• HCV treatment
• HIV/HCV coinfection
• PBMCs
• RNA-seq
• gene expression
• liver stiffness
• sustained virological response

• Advanced cirrhosis
• Gene expression
• HIV/HCV coinfection
• Liver stiffness
• PBMCs
• RNA-seq

• Humans
• Transcriptome/genetics
• Coinfection/genetics
• Cross-Sectional Studies
• Leukocytes, Mononuclear
• HIV Infections/complications
• HIV Infections/genetics
• HIV Infections/pathology
• Liver Cirrhosis/complications
• Liver Cirrhosis/genetics
• Liver Cirrhosis/pathology
• Hypertension, Portal/genetics
• Hypertension, Portal/pathology
• Hepatitis C/complications
• Hepatitis C/genetics
• Elasticity Imaging Techniques
• Liver/pathology
• Vesicular Transport Proteins

• HIV infection
• Hepatitis C
• Liver fibrosis
• Liver stiffness
• Steatosis

• Chronic hepatitis C
• Cirrhosis
• DAAs therapy
• HCV elimination
• HIV
• Metabolomics

• SNPs
• TRPM5
• chronic hepatitis C
• cirrhosis
• hepatic fibrosis
• liver stiffness

• PI20CIII/00004 Instituto de Salud Carlos III
• CP17CIII/00007 Instituto de Salud Carlos III
• CP14CIII/00010 Instituto de Salud Carlos III

• MTHFR (C677T)
• SNPs (single nucleotide polymorphism)
• chronic hepatitis C
• cirrhosis
• hepatic fibrosis
• liver stiffness measure

• DARC
• chronic hepatitis C
• cirrhosis
• hepatic fibrosis
• liver stiffness
• single nucleotide polymorphisms

• Adult
• Duffy Blood-Group System/genetics
• Female
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/genetics
• Hepatitis C, Chronic/pathology
• Humans
• Liver/pathology
• Liver Cirrhosis/etiology
• Liver Cirrhosis/genetics
• Liver Cirrhosis/pathology
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Receptors, Cell Surface/genetics

Background: The myeloid-epithelial-reproductive tyrosine kinase (MERTK) is involved in hepatic steatosis, inflammation, and liver fibrosis. Here we evaluated the association between the MERTK rs4374383 single nucleotide polymorphism (SNP) and liver fibrosis progression in hepatitis C virus (HCV)-infected patients. Methods: We performed a retrospective study (repeated measures design) in 208 patients who had liver stiffness measurement (LSM), which was assessed using transient elastography. No patient had cirrhosis at baseline (LSM ≥ 12.5 kPa). Results: At baseline, 53.8% were male, the median age was 47.1 years, 13.5% reported a high intake of alcohol, 10.1% were prior injection drug users, 85.3% were infected with HCV genotype 1, and 22.6% had previously failed antiviral therapy (pegylated-interferon-alpha/ribavirin). During a median follow-up of 46.6 months, 26 patients developed cirrhosis. The rs4374383 G carriers had a higher risk of increasing LSM (adjusted arithmetic mean ratio (aAMR) = 1.14; p = 0.006) and a higher likelihood of having an increase in LSM greater than 5 kPa (ΔLSM ≥ 5 kPa) (adjusted odds ratio (aOR) = 2.37; p = 0.029), and greater than 7 kPa (ΔLSM ≥ 7 kPa) (aOR = 3.24; p = 0.032), after controlling for confounding. The SNP’s association with cirrhosis progression was close to statistical significance (aOR = 2.18; p = 0.070). Conclusions: MERTK rs4374383 A carriers had a lower risk of liver fibrosis progression than G carriers, supporting the hypothesis that this SNP seems to have a critical role in the pathogenesis of liver disease in HCV-infected patients.

• MERTK
• SNPs
• chronic hepatitis C
• cirrhosis
• liver stiffness

• AIDS
• Chronic hepatitis C
• Inflammation
• Liver fibrosis
• SNPs
• TNFAIP3

• Adenosine Deaminase/genetics
• Adult
• Coinfection/genetics
• Coinfection/virology
• Computer Simulation
• Female
• Gene Frequency
• Genetic Predisposition to Disease
• HIV Infections/genetics
• Haplotypes/genetics
• Hepatitis C, Chronic/genetics
• Humans
• Linkage Disequilibrium/genetics
• Liver Cirrhosis/genetics
• Male
• Polymorphism, Single Nucleotide/genetics
• RNA-Binding Proteins/genetics
• Severity of Illness Index

CXCL9-11 polymorphisms are related to various infectious diseases, including hepatitis C virus (HCV) infection. In this study, we analyzed the association between CXCL9-11 polymorphisms and liver fibrosis in HCV-infected patients.

We performed a cross-sectional study in 389 patients who were genotyped for CXCL9-11 polymorphisms (CXCL9 rs10336, CXCL10 rs3921, and CXCL11 rs4619915) using the Sequenom’s MassARRAY platform. The primary outcome variable was the liver stiffness measurement (LSM). We established three cut-offs of LSM: LSM ≥ 7.1 kPa (F ≥ 2—significant fibrosis), LSM ≥ 9.5 kPa (F ≥ 3—advanced fibrosis), and LSM ≥ 12.5 kPa (F4—cirrhosis).

Recessive, overdominant and codominant models of inheritance showed significant values, but the overdominant model was the best fitting our data. In this case, CXCL9 rs10336 AG, CXCL10 rs3921 CG and CXCL11 rs4619915 AG were mainly associated with lower values of LSM [(adjusted GMR (aGMR) = 0.85 (p = 0.005), aGMR = 0.84 (p = 0.003), and aGMR = 0.84 (p = 0.003), respectively]. Patients with CXCL9 rs10336 AG genotype had lower odds of significant fibrosis (LSM ≥ 7.1 kPa) [adjusted OR (aOR) = 0.59 (p = 0.016)], advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 0.54 (p = 0.010)], and cirrhosis (LSM ≥ 12.5 kPa) [aOR = 0.56 (p = 0.043)]. Patients with CXCL10 rs3921 CG or CXCL11 rs4619915 AG genotypes had lower odds of significant fibrosis (LSM ≥ 7.1 kPa) [adjusted OR (aOR) = 0.56 (p = 0.008)], advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 0.55 (p = 0.013)], and cirrhosis (LSM ≥ 12.5 kPa) [aOR = 0.57 (p = 0.051)]. Additionally, CXCL9-11 polymorphisms were related to lower liver stiffness under a codominant model of inheritance, being the heterozygous genotypes also protective against hepatic fibrosis. In the recessive inheritance model, the CXCL9 rs10336 AA, CXCL10 rs3921 CC and CXCL11 rs4619915 AA were associated with higher LSM values [(adjusted GMR (aGMR) = 1.19 (p = 0.030), aGMR = 1.21 (p = 0.023), and aGMR = 1.21 (p = 0.023), respectively]. Moreover, patients with CXCL9 rs10336 AA genotype had higher odds of significant fibrosis (LSM ≥ 7.1 kPa) [adjusted OR (aOR) = 1.83 (p = 0.044)] and advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 1.85 (p = 0.045)]. Furthermore, patients with CXCL10 rs3921 CC or CXCL11 rs4619915 AA genotypes had higher odds of advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 1.89 (p = 0.038)].

CXCL9-11 polymorphisms were related to likelihood of having liver fibrosis in HCV-infected patients. Our data suggest that CXCL9-11 polymorphisms may play a significant role against the progression of CHC and could help prioritize antiviral therapy.

• CXCL9-11
• Chronic hepatitis C
• Cirrhosis
• Liver fibrosis
• Liver stiffness
• SNPs

• AIDS
• Fibrosis
• HCV therapy
• SNPs
• TRIM22
• TRIM5

• Adult
• Antiviral Agents/therapeutic use
• Antiviral Restriction Factors
• Carrier Proteins/genetics
• Chemokines/blood
• Coinfection/drug therapy
• Coinfection/genetics
• Female
• Gene Frequency/genetics
• Genetic Association Studies
• Genetic Predisposition to Disease
• HIV Infections/blood
• HIV Infections/complications
• HIV Infections/genetics
• Haplotypes/genetics
• Hepacivirus/physiology
• Hepatitis C, Chronic/blood
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/genetics
• Humans
• Male
• Middle Aged
• Minor Histocompatibility Antigens/genetics
• Polymorphism, Single Nucleotide/genetics
• Repressor Proteins/genetics
• Tripartite Motif Proteins/genetics
• Ubiquitin-Protein Ligases

• Instituto de Salud Carlos III

• antiretroviral therapy
• clinical events
• fib-4
• hcv
• hiv
• liver fibrosis

• Adult
• Antiretroviral Therapy, Highly Active
• CD4 Lymphocyte Count
• Coinfection
• Disease Progression
• Female
• HIV Infections/complications
• HIV Infections/drug therapy
• Hepatitis C/complications
• Hepatitis C/drug therapy
• Humans
• Incidence
• Interferons/administration & dosage
• Kaplan-Meier Estimate
• Liver Cirrhosis/mortality
• Liver Cirrhosis/virology
• Longitudinal Studies
• Male
• RNA, Viral/analysis
• Retrospective Studies
• Ribavirin/administration & dosage
• Risk Factors
• Treatment Outcome

• HIV
• cohort study
• hepatitis C virus
• hepatocellular carcinoma
• liver disease

To evaluate the Fibrosis (FIB)-4 index as a predictor of major liver-related events (LRE) and liver-related death (LRD) in human immunodeficiency virus (HIV) type-1 patients initiating combination antiretroviral therapy (cART).

Retrospective analysis of a prospective cohort study.

Italian HIV care centers participating to the ICONA Foundation cohort.

Treatment-naive patients enrolled in ICONA were selected who: initiated cART, had hepatitis C virus (HCV) serology results, were HBsAg negative, had an available FIB-4 index at cART start and during follow up.

Cox regression models were used to determine the association of FIB4 with the risk of major LRE (gastrointestinal bleeding, ascites, hepatic encephalopathy, hepato-renal syndrome or hepatocellular carcinoma) or LRD.

Three-thousand four-hundred seventy-five patients were enrolled: 73.3% were males, 27.2% HCV seropositive. At baseline (time of cART initiation) their median age was 39 years, had a median CD4+ T cell count of 260 cells/uL, and median HIV RNA 4.9 log copies/mL, 65.9% had a FIB-4 <1.45, 26.4% 1.45–3.25 and 7.7% >3.25. Over a follow up of 18,662 person-years, 41 events were observed: 25 major LRE and 16 LRD (incidence rate, IR, 2.2 per 1,000 PYFU [95% confidence interval, CI 1.6–3.0]). IR was higher in HCV seropositives as compared to negatives (5.9 vs 0.5 per 1,000 PYFU). Higher baseline FIB-4 category as compared to <1.45 (FIB-4 1.45–3.25: HR 3.55, 95% CI 1.09–11.58; FIB-4>3.25: HR 4.25, 1.21–14.92) and time-updated FIB-4 (FIB-4 1.45–3.25: HR 3.40, 1.02–11.40; FIB-4>3.25: HR 21.24, 6.75–66.84) were independently predictive of major LRE/LRD, after adjusting for HIV- and HCV-related variables, alcohol consumption and type of cART.

The FIB-4 index at cART initiation, and its modification over time are risk factors for major LRE or LRD, independently of infection with HCV and could be used to monitor patients on cART.

• Fibroscan
• Human immunodeficiency virus/hepatitis C virus coinfection
• Liver biopsy
• Liver fibrosis
• Liver ultrasonography

• hiv/aids
• hepatic fibrosis
• chronic hepatitis c
• il7r
• snps

• Adult
• Coinfection/complications
• Coinfection/genetics
• Coinfection/virology
• Cross-Sectional Studies
• Female
• Genetic Association Studies
• Genetic Predisposition to Disease
• HIV
• HIV Infections/complications
• HIV Infections/epidemiology
• HIV Infections/genetics
• HIV Infections/virology
• Haplotypes/genetics
• Hepacivirus/physiology
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/epidemiology
• Hepatitis C, Chronic/genetics
• Hepatitis C, Chronic/virology
• Humans
• Linkage Disequilibrium/genetics
• Male
• Polymorphism, Single Nucleotide/genetics
• Receptors, Interleukin-7/genetics

• Acute-Phase Proteins
• Adult
• Anti-HIV Agents/pharmacology
• Anti-HIV Agents/therapeutic use
• Aspartate Aminotransferases/metabolism
• Biomarkers/blood
• Carrier Proteins/blood
• Coinfection/drug therapy
• Coinfection/immunology
• Coinfection/metabolism
• Coinfection/microbiology
• Female
• HIV Infections/drug therapy
• HIV Infections/immunology
• HIV Infections/metabolism
• HIV Infections/microbiology
• HIV-1/drug effects
• HIV-1/physiology
• Hepacivirus/drug effects
• Hepacivirus/physiology
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/immunology
• Hepatitis C, Chronic/metabolism
• Hepatitis C, Chronic/microbiology
• Humans
• Interferon-alpha/pharmacology
• Interferon-alpha/therapeutic use
• Kinetics
• Lipopolysaccharide Receptors/blood
• Lipopolysaccharide Receptors/chemistry
• Lipopolysaccharides/blood
• Male
• Membrane Glycoproteins/blood
• Middle Aged
• Retrospective Studies
• Ribavirin/pharmacology
• Ribavirin/therapeutic use
• Solubility
• Time Factors
• Treatment Outcome

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) share the same transmission routes; therefore, coinfection is frequent. An estimated 5-10 million individuals alone in the western world are infected with both viruses. The majority of people acquire HCV by injection drug use and, to a lesser extent, through blood transfusion and blood products. Recently, there has been an increase in HCV infections among men who have sex with men. In the context of effective antiretroviral treatment, liver-related deaths are now more common than Acquired Immune Deficiency Syndrome-related deaths among HIV-HCV coinfected individuals. Morbidity and mortality rates from chronic HCV infection will increase because the infection incidence peaked in the mid-1980s and because liver disease progresses slowly and is clinically silent to cirrhosis and end-stage-liver disease over a 15-20 year time period for 15%-20% of chronically infected individuals. HCV treatment has rapidly changed with the development of new direct-acting antiviral agents; therefore, cure rates have greatly improved because the new treatment regimens target different parts of the HCV life cycle. In this review, we focus on the epidemiology, diagnosis and the natural course of HCV as well as current and future strategies for HCV therapy in the context of HIV-HCV coinfection in the western world.

• Human immunodeficiency virus - hepatitis C virus coinfection
• Hepatitis C virus epidemiology
• Natural course of hepatitis C virus infection
• Hepatitis C virus treatment

• Antiviral Agents/therapeutic use
• Coinfection
• HIV Infections/diagnosis
• HIV Infections/drug therapy
• HIV Infections/epidemiology
• HIV Infections/transmission
• Hepatitis C, Chronic/diagnosis
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/epidemiology
• Hepatitis C, Chronic/transmission
• Humans
• Incidence
• Predictive Value of Tests
• Risk Assessment
• Risk Factors
• Time Factors
• Treatment Outcome

• HCV genotype 1
• HIV/HCV coinfection
• Protease inhibitors

• HIV
• hepatitis C virus
• liver transplantation

• Co-infection
• HIV
• Hepatitis C virus
• Human immunodeficiency virus
• Liver transplantation

• EuroSIDA
• HIV/HCV coinfection
• PEG-interferon
• ribavirin
• treatment completion

Metabolic abnormalities are common in HIV-infected individuals on antiretroviral therapy (ART), but the biochemical details and underlying mechanisms of these disorders have not been defined.

Untargeted metabolomic profiling of plasma was performed for 32 HIV patients with low nadir CD4 counts (<300 cells/ul) on protease inhibitor (PI)-based ART and 20 healthy controls using liquid or gas chromatography and mass spectrometry. Effects of Hepatitis C (HCV) co-infection and relationships between altered lipid metabolites and markers of inflammation, microbial translocation, and hepatic function were examined. Unsupervised hierarchical clustering, principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), Random forest, pathway mapping, and metabolite set enrichment analysis (MSEA) were performed using dChip, Metaboanalyst, and MSEA software.

A 35-metabolite signature mapping to lipid, amino acid, and nucleotide metabolism distinguished HIV patients with advanced disease on PI-based ART from controls regardless of HCV serostatus (p<0.05, false discovery rate (FDR)<0.1). Many altered lipids, including bile acids, sulfated steroids, polyunsaturated fatty acids, and eicosanoids, were ligands of nuclear receptors that regulate metabolism and inflammation. Distinct clusters of altered lipids correlated with markers of inflammation (interferon-α and interleukin-6), microbial translocation (lipopolysaccharide (LPS) and LPS-binding protein), and hepatic function (bilirubin) (p<0.05). Lipid alterations showed substantial overlap with those reported in non-alcoholic fatty liver disease (NALFD). Increased bile acids were associated with noninvasive markers of hepatic fibrosis (FIB-4, APRI, and YKL-40) and correlated with acylcarnitines, a marker of mitochondrial dysfunction.

Lipid alterations in HIV patients receiving PI-based ART are linked to markers of inflammation, microbial translocation, and hepatic function, suggesting that therapeutic strategies attenuating dysregulated innate immune activation and hepatic dysfunction may be beneficial for prevention and treatment of metabolic disorders in HIV patients.