Fc Glycan-Mediated Regulation of Placental Antibody Transfer.

Despite the worldwide success of vaccination, newborns remain vulnerable to infections. While neonatal vaccination has been hampered by maternal antibody-mediated dampening of immune responses, enhanced regulatory and tolerogenic mechanisms, and immune system immaturity, maternal pre-natal immunization aims to boost neonatal immunity via antibody transfer to the fetus. However, emerging data suggest that antibodies are not transferred equally across the placenta. To understand this, we used systems serology to define Fc features associated with antibody transfer. The Fc-profile of neonatal and maternal antibodies differed, skewed toward natural killer (NK) cell-activating antibodies. This selective transfer was linked to digalactosylated Fc-glycans that selectively bind FcRn and FCGR3A, resulting in transfer of antibodies able to efficiently leverage innate immune cells present at birth. Given emerging data that vaccination may direct antibody glycosylation, our study provides insights for the development of next-generation maternal vaccines designed to elicit antibodies that will most effectively aid neonates.

Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans.

T cell exhaustion is an induced state of dysfunction that arises in response to chronic infection and cancer. Exhausted CD8+ T cells acquire a distinct epigenetic state, but it is not known whether that chromatin landscape is fixed or plastic following the resolution of a chronic infection. Here we show that the epigenetic state of exhaustion is largely irreversible, even after curative therapy. Analysis of chromatin accessibility in HCV- and HIV-specific responses identifies a core epigenetic program of exhaustion in CD8+ T cells, which undergoes only limited remodeling before and after resolution of infection. Moreover, canonical features of exhaustion, including super-enhancers near the genes TOX and HIF1A, remain 'epigenetically scarred.' T cell exhaustion is therefore a conserved epigenetic state that becomes fixed and persists independent of chronic antigen stimulation and inflammation. Therapeutic efforts to reverse T cell exhaustion may require new approaches that increase the epigenetic plasticity of exhausted T cells.

Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory.

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8+ T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally stable exhausted T cell populations suggested differentiation toward a memory-like profile. However, functionally, the cells showed little improvement, and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for less time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved HCV infection. Thus, the duration of T cell stimulation impacts exhaustion recovery, with antigen removal after long-term exhaustion being insufficient for the development of functional T cell memory.

Early Transcriptional Divergence Marks Virus-Specific Primary Human CD8+ T Cells in Chronic versus Acute Infection.

Distinct molecular pathways govern the differentiation of CD8+ effector T cells into memory or exhausted T cells during acute and chronic viral infection, but these are not well studied in humans. Here, we employed an integrative systems immunology approach to identify transcriptional commonalities and differences between virus-specific CD8+ T cells from patients with persistent and spontaneously resolving hepatitis C virus (HCV) infection during the acute phase. We observed dysregulation of metabolic processes during early persistent infection that was linked to changes in expression of genes related to nucleosomal regulation of transcription, T cell differentiation, and the inflammatory response and correlated with subject age, sex, and the presence of HCV-specific CD4+ T cell populations. These early changes in HCV-specific CD8+ T cell transcription preceded the overt establishment of T cell exhaustion, making this signature a prime target in the search for the regulatory origins of T cell dysfunction in chronic viral infection.

Trans-ancestral fine-mapping of MHC reveals key amino acids associated with spontaneous clearance of hepatitis C in HLA-DQß1.

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-DQß1Leu26 (p valueMeta = 1.24 × 10-14) located in pocket 4 was negatively associated with HCV spontaneous clearance and HLA-DQß1Pro55 (p valueMeta = 8.23 × 10-11) located in the peptide binding region was positively associated, independently of HLA-DQß1Leu26. 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-DQß1Leu26 had fewer HCV binding epitopes and lower predicted binding affinities compared to clearance alleles (geometric mean of combined IC50 nM of persistence versus clearance; 2,321 nM versus 761.7 nM, p value = 1.35 × 10-38). In summary, MHC class II fine-mapping revealed key amino acids in HLA-DQß1 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.

Optimal hepatitis C treatment adherence patterns and sustained virologic response among people who inject drugs: The HERO study.

BACKGROUND & AIMS: Direct-acting antivirals (DAAs) are highly effective for treating HCV infection even among people who inject drugs (PWID). Yet, little is known about patients' adherence patterns and their association with sustained virologic response (SVR) rates. We aimed to summarize various adherence patterns and determine their associations with SVR. METHODS: Electronic blister packs were used to measure daily adherence to once-a-day sofosbuvir/velpatasvir during the 12-week treatment period among active PWIDs. Blister pack data were available for 496 participants who initiated DAAs for whom SVR status was known. Adherence was summarized in multiple patterns, such as total adherent days, consecutive missed days, and early discontinuations. Thresholds for adherence patterns associated with >90% SVR rates were also determined. RESULTS: The overall SVR rate was 92.7%, with a median adherence rate of 75%. All adherence patterns indicating greater adherence were significantly associated with achieving SVR. Participant groups with ≥50% (>42/84) adherent days or <26 consecutive missed days achieved an SVR rate of >90%. Greater total adherent days during 9-12 weeks and no early discontinuation were significantly associated with higher SVR rates only in those with <50% adherence. Participants with first month discontinuation and ≥2 weeks of treatment interruption had low SVR rates, 25% and 85%, respectively. However, greater adherent days were significantly associated with SVR (adjusted odds ratio 1.10; 95% CI 1.04-1.16; p <0.001) even among participants with ≥14 consecutive missed days. CONCLUSIONS: High SVR rates can be achieved in the PWID population despite suboptimal adherence. Encouraging patients to take as much medication as possible, with <2 weeks consecutive missed days and without early discontinuation, was found to be important for achieving SVR. IMPACT AND IMPLICATIONS: People who inject drugs can be cured of HCV in >90% of cases, even with relatively low adherence to direct-acting antivirals, but early discontinuations and long treatment interruptions can significantly reduce the likelihood of achieving cure. Clinicians should encourage people who inject drugs who are living with HCV to adhere daily to direct-acting antivirals as consistently as possible, but if any days are interrupted, to continue and complete treatment. These results from the HERO study are important for patients living with HCV, clinicians, experts writing clinical guidelines, and payers. CLINICAL TRIAL NUMBER: NCT02824640.

Single-cell atlas of the liver myeloid compartment before and after cure of chronic viral hepatitis.

BACKGROUND & AIMS: Chronic viral infections present serious public health challenges; however, direct-acting antivirals (DAAs) are now able to cure nearly all patients infected with hepatitis C virus (HCV), representing the only cure of a human chronic viral infection to date. DAAs provide a valuable opportunity to study immune pathways in the reversal of chronic immune failures in an in vivo human system. METHODS: To leverage this opportunity, we used plate-based single-cell RNA-seq to deeply profile myeloid cells from liver fine needle aspirates in patients with HCV before and after DAA treatment. We comprehensively characterised liver neutrophils, eosinophils, mast cells, conventional dendritic cells, plasmacytoid dendritic cells, classical monocytes, non-classical monocytes, and macrophages, and defined fine-grained subpopulations of several cell types. RESULTS: We discovered cell type-specific changes post-cure, including an increase in MCM7+STMN1+ proliferating CD1C+ conventional dendritic cells, which may support restoration from chronic exhaustion. We observed an expected downregulation of interferon-stimulated genes (ISGs) post-cure as well as an unexpected inverse relationship between pre-treatment viral load and post-cure ISG expression in each cell type, revealing a link between viral loads and sustained modifications of the host's immune system. We found an upregulation of PD-L1/L2 gene expression in ISG-high neutrophils and IDO1 expression in eosinophils, pinpointing cell subpopulations crucial for immune regulation. We identified three recurring gene programmes shared by multiple cell types, distilling core functions of the myeloid compartment. CONCLUSIONS: This comprehensive single-cell RNA-seq atlas of human liver myeloid cells in response to cure of chronic viral infections reveals principles of liver immunity and provides immunotherapeutic insights. CLINICAL TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT02476617). IMPACT AND IMPLICATIONS: Chronic viral liver infections continue to be a major public health problem. Single-cell characterisation of liver immune cells during hepatitis C and post-cure provides unique insights into the architecture of liver immunity contributing to the resolution of the first curable chronic viral infection of humans. Multiple layers of innate immune regulation during chronic infections and persistent immune modifications after cure are revealed. Researchers and clinicians may leverage these findings to develop methods to optimise the post-cure environment for HCV and develop novel therapeutic approaches for other chronic viral infections.

Overreporting of adherence to hepatitis C direct-acting antiviral therapy and sustained virologic response among people who inject drugs in the HERO study.

BACKGROUND: Self-reported adherence to direct-acting antivirals (DAAs) to treat hepatitis C virus (HCV) among persons who inject drugs (PWID) is often an overreport of objectively measured adherence. The association of such overreporting with sustained virologic response (SVR) is understudied. This study among PWID aimed to determine a threshold of overreporting adherence that optimally predicts lower SVR rates, and to explore correlates of the optimal overreporting threshold. METHODS: This study analyzed per-protocol data of participants with adherence data (N = 493) from the HERO (Hepatitis C Real Options) study. Self-reported and objective adherence to a 12-week DAA regimen were measured using visual analogue scales and electronic blister packs, respectively. The difference (Δ) between self-reported and objectively measured adherence was calculated. We used the Youden index based on receiver operating characteristic (ROC) curve analysis to identify an optimal threshold of overreporting for predicting lower SVR rates. Factors associated with the optimal threshold of overreporting were identified by comparing baseline characteristics between participants at/above versus those below the threshold. RESULTS: The self-reported, objective, and Δ adherence averages were 95.1% (SD = 8.9), 75.9% (SD = 16.3), and 19.2% (SD = 15.2), respectively. The ≥ 25% overreporting threshold was determined to be optimal. The SVR rate was lower for ≥ 25% vs. < 25% overreporting (86.7% vs. 95.8%, p <.001). The factors associated with ≥ 25% Δ adherence were unemployment; higher number of days and times/day of injecting drugs; higher proportion of positive urine drug screening for amphetamine, methamphetamine, and oxycodone, and negative urine screening for THC (tetrahydrocannabinol)/cannabis. CONCLUSIONS: Self-reported DAA adherence was significantly greater than objectively measured adherence among PWID by 19.2%. Having ≥ 25% overreported adherence was associated with optimal prediction of lower SVR rates. PWID with risk factors for high overreporting may need to be more intensively managed to promote actual adherence.

Nirmatrelvir Plus Ritonavir for Early COVID-19 in a Large U.S. Health System : A Population-Based Cohort Study.

BACKGROUND: In the EPIC-HR (Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients) trial, nirmatrelvir plus ritonavir led to an 89% reduction in hospitalization or death among unvaccinated outpatients with early COVID-19. The clinical impact of nirmatrelvir plus ritonavir among vaccinated populations is uncertain. OBJECTIVE: To assess whether nirmatrelvir plus ritonavir reduces risk for hospitalization or death among outpatients with early COVID-19 in the setting of prevalent SARS-CoV-2 immunity and immune-evasive SARS-CoV-2 lineages. DESIGN: Population-based cohort study analyzed to emulate a clinical trial using inverse probability-weighted models to account for anticipated bias in treatment. SETTING: A large health care system providing care for 1.5 million patients in Massachusetts and New Hampshire during the Omicron wave (1 January to 17 July 2022). PATIENTS: 44 551 nonhospitalized adults (90.3% with ≥3 vaccine doses) aged 50 years or older with COVID-19 and no contraindications for nirmatrelvir plus ritonavir. MEASUREMENTS: The primary outcome was a composite of hospitalization within 14 days or death within 28 days of a COVID-19 diagnosis. RESULTS: During the study period, 12 541 (28.1%) patients were prescribed nirmatrelvir plus ritonavir, and 32 010 (71.9%) were not. Patients prescribed nirmatrelvir plus ritonavir were more likely to be older, have more comorbidities, and be vaccinated. The composite outcome of hospitalization or death occurred in 69 (0.55%) patients who were prescribed nirmatrelvir plus ritonavir and 310 (0.97%) who were not (adjusted risk ratio, 0.56 [95% CI, 0.42 to 0.75]). Recipients of nirmatrelvir plus ritonavir had lower risk for hospitalization (adjusted risk ratio, 0.60 [CI, 0.44 to 0.81]) and death (adjusted risk ratio, 0.29 [CI, 0.12 to 0.71]). LIMITATION: Potential residual confounding due to differential access to COVID-19 vaccines, diagnostic tests, and treatment. CONCLUSION: The overall risk for hospitalization or death was already low (1%) after an outpatient diagnosis of COVID-19, but nirmatrelvir plus ritonavir reduced this risk further. PRIMARY FUNDING SOURCE: National Institutes of Health.

Efficacy of Tocilizumab in Patients Hospitalized with Covid-19.

BACKGROUND: The efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear. METHODS: We performed a randomized, double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hyperinflammatory states, and at least two of the following signs: fever (body temperature >38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses. RESULTS: We enrolled 243 patients; 141 (58%) were men, and 102 (42%) were women. The median age was 59.8 years (range, 21.7 to 85.4), and 45% of the patients were Hispanic or Latino. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P = 0.64), and the hazard ratio for disease worsening was 1.11 (95% CI, 0.59 to 2.10; P = 0.73). At 14 days, 18.0% of the patients in the tocilizumab group and 14.9% of the patients in the placebo group had had worsening of disease. The median time to discontinuation of supplemental oxygen was 5.0 days (95% CI, 3.8 to 7.6) in the tocilizumab group and 4.9 days (95% CI, 3.8 to 7.8) in the placebo group (P = 0.69). At 14 days, 24.6% of the patients in the tocilizumab group and 21.2% of the patients in the placebo group were still receiving supplemental oxygen. Patients who received tocilizumab had fewer serious infections than patients who received placebo. CONCLUSIONS: Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide. (Funded by Genentech; ClinicalTrials.gov number, NCT04356937.).

A Video-Observed Treatment Strategy to Improve Adherence to Treatment Among Persons Who Inject Drugs Infected With Hepatitis C Virus: Qualitative Study of Stakeholder Perceptions and Experiences.

BACKGROUND: Direct-acting antiviral medications have the potential to eliminate the hepatitis C virus (HCV) epidemic among people who inject drugs; yet, suboptimal adherence remains a barrier. Directly observed treatment (DOT), an effective strategy for optimizing adherence, has been frequently implemented in opioid treatment programs but less commonly in community health settings due to the heavy burden of daily visits. An alternative is video-observed therapy (VOT), which uses mobile health technology to monitor adherence. VOT has not been widely studied among people who inject drugs with HCV. OBJECTIVE: This qualitative study, part of a larger implementation evaluation, investigates stakeholder perceptions and experiences with VOT in Project HERO (Hepatitis C Real Outcomes), a multisite pragmatic trial testing treatment delivery models for people who inject drugs with HCV. Our goal was to understand the potential barriers and facilitators to the implementation of the VOT technology. METHODS: Qualitative interviews were conducted with 27 Project HERO study staff and 7 patients. Interviews focused on perceptions and experiences with the VOT app and barriers and facilitators to implementation. Team meeting minutes over the first 2 years of the project were transcribed. A coding system was developed and applied to the data. We summarized thematic data and compared participant perceptions to generate a close understanding of the data. RESULTS: Frequent barriers to VOT included mechanical failure, stolen or lost phones, and a steep learning curve for participants and study staff. In sites with older and less technically skilled participants, staff found it difficult to implement the VOT app. Research staff found that the routine monitoring of app use led to closer engagement with participants. This was both a benefit and a potential threat to the validity of this pragmatic trial. Patient participants reported mixed experiences. CONCLUSIONS: VOT may be a useful alternative to DOT for some patients, but it may not be feasible for all. Significant staff involvement may be required.

Clearance of Hepatitis B e Antigen in Untreated Chronic Hepatitis B Virus Infection: A Systematic Review and Meta-analysis.

BACKGROUND: In people with hepatitis B virus (HBV) infection, persistence of hepatitis B e antigen (HBeAg) is associated with clinical progression and need for treatment. HBeAg loss represents partial immune control and is a critical event in the natural history of chronic HBV. METHODS: We conducted a systematic review and meta-analysis of cohort studies that report HBeAg loss among people with untreated chronic HBV. We evaluated HBeAg loss using a random-effects model and conducted subanalysis on region. RESULTS: We screened 10 560 publications, performed 196 full-text analyses, and included 26 studies for meta-analysis. The pooled rate of HBeAg loss was 6.46/100 person-years (PYs) (95% confidence interval, 5.17-8.08). Meta-regression showed that older age of participants and studies in Europe were associated with higher rate of HBeAg loss. Rates per 100 PYs were 7.43 (95% confidence interval, 6.30-8.75; 1 study) in Africa, 3.24 (2.61--4.02; 1 study) in the Eastern Mediterranean, 13.67 (11.21-16.66; 4 studies) in Europe, 7.34 (4.61--11.70; 5 studies) in North America, and 5.53 (4.05--7.55; 15 studies) in the Western Pacific. CONCLUSIONS: Spontaneous HBeAg loss occurs at a rate of 6.46/100 PYs. Variations by region and age group may reflect epidemiological, immunological, or HBV genotype-related differences.

Hepatitis B virus-specific CD4 T cell responses differentiate functional cure from chronic surface antigen+ infection.

BACKGROUND & AIMS: With or without antiviral treatment, few individuals achieve sustained functional cure of chronic hepatitis B virus (HBV) infection. A better definition of what mediates functional cure is essential for improving immunotherapeutic strategies. We aimed to compare HBV-specific T cell responses in patients with different degrees of viral control. METHODS: We obtained blood from 124 HBV-infected individuals, including those with acute self-limiting HBV infection, chronic infection, and chronic infection with functional cure. We screened for HBV-specific T cell specificities by ELISpot, assessed the function of HBV-specific T cells using intracellular cytokine staining, and characterized HBV-specific CD4 T cells using human leukocyte antigen (HLA) class II tetramer staining, all directly ex vivo. RESULTS: ELISpot screening readily identified HBV-specific CD4 and CD8 T cell responses in acute resolving infection compared with more limited reactivity in chronic infection. Applying more sensitive assays revealed higher frequencies of functional HBV-specific CD4 T cells, but not CD8 T cells, in functional cure compared to chronic infection. Function independent analysis using HLA multimers also identified more HBV-specific CD4 T cell responses in functional cure compared to chronic infection, with the emergence of CD4 T cell memory both after acute and chronic infection. CONCLUSIONS: Functional cure is associated with higher frequencies of functional HBV-specific CD4 memory T cell responses. Thus, immunotherapeutic approaches designed to induce HBV functional cure should also aim to improve CD4 T cell responses. LAY SUMMARY: Immunotherapy is a form of treatment that relies on harnessing the power of an individual's immune system to target a specific disease or pathogen. Such approaches are being developed for patients with chronic HBV infection, in an attempt to mimic the immune response in patients who control HBV infection spontaneously, achieving a so-called functional cure. However, what exactly defines protective immune responses remains unclear. Herein, we show that functional cure is associated with robust responses by HBV-specific CD4 T cells (a type of immune cell).

Liver Biochemistries in Hospitalized Patients With COVID-19.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) leads to elevated liver biochemistries in approximately half of patients on presentation. To date, data are limited regarding the trend of liver biochemistries over the course of illness. We aimed to evaluate the trend, etiology, and outcomes associated with liver biochemistries in COVID-19. APPROACH AND RESULTS: A total of 60 patients with COVID-19 were admitted between March 21 and March 28, 2020. The mean age was 57 years, 65% were male, and 28% were Hispanic. At the study conclusion, 6 patients were deceased, 28 were discharged, and 26 remained admitted. Patients who remained admitted were followed for a median of 12 days. Of 60 patients, 41 (69%) had at least one abnormal liver biochemistry on admission. Median aspartate aminotransferase (AST) was higher than alanine aminotransferase (ALT) at admission (46 vs. 30 U/L) and during the hospital course. Aminotransferases rose above normal in 54 (93%) patients, whereas alkaline phosphatase and total bilirubin elevations were rare. Ten (17%) patients developed aminotransferases more than 5 times the upper limit of normal. AST highly correlated with ALT throughout the illness course (r = 0.97; P < 0.0001), whereas correlations with markers of muscle injury and inflammation were weak. Statin use was common before (40%) and during admission (80%) at our center, with no difference in peak liver biochemistries between users and nonusers. No demographic or comorbid illness was associated with liver injury. Admission AST (69 vs. 49; P < 0.05), peak AST (364 vs. 77; P = 0.003), and peak ALT (220 vs. 52; P = 0.002) were higher in intubated patients. CONCLUSIONS: AST-dominant aminotransferase elevation is common in COVID-19, mirrors disease severity, and appears to reflect true hepatic injury.

Developing Treatment Guidelines During a Pandemic Health Crisis: Lessons Learned From COVID-19.

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.

A Multiancestry Sex-Stratified Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus.

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

Immunomodulation as Treatment for Severe Coronavirus Disease 2019: A Systematic Review of Current Modalities and Future Directions.

In severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, viral load peaks early and declines quickly after symptom onset. Severe coronavirus disease 2019 (COVID-19) is marked by aberrant innate and adaptive immune responses with an abnormal cytokine profile and multiorgan system dysfunction that persists well after viral clearance. A purely antiviral treatment strategy may therefore be insufficient, and antiviral agents have not shown a benefit later in the illness course. A number of immunomodulatory strategies are being tested, including corticosteroids, cytokine and anticytokine therapies, small molecule inhibitors, and cellular therapeutics. To date, the only drug to show a mortality benefit for COVID-19 in a randomized, controlled trial is dexamethasone. However, there remains uncertainty about which patients may benefit most and about longer-term complications, including secondary infections. Here, we review the immune dysregulation of severe COVID-19 and the existing data behind various immunomodulatory strategies, and we consider future directions of study.

Rethinking the role of hydroxychloroquine in the treatment of COVID-19.

There are currently no proven or approved treatments for coronavirus disease 2019 (COVID-19). Early anecdotal reports and limited in vitro data led to the significant uptake of hydroxychloroquine (HCQ), and to lesser extent chloroquine (CQ), for many patients with this disease. As an increasing number of patients with COVID-19 are treated with these agents and more evidence accumulates, there continues to be no high-quality clinical data showing a clear benefit of these agents for this disease. Moreover, these agents have the potential to cause harm, including a broad range of adverse events including serious cardiac side effects when combined with other agents. In addition, the known and potent immunomodulatory effects of these agents which support their use in the treatment of auto-immune conditions, and provided a component in the original rationale for their use in patients with COVID-19, may, in fact, undermine their utility in the context of the treatment of this respiratory viral infection. Specifically, the impact of HCQ on cytokine production and suppression of antigen presentation may have immunologic consequences that hamper innate and adaptive antiviral immune responses for patients with COVID-19. Similarly, the reported in vitro inhibition of viral proliferation is largely derived from the blockade of viral fusion that initiates infection rather than the direct inhibition of viral replication as seen with nucleoside/tide analogs in other viral infections. Given these facts and the growing uncertainty about these agents for the treatment of COVID-19, it is clear that at the very least thoughtful planning and data collection from randomized clinical trials are needed to understand what if any role these agents may have in this disease. In this article, we review the datasets that support or detract from the use of these agents for the treatment of COVID-19 and render a data informed opinion that they should only be used with caution and in the context of carefully thought out clinical trials, or on a case-by-case basis after rigorous consideration of the risks and benefits of this therapeutic approach.

Multi-ancestry fine mapping of interferon lambda and the outcome of acute hepatitis C virus infection.

Clearance of acute infection with hepatitis C virus (HCV) is associated with the chr19q13.13 region containing the rs368234815 (TT/ΔG) polymorphism. We fine-mapped this region to detect possible causal variants that may contribute to HCV clearance. First, we performed sequencing of IFNL1-IFNL4 region in 64 individuals sampled according to rs368234815 genotype: TT/clearance (N = 16) and ΔG/persistent (N = 15) (genotype-outcome concordant) or TT/persistent (N = 19) and ΔG/clearance (N = 14) (discordant). 25 SNPs had a difference in counts of alternative allele >5 between clearance and persistence individuals. Then, we evaluated those markers in an association analysis of HCV clearance conditioning on rs368234815 in two groups of European (692 clearance/1 025 persistence) and African ancestry (320 clearance/1 515 persistence) individuals. 10/25 variants were associated (P < 0.05) in the conditioned analysis leaded by rs4803221 (P value = 4.9 × 10-04) and rs8099917 (P value = 5.5 × 10-04). In the European ancestry group, individuals with the haplotype rs368234815ΔG/rs4803221C were 1.7× more likely to clear than those with the rs368234815ΔG/rs4803221G haplotype (P value = 3.6 × 10-05). For another nearby SNP, the haplotype of rs368234815ΔG/rs8099917T was associated with HCV clearance compared to rs368234815ΔG/rs8099917G (OR: 1.6, P value = 1.8 × 10-04). We identified four possible causal variants: rs368234815, rs12982533, rs10612351 and rs4803221. Our results suggest a main signal of association represented by rs368234815, with contributions from rs4803221, and/or nearby SNPs including rs8099917.

Sex Discrepancies in the Protective Effect of Opioid Agonist Therapy on Incident Hepatitis C Infection.

BACKGROUND: While opioid agonist therapy (OAT) reduces the risk of hepatitis C virus (HCV) acquisition among people who inject drugs (PWID), protective effects may be attenuated in females. We used pooled data from an international collaboration of prospective cohorts to assess sex disparities in HCV incidence among PWID exposed to OAT. METHODS: Independent predictors of HCV infection were identified using Cox regression models with random effects after accounting for the clustering effect of study sites. Unadjusted and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) are presented in sex-specific analyses. RESULTS: Among 701 participants exposed to OAT, HCV incidence was 16.5/100 person-years of observation (PYO) (95% CI, 13.1-20.7) in females and 7.6/100 PYO (95% CI, 6.0-9.5) in males (female:male adjusted HR [aHR], 1.80 [95% CI, 1.37-2.22]; P < .001). Factors associated with HCV acquisition among females exposed to OAT included nonwhite race (aHR, 1.79 [95% CI, 1.25-2.56]; P = .001), unstable housing (aHR, 4.00 [95% CI, 3.62-4.41]; P < .001), daily or more frequent injection (aHR, 1.45 [95% CI, 1.01-2.08]; P = .042), and receptive syringe sharing (aHR, 1.43 [95% CI, 1.33-1.53]; P < .001). CONCLUSIONS: Female PWID exposed to OAT are twice as likely as their male counterparts to acquire HCV. While there is a need for better understanding of sex differences in immune function and opioid pharmacokinetic and pharmacodynamic parameters, structural and behavioral interventions that target women are required to bolster the efficacy of OAT in preventing HCV transmission.