title: Revisiting liver disease progression in HIV/HCV-coinfected patients: the influence of vitamin D, insulin resistance, immune status, IL28B and PNPLA3.
abstract: OBJECTIVE
  To perform a comprehensive study on independent modulators of liver fibrosis progression and determinants of portal pressure considering immune status, insulin resistance (IR), serum 25-hydroxyvitamin D (25(OH)D) levels, genetic variants of patatin-like phospholipase domain-containing protein 3 (PNPLA3) and interleukin 28B (IL28B) in a thoroughly documented cohort of HIV/hepatitis C-coinfected (HIV/HCV) patients.
  
  
  METHODS
  25(OH)D deficiency (25(OH)DDEF), IR and low CD4(+) T-lymphocyte nadir (lowCD4NAD) were defined as 25(OH)D <20 ng × ml(-1) , HOMA-IR >2 and CD4nadir <200 cells × μl(-1) respectively. Liver fibrosis progression rate (FPR) was calculated as METAVIR F units divided by the number of years since HCV infection. Patients with a FPR > median FPR were assigned to the highFPR group.
  
  
  RESULTS
  Among 86 HIV/HCV, the median FPR was 0.167 units × years(-1) . While the prevalence of prior alcohol abuse, lowCD4NAD and 25(OH)DDEF was higher among highFPR patients, the prevalence of IR was comparable. The association between 25(OH)DDEF and FPR was confirmed in a subgroup of patients with METAVIR stage F0/F1/F2 in which 25(OH)D levels are not affected by the severity of liver disease. The distribution of IL28B C/C and PNPLA3 non-C/C was similar, while PNPLA3 G/G was exclusively observed in highFPR patients. LowCD4NAD (OR: 2.95; 95% CI: 1.05-8.24; P = 0.039) and 25(OH)DDEF (OR: 5.62; 95% CI: 2.05-15.38; P = 0.001) were independently associated with highFPR and showed an additive effect. Portal pressure correlated with prior alcohol abuse, HCV-genotype 3, CD4(+) nadir and 25(OH)D levels.
  
  
  CONCLUSIONS
  Two potentially modifiable factors, CD4(+) nadir and 25(OH)D levels, were both independent modulators of liver fibrosis progression and determinants of portal pressure. Further studies are warranted to assess the relevance of PNPLA3 for FPR in HIV/HCV.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna HIV & Liver Study Group, Vienna, Austria.
authors.forename: Mattias
authors.initials: M
authors.lastname: Mandorfer
authors.forename: Berit A
authors.initials: BA
authors.lastname: Payer
authors.forename: Philipp
authors.initials: P
authors.lastname: Schwabl
authors.forename: Sebastian
authors.initials: S
authors.lastname: Steiner
authors.forename: Arnulf
authors.initials: A
authors.lastname: Ferlitsch
authors.forename: Maximilian C
authors.initials: MC
authors.lastname: Aichelburg
authors.forename: Albert F
authors.initials: AF
authors.lastname: Stättermayer
authors.forename: Peter
authors.initials: P
authors.lastname: Ferenci
authors.forename: Barbara
authors.initials: B
authors.lastname: Obermayer-Pietsch
authors.forename: Katharina
authors.initials: K
authors.lastname: Grabmeier-Pfistershammer
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.forename: Markus
authors.initials: M
authors.lastname: Peck-Radosavljevic
authors.forename: Thomas
authors.initials: T
authors.lastname: Reiberger
mesh_terms: D000328:Adult; D060085:Coinfection / Q000276:immunology / Q000821:virology; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006678:HIV; D015658:HIV Infections / Q000150:complications / Q000276:immunology*; D006526:Hepatitis C; D019698:Hepatitis C, Chronic / Q000150:complications / Q000276:immunology*; D006801:Humans; D007333:Insulin Resistance; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008049:Lipase / Q000235:genetics*; D008099:Liver / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000150:complications / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D015999:Multivariate Analysis; D017082:Portal Pressure; D012189:Retrospective Studies; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood; D000095022:Interferon Lambda; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D007372:Interferons; D007378:Interleukins; D008049:Lipase; D008565:Membrane Proteins; D014807:Vitamin D; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C104450:25-hydroxyvitamin D; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
keywords: chronic hepatitis C; cirrhosis; human immunodeficiency virus; liver fibrosis; portal hypertension