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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

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 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.

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.

Objective The COVID-19 pandemic has dramatically impacted mental health, increasing rates of substance misuse. Resilience is a positive adaptation to stress that may act as a buffer against adverse mental health outcomes. Based on prior knowledge, we hypothesized that PLWH would display higher resilience than HIV-uninfected peers, and that high resilience would be associated with lower risk of substance misuse. Methods This analysis of the Collaborating Consortium of Cohorts Producing NIDA Opportunities (C3PNO) included data from six USA cohorts that administered a COVID-19-related survey with a 3-month follow-up during May 2020 and March 2021. All data was self-reported. The Brief Resilience Scale and General Anxiety Disorder-7 were utilized. Primary analyses consisted of multivariate generalized linear mixed models with random intercepts using binary logistic regression. Results A total of 1,430 participants completed both surveys, of whom 670 (46.9%) were PLWH. PLWH had lower odds of anxiety (OR=0.67, 95% CI: 0.51-0.89) and higher odds of high resilience (OR=1.21, 95% CI: 1.02-1.44) than HIV-uninfected participants, adjusted for covariates. The presence of anxiety was associated with higher risk of misuse of all substances. High resilience was associated with lower risk of anxiety and misuse of substances, adjusted for covariates. Conclusions Psychological resilience was associated with lower risk of anxiety and substance misuse, potentially serving as a buffer against poor mental and behavioral health during the COVID-19 pandemic. Further research is needed to identify pathways of resilience in the context of substance misuse and comprehensive resilience-focused interventions.