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African Americans coinfected with HIV and hepatitis C virus (HCV) have lower liver-related mortality than Caucasians and Hispanics. While genetic polymorphisms near the IFNL3 and IFNL4 genes explain a significant fraction of racial differences in several HCV-related outcomes, the impact of these variants on liver-related mortality has not been investigated. We conducted a cohort study of HIV/HCV-coinfected women followed in the multicentre, NIH-funded Women's Interagency HIV Study (WIHS) to investigate whether 10 polymorphisms spanning the IFN-λ region were associated with liver-related mortality by dominant, recessive or additive genetic models. We also considered whether these polymorphisms contributed to previously reported differences in liver-related death by race/ethnicity (ascertained by self-report and ancestry informative markers). Among 794 coinfected women, there were 471 deaths including 55 liver-related deaths during up to 18 years of follow-up. On adjusted analysis, rs12980275 GG genotype compared to AG+AA hazards ratios [(HR) 0.36, 95% CI 0.14-0.90, P = 0.029] and rs8109886 AA genotype compared to CC+AC (HR 0.67, 95% CI 0.45-0.99, P = 0.047) were most strongly associated with liver-related death although these associations were no longer significant after adjusting for race/ethnicity (HR 0.41, 95% CI 0.16-1.04, P = 0.060 and HR 0.78, 95% CI 0.51-1.19, P = 0.25, respectively). African American women had persistently lower liver-related death independent of IFN-λ variants (HRs ≤ 0.44, P values ≤ 0.04). The lower risk of death among African American HIV/HCV-coinfected women is not explained by genetic variation in the IFN-λ region suggesting, that other genetic, behavioural and/or environmental factors may contribute to racial/ethnic differences in liver-related mortality.

IFNL4-δG/TT (rs368234815) genotype is associated with hepatitis C virus clearance and may play a role in other infections. IFN-ë4 protein is generated only in individuals who carry the IFNL4-δG allele. The IFNL4 rs12979860-T allele, which is in strong link

© 2015 Decaris et al.Accumulation and degradation of scar tissue in fibrotic liver disease occur slowly, typically over many years. Direct measurement of fibrogenesis, the rate of scar tissue deposition, may provide valuable therapeutic and prognostic info

The aim of this study was to determine the test characteristics of direct and indirect biomarkers for liver fibrosis compared with transient elastography (TE) among a group of human immunodeficiency virus (HIV)-infected and uninfected women with or without

Hepatitis C virus (HCV) infects an estimated 3% of the global population with the majority of individuals (75-85%) failing to clear the virus without treatment, leading to chronic liver disease. Individuals of African descent have lower rates of clearance compared with individuals of European descent and this is not fully explained by social and environmental factors. This suggests that differences in genetic background may contribute to this difference in clinical outcome following HCV infection. Using 473 individuals and 792,721 single-nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS), we estimated local African ancestry across the genome. Using admixture mapping and logistic regression, we identified two regions of interest associated with spontaneous clearance of HCV (15q24, 20p12). A genome-wide significant variant was identified on chromosome 15 at the imputed SNP, rs55817928 (P=6.18 × 10(-8)) between the genes SCAPER and RCN. Each additional copy of the African ancestral C allele is associated with 2.4 times the odds of spontaneous clearance. Conditional analysis using this SNP in the logistic regression model explained one-third of the local ancestry association. Additionally, signals of selection in this area suggest positive selection due to some ancestral pathogen or environmental pressure in African, but not in European populations.

For solid organ transplant (SOT) donors, nucleic acid-amplification testing (NAT) may reduce human immunodeficiency virus (HIV) and hepatitis C virus (HCV) transmission over antibody (Ab) testing given its shorter detection window period. We compared SOT donor NAT + Ab versus Ab alone using decision models to estimate incremental cost-effectiveness ratios (ICERs; cost per quality-adjusted life year [QALY] gained) from the societal perspective across a range of HIV/HCV prevalence values and NAT costs. The cost per QALY gained was calculated for two scenarios: (1) favorable: low cost ($150/donor)/high prevalence (HIV: 1.5%; HCV: 18.2%) and (2) unfavorable: high cost ($500/donor)/low prevalence (HIV: 0.1%; HCV: 1.5%). In the favorable scenario, adding NAT screening cost $161 013 per QALY gained for HIV was less costly) for HCV, and cost $86 653 per QALY gained for HIV/HCV combined. For the unfavorable scenario, the costs were $15 568 484, $221 006 and $10 077 599 per QALY gained, respectively. Universal HCV NAT + Ab for donors appears cost-effective to reduce infection transmission from SOT donors, while HIV NAT + Ab is not, except where HIV NAT is ≤$150/donor and prevalence is ≥1.5%. Our analyses provide important data to facilitate the decision to implement HIV and HCV NAT for deceased SOT donors and shape national policy regarding how to reduce infection transmission in SOT.

The process of B cell growth and differentiation into plasma cells is highly regulated and may be influenced by a large number of inflammatory mediators, including complement components. We have studied the regulatory influence of Bb, a 60-kD peptide created during the cleavage of complement Factor B by Factor D and C3b. Purified Bb alone had no effect on proliferation and differentiation of human splenic or tonsillar B cells. However, when B cells were activated by Staphylococcus aureus Cowan I (SAC), Bb enhanced proliferation in a dose-dependent manner. Bb also enhanced proliferation when cocultured with SAC and suboptimal concentrations of purified 60-kD B cell growth factor (HMW-BCGF), a previously described lymphokine that is known to possess growth-promoting activity. However, Bb had no effect on cells treated with optimal concentrations of HMW-BCGF. Like HMW-BCGF, Bb's major effect was on the larger in vivo activated B cells. Half-maximal enhancement of proliferation was reached at a Bb concentration of 1-10 nM. Of note is the fact that antibody to Factor B recognized HMW-BCGF, and an mAb to HMW-BCGF also recognized Factor B and Bb, but not Ba. Moreover, radiolabeled Bb bound saturably to activated B cells and to an EBV-transformed human B cell line. The binding of Bb was inhibited by HMW-BCGF but not by Ba or IgG. Thus, Bb is antigenically and functionally related to HMW-BCGF, and can act as a B cell growth and differentiation factor at potentially physiologic concentrations. These data suggest that Bb may be important in amplifying the immune response in areas of inflammation. Since complement activation occurs at inflammatory sites long before induction of HMW-BCGF synthesis, Bb may be an early signal for the clonal expansion of antigen-activated B cells.

Background: Human leukocyte antigen (HLA) class I and II genotype is associated with clearance of hepatitis C virus (HCV) infection, but little is known regarding its relation with HCV viral load or risk of liver disease in patients with persistent HCV infection.Methods: High-resolution HLA class I and II genotyping was conducted in a prospective cohort of 519 human immunodeficiency virus (HIV)-seropositive and 100 HIV-seronegative women with persistent HCV infection. The end points were baseline HCV viral load and 2 noninvasive indexes of liver disease, fibrosis-4 (FIB-4), and the aspartate aminotransferase to platelet ratio index (APRI), measured at baseline and prospectively.Results: DQB1*0301 was associated with low baseline HCV load (β = -.4; 95% confidence interval [CI], -.6 to -.3; P < .00001), as well as with low odds of FIB-4-defined (odds ratio [OR], .5; 95% CI, .2-.9; P = .02) and APRI-defined liver fibrosis (OR, .5; 95% CI, .3-1.0; P = .06) at baseline and/or during follow-up. Most additional associations with HCV viral load also involved HLA class II alleles. Additional associations with FIB-4 and APRI primarily involved class I alleles, for example, the relation of B*1503 with APRI-defined fibrosis had an OR of 2.0 (95% CI, 1.0-3.7; P = .04).Conclusions: HLA genotype may influence HCV viral load and risk of liver disease, including DQB1*0301, which was associated with HCV clearance in prior studies. [ABSTRACT FROM AUTHOR]

Background: How coinfection with hepatitis C virus (HCV) impacts on the trajectory of kidney function in human immunodeficiency virus (HIV)-infected patients is unclear. This study examined the effect of HCV infection on kidney function over time in women infected with HIV.Study Design: Retrospective observational cohort.Setting& Participants: Study sample included participants from the Women's Interagency HIV Study who were HIV infected and had undergone HCV antibody testing and serum creatinine measurement at baseline.Predictor: HCV seropositivity.Outcomes& Measurement: Estimated glomerular filtration rate (eGFR) calculated from semi-annual serum creatinine measurements using the 4-variable Modification of Diet in Renal Diseases (MDRD) Study equation. Linear mixed models were used to evaluate the independent effect of HCV seropositivity on eGFR over time, adjusting for demographic factors, comorbid conditions, illicit drug use, measures of HIV disease status, use of medications, and interactions with baseline low eGFR (<60 mL/min/1.73 m(2)).Results: Of 2,684 HIV-infected women, 952 (35%) were found to be HCV seropositive. In 180 women with chronic kidney disease (CKD) at baseline (eGFR < 60 mL/min/1.73 m(2)), HCV seropositivity was independently associated with a fully adjusted net decrease in eGFR of approximately 5% per year (95% confidence interval, 3.2 to 7.2) relative to women who were seronegative. In contrast, HCV infection was not independently associated with a decrease in eGFR in women without low eGFR at baseline (P < 0.001 for interaction).Limitations: The MDRD Study equation has not been validated as a measure of GFR in persons with HIV or HCV infection. Proteinuria was not included in the study analysis. Because the study is observational, effects of residual confounding cannot be excluded.Conclusions: In HIV-infected women with CKD, coinfection with HCV is associated with a modest, but statistically significant, decrease in eGFR over time. More careful monitoring of kidney function may be warranted for HIV-infected patients with CKD who are also coinfected with HCV. [ABSTRACT FROM AUTHOR]

Background: Chronic hepatitis C virus (HCV) infection is a cause of major complications in persons who are also infected with the human immunodeficiency virus (HIV). However, the treatment of HCV infection in such persons has been associated with a high rate of intolerance and a low rate of response. We conducted a multicenter, randomized trial comparing peginterferon plus ribavirin with interferon plus ribavirin for the treatment of chronic hepatitis C in persons coinfected with HIV.Methods: A total of 66 subjects were randomly assigned to receive 180 microg of peginterferon alfa-2a weekly for 48 weeks, and 67 subjects were assigned to receive 6 million IU of interferon alfa-2a three times weekly for 12 weeks followed by 3 million IU three times weekly for 36 weeks. Both groups received ribavirin according to a dose-escalation schedule. At week 24, subjects who did not have a virologic response (those who had an HCV RNA level greater than or equal to 60 IU per milliliter) underwent liver biopsy, and medications were continued in subjects with either a virologic response or histologic improvement.Results: Treatment with peginterferon and ribavirin was associated with a significantly higher rate of sustained virologic response (an HCV RNA level of less than 60 IU per milliliter 24 weeks after completion of therapy) than was treatment with interferon and ribavirin (27 percent vs. 12 percent, P=0.03). In the group given peginterferon and ribavirin, only 14 percent of subjects with HCV genotype 1 infection had a sustained virologic response (7 of 51), as compared with 73 percent of subjects with an HCV genotype other than 1 (11 of 15, P<0.001). Histologic responses were observed in 35 percent of subjects with no virologic response who underwent liver biopsy.Conclusions: In persons infected with HIV, the combination of peginterferon and ribavirin is superior to the combination of interferon and ribavirin in the treatment of chronic hepatitis C. These regimens may provide clinical benefit even in the absence of virologic clearance. The marked discrepancy in the rates of sustained virologic response between HCV genotypes indicates that strategies are needed to improve the outcome in persons infected with HCV genotype 1. [ABSTRACT FROM AUTHOR]

Background: Newer biomarkers of Hepatitis B virus (HBV) infection and treatment response have not been well-characterized in individuals with HBV/HIV coinfection., Methods: Pre-genomic RNA (pgRNA) and quantitative HBsAg (qHBsAg) were used to evaluate the associations with baseline characteristics. Participants included two separate groups - 236 with HBV/HIV coinfection enrolled in a cross-sectional cohort in Ghana and 47 from an HBV nucleoside/nucleotide treatment trial comparing tenofovir to adefovir in the United States., Results: In both cohorts, HBe antigenemia was highly associated with pgRNA and HBV DNA levels. In the treatment cohort, pre-treatment pgRNA serum concentration was 7.0 log 10 U/mL, and mean qHBsAg was 201,297 IU/mL. The observed treatment-associated decrease in pgRNA was consistent with a biphasic decline curve that reached second-phase kinetics following treatment week 12. Changes from baseline were significantly correlated with changes in serum ALT (r = - 0.518; P = 0.023) but not with changes in HBV DNA (r = 0.132, P = NS). qHBsAg also correlated with ALT change (r = - 0.488, P = 0.034)., Conclusion: pgRNA and qHBsAg represent newer biomarkers of HBV replication that may help monitor response and treatment outcomes. HBV pgRNA is highly associated with both HBeAg and ALT and may predict both active replication from the closed circular DNA (cccDNA) template as well as hepatic injury., Competing Interests: MA, MS, and GC are employees and shareholders of Abbott Laboratories. All other authors have no conflicts of interest., (Copyright © 2024 Pathogens and Immunity.)

Chronic hepatitis B, a major cause of liver disease and cancer, affects >250 million people worldwide. Currently there is no cure, only suppressive therapies. Efforts to develop finite curative hepatitis B virus (HBV) therapies are underway, consisting of combinations of multiple novel agents with or without nucleos(t)ide reverse-transcriptase inhibitors. The HBV Forum convened a webinar in July 2021, along with subsequent working group discussions to address how and when to stop finite therapy for demonstration of sustained off-treatment efficacy and safety responses. Participants included leading experts in academia, clinical practice, pharmaceutical companies, patient representatives, and regulatory agencies. This Viewpoints article outlines areas of consensus within our multistakeholder group for stopping finite therapies in chronic hepatitis B investigational studies, including trial design, patient selection, outcomes, biomarkers, predefined stopping criteria, predefined retreatment criteria, duration of investigational therapies, and follow-up after stopping therapy. Future research of unmet needs are discussed., Competing Interests: Conflicts of interest. M. G. P. received honoraria from Wainright Corporation, received consulting fees (to the author) from Aligos Therapeutics and Antios Therapeutics, and participates on a data safety monitoring board for Excision Biotherapeutics. M. F. Y. reports grants and research support from AbbVie, Assembly Biosciences, Arrowhead Pharmaceuticals, Bristol Myers Squibb (BMS), Fujirebio, Gilead Sciences, Immunocore, Merck Sharp and Dohme (MSD), Springbank Pharmaceuticals, Sysmex Corporation, and Roche and reports honoraria for advisory boards/lectures from AbbVie, Aligos Therapeutics, AiCuris, Antios Therapeutics, Arbutus Biopharma, Arrowhead Pharmaceuticals, Assembly Biosciences, BMS, Clear B Therapeutics, Dicerna Pharmaceuticals, Finch Therapeutics, Fujirebio, GlaxoSmithKline (GSK), Gilead Sciences, Immunocore, Janssen, MSD, Roche, Springbank Pharmaceuticals, Silverback Therapeutics, Sysmex, and Vir Biotechnology. N. T. reports institutional grant support from the National Institutes of Health, GSK, Genentech-Roche, Helio Health, Durect, Gilead Sciences, Eiger Pharmaceuticals, and Madrigal; provision of educational materials from Clinical Care Options and Simply Speaking; honoraria for invited lectures in conferences from the Canadian Association for the Study of the Liver (CASL), the European Association for the Study of the Liver (EASL), Pakistan Society for the Study of Liver Diseases (PSSLD), the Asian Pacific Association for the Study of the Liver, GUILD, and the International Liver Transplantation Society (ILTS) and for invited lectures from University of Alabama, Duke University, Houston Methodist, University of California, Iowa University; support for travel for invited lectures from the American Association for the Study of Liver Diseases (AASLD), EASL, GUILD, CASL, PSSLD, International Association for the Study of the Liver (IASL), and ILTS; and roles as president of the governing board for the AASLD and a steering committee member for the Hepatitis B Foundation and HBV Forum. J. F. is a former employee of and owns stock in Aligos Therapeutics. P. L. reports honoraria for lectures or presentations from BMS, Roche, Gilead Sciences, GSK, AbbVie, MSD, Arrowhead, Alnylam, Janssen, Vir Biotechnology, Springbank, MYR, Eiger, Antios, and Aligos. E. G. is an advisory board member/consultant for AbbVie, Gilead Sciences, Intellia Pharmaceuticals, Janssen, and Roche. C. H. is an employee of and owns stock in Vir Biotechnology. L. M. S. is a former employee of and owns stock in Assembly Biosciences. M. K. M. reports being an advisor to Gilead, GSK, and Roche (advisory board payments to University College London Consultants); is a minor coapplicant on patent application 1200281465; and reports the following pending patents: international patent application PCT/GB2020/053034 (ACAT inhibitors for liver disease) and UK patent application 2109807.4 (CD14/CD8 T cells). P. Mendez is a former employee of Gilead Sciences and owns stock or stock options in Gilead Sciences Inc. I. L. D. owns stock in Johnson & Johnson. T. B. reports institutional grant support from AbbVie, BMS, Gilead, MSD/Merck, Humedics, Intercept, Merz, Norgine, Novartis, Orphalan, and Sequana Medical; consulting fees and honararia from AbbVie, Alexion, Bayer, Falk Foundation, Gilead, GSK, Eisai, ENYO Pharma, HepaRegeniX, Humedics, Intercept, Ipsen, Janssen, MedUpdate, MSD/Merck, Novartis, Orphalan, Roche, Sequena Medical, SIRTEX, SOBI, and Shionogi; and support for attending meetings and/or travel from Gilead, AbbVie, Intercept, and Janssen. S. W. reports institutional support from Gilead and is an unpaid board member for the Hepatitis B Foundation. S. B. reports travel support, direct booking, and payment for travel by the HBV Forum for HBV Forum 10 in Vienna, Austria, and by AASLD for the EASL/AASLD HBV Endpoints 2022 meeting in Washington, DC. V. M. reports grant funding for the HBV Forum from Abbott, Aligos Therapeutics, AlloVir, Altimmune, Antios Therapeutics, Arrowhead Pharmaceuticals, Assembly Biosciences, DDL Diagnostic Laboratory, Eiger, Enyo Pharma, Gilead Sciences, GSK, the Hepatitis B Foundation, Immunocore, Janssen, LabCorp, Monogram Biosciences, Quest Diagnostics, the RFS Family Foundation, Roche, VenatorX, Vir Biotechnology, Virion Therapeutics, and Viroclinics. O. L. is an employee of Janssen and owns stock in Johnson & Johnson. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Penetrating cardiac injuries usually require emergent surgical intervention. Our patient presented to the trauma centre with multiple stab wounds to the neck, chest, epigastric region and abdomen. She arrived haemodynamically stable, and her initial Focused Assessment with Sonography for Trauma exam was negative. Her chest X-ray did not show any evident pneumothorax or haemothorax. Due to her injury pattern, she was taken to the operating room for exploratory laparotomy and neck exploration. Postoperatively, she was taken for CT and found to have a contained cardiac rupture. The injury was contained within previous scar tissue from her prior cardiac surgery. Further evaluation revealed that the injury included a penetrating stab wound to the right ventricle and a traumatic ventricular septal defect (VSD). She subsequently underwent a redo sternotomy with the repair of the penetrating stab wound and the VSD. Cardiology, intensive care, trauma surgery and cardiothoracic surgery coordinated her care from diagnosis, management and recovery. This case highlights the challenges in the management of cardiac injuries and the benefits of a multidisciplinary approach to care for complex cardiac injuries., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To describe the anti-hepatitis B virus (HBV) efficacy, HBeAg serologic changes, HBV perinatal transmission, and safety in pregnant women who are living with human immunodeficiency virus (HIV) and HBV co-infection who were randomized to various antiretroviral therapy (ART) regimens., Methods: The PROMISE (Promoting Maternal and Infant Survival Everywhere) trial was a multicenter randomized trial for ART-naive pregnant women with HIV infection. Women with HIV and HBV co-infection at 14 or more weeks of gestation were randomized to one of three ART arms: one without HBV treatment (group 1) and two HBV treatment arms with single (group 2) or dual anti-HBV activity (group 3). The primary HBV outcome was HBV viral load antepartum change from baseline (enrollment) to 8 weeks; safety assessments included alanine aminotransferase (ALT) level, aspartate aminotransferase (AST) level, and anemia (hemoglobin less than 10 g/dL). Primary comparison was for the HBV-active treatment arms. Pairwise comparisons applied t test and the Fisher exact tests., Results: Of 3,543 women, 3.9% were HBsAg-positive; 42 were randomized to group 1, 48 to group 2, and 48 to group 3. Median gestational age at enrollment was 27 weeks. Among HBV-viremic women, mean antepartum HBV viral load change at week 8 was -0.26 log 10 international units/mL in group 1, -1.86 in group 2, and -1.89 in group 3. In those who were HBeAg-positive, HBeAg loss occurred in 44.4% at delivery. Two perinatal HBV transmissions occurred in group 2. During the antepartum period, one woman (2.4%) in group 1 had grade 3 or 4 ALT or AST elevations, two women (4.2%) in group 2, and three women (6.3%) in group 3., Conclusion: Over a short period of time, HBV DNA suppression was not different with one or two HBV-active agents. HbeAg loss occurred in a substantial proportion of participants. Perinatal transmission of HBV infection was low. Hepatitis B virus-active ART was well-tolerated in pregnancy, with few grade 3 or 4 ALT or AST elevations., Clinical Trial Registration: ClinicalTrials.gov , NCT01061151., Competing Interests: Financial Disclosure Debika Bhattacharya reports research support from the National Institutes of Health for the submitted work. She also reports research support from Gilead Sciences and clinical trial support from AbbVie and Regeneron, outside the submitted work. Marion G. Peters reports personal fees from Wainright, Silberback, Excision BioTherapeutics, Aligos, and Antios, as well as spousal employment with Roche, outside the submitted work. Camlin Tierney reports grants from the NIH during the conduct of the study. Mary Glenn Fowler reports IMPAACT Leadership LOC support for the present manuscript. Judith S. Currier reports research support from Resverologix and Merck and Company outside the submitted work. Vani Govender reports support from DAIDS. The other authors did not report any potential conflicts of interest., (Copyright © 2023 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

With growing interest and efforts to achieve a hepatitis B (HBV) cure, HBV therapeutics have increasingly entered the clinical testing phase. In designing an early phase clinical trial aimed at HBV cure, the heterogeneity in participants and the choice of a biomarker endpoint that signals a cure requires careful consideration. We describe the key elements to consider during the development of HBV clinical trials aimed at a functional cure, and how we have addressed them in the design of a phase II AIDS Clinical Trials Group (ACTG) study, A5394 (NCT05551273). The trial we present is for persons with both HIV and HBV, a unique population that has much to gain from an HBV cure. Our decisions on the design elements are specific to the study agent and the targeted population, but our deliberations may be informative in the emerging field of early phase HBV trials aimed at cure., Competing Interests: The author authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Introduction: Hepatocellular carcinoma (HCC) is an increasing cause of mortality in Nigeria among persons with HIV (PLH), as access to antiretroviral therapy (ART) improves. In this study we describe clinical, radiological, and laboratory characteristics in Nigerian adults with HCC, with and without HIV, and examine how HIV impacts survival., Methods: This prospective observational study was conducted between August 2018 and November 2021 at two Nigerian hospitals [Jos University Teaching Hospital (JUTH) and Lagos University Teaching Hospital (LUTH)]. Subjects ≥18 years with HCC diagnosed according to American Association for the Study of Liver Diseases (AASLD) criteria were included. Baseline characteristics were compared, and Kaplan-Meier curves were generated to estimate survival., Results: 213 subjects [177 (83%) without HIV and 36 (17%) with HIV (PLH)] were enrolled. Median age was 52 years (IQR 42,60) and most subjects were male (71%). 83% PLH were on antiretroviral therapy (ART). Hepatitis B surface antigen (HBsAg) positivity was similar between the two groups [91/177 (51%) without HIV vs. 18/36 (50%) with HIV; p = 0.86]. 46/213 (22%) subjects had active hepatitis C (anti-HCV+/HCV RNA>10 IU/mL). Cirrhosis was more common in PLH but there were no other significant differences in clinical and tumor characteristics between the groups. Overall, 99% subjects were symptomatic and 78% in late-stage HCC. Median overall survival was significantly shorter in PLH vs. without HIV (0.98 months vs 3.02 months, HR = 1.55, 95%CI 1.02, 2.37, p = 0.04). This association was not significant after adjusting for known risk factors including gender, current alcohol use, alpha-fetoprotein (AFP), albumin, and total bilirubin (HR = 1.38, 95%CI 0.84, 2.29, p = 0.21)., Conclusion: HCC presented late with an extremely poor overall prognosis, highlighting the urgent need for more intensive surveillance in Nigeria to diagnose HCC at earlier stages. Early diagnosis and management of viral hepatitis, and access to HCC therapies, could prevent early mortality among persons with HCC, especially among PLH., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Davwar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Long-term outcome data after hepatitis C virus (HCV) treatment are limited, particularly for comparisons between persons with and without HIV., Methods: A5320 was a prospective cohort study that enrolled participants within 12 months of completing HCV DAA therapy, with or without sustained virologic response (SVR). The primary end point was composite: time to death or development of a targeted diagnosis. Component outcomes (death and targeted diagnosis) and liver-related events were also analyzed. The effects of HIV serostatus, HIV RNA and CD4, and liver disease stage on the outcomes were assessed. Follow-up was designated for 5 years., Results: Three hundred thirty-two participants enrolled: 184 with HIV/HCV (130 SVR) and 148 with HCV (125 SVR). The primary analysis was dominated by targeted diagnoses. Increased rates of targeted diagnoses were seen in HCV-HIV/SVR compared with HCV/SVR ( P = .016), with an incidence rate of 6.7 and 3.4 per 100 person-years, respectively. Among persons without HIV, higher rates of targeted diagnoses were observed in non-SVRs ( P = .007), 10.8 vs 3.4/100 person-years. No significant difference was seen by SVR status among those with HIV. There were 15 deaths; all liver-related deaths (n = 4) occurred in non-SVR groups., Conclusions: HCV cure following therapy reduces subsequent development of new clinical events, supporting the use of SVR as a predictor for clinical outcomes. Despite HIV control, a significant decrease in incident events or mortality was not demonstrated for people with HIV who achieved SVR, suggesting that coinfection attenuates the beneficial impact of SVR. Research is needed to better define mechanisms accounting for the long-term negative impact of controlled HIV infection., Competing Interests: Potential conflicts of interest. D.L.W.: research funds paid to his institution from Gilead Sciences outside the submitted work. M.K., R.L.M., R.M.M., and M.G.P.: no disclosure relevant to the current work., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: There are limited data on the impact of antenatal antiretroviral regimens (ARV) on pregnancy and infant outcomes in HIV/HBV coinfection. We compared outcomes among 3 antenatal antiretroviral regimens for pregnant women with HIV/HBV., Methods: The PROMISE study enrolled ARV-naive pregnant women with HIV. Women with HBV were randomized to (no anti-HBV)-zidovudine (ZDV) + intrapartum nevirapine and 1 week of tenofovir disoproxil fumarate and emtricitabine (TDF-FTC); (3TC)-3TC + ZDV + LPV/r; or (FTC-TDF)-FTC + TDF + LPV/r. Pairwise group comparisons were performed with Fisher exact, t , or log rank tests. Adverse pregnancy outcome (APO) was a composite of low birth weight, preterm delivery, spontaneous abortion, stillbirth, or congenital anomaly., Results: Of 138 women with HIV/HBV, 42, 48, and 48 were analyzed in the no anti-HBV, 3TC, and FTC-TDF arms. Median age was 27 years. APOs trended lower in the no anti-HBV (26%) vs 3TC (38%), and FTC-TDF arms (35%), P ≥ 0.25). More infant deaths occurred among the FTC-TDF [6 (13%)] vs no anti-HBV [2 (5%)] and 3TC [3 (7%)] arms. There were no differences in time-to-death, HIV-free survival, birth or one-year WHO Z-score length-for-age, and head circumference. Hepatitis B e antigen (HBeAg) was associated with an increased risk of APO, 48% vs 27% (odds ratio 2.79, 95% confidence interval: 1.19 to 6.67, post hoc )., Conclusion: With HBV/HIV coinfection, the risk of an APO was increased with maternal ARV compared with ZDV alone, although the differences were not statistically significant. Maternal HBeAg was associated with a significantly increased risk of APO. Infant mortality was highest with FTC + TDF + LPV/r. Early assessment of HBeAg could assist in identifying high-risk pregnancies for close monitoring., Competing Interests: D.B. and F.M. report research grant support from Gilead Sciences Inc, under award numbers IN-US-987-5950 and GPHA 07844 respectively). M.G.P. has been a consultant to Aligos and Antios. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH), all components of the National Institutes of Health (NIH), under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), and by NICHD contract number HHSN275201800001I. Additional funding from NIAID UM1AI069465 to A.G., NIAID R01 01AI100748-01 and NICHD R01 HD085862 to D.B. Study products were provided free by AbbVie, Gilead Sciences, Boehringer Ingelheim, and ViiV/GlaxoSmithKline. Award Numbers UM1AI068632-15 (IMPAACT LOC), UM1AI068616-15 (IMPAACT SDMC) and UM1AI106716-15 (IMPAACT LC), and by NICHD contract number HHSN275201800001I. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The other authors have no conflicts of interest to disclose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background & Aims: Chronic hepatitis B (CHB) infection remains the most frequent etiology of hepatocellular carcinoma globally as well as a major cause of cirrhosis. Despite vaccination, substantial numbers of persons have already been infected with hepatitis B virus and remain at risk of progressive liver disease., Methods: In 2004, a CHB management algorithm was developed by a panel of North American hepatologists, which was subsequently updated in 2006, 2008, and 2015. Since the most recent version, several developments have altered the management of CHB. Tenofovir alafenamide, with a more favorable safety profile than tenofovir disoproxil fumarate, has been introduced as an initial antiviral choice as well as an alternative for long-term therapy. Quantitation of hepatitis B surface antigen is becoming more widely available in clinical practice, with implications for monitoring response to treatment. Additionally, there has been a shift in how the natural history of CHB is perceived, as newer evidence has challenged the concept that during the immunotolerant phase of infection disease progression is not a concern. Finally, recent analyses indicate that in the United States, the average age of patients with CHB has increased, implying that the presence of comorbidities, including metabolic liver disease, increasing use of biologics associated with aging will increasingly affect disease management., Results: This updated algorithm is intended to serve as a guide to manage CHB while new antiviral strategies are developed., Conclusions: Recommendations have been based on evidence from the scientific literature, when possible, as well as clinical experience and consensus expert opinion. Points of continued debate and areas of research need are also described., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Final results from the long-term Viral Hepatitis C Infection Long-term Cohort Study (V-HICS) found low rates of hepatitis C virus (HCV) recurrence after direct-acting antiviral therapy in both HCV/human immunodeficiency virus (HIV)-coinfected (0.67/100 person-years) and HCV-infected (0.2/100 person-years) groups with >500 person-years of follow-up. Confirmed reinfections were in participants with HIV who reported high-risk behaviors., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background and Aims: Chronic HBV is the predominant cause of HCC worldwide. Although HBV coinfection is common in HIV, the determinants of HCC in HIV/HBV coinfection are poorly characterized. We examined the predictors of HCC in a multicohort study of individuals coinfected with HIV/HBV., Approach and Results: We included persons coinfected with HIV/HBV within 22 cohorts of the North American AIDS Cohort Collaboration on Research and Design (1995-2016). First occurrence of HCC was verified by medical record review and/or cancer registry. We used multivariable Cox regression to determine adjusted HRs (aHRs [95% CIs]) of factors assessed at cohort entry (age, sex, race, body mass index), ever during observation (heavy alcohol use, HCV), or time-updated (HIV RNA, CD4+ percentage, diabetes mellitus, HBV DNA). Among 8,354 individuals coinfected with HIV/HBV (median age, 43 years; 93% male; 52.4% non-White), 115 HCC cases were diagnosed over 65,392 person-years (incidence rate, 1.8 [95% CI, 1.5-2.1] events/1,000 person-years). Risk factors for HCC included age 40-49 years (aHR, 1.97 [1.22-3.17]), age ≥50 years (aHR, 2.55 [1.49-4.35]), HCV coinfection (aHR, 1.61 [1.07-2.40]), and heavy alcohol use (aHR, 1.52 [1.04-2.23]), while time-updated HIV RNA >500 copies/mL (aHR, 0.90 [0.56-1.43]) and time-updated CD4+ percentage <14% (aHR, 1.03 [0.56-1.90]) were not. The risk of HCC was increased with time-updated HBV DNA >200 IU/mL (aHR, 2.22 [1.42-3.47]) and was higher with each 1.0 log 10 IU/mL increase in time-updated HBV DNA (aHR, 1.18 [1.05-1.34]). HBV suppression with HBV-active antiretroviral therapy (ART) for ≥1 year significantly reduced HCC risk (aHR, 0.42 [0.24-0.73])., Conclusion: Individuals coinfected with HIV/HBV on ART with detectable HBV viremia remain at risk for HCC. To gain maximal benefit from ART for HCC prevention, sustained HBV suppression is necessary., (© 2021 by the American Association for the Study of Liver Diseases.)

Background: Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors., Methods: To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 male, 1520 female) of European, African, and Hispanic ancestry. We performed autosomal, and X chromosome sex-stratified and combined association analyses in each ancestry group., Results: A male-specific region near the adenosine diphosphate-ribosylation factor-like 5B (ARL5B) gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have chronic HCV infection than individuals with the T allele (OR, 0.69; P = 1.98 × 10-07), and this was not seen in females. The ARL5B gene encodes an interferon-stimulated gene that inhibits immune response to double-stranded RNA viruses. We also identified suggestive associations near septin 6 and ribosomal protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared with the A allele (OR, 1.4; P = 2.46 × 10-06). Septin 6 facilitates HCV replication via interaction with the HCV NS5b protein, and ribosomal protein L39 acts as an HCV core interactor., Conclusions: These novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Direct-acting antiviral (DAA) therapy has transformed the management of human immunodeficiency virus (HIV) and hepatitis C (HCV) coinfected patients with advanced liver disease. STOP-Coinfection was a multicenter prospective and retrospective, open-label study using sofosbuvir-based DAA therapy to treat HIV/HCV-coinfected participants pre- or post-liver transplant (LT). Sixty-eight participants with end-stage liver disease (Child-Turcotte-Pugh score ≥7 and Model for End-Stage Liver Disease score 6-29) were enrolled, 26 had hepatocellular carcinoma. Forty-two participants were treated pre-LT and 26 post-LT. All participants completed therapy without need for dose reduction or transfusion; eight required two or more courses of therapy. Ninety-three percent achieved a sustained virologic response and DAA therapy was well tolerated. Despite HCV cure, 12 end-stage liver disease participants required subsequent LT, 7 for decompensated liver disease. Thirteen participants died, 10 with decompensated liver disease pre-LT and three post-LT. Overall, transplant free survival was 42.8% at 4 years and post-LT survival was 87.9% at 5 years. We conclude that sofosbuvir-based DAA therapy is safe and highly effective in HCV-HIV patients with decompensated liver disease and post-LT, with post-LT survival rates comparable to other indications. This removes one of the last barriers to liver transplantation in this challenging cohort of recipients., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Severe hepatotoxicity in people with human immunodeficiency virus (HIV) receiving efavirenz (EFV) has been reported. We assessed the incidence and risk factors of hepatotoxicity in women of childbearing age initiating EFV-containing regimens., Methods: In the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, ART-naive pregnant women with HIV and CD4 count ≥ 350 cells/μL and alanine aminotransferase ≤ 2.5 the upper limit of normal were randomized during the antepartum and postpartum periods to antiretroviral therapy (ART) strategies to assess HIV vertical transmission, safety, and maternal disease progression. Hepatotoxicity was defined per the Division of AIDS Toxicity Tables. Cox proportional hazards models were constructed with covariates including participant characteristics, ART regimens, and timing of EFV initiation., Results: Among 3576 women, 2435 (68%) initiated EFV at a median 121.1 weeks post delivery. After EFV initiation, 2.5% (61/2435) had severe (grade 3 or higher) hepatotoxicity with an incidence of 2.3 (95% confidence interval [CI], 2.0-2.6) per 100 person-years. Events occurred between 1 and 132 weeks postpartum. Of those with severe hepatotoxicity, 8.2% (5/61) were symptomatic, and 3.3% (2/61) of those with severe hepatotoxicity died from EFV-related hepatotoxicity, 1 of whom was symptomatic. The incidence of liver-related mortality was 0.07 (95% CI, .06-.08) per 100 person-years. In multivariable analysis, older age was associated with severe hepatotoxicity (adjusted hazard ratio per 5 years, 1.35 [95% CI, 1.06-1.70])., Conclusions: Severe hepatotoxicity after EFV initiation occurred in 2.5% of women and liver-related mortality occurred in 3% of those with severe hepatotoxicity. The occurrence of fatal events underscores the need for safer treatments for women of childbearing age., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Breast cancer is the leading cause of cancer death among women worldwide. Blocking a single signaling pathway is often an ineffective therapy, especially in the case of aggressive or drug-resistant tumors. Since we have previously described the mechanism involved in the crosstalk between Retinoic Acid system and protein kinase C (PKC) pathway, the rationale of our study was to evaluate the effect of combining all-trans-retinoic acid (ATRA) with a classical PCK inhibitor (Gö6976) in preclinical settings. Employing hormone-independent mammary cancer models, Gö6976 and ATRA combined treatment induced a synergistic reduction in proliferative potential that correlated with an increased apoptosis and RARs modulation towards an anti-oncogenic profile. Combined treatment also impairs growth, self-renewal and clonogenicity potential of cancer stem cells and reduced tumor growth, metastatic spread and cancer stem cells frequency in vivo. An in-silico analysis of "Kaplan-Meier plotter" database indicated that low PKCα together with high RARα mRNA expression is a favorable prognosis factor for hormone-independent breast cancer patients. Here we demonstrate that a classical PKC inhibitor potentiates ATRA antitumor effects also targeting cancer stem cells growth, self-renewal and frequency.

Background & Aims: Seroclearance of hepatitis B surface antigen (HBsAg) is the desired end point of treatment for chronic hepatitis B virus (HBV) infection, according to guidelines. We performed a systematic review and meta-analysis to evaluate the strength of the association between HBsAg seroclearance and long-term clinical outcomes., Methods: We performed a systematic review of the PubMed, EMBASE, and Cochrane Library databases for articles that assessed HBsAg status and reported the incidence of hepatocellular carcinoma (HCC), liver decompensation, liver transplantation, and/or all-cause mortality during follow-up evaluation. We performed a meta-analysis of rate ratios (RR) using a random-effects model independently for each end point and for a composite end point., Results: We analyzed data from 28 studies, comprising a total of 188,316 patients with chronic HBV infection (treated and untreated), and 1,486,081 person-years (PY) of follow-up evaluation; 26 reported data on HCC, 7 on liver decompensation, and 13 on liver transplantation and/or death. The composite event rates were 0.19/1000 PY for the HBsAg seroclearance group and 2.45/1000 PY for the HBsAg-persistent group. Pooled RRs for the HBsAg seroclearance group were 0.28 for liver decompensation (95% CI, 0.13-0.59; P = .001), 0.30 for HCC (95% CI, 0.20-0.44; P < .001), 0.22 for liver transplantation and/or death (95% CI, 0.13-0.39; P < .001), and 0.31 for the composite end point (95% CI, 0.23-0.43; P < .001). No differences in RR estimates were observed among subgroups of different study or patient characteristics., Conclusions: In a systematic review and meta-analysis, we found seroclearance of HBsAg to be associated significantly with improved patient outcomes. The results are consistent among different types of studies, in all patient subpopulations examined, and support the use of HBsAg seroclearance as a primary end point of trials of patients with chronic HBV infection., (Copyright © 2021. Published by Elsevier Inc.)

Importance: People with HIV (PWH) are often coinfected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), leading to increased risk of developing hepatocellular carcinoma (HCC), but few cohort studies have had sufficient power to describe the trends of HCC incidence and risk among PWH in the combination antiretroviral therapy (cART) era., Objective: To determine the temporal trends of HCC incidence rates (IRs) and to compare rates by risk factors among PWH in the cART era., Design, Setting, and Participants: This cohort study used data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) study, which was conducted between 1996 and 2015. NA-ACCORD pooled individual-level data from 22 HIV clinical and interval cohorts of PWH in the US and Canada. PWH aged 18 years or older with available CD4 cell counts and HIV RNA data were enrolled. Data analyses were completed in March 2020., Exposures: HBV infection was defined as detection of either HBV surface antigen, HBV e antigen, or HBV DNA in serum or plasma any time during observation. HCV infection was defined by detection of anti-HCV seropositivity, HCV RNA, or detectable genotype in serum or plasma at any time under observation., Main Outcomes and Measures: HCC diagnoses were identified on the basis of review of medical records or cancer registry linkage., Results: Of 109 283 PWH with 723 441 person-years of follow-up, the median (interquartile range) age at baseline was 43 (36-51) years, 93 017 (85.1%) were male, 44 752 (40.9%) were White, 44 322 (40.6%) were Black, 21 343 (19.5%) had HCV coinfection, 6348 (5.8%) had HBV coinfection, and 2082 (1.9%) had triple infection; 451 individuals received a diagnosis of HCC by 2015. Between the early (1996-2000) and modern (2006-2015) cART eras, the crude HCC IR increased from 0.28 to 0.75 case per 1000 person-years. HCC IRs remained constant among HIV-monoinfected persons or those coinfected with HBV, but from 1996 to 2015, IRs increased among PWH coinfected with HCV (from 0.34 cases/1000 person-years in 1996 to 2.39 cases/1000 person-years in 2015) or those with triple infection (from 0.65 cases/1000 person-years in 1996 to 4.49 cases/1000 person-years in 2015). Recent HIV RNA levels greater than or equal to 500 copies/mL (IR ratio, 1.8; 95% CI, 1.4-2.4) and CD4 cell counts less than or equal to 500 cells/μL (IR ratio, 1.3; 95% CI, 1.0-1.6) were associated with higher HCC risk in the modern cART era. People who injected drugs had higher HCC risk compared with men who had sex with men (IR ratio, 2.0; 95% CI, 1.3-2.9), adjusted for HBV-HCV coinfection., Conclusions and Relevance: HCC rates among PWH increased significantly over time from 1996 to 2015. PWH coinfected with viral hepatitis, those with higher HIV RNA levels or lower CD4 cell counts, and those who inject drugs had higher HCC risk.

Attention-Deficit Hyperactivity Disorder (ADHD) is a predominant neurobehavioral disorder of childhood with motor and sensory symptoms often persisting into adulthood. Motor control theories highlight the importance of the bidirectional relationship between sensation and movement for maintaining skilled behaviors like speech. The impact of ADHD on speech in adults has not been well established. The purpose of this study is to assess group differences in quantitative speech and oral somatosensory measures in adults with and without ADHD and to describe the relationship between ADHD symptomology and speech production. A total of 50 adults (18-26 years) were recruited and divided in two groups based on diagnosis: those with (n = 28) and those without (n = 22) ADHD. All participants provided a speech sample to measure articulatory accuracy and speech rate and completed quantitative point-pressure testing using tactile detection and discrimination on bilateral sites on the lower lip and lateral edge of the tongue tip. Independent t-tests corrected for multiple comparisons identified significant group differences using FDR corrected q values in speech production for correct syllables per second and overall speech rate (q<.05). Additionally, there were significant group differences (q<.05) for detection and discrimination threshold estimates at one testing location. Bivariate correlations identified a relationship between several speech measures and self-reported ADHD symptoms such that as symptom severity increased, speech accuracy for correct syllables per second decreased. Young adults with ADHD have subtle differences in speech production compared to non-ADHD control participants. Speech scientists might consider screening for ADHD when collecting normative data samples., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Retinoids have proved to be effective for hematologic malignancies treatment but till nowadays, their use as single agent for the solid tumor's management is still controversial. All-trans retinoic acid (ATRA), the main active metabolite of vitamin A, exerts non-genomic interactions with different members of the protein kinase C (PKC) family, recognized modulators of different tumor progression pathways. To determine whether a group of patients could become benefited employing a retinoid therapy, in this study we have evaluated whether PKCα expression (a poor prognosis marker in breast cancer) could sensitizes mammary cells to ATRA treatment., Methods: PKCα overexpression was achieved by stable transfection and confirmed by western blot. Transfected PKC functionality was determined by nuclear translocation-induction and confocal microscopy. In vitro proliferation was evaluated by cell counting and cell cycle distribution was analyzed by flow cytometry. In vivo studies were performed to evaluate orthotopic tumor growth and experimental lung colonization. Retinoic acid response elements (RARE) and AP1 sites-dependent activity was studied by gene reporter assays and retinoic acid receptors (RARs) were measured by RT-qPCR., Results: Our findings suggest that high PKCα levels improve the differentiation response to ATRA in a RAR signaling-dependent manner. Moreover, RARβ expression appears to be critical to induce ATRA sensitization, throughout AP1 trans-repression., Conclusion: Here we propose that retinoids could lead a highly personalized anticancer treatment, bringing benefits to patients with aggressive breast tumors resulting from high PKCα expression but, an adequate expression of the RARβ receptor is required to ensure the effect on this process.

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.

GPC3 is a proteoglycan involved in the control of proliferation and survival, which has been linked to several tumor types. In this respect, we previously demonstrated that normal breast tissues exhibit high levels of GPC3, while its expression is diminished in tumors. However, the role of the GPC3 downregulation in breast cancer progression and its molecular and cellular operational machineries are not fully understood. In this study we showed that GPC3 reverts the epithelial-to-mesenchymal transition (EMT) underwent by mammary tumor cells, blocks metastatic spread and induces dormancy at secondary site. Using genetically modified murine breast cancer cell sublines, we demonstrated that the phospho-Erk/phospho-p38 ratio is lower in GPC3 reexpressing cells, while p21, p27 and SOX2 levels are higher, suggesting a dormant phenotype. In vivo metastasis assays confirmed that GPC3 reexpressing cells reduce their metastatic ability. Interestingly, the presence of dormant cells was evidenced in the lungs of inoculated mice. Dormant cells could reactivate their proliferative capacity, remain viable as well as tumorigenic, but they reentered in dormancy upon reaching secondary site. We also proved that GPC3 inhibits metastasis through p38 pathway activation. The in vivo inhibition of p38 induced an increase in cell invasion of GPC3 reexpressing orthotropic tumors as well as in spontaneous and experimental metastatic dissemination. In conclusion, our study shows that GPC3 returns mesenchymal-like breast cancer cells to an epithelial phenotype, impairs in vivo metastasis and induces tumor dormancy through p38 MAPK signaling activation. These results help to identify genetic determinants of dormancy and suggest the translational potential of research focusing in GPC3., Competing Interests: Declaration of Competing Interest None. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Background: Well-tolerated, highly effective HCV treatment, known as direct-acting antivirals (DAAs), is now recommended for all people living with HCV, providing the tools for HCV elimination. We sought to understand treatment barriers among low-income HIV/HCV coinfected patients and providers with the goal of increasing uptake., Methods: In 2014, we conducted 26 interviews with HIV/HCV co-infected patients and providers from a San Francisco clinic serving underinsured and publically-insured persons to explore barriers impacting treatment engagement and completion. Interview transcripts were coded, and a thematic analysis was conducted to identify emerging patterns., Results: Conditions of poverty-specifically, meeting basic needs for food, shelter, and safety-undermined patient perceptions of self-efficacy to successfully complete HCV treatment programs. While patient participants expressed interest in HCV treatment, the perceived burden of taking daily medications without strong social support was an added challenge. This need for support contradicted provider assumptions that, due to the shorter-course regimens, support is unnecessary in the DAA era., Conclusions: Interferon-free treatments alone are not sufficient to overcome social-structural barriers to HCV treatment and care among low-income HIV/HCV co-infected patients. Support for patients with unmet social needs may facilitate treatment initiation and completion, particularly among those in challenging socioeconomic situations., (© The Author(s) 2019. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

HIV/HCV coinfected patients are a priority for direct acting antiretroviral (DAA) treatment, yet barriers to treating vulnerable patients persist. This study surveyed safety net clinic patients and providers to quantify their preferences for DAA treatment and prioritize modifiable barriers. Preferences were assessed using best-worst scaling. General linear mixed models were used to determine whether attributes differed in importance and whether patients and providers valued attributes differently. 158 HIV/HCV coinfected patients and 49 providers participated. Patients and providers had strong preferences for treatment within the medical homes where patients receive HIV care. Support such as reminders and advice numbers were also important, but were more important to providers than patients. Providers identified lack of insurance coverage for DAA as the most significant barrier. Providers rated HIV primary care providers as best suited to deliver DAA to HIV+ patients. Addressing structural barriers is essential for increasing DAA treatment in safety net settings.

We have previously shown that ultrasound identifies significant steatosis in patients with chronic HBV (CHB). However, the relationship between CHB, metabolic syndrome (MS) and steatosis is poorly understood. In this tertiary care, single-centre retrospective cohort study of 617 CHB patients, we examined the prevalence of MS and steatosis in a predominantly Asian US cohort. Patients were predominantly male (57%) with a mean age of 53 years, Asian (88%), on HBV therapy (64%) and had undetectable DNA (65%). 21% had MS, of which hypertension (41%), dyslipidemia (41%) and obesity (32%) were most common. Patients with MS were more likely to be older (60 vs 52 [P < 0.001]), have steatosis (40% vs 17% [P < 0.001]) and have a higher ALT (29 vs 25 [P = 0.003]). Of the 22% of patients with steatosis by ultrasound, a higher prevalence of MS (38% vs 16% [P < 0.001]) and higher ALT (31 vs 24 [P < 0.001]) was observed. Asian patients had a lower BMI than non-Asians (mean 24 vs 26 [P = 0.001]) but similar prevalence of MS risk factors and steatosis. Asian patients with a BMI between 25 and 30 and two other MS risk factors had steatosis at the same rate as patients with a BMI > 30 and at least two other MS risk factors. We found a strong association between MS, steatosis and elevated ALT in HBV patients. Asian HBV patients have lower BMI than non-Asians yet have the same prevalence of steatosis and other MS risk factors, supporting guidelines for lower BMI targets in Asians., (© 2019 John Wiley & Sons Ltd.)

Among individuals with HIV infection, liver disease remains an important cause of morbidity and mortality, even with the availability of agents that cure hepatitis C infection and suppress hepatitis B replication. The causes of liver disease are multifaceted and continue to evolve as the population ages and new etiologies arise. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis and hepatitis viruses such as A, D, and E have emerged even as hepatitis C has receded. Newer antiretroviral agents may increase risk of weight gain and subsequent fatty infiltration, and prior use of nucleotide-based therapies may continue to impact liver health. Several barriers including economics, social stigma, and psychiatric disease impact identification of liver disease, as well as management and treatment interventions. Hepatocellular carcinoma is emerging as a more common and late-diagnosed complication in those with HIV infection and liver disease.

Background: Hepatitis B virus (HBV) infection is a leading cause of end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC) in HIV. Factors contributing to the high rates of liver complications among HIV/HBV-coinfected individuals remain unknown., Setting: North American AIDS Cohort Collaboration on Research and Design., Methods: We performed a retrospective cohort study among HIV/HBV-coinfected patients in 10 US and Canadian cohorts of the North American AIDS Cohort Collaboration on Research and Design that validated ESLD (ascites, spontaneous bacterial peritonitis, variceal hemorrhage, and/or hepatic encephalopathy) and HCC diagnoses from 1996 to 2010. Multivariable Cox regression was used to examine adjusted hazard ratios [aHRs with 95% confidence interval (CIs)] of liver complications (first occurrence of ESLD or HCC) associated with hypothesized determinants and with increasing durations of HIV suppression (≤500 copies/mL)., Results: Among 3573 HIV/HBV patients with 13,790 person-years of follow-up, 111 liver complications occurred (incidence rate = 8.0 [95% CI: 6.6 to 9.7] events/1000 person-years). Rates of liver complication were increased with non-black/non-Hispanic race [aHR = 1.76 (1.13-2.74)], diabetes mellitus [aHR = 2.07 (1.20-3.57)], lower time-updated CD4 cell count [<200 cells/mm: aHR = 2.59 (1.36-4.91); 201-499 cells/mm: aHR = 1.75 (1.01-3.06) versus ≥500 cells/mm], heavy alcohol use [aHR = 1.58 (1.04-2.39)], and higher FIB-4 at start of follow-up [>3.25: aHR = 9.79 (5.73-16.74); 1.45-3.25: aHR = 3.20 (1.87-5.47) versus FIB-4 <1.45]. HIV suppression for ≥6 months was associated with lower liver complication rates compared with those with unsuppressed HIV [aHR = 0.56 (0.35-0.91)]., Conclusions: Non-black/non-Hispanic race, diabetes, lower CD4 cell count, heavy alcohol use, and advanced liver fibrosis were determinants of liver complications among HIV/HBV patients. Sustained HIV suppression should be a focus for HIV/HBV-coinfected patients to reduce the risks of ESLD/HCC.

Patients with malignancies require chemotherapy and other immunosuppressive therapies for treatment. Because of this immunosuppression, in patients who have ever been exposed to hepatitis B it is possible for reactivation to occur. This reactivation can be fatal. Reactivation is particularly likely in patients who receive B cell-active agents such as rituximab. The occurrence of reactivation flares may also delay further chemotherapy, which can negatively affect the outcome of the underlying malignancy. Accordingly, it is important to screen patients for markers of hepatitis B and institute antiviral prophylaxis to prevent reactivation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Because of the relatively high prevalence of both hepatitis B infection and various forms of autoimmune inflammatory diseases treated with aggressive immunotherapy, reactivation of hepatitis B occurs in a substantial number of patients. The risk of reactivation depends on the degree and duration of immunosuppression. A large number of drug treatments have resulted in reactivation of hepatitis B virus infection and, based on the mechanisms and extent of immunosuppression, recommendations for some of the newer classes of immunosuppressive drugs are provided., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Organ transplantation is a lifesaving procedure for many patients. To prevent rejection or graft-versus-host disease, recipients require long-term immunosuppression. In patients who have ever been exposed to hepatitis B, it is possible for reactivation to occur; this includes patients who are anti-hepatitis B core antibody-positive only or both anti-hepatitis B core antibody-positive and hepatitis B surface antibody-positive. The susceptibility to this varies with the nature of the transplant. Hepatitis B can be transmitted from donor to recipient. It is important to assess the hepatitis B status and formulate a strategy to prevent transmission and prevent reactivation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Current recommendations concerning hepatitis C virus (HBV) reactivation are limited, with nearly all guidelines focused on its occurrence in patients with hematological malignancies or some solid tumors, who are treated with immunosuppressive therapies. Few of the guidelines address reactivation in patients receiving immunosuppression with organ transplants or treatment with any of the many immunosuppressive agents in use today for the treatment of multiple different diseases, or in patients receiving the direct-acting antivirals used in the treatment of hepatitis C virus (HCV). This article covers the immunology of HBV reactivation, mechanisms of viral clearance, and recommendations for screening and prophylaxis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Current guidelines for the management of hepatitis C virus (HCV) infections provide varying recommendations for the optimal treatment of acute HCV infections. There are limited data from small cohort studies to provide guidance on the best approach to treatment of this important patient population., Methods: Sofosbuvir-Containing Regimens Without Interferon for Treatment of Acute HCV in HIV-1 Infected Individuals is an open-label, 2-cohort, Phase 1 clinical trial in which the second cohort assessed the safety and efficacy of 8 weeks of ledipasvir/sofosbuvir for the treatment of acute HCV infections in participants with chronic human immunodeficiency virus (HIV)-1 infections. This final analysis of the second cohort had a planned accrual of 27 participants, based on non-inferiority criteria, compared to the study-defined, historical, sustained virologic response (SVR) of 60% with pegylated-interferon/ribavirin., Results: We enrolled 27 men (9 Hispanic; 11 White, non-Hispanic; 5 Black, non-Hispanic; 2 Asian or Pacific Islander; median age 46 years). Most (96%) had HCV genotype-1 infection and 59% had the favorable interleukin 28B CC genotype. The median baseline HCV RNA load was 6.17 log10 IU/mL (interquartile range 4.51 - 6.55). All participants (100%) achieved the primary outcome of a sustained virologic response 12 weeks after the date of the last dose of study treatment (90% confidence interval 90-100%), achieving non-inferiority versus the 60% historic benchmark. No treatment discontinuations occurred., Conclusions: This multicenter clinical trial, investigating 8 weeks of ledipasvir/sofosbuvir for acute HCV infections in men with HIV infections, reports a 100% SVR. This study provides the rationale for larger studies of shortened courses of direct-acting antiviral therapies in persons with HIV infections, including those with high baseline HCV RNA loads., Clinical Trials Registration: NCT02128217., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)