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Vaporized nicotine (VN) use is increasing among people with HIV (PWH). We examined demographics, patterns of use, depression, and panic symptoms associated with VN and combustible cigarette (CC) use among PWH.We analyzed VN use among PWH in care at 7 US sites. PWH completed a set of patient-reported outcomes, including substance use and mental health. We categorized VN use as never vs. ever with frequency of use (days/month) and CC use as never, former, or current. We used relative risk regression to associate VN and CC use, depression, and panic. Linear regression estimated each relationship with VN frequency. Models were adjusted for demographics.Among 7,431 PWH, 812 (11%) reported ever-using VN, and 264 (4%) reported daily use. Half (51%) of VN users concurrently used CC. VN users were more likely than those without use to be younger, white, and to report ever-using CC. PWH reporting former CC use reported ≥8.5 more days per month of VN use compared to never CC use (95%CI: 5.5-11.5 days/month) or current (95%CI: 6.6-10.5 days/month). Depression (RR: 1.20 [95%CI: 1.02-1.42]) and panic disorder (1.71 [95%CI: 1.43-2.05]) were more common among PWH ever-using VN. Depression was common among PWH using VN (27%) and CC (22%), as was panic disorder (21% for VN, 16% for CC).Our study elucidated demographic associations with VN use among PWH, revealed overlap of VN and CC use, and associations with depression/panic symptoms, suggesting roles of VN in self-medication and CC substitution, warranting further longitudinal/qualitative research.

Chronic hepatitis C can lead to cirrhosis and hepatocellular carcinoma. We studied the safety and immunogenicity of a novel therapeutic hepatitis C virus (HCV) genotype 1a/1b consensus DNA vaccine, INO-8000, encoding HCV NS3, NS4A, NS4B, and NS5A proteins alone or co-administered with DNA-encoding IL12 (INO-9012), a human cytokine that stimulates cellular immune function, in individuals with chronic hepatitis C. This was a phase I, multisite dose-escalation trial with an expansion cohort evaluating doses of 0, 0.3, 1.0, and 3.0 mg of INO-9012 (IL12 DNA) as an addition to 6.0 mg of (INO-8000; HCV DNA vaccine). Vaccines were administered by intramuscular injection followed by electroporation at study entry and at weeks 4, 12, and 24. HCV-specific CD4+ and CD8+ T-cell immune responses were measured by IFNγ ELISpot and flow cytometry–based assays. Transient, mild-to-moderate injection site reactions unrelated to IL12 DNA dose were common. Increases in HCV-specific IFNγ production occurred in 15/20 (75%) participants. Increases in the frequency of HCV-specific CD4+ and CD8+ T cells occurred at all dose levels, with the greatest increases seen at 1.0 mg of INO-9012. HCV-specific CD8+ and CD4+ T-cell activities increased in 16/18 (89%) and 14/17 (82%) participants with available data, respectively. The vaccine regimen was safe and induced HCV-specific CD4+ and CD8+ cellular immune responses of modest magnitude in most HCV-infected participants. The addition of 1.0 mg of IL12 DNA provided the best enhancement of immune responses. The vaccine regimen had little effect on controlling HCV viremia.Prevention Relevance:The administration of IL12 DNA along with a hepatitis C viral antigen DNA vaccine enhanced the HCV-specific immune responses induced by the vaccine in individuals with chronic hepatitis C, an important cause of hepatocellular carcinoma. IL12 could be an effective adjuvant in vaccines targeting HCV and other oncogenic viruses.

Background: The high soft-tissue contrast of magnetic resonance imaging (MRI) makes it useful for evaluation of hand injuries, but its limitations include cost, imaging artifacts, and patient claustrophobia. Ultrasound is readily available, fast, noninvasive, and radiation free, but its utility for the evaluation of hand soft-tissue injury and pathology is less well known. Purpose: We sought to examine the accuracy of ultrasound for the evaluation of hand injury at a single institution. Methods: We queried a radiology information system for ultrasound cases between 2014 and 2020 at a tertiary care institution using the keyword “hand” and injury terms. We performed a retrospective chart review of cases found according to the type of injury detected on ultrasound. To evaluate the diagnostic accuracy of ultrasound in hand injury and pathology, we recorded postimaging clinical diagnoses and surgical findings. Results: We found 154 patients who underwent ultrasound for hand injuries and had confirmed surgical diagnosis and/or robust clinical follow-up. Tendon injury was the most commonly diagnosed condition on ultrasound (70/154); others detected were retained foreign body (31), mass (21), ligamentous injury (9), pulley injury (8), nerve injury (11), and traumatic arthropathy (4). Ultrasound correctly characterized hand injury in 150/154 cases (97.4%) based on surgical and/or clinical follow-up. Ultrasound failed to diagnose 3 cases of partial tendon tear and 1 case of digital nerve injury. Conclusion: In this retrospective, single-institution review, ultrasound was found to be highly accurate in the detection of soft tissue hand injury and pathology, demonstrating a high concordance rate with surgical and clinical findings. Further study is warranted.

OBJECTIVE: To describe retention in HIV care based on various definitions of retention in the modern treatment era. DESIGN: A cohort study of people enrolled in care at 7 mostly urban HIV clinics across the United States, 2010-2018. METHODS: We estimated retention based on missed visits, kept visits, kept encounters (clinical visits, CD4 counts, and viral loads), and HIV labs. We contrasted risk factors for retention by different definitions and estimated odds ratios for of viral suppression and hazard ratios for mortality in 2 years immediately following the year in which retention was defined (the study year). RESULTS: Across 108,171 person-years (N=21,481 people), in 71% of years people kept ≥75% of scheduled visits; in 78%, people kept ≥2 visits >90 days apart; in 74%, people had ≥2 HIV labs >90 days apart; and in 47%, people had no gaps >6 months in clinic visits. Missing >25% of scheduled visits despite attending ≥2 visits >90 days apart was associated with non-white non-Hispanic race/ethnicity, history of injection drug use, and prior AIDS diagnosis. In contrast, attending ≥75% of scheduled visits while not attending ≥2 visits >90 days apart was associated with male sex, white race, no injection drug use history, and no prior AIDS diagnosis. Subsequent viral non-suppression was more strongly associated with missed- than kept-visit measures of retention; 2-year mortality was only associated with failure to be retained by missed-visit measures. DISCUSSION: Missed and kept-visit definitions of retention capture different constructs. Missed-visit measures are more strongly associated with poor HIV outcomes.

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.

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.

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

Posttreatment controllers (PTCs) are rare HIV-infected individuals who can limit viral rebound after antiretroviral therapy interruption (ATI), but the mechanisms of this remain unclear. To investigate these mechanisms, we quantified various HIV RNA transcripts (via reverse transcription droplet digital PCR [RT-ddPCR]) and cellular transcriptomes (via RNA-seq) in blood cells from PTCs and noncontrollers (NCs) before and two time points after ATI. HIV transcription initiation did not significantly increase after ATI in PTCs or in NCs, whereas completed HIV transcripts increased at early ATI in both groups and multiply-spliced HIV transcripts increased only in NCs. Compared to NCs, PTCs showed lower levels of HIV DNA, more cell-associated HIV transcripts per total RNA at all times, no increase in multiply-spliced HIV RNA at early or late ATI, and a reduction in the ratio of completed/elongated HIV RNA after early ATI. NCs expressed higher levels of the IL-7 pathway before ATI and expressed higher levels of multiple cytokine, inflammation, HIV transcription, and cell death pathways after ATI. Compared to the baseline, the NCs upregulated interferon and cytokine (especially TNF) pathways during early and late ATI, whereas PTCs upregulated interferon and p53 pathways only at early ATI and downregulated gene translation during early and late ATI. In NCs, viral rebound after ATI is associated with increases in HIV transcriptional completion and splicing, rather than initiation. Differences in HIV and cellular transcription may contribute to posttreatment control, including an early limitation of spliced HIV RNA, a delayed reduction in completed HIV transcripts, and the differential expression of the IL-7, p53, and TNF pathways. IMPORTANCE The findings presented here provide new insights into how HIV and cellular gene expression change after stopping ART in both noncontrollers and posttreatment controllers. Posttreatment control is associated with an early ability to limit increases in multiply-spliced HIV RNA, a delayed (and presumably immune-mediated) ability to reverse an initial rise in processive/completed HIV transcripts, and multiple differences in cellular gene expression pathways. These differences may represent correlates or mechanisms of posttreatment control and may provide insight into the development and/or monitoring of therapeutic strategies that are aimed at a functional HIV cure.

BackgroundThe molecular basis of heterotaxy and congenital heart malformations associated with disruption of left–right asymmetry is broad and heterogenous, with over 25 genes implicated in its pathogenesis thus far.ObjectiveWe sought to elucidate the molecular basis of laterality disorders and associated congenital heart defects in a cohort of 30 unrelated probands of Arab–Muslim descent, using next-generation sequencing techniques.MethodsDetailed clinical phenotyping followed by whole-exome sequencing (WES) was pursued for each of the probands and their parents (when available). Sanger sequencing was used for segregation analysis of disease-causing mutations in the families.ResultsUsing WES, we reached a molecular diagnosis for 17 of the 30 probands (56.7%). Genes known to be associated with heterotaxy and/or primary ciliary dyskinesia, in which homozygous pathogenic or likely pathogenic variants were detected, included CFAP53 (CCDC11), CFAP298 (C21orf59), CFAP300, LRRC6, GDF1, DNAAF1, DNAH5, CCDC39, CCDC40, PKD1L1 and TTC25. Additionally, we detected a homozygous disease causing mutation in DAND5, as a novel recessive monogenic cause for heterotaxy in humans. Three additional probands were found to harbour variants of uncertain significance. These included variants in DNAH6, HYDIN, CELSR1 and CFAP46.ConclusionsOur findings contribute to the current knowledge regarding monogenic causes of heterotaxy and its associated congenital heart defects and underscore the role of next-generation sequencing techniques in the diagnostic workup of such patients, and especially among consanguineous families.

Direct-acting antivirals (DAA) are highly effective against hepatitis C virus (HCV) infection among persons with human immunodeficiency virus (PWH). However, alcohol use post-DAA treatment poses a continued threat to the liver. Whether the focus on liver health alone during HCV treatment can impact alcohol consumption is unclear. Therefore, we examined the change in alcohol use among HCV-coinfected PWH who received DAA therapy by non-addiction medical providers.In our longitudinal clinical cohort study, we identified HCV-coinfected PWH who received interferon-free DAA therapy between January 2014 and June 2019 in the Centers for AIDS Research Network of Integrated Clinical Systems. The Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) was the alcohol screening instrument. We used mixed-effects logistic regression models to estimate the longitudinal change in alcohol use upon DAA therapy.Among 738 HCV-coinfected PWH, 339 (46 %) reported any alcohol use at the end of HCV treatment, including 113 (15 %) with high-risk use (i.e., AUDIT-C ≥3 for women, ≥4 for men). Concurrently, 280 (38 %) PWH noted active drug use, and 357 (48 %) were currently smoking. We observed no changes in the odds of any alcohol or high-risk alcohol use over time with DAA therapy. Findings were similar in the PWH subgroup with a history of alcohol use before DAA treatment.For PWH with HCV, alcohol use did not change following interferon-free DAA treatment by non-addiction medical providers. Thus, clinicians should consider integrating targeted alcohol use interventions into HCV care to motivate reduced alcohol consumption and safeguard future liver health.

MazF is an Escherichia coli-derived endoribonuclease that selectively cleaves ACA sequences of mRNA prevalent in HIV. We administered a single infusion of autologous CD4 T lymphocytes modified to express a Tat-dependent MazF transgene to 10 HIV-infected individuals (six remaining on antiretroviral therapy [ART]; four undergoing treatment interruption post-infusion) in order to provide a population of HIV-resistant immune cells. In participants who remained on ART, increases in CD4 and CD8 T cell counts of ~200 cells/mm(3) each occurred within 2 weeks of infusion and persisted for at least 6 months. Modified cells were detectable for several months in the blood and trafficked to gastrointestinal lymph tissue. HIV-1 Tat introduced ex vivo to the modified CD4(+) T cells induced MazF expression in both pre- and post-infusion samples, and MazF expression was detected in vivo post-viral-rebound during ATI. One participant experienced mild cytokine release syndrome. In sum, this study of a single infusion of MazF-modified CD4 T lymphocytes demonstrated safety of these cells, distribution to lymph tissue and maintenance of Tat-inducible MazF endoribonuclease activity, as well as sustained elevation of blood CD4 and CD8 T cell counts. Future studies to assess effects on viremia and latent proviral reservoir are warranted.

HIV-1 persists in cellular reservoirs that can reignite viremia if antiretroviral therapy (ART) is interrupted. Therefore, insight into the nature of those reservoirs may be revealed from the composition of recrudescing viremia following treatment cessation. A minor population of macrophage-tropic (M-tropic) viruses was identified in a library of recombinant viruses constructed with individual envelope genes that were obtained from plasma of six individuals undergoing analytic treatment interruption (ATI). M-tropic viruses could also be enriched from post-ATI plasma using macrophage-specific (CD14) but not CD4+ T cell-specific (CD3) antibodies, suggesting that M-tropic viruses had a macrophage origin. Molecular clock analysis indicated that the establishment of M-tropic HIV-1 variants predated ATI. Collectively, these data suggest that macrophages are a viral reservoir in HIV-1–infected individuals on effective ART and that M-tropic variants can appear in rebounding viremia when treatment is interrupted. These findings have implications for the design of curative strategies for HIV-1.

Among 14 049 people with human immunodeficiency virus in care in 2019–2020, 96% were treated with antiretroviral therapy (ART). Current antiretroviral treatment patterns highlight high uptake of guideline-recommended ART regimens including second-generation integrase strand transfer inhibitors (dolutegravir and bictegravir) and tenofovir alafenamide, especially in antiretroviral-naive individuals initiating ART.

HIV-1 establishes a life-long reservoir of virally infected cells which cannot be eliminated by antiretroviral therapy (ART). Here, we demonstrate a markedly altered viral reservoir profile of long-term ART-treated individuals, characterized by large clones of intact proviruses preferentially integrated in heterochromatin locations, most prominently in centromeric satellite/micro-satellite DNA. Longitudinal evaluations suggested that this specific reservoir configuration results from selection processes that promote the persistence of intact proviruses in repressive chromatin positions, while proviruses in permissive chromosomal locations are more likely to be eliminated. A bias toward chromosomal integration sites in heterochromatin locations was also observed for intact proviruses in study participants who maintained viral control after discontinuation of antiretroviral therapy. Together, these results raise the possibility that antiviral selection mechanisms during long-term ART may induce an HIV-1 reservoir structure with features of deep latency and, possibly, more limited abilities to drive rebound viremia upon treatment interruptions.

BackgroundUnderstanding the spectrum of SARS-CoV-2 infection and COVID-19 disease in people with HIV (PWH) is critical to provide clinical guidance and implement risk-reduction strategies.ObjectiveTo characterize COVID-19 in PWH in the United States and identify predictors of disease severity.DesignObservational cohort study.SettingGeographically diverse clinical sites in the CFAR Network of Integrated Clinical Systems (CNICS)ParticipantsAdults receiving HIV care through December 31, 2020.MeasurementsCOVID-19 cases and severity (hospitalization, intensive care, death).ResultsOf 16,056 PWH in care, 649 were diagnosed with COVID-19 between March-December 2020. Case fatality was 2%; 106 (16.3%) were hospitalized and 12 died. PWH with current CD4 count 3(aRR 2.68; 95%CI 1.93-3.71; PLimitationsUnable to compare directly to persons without HIV; underestimate of total COVID-19 cases.ConclusionsPWH with CD4 3, low CD4/CD8 ratio, and history of CD4

This chapter explores the AIDS epidemic, which presents severe manifestations of various opportunistic infections (OIs) in hosts whose immune systems were compromised. It describes how individuals with AIDS succumbed to pneumocystic pneumonia, toxoplasmosis, disseminated mycobacterium, and several other OIs and malignancies. It explains how HIV-positive persons can be largely unaffected by OI when they remain well-adherent to antiretroviral therapy (ART). The chapter mentions barriers to care and medication adherence that allow HIV to progress, leaving patients susceptible to OI. It focuses on prophylaxis for OI in HIV-positive patients as an important topic and cornerstone of providing care for this patient population.

Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity, and immunodeficiency. We here investigated 4 patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified 4 distinct homozygous mutations in TNFRSF9 encoding the tumor necrosis factor receptor superfamily member CD137/4-1BB, leading to reduced, or loss of, protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, and differentiation, were impaired. Genetic reconstitution of CD137 reversed these defects. CD137 deficiency is a novel inborn error of human immunity characterized by lymphocytic defects with early-onset Epstein-Barr virus (EBV)-associated lymphoma. Our findings elucidate a functional role and relevance of CD137 in human immune homeostasis and antitumor responses.

Introduction: HIV-infected individuals have evidence of intestinal microbial translocation which is associated with immune activation and unfavorable clinical outcomes. Rifaximin, a non-absorbable antibiotic which reduces microbial translocation in other disease states, was shown to have a marginal beneficial effect on microbial translocation, T-cell activation, and inflammation in a multisite randomized trial (ACTG A5286; NCT01466595) of HIV-infected persons with poor immunologic recovery receiving ART. Here, we report analysis of the rectal microbiome changes associated with that trial.Methods: HIV-1-infected individuals receiving ART with CD4-T cell count

We previously reported that pegylated IFN-α2a (Peg–IFN-α2a) added to antiretroviral therapy (ART)–suppressed, HIV-infected subjects resulted in plasma HIV control and integrated HIV DNA decrease. We now evaluated whether innate NK cell activity or PBMC transcriptional profiles were associated with decreases in HIV measures. Human peripheral blood was analyzed prior to Peg–IFN-α2a administration (ART, baseline), after 5 wk of ART+Peg–IFN-α2a, and after 12 wk of Peg–IFN-α2a monotherapy (primary endpoint). After 5 wk of ART+Peg–IFN-α2a, immune subset frequencies were preserved, and induction of IFN-stimulated genes was noted in all subjects except for a subset in which the lack of IFN-stimulated gene induction was associated with increased expression of microRNAs. Viral control during Peg–IFN-α2a monotherapy was associated with 1) higher levels of NK cell activity and IFN-γ–induced protein 10 (IP-10) on ART (preimmunotherapy) and 2) downmodulation of NK cell KIR2DL1 and KIR2DL2/DL3 expression, transcriptional enrichment of expression of genes associated with NK cells in HIV controller subjects, and higher ex vivo IFN-α–induced NK cytotoxicity after 5 wk of ART+Peg–IFN-α2a. Integrated HIV DNA decline after immunotherapy was also associated with gene expression patterns indicative of cell-mediated activation and NK cytotoxicity. Overall, an increase in innate activity and NK cell cytotoxicity were identified as correlates of Peg–IFN-α2a–mediated HIV control.

Elimination of HIV-1 requires clearance and removal of integrated proviral DNA from infected cells and tissues. Here, sequential long-acting slow-effective release antiviral therapy (LASER ART) and CRISPR-Cas9 demonstrate viral clearance in latent infectious reservoirs in HIV-1 infected humanized mice. HIV-1 subgenomic DNA fragments, spanning the long terminal repeats and the Gag gene, are excised in vivo, resulting in elimination of integrated proviral DNA; virus is not detected in blood, lymphoid tissue, bone marrow and brain by nested and digital-droplet PCR as well as RNAscope tests. No CRISPR-Cas9 mediated off-target effects are detected. Adoptive transfer of human immunocytes from dual treated, virus-free animals to uninfected humanized mice fails to produce infectious progeny virus. In contrast, HIV-1 is readily detected following sole LASER ART or CRISPR-Cas9 treatment. These data provide proof-of-concept that permanent viral elimination is possible., Here, the authors show that sequential treatment with long-acting slow-effective release ART and AAV9- based delivery of CRISPR-Cas9 results in undetectable levels of virus and integrated DNA in a subset of humanized HIV-1 infected mice. This proof-of-concept study suggests that HIV-1 elimination is possible.

Background A5350, a phase II, randomized, double-blind study, evaluated the safety and tolerability of the probiotic Visbiome Extra Strength (ES) over 24 weeks and measured effects on inflammation and intestinal barrier function. Methods The primary outcome was change in soluble CD14 (sCD14) levels; secondary outcomes included safety and tolerability, markers of inflammation and cellular activation, and microbiome. In a substudy, gut permeability was assessed by paired colonic biopsies measuring the area of lamina propria occupied by CD4+ cells, interleukin (IL)-17+ cells, and myeloperoxidase (MPO). Changes between arms were compared with the 2-sample t test with equal variance or the Wilcoxon rank-sum test. For safety, the highest graded adverse events (AEs) were compared between arms using the Fisher exact test. Results Overall, 93 participants enrolled: 86% male, median age 51 years, median CD4 count 712 cells/mm3. Visbiome ES was safe and well tolerated. There was no difference in mean change in sCD14 from baseline to week 25/26 between placebo (mean change, 92.3 µg/L; 95% CI, –48.5 to 233 µg/L) and Visbiome ES (mean change, 41.0 µg/L; 95% CI, –94.1 to 176.2 µg/L; P=.60). Similarly, no statistically significant differences between arms in inflammatory marker changes were identified. In substudy participants, no statistical differences between arms for change in cellular marker expression or gut permeability were observed (P>.05 for all). The microbiome demonstrated increased probiotic species and a significant decrease in Gammaproteobacteria (P=.044) in the Visbiome ES arm. Conclusions Visbiome ES was safe and altered the microbiome but demonstrated no effect on systemic inflammatory markers, pathology, or gut permeability in antiretroviral therapy–treated people with HIV.

Background Direct-acting antivirals can cure hepatitis C virus (HCV). Persons with HCV/HIV and living with substance use are disadvantaged in benefiting from advances in HCV treatment. Methods In this randomized controlled trial, participants with HCV/HIV were randomized between February 2016 and January 2017 to either care facilitation or control. Twelve-month follow-up assessments were completed in January 2018. Care facilitation group participants received motivation and strengths-based case management addressing retrieval of HCV viral load results, engagement in HCV/HIV care, and medication adherence. Control group participants received referral to HCV evaluation and an offer of assistance in making care appointments. Primary outcome was number of steps achieved along a series of 8 clinical steps (eg, receiving HCV results, initiating treatment, sustained virologic response [SVR]) of the HCV/HIV care continuum over 12 months postrandomization. Results Three hundred eighty-one individuals were screened and 113 randomized. Median age was 51 years; 58.4% of participants were male and 72.6% were Black/African American. Median HIV-1 viral load was 27 209 copies/mL, with 69% having a detectable viral load. Mean number of steps completed was statistically significantly higher in the intervention group vs controls (2.44 vs 1.68 steps; χ 2 [1] = 7.36, P = .0067). Men in the intervention group completed a statistically significantly higher number of steps than controls. Eleven participants achieved SVR with no difference by treatment group. Conclusions The care facilitation intervention increased progress along the HCV/HIV care continuum, as observed for men and not women. Study findings also highlight continued challenges to achieve individual-patient SVR and population-level HCV elimination. Clinical Trials Registration NCT02641158., In this era of direct-acting antivirals that can cure hepatitis C virus (HCV) infection in 1–3 months, a short-term care facilitation intervention for persons living with HIV and HCV who use drugs is efficacious in making meaningful advances toward HCV cure.

Background The updated Veterans Aging Cohort Study (VACS) Index 2.0 combines general and human immunodeficiency virus (HIV)–specific biomarkers to generate a continuous score that accurately discriminates risk of mortality in diverse cohorts of persons with HIV (PWH), but a score alone is difficult to interpret. Using data from the North American AIDS Cohort Collaboration (NA-ACCORD), we translate VACS Index 2.0 scores into validated probability estimates of mortality. Methods Because complete mortality ascertainment is essential for accurate calibration, we restricted analyses to cohorts with mortality from the National Death Index or equivalent sources. VACS Index 2.0 components were ascertained from October 1999 to April 2018. Mortality was observed up to March 2019. Calibration curves compared predicted (estimated by fitting a gamma model to the score) to observed mortality overall and within subgroups: cohort (VACS/NA-ACCORD subset), sex, age 500 copies/mL, CD4 count Results Among 37230 PWH in VACS and 8061 PWH in the NA-ACCORD subset, median age was 53 and 44 years; 3% and 19% were women; and 48% and 39% were black. Discrimination in NA-ACCORD (C-statistic = 0.842 [95% confidence interval {CI}, .830–.854]) was better than in VACS (C-statistic = 0.813 [95% CI, .809–.817]). Predicted and observed mortality largely overlapped in VACS and the NA-ACCORD subset, overall and within subgroups. Conclusions Based on this validation, VACS Index 2.0 can reliably estimate probability of all-cause mortality, at various follow-up times, among PWH in North America.

Noncommunicable diseases (NCDs) are a growing public health concern in low- and middle-income countries and disproportionately affect people living with HIV (PWH). Hepatitis B virus (HBV) and tuberculosis (TB) coinfection are presumed risk factors in endemic settings; however, supporting evidence is conflicting. We analyzed baseline data of newly diagnosed PWH prospectively enrolled in the Sierra Leone HIV Cohort Study in Freetown, Sierra Leone, from March to September 2021. Logistic regression was used to identify associations between NCDs, HBV and TB. A total of 275 PWH aged ≥18 years were studied (55% female, median age 33 years, median CD4 307 cells/mm3, 15.3% HIV/HBV, 8.7% HIV/TB). NCDs were bimodally distributed, with 1 in 4 PWH clustered around liver disease (fibrosis/cirrhosis), diabetes/prediabetes and obesity/preobesity, while 1 in 8 had renal impairment or hypertension (HTN). Overall, 41.5% had ≥1 NCD, while 17.5% were multimorbid (≥2 NCDs). After adjusting for age, sex, sociodemographic factors and CD4 count, liver fibrosis/cirrhosis was strongly associated with HBV (aOR 8.80, 95% CI [2.46–31.45]; p < 0.001) and diabetes/prediabetes (aOR 9.89, 95% CI [1.14–85.67]; p < 0.037). TB independently predicted diabetes/prediabetes (aOR 7.34, 95% CI [1.87–28.74]; p < 0.004), while renal impairment was associated with proteinuria (aOR 9.34, 95% CI [2.01–43.78]; p < 0.004) and HTN (aOR 6.00, 95% CI [1.10–35.39]; p < 0.049). Our findings warrant the implementation of NCD-aware HIV programs for the prevention, early detection and management of comorbidities.

Background There are limited data to help guide implementation of differentiated HIV service delivery (DSD) in resource-limited settings in sub-Saharan Africa. Objectives This pre-implementation study sought to assess the proportion of patients eligible for DSD and HIV services utilization, as well as risk factor analysis of virologic failure in Sierra Leone. Methods We conducted a retrospective study of adult HIV-infected patients aged 18 years and older receiving care at the largest HIV treatment center in Sierra Leone 2019–2020. Multiple logistic regression was used to identify predictors of virologic failure. Results Of 586 unique patients reviewed, 210 (35.8%) qualified as ‘stable’ for antiretroviral therapy (ART) delivery. There was high utilization of certain HIV service programs (e.g. HIV status disclosure to partners (83%) and treatment ‘buddy’ program participation (62.8%)), while other service programs (e.g. partner testing and community HIV support group participation) had low utilization (

Non-invasive biomarkers that predict HIV remission after antiretroviral therapy (ART) interruption are urgently needed. Such biomarkers can improve the safety of analytic treatment interruption (ATI) and provide mechanistic insights into the pathways involved in post-ART HIV control. We identified plasma glycomic and metabolic signatures of time-to-viral-rebound and probability-of-viral-rebound using samples from two independent cohorts. These samples include a large number of post-treatment controllers, a rare population demonstrating sustained virologic suppression after ART-cessation. The signatures remained significant after adjusting for key demographic and clinical confounders. We also confirmed a mechanistic link between biomarkers and HIV latency reactivation and myeloid inflammation in vitro. Finally, machine learning algorithms selected sets of biomarkers that predict time-to-viral-rebound with 74-76% capacity and probability-of-viral-rebound with 97.5% capacity. In summary, we fill a major gap in HIV cure research by identifying non-invasive biomarkers, with potential functional significance, that predict duration and probability of viral remission after treatment interruption.

OBJECTIVE: Glycosylation plays a critical role in mediating several antibody (mainly immunoglobulin G; IgG) immunological functions, including antibody-dependent cell-mediated cytotoxicity (ADCC), and anti-inflammatory activities. We investigated whether IgG glycosylation and immune profile patterns are differentially modulated in mono and dual infection using samples from untreated hepatitis C virus (HCV) infected individuals with and without co-infection with antiretroviral therapy (ART)-suppressed human immunodeficiency virus (HIV). DESIGN: IgG glycosylation, immune subsets, natural killer cell function, and liver enzymes were assessed in 14 HCV mono-infected and 27 ART-suppressed HIV/HCV co-infected participants naïve to HCV treatment. Historic IgG glycosylation data from 23 ART-suppressed chronically HIV-infected individuals were also used for comparisons. METHODS: Plasma IgG glycosylation was assessed using capillary electrophoresis. Whole blood was used for immune subset characterization by flow cytometry. Peripheral blood mononuclear cells were used to measure constitutive and interferon-α-induced K562 target cell lysis. Statistical analysis was performed using R (3.5.0). RESULTS: HIV/HCV had lower levels of pro-ADCC-associated non-fucosylated glycans when compared to HIV [e.g. di-sialylated A2 percent (%): p=0.04], and higher levels of T and myeloid cells activation/exhaustion when compared to HCV (e.g. CD3(+)CD8(+)CD38(+) %: p

Hajdu Cheney syndrome is a rare autosomal dominant skeletal dysplasia, with multi-organ involvement, caused by pathogenic variants in NOTCH2. It is characterized by progressive focal bone destruction, including acro-osteolysis and generalized osteoporosis, craniofacial anomalies, hearing loss, cardiovascular involvement and polycystic kidneys. Distinct radiographic findings, such as a serpentine fibula, may aid in facilitating the diagnosis. Despite several dozens of cases described in the literature, diagnosis often remains elusive, resulting in many cases in a delay in diagnosis reaching adolescence or adulthood. We report herein two unrelated patients of Turkish/Lebanese Jewish and Ashkenazi Jewish descent, each presenting with distinct clinical challenges and subsequently distinct diagnostic odysseys leading to their molecular diagnosis. These illustrative clinical descriptions underscore the wide phenotypic variability of HCS, and further contribute to the current knowledge regarding this rare entity.

HIV posttreatment controllers (PTCs) represent a natural model of sustained HIV remission, but they are rare and little is known about their viral reservoir. We obtained 1,450 proviral sequences after near-full-length amplification for 10 PTCs and 16 posttreatment noncontrollers (NCs). Before treatment interruption, the median intact and total reservoir size in PTCs was 7-fold lower than in NCs, but the proportion of intact, defective, and total clonally expanded proviral genomes was not significantly different between the 2 groups. Quantification of total but not intact proviral genome copies predicted sustained HIV remission as 81% of NCs, but none of the PTCs had a total proviral genome greater than 4 copies per million peripheral blood mononuclear cells (PBMCs). The results highlight the restricted intact and defective HIV reservoir in PTCs and suggest that total proviral genome burden could act as the first biomarker for identifying PTCs. Total and defective but not intact proviral copy numbers correlated with levels of cell-associated HIV RNA, activated NK cell percentages, and both HIV-specific CD4+ and CD8+ responses. These results support the concept that defective HIV genomes can lead to viral antigen production and interact with both the innate and adaptive immune systems.

We used NOD/SCID mice, also known as NRG, to assess the ability of lentivirus-mediated intravenous delivery of CRISPR in editing the HIV-1 genome from the circulating PBMC engrafts, some of which homed within several animal solid tissues. Lentivirus-mediated delivery of a multiplex of guide RNAs accompanied by Cas9 endonuclease led to the excision of the targeted region of the viral genome positioned within the HIV-1 LTR from the in-vitro-infected human peripheral blood mononuclear cells (PBMCs) embedded in the spleens of NRG mice. Similarly, the treatment of NRG mice harboring PBMC engrafts derived from HIV-1-positive patients with the therapeutic lentivirus eliminated the presence of the viral DNA fragment in the blood, as well as in the spleen, lung, and liver, of the engrafted animals. Sanger sequence analysis of the viral DNA after treatment with the lentiviral vectors expressing Cas9 and gRNAs verified the editing and removal of the proviral DNA fragment from the viral genome at the predicted sites. This proof-of-concept study, for the first time, demonstrates successful excision of the HIV-1 proviral DNA from patient immune cell engrafts in humanized mice upon treatment with lentivirus-expressing CRISPR and causes a decline in the level of replication-competent virus. Keywords: HIV-1, CRISPR/Cas9, gene editing

A practical synthetic approach to Δ9-tetrahydrocannabinol (1) and cannabidiol (2) that provides scalable access to these natural products and should enable the generation of novel synthetic analogues is reported.