PBMCs gene expression signature of advanced cirrhosis with high risk for clinically significant portal hypertension in HIV/HCV coinfected patients: A cross-control study.

Corrigendum to "PBMCs gene expression signature of advanced cirrhosis with high risk for clinically significant portal hypertension in HIV/HCV coinfected patients: A cross-control study" [Biomed. Pharmacother. 159 (2023) 114220]. Biomed Pharmacother. 2023 Apr 27;114803. doi: 10.1016/j.biopha.2023.114803. PMID: 37120412.Background: Patients with advanced cirrhosis are at high risk of developing clinically significant portal hypertension (CSPH). We analyzed the gene expression profile of peripheral blood mononuclear cells (PBMCs) from HIV/HCV coinfected patients to identify a gene expression signature of advanced cirrhosis with high risk for CSPH. Methods: We conducted a cross-sectional study on 68 patients. Liver stiffness measurement (LSM) was used to stratify patients into < 12.5 kPa (no cirrhosis, n = 19), 12.5 - 24.9 kPa (cirrhosis, n = 20), and ≥ 25 kPa (advanced cirrhosis with high risk for CSPH, n = 29). Besides, we further evaluated LSM < 25 kPa (n = 39) vs. ≥ 25 kPa (n = 29). Total RNA was extracted from PBMCs, and poly(A) RNA sequencing was performed. Two significant differentially expressed (SDE) transcripts were validated by quantitative PCR in a different cohort (n = 46). Results: We found 60 SDE transcripts between patients with LSM < 12.5 kPa and ≥ 25 kPa. Partial least squares discriminant analysis showed that those 60 SDE transcripts collectively discriminated LSM ≥ 25 kPa, with an area under the receiver operating characteristic curve (AUROC) of 0.84. Eight genes had an AUROC ≥ 0.75 for LSM ≥ 25 kPa: five were positively associated with LSM values (SCAMP1, ABHD17B, GPR146, GTF2A1, and TMEM64), while three were inversely associated (ZFHX2-AS1, MDK, and STAG3L2). We validated the two SDE transcripts with the highest discrimination capacity in a different cohort, finding significant differences between < 25 kPa and ≥ 25 kPa (MDK (p = 0.006) and STAG3L2 (p = 0.021)). Conclusions: A gene expression signature of 60 transcripts was associated with advanced cirrhosis with high risk for CSPH in HIV/HCV coinfected patients.This study was supported by grants from Instituto de Salud Carlos III (ISCIII; grant numbers CP17CIII/00007 and PI18CIII/00028 to MAJS, PI17/00657 and PI20/00474 to JB, PI17/00903 and PI20/00507 to JGG, PI18CIII/00020 to AFR, and PI17CIII/00003 and PI20CIII/00004 to SR) and Ministerio de Ciencia e Innovación (AEI, PID2021-126781OB-I00 to AFR). The study was also funded by the CIBER -Consorcio Centro de Investigación Biomédica en Red- (CB 2021), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea – NextGenerationEU (CB21/13/00044).S

HCV eradication with IFN-based therapy does not completely restore gene expression in PBMCs from HIV/HCV-coinfected patients.

To evaluate the impact of hepatitis C virus (HCV) elimination via interferon (IFN)-based therapy on gene expression profiles related to the immune system in HIV/HCV-coinfected patients. We conducted a prospective study in 28 HIV/HCV-coinfected patients receiving IFN-based therapy at baseline (HIV/HCV-b) and week 24 after sustained virological response (HIV/HCV-f). Twenty-seven HIV-monoinfected patients (HIV-mono) were included as a control. RNA-seq analysis was performed on peripheral blood mononuclear cells (PBMCs). Genes with a fold-change (FC) ≥ 1.5 (in either direction) and false discovery rate (FDR) ≤ 0.05 were identified as significantly differentially expressed (SDE). HIV/HCV-b showed six SDE genes compared to HIV-mono group, but no significantly enriched pathways were observed. For HIV/HCV-f vs. HIV/HCV-b, we found 58 SDE genes, 34 upregulated and 24 downregulated in the HIV/HCV-f group. Of these, the most overexpressed were CXCL2, PDCD6IP, ATP5B, IGSF9, RAB26, and CSRNP1, and the most downregulated were IFI44 and IFI44L. These 58 SDE genes revealed two significantly enriched pathways (FDR < 0.05), one linked to Epstein-Barr virus infection and another related to p53 signaling. For HIV/HCV-f vs. HIV-mono group, we found 44 SDE genes that revealed 31 enriched pathways (FDR < 0.05) related to inflammation, cancer/cell cycle alteration, viral and bacterial infection, and comorbidities associated with HIV/HCV-coinfection. Five genes were overrepresented in most pathways (JUN, NFKBIA, PIK3R2, CDC42, and STAT3). HIV/HCV-coinfected patients who eradicated hepatitis C with IFN-based therapy showed profound gene expression changes after achieving sustained virological response. The altered pathways were related to inflammation and liver-related complications, such as non-alcoholic fatty liver disease and hepatocellular carcinoma, underscoring the need for active surveillance for these patients.This study was supported by grants from Instituto de Salud Carlos III (ISCII; Grant Numbers PI20/00474 and PI17/00657 to JB, PI20/00507 and PI17/00903 to JGG, PI18CIII/00020 to AFR, and PI20CIII/00004 and PI17CIII/00003 to SR). The study was also funded by the RD16CIII/0002/0002 and RD16/0025/0017, and RD16/0025/0018 projects as part of the Plan Nacional R + D + I and co-funded by ISCIII- Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER). JB is an investigator from the Programa de Intensificación de la Actividad Investigadora en el Sistema Nacional de Salud (I3SNS), Ref. INT16/00100.S

Negative impact of HIV infection on broad-spectrum anti-HCV neutralizing antibody titers in HCV-infected patients with advanced HCV-related cirrhosis

Objectives: The current study aimed to assess the impact of HIV on the production of anti-HCV antibodies in HCV-infected individuals with advanced HCV-related cirrhosis before and 36 weeks after the sustained virological response (SVR) induced by direct-acting antivirals (DAAs) therapy. Methods: Prospective study on 62 patients (50 HIV/HCV-coinfected and 12 HCV-monoinfected). Plasma anti-E2 and HCV-nAbs were determined respectively by ELISA and microneutralization assays. Results: At baseline, the HCV-group had higher anti-E2 levels against Gt1a (p = 0.012), Gt1b (p = 0.023), and Gt4a (p = 0.005) than the HIV/HCV-group. After SVR, anti-E2 titers against Gt1a (p < 0.001), Gt1b (p = 0.001), and Gt4a (p = 0.042) were also higher in the HCV-group than HIV/HCV-group. At 36 weeks post-SVR, plasma anti-E2 titers decreased between 1.3 and 1.9-fold in the HIV/HCV-group (p < 0.001) and between 1.5 and 1.8-fold in the HCV-group (p ≤ 0.001). At baseline, the HCV-group had higher titers of HCV-nAbs against Gt1a (p = 0.022), Gt1b (p = 0.002), Gt2a (p < 0.001), and Gt4a (p < 0.001) than the HIV/HCV-group. After SVR, HCV-nAbs titers against Gt1a (p = 0.014), Gt1b (p < 0.001), Gt2a (p = 0.002), and Gt4a (p = 0.004) were also higher in the HCV-group. At 36 weeks post-SVR, HCV-nAbs decreased between 2.6 and 4.1-fold in the HIV/HCV-group (p < 0.001) and between 1.9 and 4.0-fold in the HCV-group (p ≤ 0.001). Conclusions: HIV/HCV-coinfected patients produced lower levels of broad-spectrum anti-HCV antibodies than HCV-monoinfected patients.This study was supported by grants from Instituto de Salud Carlos III (ISCII; grant numbers PI20/00474 and PI17/00657 to JB, PI20/00507 and PI17/00903 to JGG, PI19CIII/00009 to IM, and PI20CIII/00004 and PI17CIII/00003 to SR). The study was also funded by the Spanish AIDS Research Network (RD16/0025/0017, RD16/0025/0018 and RD16CIII/0002/0002) and CIBER -Consorcio Centro de Investigación Biomédica en Red- (CB 2021), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea – NextGenerationEU (CB21/13/00044 and CB21/13/00039). DSC is a ‘Sara Borrell’ researcher from ISCIII (grant number CD20CIII/00001).S

HCV Cure With Direct-Acting Antivirals Improves Liver and Immunological Markers in HIV/HCV-Coinfected Patients

Hepatitis C virus (HCV) cure after all-oral direct-acting antiviral (DAA) therapy greatly improves the liver and immune system. We aimed to assess the impact of this HCV clearance on immune system-related markers in plasma and the gene expression profile in human immunodeficiency virus (HIV)/HCV-coinfected patients with advanced cirrhosis. We performed a prospective study on 33 HIV/HCV-coinfected patients at baseline and 36 weeks after the sustained virological response. Gene expression was evaluated by RNA-seq analysis on peripheral blood mononuclear cells (PBMCs) and plasma biomarkers by multiplex immunoassays. We found a decrease in plasma biomarkers (PD1, PDL1, CXCL10, CXCL8, IL12p70, IL10, and TGFβ) and liver disease markers (stiffness measurement (LSM), hepatic venous pressure gradient (HVPG), and transaminases, among others). Furthermore, decreased plasma levels of CXCL8, CXCL10, IL10, and PD1 were associated with reduced LSM values. We also found two upregulated (HAS1 and IRG1) and 15 downregulated (CXCL11, CCL8, CCL7, CCL2, ADARB2, RRAD, MX1, SIGLEC1, IFI44L, IFI44, IFI27, IFI6, IFIT3, IFIT1B, and IFIT1) genes at the end of follow-up, all interferon-stimulated genes (ISGs) grouped into four pathways ("cytokine-cytokine receptor interaction", "viral protein interaction with cytokine and cytokine receptor", "chemokine signaling pathway", and "hepatitis C"). Additionally, the decrease in most of these ISGs was significantly related to reduced LSM and HVPG values. In conclusion, HIV/HCV-coinfected patients with advanced-HCV-related cirrhosis who eradicated HCV following DAA therapy exhibited an improvement in liver disease markers and a significant decrease in plasma biomarkers and gene expression related to antiviral/inflammatory response, particularly in levels of several chemokines and ISGs.This study was supported by grants from Instituto de Salud Carlos III (ISCII; grant numbers PI20/00474 and PI17/00657 to JB, PI20/00507 and PI17/00903 to JGG, PI18CIII/00020 to AF-R, PI18CIII/00028 to MA, and PI20CIII/00004 and PI17CIII/00003 to SR). AF-R and MA are Miguel Servet researchers supported and funded by ISCIII (grant numbers: CP14CIII/00010 to AFR and CP17CIII/00007 to MAJS). The study was also funded by the RD16/0025/0017, RD16/0025/0018 and RD16CIII/0002/0002 projects as part of the Plan Nacional R + D + I and co-funded by ISCIII- Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER). JB is an investigator from the Programa de Intensificación de la Actividad Investigadora en el Sistema Nacional de Salud (I3SNS), Ref. INT16/00100. DS-C is a ‘Sara Borrell’ researcher from ISCIII (grant number CD20CIII/00001) and has also been supported through Fundación SEIMC-GESIDA by a fellowship award from Fundación ONCE ‘Oportunidad al Talento, 2019/20 and 2020/21’ co-financed by Fondo Social Europeo.S

Effects of HCV Eradication on Bone mineral density in HIV/HCV Coinfected Patients

Little is known about the effects of eradication of HCV on bone mineral density (BMD) and biomarkers of bone remodeling in HIV/HCV coinfected patients. We prospectively assessed standardized BMD (sBMD) at the lumbar spine and femoral neck, World Health Organization (WHO) BMD categories at both sites, and plasma concentrations of soluble receptor activator of nuclear factor-kappaβ ligand (sRANKL), and osteoprotegerin (OPG) at baseline (the date of initiation of anti-HCV therapy) and at 96 weeks. A total of 238 patients were included, median age 49.5 years, 76.5% males, 48.3% with cirrhosis, 98.3% on antiretroviral therapy, median CD4+ cell count 527 cells/mm 3, 86.6% with HIV-1 RNA < 50 copies/mL. The prevalence of osteoporosis at baseline at the lumbar spine (LS) and femoral neck (FN) was 17.6% and 7.2%, respectively. Anti-HCV therapy comprised pegylated interferon and ribavirin (PegIFN-RBV) plus one direct-acting antiviral in 53.4%, PegIFN-RBV in 34.5%, and sofosbuvir/RBV in 12.2%. A total of 145 (60.9%) patients achieved sustained viral response (SVR). No significant effect of SVR was observed on sBMD for the interaction between time and SVR either in the LS (P=0.801) or the FN (P=0.911). Likewise, no significant effect of SVR was observed in plasma levels of sRANKL (P=0.205), OPG (P=0.249), and sRANKL/OPG ratio (P=0.123) for the interaction between time and SVR. No significant correlation was found between fibrosis by transient elastography, and LS and FN sBMD, at baseline, and week 96. SVR was not associated with significant changes in BMD nor biomarkers of bone remodeling in HIV/HCV-coinfected persons.This study was supported by Instituto de Salud Carlos III (ISCII), grant numbers PI11/01556, PI14/01094, PI14/01581, and PI14CIII/00011, and by Ministerio de Sanidad, Servicios Sociales e Igualdad, grant number EC11-241. The study was also funded by the RD16/0025/0017, RD16/0025/0018 and RD16CIII/0002/0002 projects as part of the Plan Nacional R + D + I and cofunded by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER).S

Human Immunodeficiency Virus/Hepatits C Virus Coinfection in Spain: Elimination Is Feasible, but the Burden of Residual Cirrhosis Will Be Significant

Background: We assessed the prevalence of antibodies against hepatitis C virus (HCV-Abs) and active HCV infection in patients infected with human immunodeficiency virus (HIV) in Spain in 2016 and compared the results with those of similar studies performed in 2002, 2009, and 2015. Methods: The study was performed in 43 centers during October-November 2016. The sample was estimated for an accuracy of 2% and selected by proportional allocation and simple random sampling. During 2016, criteria for therapy based on direct-acting antiviral agents (DAA) were at least significant liver fibrosis, severe extrahepatic manifestations of HCV, and high risk of HCV transmissibility. Results: The reference population and the sample size were 38904 and 1588 patients, respectively. The prevalence of HCV-Abs in 2002, 2009, 2015, and 2016 was 60.8%, 50.2%, 37.7%, and 34.6%, respectively (P trend <.001, from 2002 to 2015). The prevalence of active HCV in 2002, 2009, 2015, and 2016 was 54.0%, 34.0%, 22.1%, and 11.7%, respectively (P trend <.001). The anti-HCV treatment uptake in 2002, 2009, 2015, and 2016 was 23.0%, 48.0%, 59.3%, and 74.7%, respectively (P trend <.001). In 2016, HCV-related cirrhosis was present in 7.6% of all HIV-infected individuals, 15.0% of patients with active HCV, and 31.5% of patients who cleared HCV after anti-HCV therapy. Conclusions: Our findings suggest that with universal access to DAA-based therapy and continued efforts in prevention and screening, it will be possible to eliminate active HCV among HIV-infected individuals in Spain in the short term. However, the burden of HCV-related cirrhosis will continue to be significant among HIV-infected individuals.This work was funded by grant Ref. no. GLD14-00279 from the GILEAD Fellowship Programme (Spain) and by the Spanish AIDS Research Network (RD16/0025/0017, RD16/0025/0018) that is included in the Spanish I+D+I Plan and is co-financed by ISCIII-Subdirección General de Evaluacion and European Funding for Regional Development (FEDER).S

Healthcare workers hospitalized due to COVID-19 have no higher risk of death than general population. Data from the Spanish SEMI-COVID-19 Registry

Aim To determine whether healthcare workers (HCW) hospitalized in Spain due to COVID-19 have a worse prognosis than non-healthcare workers (NHCW). Methods Observational cohort study based on the SEMI-COVID-19 Registry, a nationwide registry that collects sociodemographic, clinical, laboratory, and treatment data on patients hospitalised with COVID-19 in Spain. Patients aged 20-65 years were selected. A multivariate logistic regression model was performed to identify factors associated with mortality. Results As of 22 May 2020, 4393 patients were included, of whom 419 (9.5%) were HCW. Median (interquartile range) age of HCW was 52 (15) years and 62.4% were women. Prevalence of comorbidities and severe radiological findings upon admission were less frequent in HCW. There were no difference in need of respiratory support and admission to intensive care unit, but occurrence of sepsis and in-hospital mortality was lower in HCW (1.7% vs. 3.9%; p = 0.024 and 0.7% vs. 4.8%; p<0.001 respectively). Age, male sex and comorbidity, were independently associated with higher in-hospital mortality and healthcare working with lower mortality (OR 0.211, 95%CI 0.067-0.667, p = 0.008). 30-days survival was higher in HCW (0.968 vs. 0.851 p<0.001). Conclusions Hospitalized COVID-19 HCW had fewer comorbidities and a better prognosis than NHCW. Our results suggest that professional exposure to COVID-19 in HCW does not carry more clinical severity nor mortality

Human Immunodeficiency Virus/Hepatits C Virus Coinfection in Spain: Elimination Is Feasible, but the Burden of Residual Cirrhosis Will Be Significant

Background. We assessed the prevalence of antibodies against hepatitis C virus (HCV-Abs) and active HCV infection in patients infected with human immunodeficiency virus (HIV) in Spain in 2016 and compared the results with those of similar studies performed in 2002, 2009, and 2015. Methods. The study was performed in 43 centers during October–November 2016. The sample was estimated for an accuracy of 2% and selected by proportional allocation and simple random sampling. During 2016, criteria for therapy based on direct-acting antiviral agents (DAA) were at least significant liver fibrosis, severe extrahepatic manifestations of HCV, and high risk of HCV transmissibility. Results. The reference population and the sample size were 38 904 and 1588 patients, respectively. The prevalence of HCV-Abs in 2002, 2009, 2015, and 2016 was 60.8%, 50.2%, 37.7%, and 34.6%, respectively (P trend <.001, from 2002 to 2015). The prevalence of active HCV in 2002, 2009, 2015, and 2016 was 54.0%, 34.0%, 22.1%, and 11.7%, respectively (P trend <.001). The anti-HCV treatment uptake in 2002, 2009, 2015, and 2016 was 23.0%, 48.0%, 59.3%, and 74.7%, respectively (P trend <.001). In 2016, HCV-related cirrhosis was present in 7.6% of all HIV-infected individuals, 15.0% of patients with active HCV, and 31.5% of patients who cleared HCV after anti-HCV therapy. Conclusions. Our findings suggest that with universal access to DAA-based therapy and continued efforts in prevention and screening, it will be possible to eliminate active HCV among HIV-infected individuals in Spain in the short term. However, the burden of HCV-related cirrhosis will continue to be significant among HIV-infected individuals.Fundación SEIMC-GESIDA, Madrid, Spain3.371 JCR (2018) Q2, 74/158 Immunology, 29/89 Infectious Diseases, 46/133 Microbiology1.480 SJR (2018) Q1, 64/378 Neurology (clinical), 77/381 OncologyNo data IDR 2018UE

Successful HCV Therapy Reduces Liver Disease Severity and Inflammation Biomarkers in HIV/HCV-Coinfected Patients With Advanced Cirrhosis: A Cohort Study.

Background: Eradication of hepatitis C virus (HCV) promotes an improvement in liver disease and the deactivation of the immune system. Here, we aimed to evaluate the changes in liver disease scores and plasma biomarkers following HCV clearance with direct-acting antivirals (DAAs) in HIV-infected patients with advanced HCV-related cirrhosis. Methods: We performed an observational study of 50 patients with advanced cirrhosis who received DAAs therapy. Variables were assessed at baseline and 48 weeks after HCV treatment completion. Epidemiological and clinical data were collected through an online form. Liver stiffness measurement (LSM), hepatic venous pressure gradient (HVPG), and Child-Pugh-Turcotte (CTP) were evaluated by physicians. Plasma biomarkers were measured by multiplex immunoassay. Results: We found significant decreases in severity scores of liver disease [LSM (q-value < 0.001), HVPG (q-value = 0.011), and CTP (q-value = 0.045)] and plasma biomarkers [LBP (q-value < 0.001), IP-10 (q-value < 0.001), IL-8 (q-value < 0.001), IL-18 (q-value < 0.001), IL-1RA (q-value = 0.013), OPG (q-value < 0.001), sVCAM-1 (q-value < 0.001), sICAM-1 (q-value < 0.001), PAI-1 (q-value = 0.001), and VEGF-A (q-value = 0.006)]. We also found a significant direct association between the change in LSM values and the change in values of LBP (q-value < 0.001), IP-10 (q-value < 0.001), MCP-1 (q-value = 0.008), IL-8 (q-value < 0.001), IL-18 (q-value < 0.001), OPG (q-value = 0.004), sVCAM-1 (q-value < 0.001), sICAM-1 (q-value < 0.001), and PAI-1 (q-value = 0.002). For CTP values, we found significant positive associations with IP-10 (q-value = 0.010), IL-6 (q-value = 0.010), IL-1RA (q-value = 0.033), and sICAM-1 (q-value = 0.010). Conclusion: The HCV eradication with all-oral DAAs in HIV/HCV-coinfected patients with advanced cirrhosis promoted an improvement in the severity of advanced cirrhosis and plasma biomarkers (inflammation, coagulopathy, and angiogenesis). The decrease in plasma biomarkers was mainly related to the reduction in LSM values.This study was supported by grants from Instituto de Salud Carlos III (ISCII; Grant Numbers PI20/00474 and PI17/00657 to JB, PI20/00507 and PI17/00903 to JG-G, CP17CIII/00007 and PI18CIII/00028 to AJ-S, and PI20CIII/00004 and PI17CIII/00003 to SR). The study was also funded by the RD16CIII/0002/0002, RD16/0025/0017, and RD16/0025/0018 projects as part of the Plan Nacional R + D + I and cofunded by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER). JB is an investigator from the Programa de Intensificación de la Actividad Investigadora en el Sistema Nacional de Salud (I3SNS), Refs INT16/00100.S