Impact of the Coronavirus Disease 2019 Pandemic on Substance Use Disorder Risk Among People Living With Human Immunodeficiency Virus (HIV) Enrolled in HIV Care in the United States: An Interrupted Time Series Analysis.

Background: Rising overdose deaths globally and increased social isolation during the coronavirus disease 2019 (COVID-19) pandemic may have disproportionately impacted people with human immunodeficiency virus (PWH) with substance use disorders (SUD). We examined trends in SUD risk among PWH before and after the COVID-19 shelter-in-place (SIP) mandate. Methods: Data were collected between 2018 and 2022 among PWH enrolled across 8 US sites in the Centers for AIDS Research Network of Integrated Clinical Systems cohort. We evaluated changes in moderate/high SUD risk after SIP using interrupted time series analyses. Results: There were 7126 participants, including 21 741 SUD assessments. The median age was 51 (interquartile range, 39-58) years; 12% identified as Hispanic or Latino/Latina, 46% Black/African American, and 46% White. Moderate/high SUD risk increased continuously after the pandemic's onset, with 43% (95% confidence interval [CI], 40%-46%) endorsing moderate/high SUD risk post-SIP, compared to 24% (95% CI, 22%-26%) pre-SIP (P < .001). There were increases in the use of heroin, methamphetamine, and fentanyl, and decreases in prescription opioids and sedatives post-SIP. Further, there was a decrease in reported substance use treatment post-SIP compared to pre-SIP (P = .025). Conclusions: The rising prevalence of SUD through late 2022 could be related to an increase in isolation and reduced access to substance use and HIV treatment caused by disruptions due to COVID-19. A renewed investment in integrated substance use treatment is vital to address the combined epidemics of substance use and HIV following the COVID-19 pandemic and to support resilience in the face of future disruptions.

Prevalence and Correlates of SARS-CoV-2 Vaccine Uptake and Hesitancy Among People With HIV Across the United States.

BACKGROUND: People with HIV (PWH) have higher risk of COVID-19 mortality. SARS-CoV-2 vaccination is highly effective among PWH, although vaccine hesitancy could limit the population-level impact. SETTING: From February 2021 to April 2022, PWH from 8 sites in the Centers for AIDS Research Network of Integrated Clinical Systems completed a vaccine hesitancy instrument as part of routine care. METHODS: Participants were defined as vaccine hesitant if they had not received the SARS-CoV-2 vaccine and would probably/definitely not receive it. We assessed factors associated with SARS-CoV-2 vaccine hesitancy using logistic regression adjusted for demographics, unsuppressed viral load (VL > 200 copies/mL), month, and time on ART; using inverse probability weighting for survey nonresponse. RESULTS: Overall, 3288 PWH with a median age of 55 were included; 18% were female and 94% were virally suppressed. At the time of survey, 27% reported they had not received the SARS-CoV-2 vaccine, and 9% (n = 279) reported vaccine hesitancy. Factors associated with vaccine hesitancy included female sex (adjusted odds ratio [AOR] = 2.3; 95% confidence interval (CI): 1.6-3.2), Black vs. White race (AOR 1.7; 95% CI: 1.2 to 2.4), younger age (AOR 1.4; 95% CI: 1.2 to 1.5), and unsuppressed VL (AOR 1.9; 95% CI: 1.3 to 3.0). CONCLUSION: Overall, over one-quarter of PWH in this multisite cohort were unvaccinated for SARS-CoV-2 when interviewed February 21-April 22. Vaccine hesitancy was reported by approximately 9% of PWH and was higher among women, Black PWH, younger PWH, PWH with unsuppressed VL, and those in the South/Midwest. Renewed efforts are needed to address concerns of PWH about vaccinations against COVID-19 as the pandemic evolves, and vaccines in general, given the potential for future pandemics.

Self-reported hepatitis B testing among noninstitutionalized adults in the United States before the implementation of universal screening, 2013-2017: A nationwide population-based study.

In 2023, the US Centers for Disease Control and Prevention recommended universal screening for hepatitis B virus (HBV); however, the proportion of US adults screened before implementing this recommendation is unknown. We analysed nationally representative data from the National Health Interview Survey (2013-2017) on self-reported HBV testing among noninstitutionalized US adults ≥18 years. We employed Poisson logistic regression to identify factors associated with self-reported testing, using a conceptual framework that included four overarching factors: sociodemographic characteristics, healthcare access, health-seeking behaviours and experiences, and access to internet-based health information. Among 149,628 survey respondents, the self-reported HBV testing rate was 27.2% (95% CI 26.2-28.7) and increased by 1.7% from 2013 to 2017 (p = .006). In adjusted analysis, health-seeking behaviours and experiences had the strongest associations of self-reported testing including a history of hepatitis (AOR 2.68, 95% CI 1.92-3.73), receipt of hepatitis B vaccination (AOR 5.11, 95% CI 4.61-5.68) and prior testing for hepatitis C (AOR 9.14, 95% CI 7.97-10.48) and HIV (AOR 2.69, 95% CI 2.44-2.97). Other factors associated with testing included being male (AOR 1.14, 95% CI 1.03-1.26), ages 30-44 years (AOR 1.37, 95% CI 1.17-1.61), 45-60 years (AOR 1.55, 95% CI 1.30-1.80) and ≥60 years (AOR 1.53, 95% CI 1.28-1.84), residence in the Western US region (AOR 1.23, 95% CI 1.06-1.43), and access to internet-based health information (AOR 1.32, 95% CI 1.18-1.47). Being Hispanic was associated with lower odds of testing (AOR 0.80, 95% CI 0.66-0.97). These findings may help guide optimal HBV screening in the universal testing era.

Sonographic diagnosis of spondylodiscitis in a young child.

Sonographic diagnosis of spondylodiscitis is described in a 21-month-old girl who presented with altered gait. Spondylodiscitis, also referred to as discitis-osteomyelitis, is an infection of the intervertebral disc and adjacent vertebrae. The imaging modality of choice is spinal magnetic resonance imaging. Our case is the first description in the English language of the sonographic diagnosis of spondylodiscitis. Pediatric radiologists and sonographers should be acquainted with its features, for both incidental and intentional diagnosis.

Effective and targeted latency reversal in CD4+ T cells from individuals on long term combined antiretroviral therapy initiated during chronic HIV-1 infection.

To date, an affordable, effective treatment for an HIV-1 cure remains only a concept with most "latency reversal" agents (LRAs) lacking specificity for the latent HIV-1 reservoir and failing in early clinical trials. We assessed HIV-1 latency reversal using a multivalent HIV-1-derived virus-like particle (HLP) to treat samples from 32 people living with HIV-1 (PLWH) in Uganda, US and Canada who initiated combined antiretroviral therapy (cART) during chronic infection. Even after 5-20 years on stable cART, HLP could target CD4+ T cells harbouring latent HIV-1 reservoir resulting in 100-fold more HIV-1 release into culture supernatant than by common recall antigens, and 1000-fold more than by chemotherapeutic LRAs. HLP induced release of a divergent and replication-competent HIV-1 population from PLWH on cART. These findings suggest HLP provides a targeted approach to reactivate the majority of latent HIV-1 proviruses among individuals infected with HIV-1.

Risk Stratification of Advanced Fibrosis in Patients With Human Immunodeficiency Virus and Hepatic Steatosis Using the Fibrosis-4, Nonalcoholic Fatty Liver Disease Fibrosis, and BARD Scores.

Background: Nonalcoholic fatty liver disease (NAFLD) and subsequent progression to fibrosis is increasingly prevalent in people with HIV (PWH). We used noninvasive methods to stratify risk and identify associated factors of advanced fibrosis in PWH with NAFLD. Methods: We conducted a retrospective study of PWH in our clinic from 2005 to 2022. We used liver imaging or biopsy reports to identify cases of hepatic steatosis after excluding specified etiologies. We used the Fibrosis-4 (FIB-4), NAFLD Fibrosis (NFS), and body mass index, aspartate transaminase/alanine transaminase ratio, and diabetes score scores to stratify fibrosis. We used logistic regression to identify factors associated with advanced fibrosis. Results: Among 3959 PWH in care, 1201 had available imaging or liver biopsies. After exclusions, 114 of 783 PWH had evidence of hepatic steatosis (14.6%). Most were male (71.1%), with a median age of 47 years, and median body mass index of 30.1 kg/m2. Approximately 24% had lean NAFLD (ie, body mass index < 25 kg/m2). Based on the FIB-4 and NFS, 34 (29.8%) and 36 (31.6%) had advanced fibrosis, whereas 1 in 4 had low risk of fibrosis based on FIB-4, NFS, and BARD scores. In adjusted analysis using FIB-4, advanced fibrosis was associated with age > 45 years (adjusted odds ratio, 6.29; 95% confidence interval, 1.93-20.50) and hypoalbuminemia (adjusted odds ratio, 9.45; 95% confidence interval, 2.45-32.52) in addition to elevated transaminases and thrombocytopenia, whereas using the NFS did not identify associations with advanced fibrosis. Conclusions: We found 14.6% of PWH had NAFLD, with 1 in 3 having advanced fibrosis. Our study provides practical insights into fibrosis risk stratification in HIV primary care settings.

Association of Alcohol Use with COVID-19 Infection and Hospitalization Among People Living with HIV in the United States, 2020.

Alcohol use was associated with elevated COVID-19 risk in the general population. People with HIV (PWH) have high prevalences of alcohol use. To evaluate the effect of alcohol use on COVID-19 risks among PWH, we estimated the risk of COVID-19 diagnosis and COVID-19-related hospitalization among PWH in routine care at 8 HIV primary care centers that contributed data to the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort according to their alcohol use just prior to the COVID-19 pandemic. The CNICS data repository includes demographic characteristics, clinical diagnoses, and laboratory test results from electronic medical records and other sources. Alcohol use, substance use, and mental health symptoms were self-reported on tablet-based standardized surveys. Alcohol use was categorized according to standard, sex-specific Alcohol Use Disorder Identification Test-Consumption instrument cut-offs. We followed 5,496 PWH (79% male, 48% Black race, median age = 53 years) from March 1, 2020 to December 31, 2020. Relative to PWH with no baseline alcohol use, the adjusted hazard ratio (aHR) of COVID-19 diagnosis was 1.09 (95% confidence interval [CI]: 0.78, 1.51) for lower-risk drinking and 1.19 (95%CI: 0.81, 1.73) for unhealthy drinking. The aHR of COVID-19-related hospitalization was 0.82 (95%CI: 0.33, 1.99) for lower-risk drinking and 1.25 (95%CI: 0.50, 3.09) for unhealthy drinking. Results were not modified by recent cocaine or non-prescribed opioid use, depressive symptoms, or diagnoses of alcohol use disorder. The study suggested a slightly increased, but not statistically significant risk of COVID-19 diagnosis and hospitalization associated with unhealthy alcohol use.

Viral Suppression Trajectories Destabilized After Coronavirus Disease 2019 Among US People With Human Immunodeficiency Virus: An Interrupted Time Series Analysis.

We examined changes in the proportion of people with human immunodeficiency virus (PWH) with virologic suppression (VS) in a multisite US cohort before and since the coronavirus disease 2019 (COVID-19) pandemic. Overall, prior gains in VS slowed during COVID-19, with disproportionate impacts on Black PWH and PWH who inject drugs.

The immunogenicity of an HIV-1 gag conserved element DNA vaccine in people with HIV and receiving antiretroviral therapy.

OBJECTIVE: The primary objective of the study was to assess the immunogenicity of an HIV-1 Gag conserved element DNA vaccine (p24CE DNA) in people with HIV (PWH) receiving suppressive antiretroviral therapy (ART). DESIGN: AIDS Clinical Trials Group A5369 was a phase I/IIa, randomized, double-blind, placebo-controlled study of PWH receiving ART with plasma HIV-1 RNA less than 50 copies/ml, current CD4+ T-cell counts greater than 500 cells/µl, and nadir CD4+ T-cell counts greater than 350 cells/µl. METHODS: The study enrolled 45 participants randomized 2 : 1 : 1 to receive p24CE DNA vaccine at weeks 0 and 4, followed by p24CE DNA admixed with full-length p55Gag DNA vaccine at weeks 12 and 24 (arm A); full-length p55Gag DNA vaccine at weeks 0, 4, 12, and 24 (arm B); or placebo at weeks 0, 4, 12, and 24 (arm c). The active and placebo vaccines were administered by intramuscular electroporation. RESULTS: There was a modest, but significantly greater increase in the number of conserved elements recognized by CD4+ and/or CD8+ T cells in arm A compared with arm C (P = 0.014). The percentage of participants with an increased number of conserved elements recognized by T cells was also highest in arm A (8/18, 44.4%) vs. arm C (0/10, 0.0%) (P = 0.025). There were no significant differences between treatment groups in the change in magnitude of responses to total conserved elements. CONCLUSION: A DNA-delivered HIV-1 Gag conserved element vaccine boosted by a combination of this vaccine with a full-length p55Gag DNA vaccine induced a new conserved element-directed cellular immune response in approximately half the treated PWH on ART.

Biological and Clinical Implications of the Vascular Endothelial Growth Factor Coreceptor Neuropilin-1 in Human Immunodeficiency Virus.

Plasma vascular endothelial growth factor (VEGF) coreceptor neuropilin-1 (NRP-1) had the largest association with coronary plaque in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) proteomics analysis. With little known about NRP-1 in people with human immunodeficiency virus (PWH), we explored its relation to other proteins in REPRIEVE and validated our findings through a Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) case-cohort study by assessing its relation to host factors and incident cardiovascular disease and cancer. Within REPRIEVE, NRP-1 was associated with proteins involved in angiogenesis, signal transduction, immunoregulation, and cell migration/adhesion. Within CNICS, NRP-1 was associated with key host factors, including older age and male sex. NRP-1 was associated with an increased hazard of multiple cancers but a decreased prostate cancer risk. Finally, NRP-1 was most strongly associated with mortality and type 2 myocardial infarction. These data suggest that NRP-1 is part of a clinically relevant immunoregulatory pathway related to multiple comorbidities in PWH. Clinical Trials Registration. NCT02344290.

Assessing the associations between known genetic variants and substance use in people with HIV in the United States.

BACKGROUND: The prevalence of substance use in people with HIV (PWH) in the United States is higher than in the general population and is an important driver of HIV-related outcomes. We sought to assess if previously identified genetic associations that contribute to substance use are also observed in a population of PWH. METHODS: We performed genome-wide association studies (GWAS) of alcohol, smoking, and cannabis use phenotypes in a multi-ancestry population of 7,542 PWH from the Center for AIDS Research Network of Integrated Clinical Systems (CNICS). We conducted multi-ancestry GWAS for individuals of African (n = 3,748), Admixed American (n = 1,334), and European (n = 2,460) ancestry. Phenotype data were self-reported and collected using patient reported outcomes (PROs) and three questions from AUDIT-C, an alcohol screening tool. We analyzed nine phenotypes: 1) frequency of alcohol consumption, 2) typical number of drinks on a day when drinking alcohol, 3) frequency of five or more alcoholic drinks in a 30-day period, 4) smoking initiation, 5) smoking cessation, 6) cigarettes per day, 7) cannabis use initiation, 8) cannabis use cessation, 9) frequency of cannabis use during the previous 30 days. For each phenotype we considered a) variants previously identified as associated with a substance use trait and b) novel associations. RESULTS: We observed evidence for effects of previously reported single nucleotide polymorphisms (SNPs) related to alcohol (rs1229984, p = 0.001), tobacco (rs11783093, p = 2.22E-4), and cannabis use (rs2875907, p = 0.005). We also report two novel loci (19p13.2, p = 1.3E-8; and 20p11.21, p = 2.1E-8) associated with cannabis use cessation. CONCLUSIONS: Our analyses contribute to understanding the genetic bases of substance use in a population with relatively higher rates of use compared to the general population.

Distinct SARS-CoV-2 specific NLRP3 and IL-1ß responses in T cells of aging patients during acute COVID-19 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19) that presents with varied clinical manifestations ranging from asymptomatic or mild infections and pneumonia to severe cases associated with cytokine storm, acute respiratory distress syndrome (ARDS), and even death. The underlying mechanisms contributing to these differences are unclear, although exacerbated inflammatory sequelae resulting from infection have been implicated. While advanced aging is a known risk factor, the precise immune parameters that determine the outcome of SARS-CoV-2 infection in elderly individuals are not understood. Here, we found aging-associated (age ≥61) intrinsic changes in T cell responses when compared to those from individuals aged ≤ 60, even among COVID-positive patients with mild symptoms. Specifically, when stimulated with SARS-CoV-2 peptides in vitro, peripheral blood mononuclear cell (PBMC) CD4+ and CD8+ T cells from individuals aged ≥61 showed a diminished capacity to produce IFN-γ and IL-1ß. Although they did not have severe disease, aged individuals also showed a higher frequency of PD-1+ cells and significantly diminished IFN-γ/PD-1 ratios among T lymphocytes upon SARS-CoV-2 peptide stimulation. Impaired T cell IL-1ß expression coincided with reduced NLRP3 levels in T lymphocytes. However, the expression of these molecules was not affected in the monocytes of individuals aged ≥61. Together, these data reveal SARS-CoV-2-specific CD4+ and CD8+ T-cell intrinsic cytokine alterations in the individuals older than 61 and may provide new insights into dysregulated COVID-directed immune responses in the elderly.

African American/Black race, apolipoprotein L1 , and serum creatinine among persons with HIV.

OBJECTIVE: Accurate estimation of kidney function is critical among persons with HIV (PWH) to avoid under-dosing of antiretroviral therapies and ensure timely referral for kidney transplantation. Existing estimation equations for kidney function include race, the appropriateness of which has been debated. Given advancements in understanding of race and the necessity of accuracy in kidney function estimation, this study aimed to examine whether race, or genetic factors, improved prediction of serum creatinine among PWH. DESIGN: This cross-sectional study utilized data from the Center for AIDS Research Network of Integrated Clinical Systems cohort (2008-2018). The outcome was baseline serum creatinine. METHODS: Ordinary least squares regression was used to examine whether inclusion of race or genetic factors [ apolipoprotein-L1 ( APOL1 ) variants and genetic African ancestry] improved serum creatinine prediction. A reduction in root mean squared error (RMSE) greater than 2% was a clinically relevant improvement in predictive ability. RESULTS: There were 4183 PWH included. Among PWH whose serum creatinine was less than 1.7 mg/dl, race was significantly associated with serum creatinine ( ß â€Š= 0.06, SE = 0.01, P  < 0.001) but did not improve predictive ability. African ancestry and APOL1 variants similarly failed to improve predictive ability. Whereas, when serum creatinine was at least 1.7 mg/dl, inclusion of race reduced the RMSE by 2.1%, indicating improvement in predictive ability. APOL1 variants further improved predictive ability by reducing the RMSE by 2.9%. CONCLUSION: These data suggest that, among PWH, inclusion of race or genetic factors may only be warranted at higher serum creatinine levels. Work eliminating existing healthcare disparities while preserving the utility of estimating equations is needed.

Risk Stratification of Advanced Fibrosis in HIV Patients With Hepatic Steatosis Using the NAFLD Fibrosis and BARD Scores.

Background: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent in people with HIV (PWH), yet the risk factors for disease progression are poorly understood, due to inadequate surveillance. We employed non-invasive methods to estimate the prevalence and associated factors of advanced NAFLD in PWH. Methods: We conducted a retrospective study of PWH enrolled in our clinic from 2005 to 2022. We employed imaging (ultrasound, computer tomography, magnetic resonance imaging, and transient elastography) or biopsy reports to identify cases of hepatic steatosis. We excluded patients with harmful alcohol use, hepatitis B or C infection, and other specified etiologies. We used the NAFLD Fibrosis Score (NFS), BARD Score, AST to Platelet Index (APRI), and Fibrosis-4 (FIB-4) Score to stratify fibrosis. We used logistic regression to identify predictors of advanced fibrosis. Results: Among 3959 PWH in care, 1201 had available imaging or liver biopsies. After exclusions, 114 of the remaining 783 had evidence of hepatic steatosis (prevalence 14.6%). The majority were male (71.1%), with mean age 46.1 years, and mean body mass index (BMI) 31.4 ± 8.1 kg/m2. About 24% had lean NAFLD (BMI < 25 kg/m2). Based on the NFS, 27.2% had advanced fibrosis, which was corroborated by estimates from the other scores. In adjusted regression analysis, advanced fibrosis was associated with BMI > 35 kg/m2 (4.43, 1.27-15.48), thrombocytopenia (4.85, 1.27-18.62) and hypoalbuminemia (9.01, 2.39-33.91). Conclusion: We found a NAFLD prevalence of 14.6%, with 27.2% of cases having advanced fibrosis. Our study provides practical insights into the surveillance of NAFLD in PWH.

Interleukin 6 Blockade With Tocilizumab Diminishes Indices of Inflammation That Are Linked to Mortality in Treated Human Immunodeficiency Virus Infection.

BACKGROUND: People with human immunodeficiency virus (PWH) are at increased risk for comorbidities, and plasma interleukin 6 (IL-6) levels are among the most robust predictors of these outcomes. Tocilizumab (TCZ) blocks the receptor for IL-6, inhibiting functions of this cytokine. METHODS: This was a 40-week, placebo-controlled, crossover trial (NCT02049437) where PWH on stable antiretroviral therapy (ART) were randomized to receive 3 monthly doses of TCZ or matching placebo intravenously. Following a 10-week treatment period and a 12-week washout, participants were switched to the opposite treatment. The primary endpoints were safety and posttreatment levels of C-reactive protein (CRP) and CD4+ T-cell cycling. Secondary endpoints included changes in inflammatory indices and lipid levels. RESULTS: There were 9 treatment-related toxicities of grade 2 or greater during TCZ administration (mostly neutropenia) and 2 during placebo administration. Thirty-one of 34 participants completed the study and were included in a modified intent-to-treat analysis. TCZ reduced levels of CRP (median decrease, 1819.9 ng/mL, P < .0001; effect size, 0.87) and reduced inflammatory markers in PWH, including D-dimer, soluble CD14, and tumor necrosis factor receptors. T-cell cycling tended to decrease in all maturation subsets after TCZ administration, but was only significant among naive CD4 T cells. Lipid levels, including lipid classes that have been related to cardiovascular disease risk, increased during TCZ treatment. CONCLUSIONS: TCZ is safe and decreases inflammation in PWH; IL-6 is a key driver of the inflammatory environment that predicts morbidity and mortality in ART-treated PWH. The clinical significance of lipid elevations during TCZ treatment requires further study. Clinical Trials Registration. NCT02049437.

Plasma Interleukin-6 (IL-6), Angiopoietin-2, and C-Reactive Protein Levels Predict Subsequent Type 1 Myocardial Infarction in Persons With Treated HIV Infection.

BACKGROUND: HIV infection leads to endothelial activation, promoting platelet adhesion, and accelerating atherosclerosis. Our goal was to determine whether biomarkers of endothelial activation and hemostasis/thrombosis were elevated in people with treated HIV (PWH) before myocardial infarction (MI). METHODS: In a case-control study nested within the CFAR Network of Integrated Clinical Systems (CNICS) cohort, we compared 69 adjudicated cases with type 1 MI with 138 controls matched for antiretroviral therapy regimen. We measured angiopoietin-1, angiopoietin-2 (ANG-2), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), von Willebrand factor, C-reactive protein (CRP), interleukin-6 (IL-6), plasminogen activation inhibitor-1, P-selectin, serum amyloid-A, soluble CD14, and apolipoprotein A1 in stored plasma. Conditional logistic regression identified associations with subsequent MI, with and without adjustment for Atherosclerotic Cardiovascular Disease (ASCVD) and Veterans Aging Cohort Study (VACS) scores. RESULTS: Higher IL-6 was associated with MI after adjustment for ASCVD score (adjusted odds ratio [AOR] 1.51, 95% confidence interval [95% CI]: 1.05 to 2.17 per standard-deviation-scaled log 2 increment). In a separate model adjusting for VACS score, higher ANG-2 (AOR 1.49, 95% CI: 1.04 to 2.14), higher CRP (AOR 1.45, 95% CI: 1.06 to 2.00), and higher IL-6 (AOR 1.68, 95% CI: 1.17 to 2.41) were associated with MI. In a sensitivity analysis excluding PWH with viral load ≥400 copies/mL, higher IL-6 remained associated with MI after adjustment for ASCVD score and after adjustment for VACS score. CONCLUSIONS: Among PWH, higher levels of plasma IL-6, CRP, and ANG-2 predict subsequent type 1 MI, independent of conventional risk scores. IL-6 had the most consistent associations with type 1 MI, regardless of viral load suppression.

Early Antiretroviral Therapy Not Associated With Higher Cryptococcal Meningitis Mortality in People With Human Immunodeficiency Virus in High-Income Countries: An International Collaborative Cohort Study.

BACKGROUND: Randomized controlled trials (RCTs) from low- and middle-income settings suggested that early initiation of antiretroviral therapy (ART) leads to higher mortality rates among people with HIV (PWH) who present with cryptococcal meningitis (CM). There is limited information about the impact of ART timing on mortality rates in similar people in high-income settings. METHODS: Data on ART-naive PWH with CM diagnosed from 1994 to 2012 from Europe/North America were pooled from the COHERE, NA-ACCORD, and CNICS HIV cohort collaborations. Follow-up was considered to span from the date of CM diagnosis to earliest of the following: death, last follow-up, or 6 months. We used marginal structural models to mimic an RCT comparing the effects of early (within 14 days of CM) and late (14-56 days after CM) ART on all-cause mortality, adjusting for potential confounders. RESULTS: Of 190 participants identified, 33 (17%) died within 6 months. At CM diagnosis, their median age (interquartile range) was 38 (33-44) years; the median CD4+ T-cell count, 19/µL (10-56/µL); and median HIV viral load, 5.3 (4.9-5.6) log10 copies/mL. Most participants (n = 157 [83%]) were male, and 145 (76%) started ART. Mimicking an RCT, with 190 people in each group, there were 13 deaths among participants with an early ART regimen and 20 deaths among those with a late ART regimen. The crude and adjusted hazard ratios comparing late with early ART were 1.28 (95% confidence interval, .64-2.56) and 1.40 (.66-2.95), respectively. CONCLUSIONS: We found little evidence that early ART was associated with higher mortality rates among PWH presenting with CM in high-income settings, although confidence intervals were wide.

HIV post-treatment controllers have distinct immunological and virological features.

HIV post-treatment controllers (PTCs) are rare individuals who maintain low levels of viremia after stopping antiretroviral therapy (ART). Understanding the mechanisms of HIV post-treatment control will inform development of strategies aiming at achieving HIV functional cure. In this study, we evaluated 22 PTCs from 8 AIDS Clinical Trials Group (ACTG) analytical treatment interruption (ATI) studies who maintained viral loads ≤400 copies/mL for ≥24 wk. There were no significant differences in demographics or frequency of protective and susceptible human leukocyte antigen (HLA) alleles between PTCs and post-treatment noncontrollers (NCs, n = 37). Unlike NCs, PTCs demonstrated a stable HIV reservoir measured by cell-associated RNA (CA-RNA) and intact proviral DNA assay (IPDA) during analytical treatment interruption (ATI). Immunologically, PTCs demonstrated significantly lower CD4+ and CD8+ T cell activation, lower CD4+ T cell exhaustion, and more robust Gag-specific CD4+ T cell responses and natural killer (NK) cell responses. Sparse partial least squares discriminant analysis (sPLS-DA) identified a set of features enriched in PTCs, including a higher CD4+ T cell% and CD4+/CD8+ ratio, more functional NK cells, and a lower CD4+ T cell exhaustion level. These results provide insights into the key viral reservoir features and immunological profiles for HIV PTCs and have implications for future studies evaluating interventions to achieve an HIV functional cure.

Cellular and humoral responses to an HIV DNA prime by electroporation boosted with recombinant vesicular stomatitis virus expressing HIV subtype C Env in a randomized controlled clinical trial.

BACKGROUND: HIV subtypes B and C together account for around 60% of HIV-1 cases worldwide. We evaluated the safety and immunogenicity of a subtype B DNA vaccine prime followed by a subtype C viral vector boost. METHODS: Fourteen healthy adults received DNA plasmid encoding HIV-1 subtype B nef/tat/vif and env (n = 11) or placebo (n = 3) intramuscularly (IM) via electroporation (EP) at 0, 1, and 3 months, followed by IM injection of recombinant vesicular stomatitis virus encoding subtype C Env or placebo at 6 and 9 months. Participants were assessed for safety, tolerability of EP, and Env-specific T-cell and antibody responses. RESULTS: EP was generally well tolerated, although some device-related adverse events did occur, and vaccine reactogenicity was mild to moderate. The vaccine stimulated Env-specific CD4 + T-cell responses in greater than 80% of recipients, and CD8 + T-cell responses in 30%. Subtype C Env-specific IgG binding antibodies (bAb) were elicited in all vaccine recipients, and antibody-dependent cell-mediated cytotoxicity (ADCC) responses to vaccine-matched subtype C targets in 80%. Negligible V1/V2 and neutralizing antibody (nAb) responses were detected. CONCLUSIONS: This prime/boost regimen was safe and tolerable, with some device-related events, and immunogenic. Although immunogenicity missed targets for an HIV vaccine, the DNA/rVSV platform may be useful for other applications. CLINICALTRIALS: gov: NCT02654080.

Impact of age, antiretroviral therapy, and cancer on epigenetic aging in people living with HIV.

BACKGROUND: Premature aging has been identified as a global risk factor for cancer. Causes of premature aging are multifactorial, including inflammation, infection, chronic stress, and lifestyle factors. METHOD: We evaluated whether premature aging in people living with HIV (PLWH) was associated with antiretroviral therapy (ART) or the diagnosis of cancer. We used well-established DNA methylation patterns to assess premature aging, using Horvath et al., in individuals with HIV located in Cleveland, Ohio and compared these to standardized datasets of US historical blood samples. Some of the PLWH developed cancer over time. RESULTS: We found that DNA methylation analysis identified accelerated aging in PLWH whereas ART therapy mitigated the advancement of DNA methylation age. A variety of cancers were observed in this population, but a cancer diagnosis was not significantly associated with more advanced DNA methylation age. CONCLUSION: We find that the age acceleration detected in PLWH is mitigated by ART therapy and is not further accelerated by a diagnosis of cancer.