding (Jan 2015-Feb 2020), among participants in the AIDS Linked to the IntraVenous Experience (ALIVE) study: a community-recruited cohort of adults from Baltimore who have injected drugs. 3510 participants contributed 17,498 person-years [py] of follow-up time. Cause and dates of death were ascertained through the National Death Index. Comparisons were made for the full cohort and within subgroups with potentially differential levels of vulnerability.All-cause mortality in 2020 was 39.6 per 1000 py, as compared to 37.2 per 1000 py pre- pandemic (Adjusted Incidence Rate Ratio = 1.09, 95%: confidence interval: 0.84-1.41). Increases were mostly attributable to chronic disease deaths; injury/poisoning deaths did not increase. No pre-post differences were statistically significant.In this exploratory analysis of an older cohort of urban-dwelling adults who have injected drugs, mortality changes during the first year of the pandemic differed from national trends and varied across potentially vulnerable subgroups. More research is needed to understand determinants of increased risk of mortality during the pandemic among subgroups of people who use drugs.

BackgroundThe COVID-19 pandemic has compounded the longstanding drug poisoning crisis in Canada and the United States (US). Research is needed to understand the contributions of COVID-19 and subsequent infection control measures. We sought to estimate the prevalence of and factors associated with nonfatal overdose among participants in nine prospective cohorts of people who use unregulated drugs (PWUD) in Canada and the US.MethodsData were derived from nine cohorts of PWUD in urban centres in Canada (Vancouver, BC) and the US (Baltimore, MD; Miami, FL; Chicago, IL; Los Angeles, CA) between May, 2020 and April, 2021. Multivariable logistic regression was used to identify factors associated with nonfatal overdose among participants who used unregulated drugs in the past month.ResultsAmong 885 participants (including 253 females), 41 (4.6%) experienced a non-fatal overdose in the past month, and 453 (51.2%) reported being highly impacted day-to-day by the pandemic. In multivariable analyses, people who experienced a non-fatal overdose were more likely to be female (Adjusted Odds Ratio [AOR]=2.18;95% Confidence Interval [CI]=1.10-4.30); unstably housed/homeless (AOR=2.16;95% CI=1.11-4.26); engaged in medications for opioid use disorder (AOR=2.45;95% CI=1.19-4.97); and highly impacted day-to-day (AOR=2.42;95% CI=1.22-5.10).ConclusionOur findings may reflect characteristics of participants who experienced a compounding of vulnerabilities during the pandemic and thus are vulnerable to overdose, including women, those unstably housed/homeless, and those who perceived their daily lives were highly impacted by the pandemic. Multi-level interventions are needed to remediate the vulnerabilities and address the main driver of poisoning crisis.

Background Whereas safe, curative treatments for hepatitis C virus (HCV) have been available since 2015, there are still 58 million infected persons worldwide, and global elimination may require new paradigms. We sought to understand the acceptability of approaches to long-acting HCV treatment. Methods A cross-sectional, 43-question survey was administered to 1457 individuals with or at risk of HCV at 28 sites in 9 countries to assess comparative interest in a variety of long-acting strategies in comparison with oral pills. Results Among HCV-positive participants, 37.7% most preferred an injection, 5.6% an implant, and 6% a gastric residence device, as compared with 50.8% who stated they would most prefer taking 1–3 pills per day. When compared directly to taking pills, differences were observed in the relative preference for an injection based on age (P Conclusions These data point to high acceptability of long-acting treatments, which for a substantial minority might even be preferred to pills for the treatment of HCV infection. Long-acting treatments for HCV infection might contribute to global efforts to eliminate hepatitis C.

BackgroundThis study examines individual-level factors associated with avoiding two important health services for people who use drugs-medications for treatment of opioid use disorder and syringe service programs-during the first year of the COVID-19 pandemic.MethodsData come from two subsamples of people who use drugs who were active participants in one of nine cohort studies in Vancouver, British Columbia; Baltimore, Maryland; Los Angeles, California; Chicago, Illinois; and Miami, Florida. Participants were interviewed remotely about COVID-19-associated disruptions to healthcare. We estimated the association of demographic, social, and health factors with each outcome using logistic regression among 702 participants (medication analysis) and 304 participants (syringe service analysis.) Analyses were repeated, stratified by city of residence, to examine geographic variation in risk.ResultsThere were large differences between cities in the prevalence of avoiding picking up medications for opioid use disorder, with almost no avoidance in Vancouver (3%) and nearly universal avoidance in Los Angeles, Chicago, and Miami (>90%). After accounting for between-city differences, no individual factors were associated with avoiding picking up medications. The only factor significantly associated with avoiding syringe service programs was higher levels of self-reported worry about COVID-19.ConclusionDuring the first year of the COVID-19 pandemic, geographic differences in service and policy contexts likely influenced avoidance of health and harm reduction services by people who use drugs in the United States and Canada more than individual differences between people.

Injection drug use (IDU) is prevalent in the US and is associated with substantial risk of blood-borne infections, morbidity, and mortality. However, the spectrum of its biologic effects on DNA methylation in blood is not well characterized.401 participants (MWe found epigenome-wide significant CpG sites associated with active injection (cg10636246, AIM2, p = 2.33 × 10Findings from this study demonstrate modest, common, and specific effects on DNA methylation during a relatively short time between periods of active drug injection and abstinence.

BackgroundAlcohol use during the COVID-19 pandemic increased. People living with HIV or at risk for HIV acquisition often have psycho-social and structural barriers or co-occurring substance use making them vulnerable to the adverse effects of alcohol. We describe factors associated with alcohol use during the COVID-19 pandemic in this group.MethodsFrom May 2020 to February 2021, 1984 people enrolled in 6 existing cohort studies completed surveys about alcohol and other drug use during the COVID-19 pandemic. We describe the past-month prevalence of no alcohol use, low-risk use, and hazardous use. We use multinomial regression to describe factors associated with low-risk or hazardous alcohol use relative to no alcohol use.ResultsForty-five percent of participants reported no alcohol use, 33% low-risk use, and 22% hazardous use in the past 30 days. Cannabis and stimulant use were associated with a higher prevalence of low-risk use relative to no use. Tobacco, stimulant, cannabis use and recent overdose were associated with a higher prevalence of hazardous use relative to no use. Substance use treatment and living with HIV were associated with a lower prevalence of low-risk or hazardous use relative to no use.ConclusionsStimulant use was strongly associated with a higher prevalence of hazardous alcohol use while engagement in substance use treatment or living with HIV was associated with a lower prevalence. Ascertaining hazardous alcohol and other drug use, particularly stimulants, in clinical care could identify people at higher risk for adverse outcome and harm reduction counseling.

People who inject drugs (PWID) face disparities in human immunodeficiency virus (HIV) treatment outcomes and may be less likely to achieve durable viral suppression. We characterized transitions into and out of viral suppression from 1997 to 2017 in a long-standing community-based cohort study of PWID, the AIDS Link to Intravenous Experience (ALIVE) Study, analyzing HIV-positive participants who had made a study visit in or after 1997. We defined the probabilities of transitioning between 4 states: 1) suppressed, 2) detectable, 3) lost to follow-up, and 4) deceased. We used multinomial logistic regression analysis to examine factors associated with transition probabilities, with a focus on transitions from suppression to other states. Among 1,061 participants, the median age was 44 years, 32% were female, 93% were African-American, 59% had recently injected drugs, and 28% were virologically suppressed at baseline. Significant improvements in durable viral suppression were observed over time; however, death rates remained relatively stable. In adjusted analysis, injection drug use and homelessness were associated with increased virological rebound in earlier time periods, while only age and race were associated with virological rebound in 2012–2017. Opioid use was associated with an increased risk of death following suppression in 2012–2017. Despite significant improvements in durable viral suppression, subgroups of PWID may need additional efforts to maintain viral suppression and prevent premature mortality.