title: Liver fibrosis progression and clinical outcomes are intertwined: role of CD4+ T-cell count and NRTI exposure from a large cohort of HIV/HCV-coinfected patients with detectable HCV-RNA: A MASTER cohort study.
abstract: BACKGROUND
  Patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) suffer from faster progression of liver fibrosis (LF) and have greater risk of worse clinical outcomes. We evaluated predictors and incidence of these events in a large multicentre cohort.
  
  
  METHODS
  We selected all HIV-infected patients starting a first-line combination antiretroviral therapy (cART), with detectable HCV-RNA, without exposure to interferon/ribavirin, with ≥2 fibrosis-4 index (FIB-4) classifications before cART. Kaplan-Meier analysis was used to estimate incidence of clinical events (AIDS, non-AIDS related, deaths) and LF progression (via transitions: from FIB-4 class 1 to 2 or 3, from class 2 to class 3, and worsening by 0.5 point). Multivariate Cox regression was used to assess predictors, baseline, or time updated.
  
  
  RESULTS
  One thousand four hundred thirty-three patients were selected. Overall, 745 clinical events occurred, with an incidence of 7.6% over 9811 person-year of follow-up (PYFU) and a median survival time of 9.36 years. Incidence of LF progression from FIB-4 class 1 to 2 or 3 was 12.4%, and from FIB-4 class 2 to 3 was 7% with a median survival time of 5.67 and 10.35 years, respectively. At multivariate analyses, intravenous drug use and time-updated gamma-glutamyl transferase (γGT) were negative predictors for any outcomes, either clinical or FIB-4 progression. Higher CD4+ T-cell protected from clinical events, and lower HIV-RNA and higher CD4+ T-cell appeared to protect from FIB-4 transitions. Moreover, independently from the viro-immunological status, current FIB-4 class 3 predicted clinical events. Occurrence of AIDS and cardiovascular/kidney events were significant predictors of 0.5 point worsening and transitions of FIB-4, respectively. Prolonged exposure to nucleos(t)ide reverse transcriptase inhibitors (NRTI) was a negative predictor for any outcomes.
  
  
  CONCLUSIONS
  Both clinical and LF progression in HIV/HCV-coinfected patients depend strongly on immune status. Intravenous drug users and patients with high γGT (a possible proxy for alcohol abuse) are most-at-risk for both outcomes, as well those who had prolonged exposures to the NRTI class. Therefore, these patients should be prioritized for the access to anti-HCV therapy and a test-and-treat strategy should be implemented for early initiation of cART. Possible benefits of NRTI sparing regimens in HIV/HCV-coinfected patients should be investigated.
authors.affiliation: University Department of Infectious and Tropical Diseases, University of Brescia and Brescia Spedali Civili General Hospital, Brescia Clinic of Infectious Diseases, "San Gerardo de' Tintori" Hospital, Monza, Italy Department of Epidemiology, College of Public Health and Health Professions & College of Medicine, University of Florida, Gainesville, FL Clinic of Infectious Diseases of "Papa Giovanni XXIII" Hospital, Bergamo Institute of Clinical Infectious Diseases of Catholic University of Sacred Heart, Rome Clinic of Infectious Diseases, University of Bari, Bari Clinic of Infectious Diseases of "Azienda Ospedaliera SM. Annunziata", Firenze Clinic of Infectious Diseases of "Azienda Ospedaliera S. Anna", Ferrara Clinic of Infectious Diseases of "Istituti Ospitalieri", Cremona Infectious Diseases Unit, University "Magna Graecia", Catanzaro, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Focà
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Fabbiani
authors.forename: Mattia
authors.initials: M
authors.lastname: Prosperi
authors.forename: Eugenia
authors.initials: E
authors.lastname: Quiros Roldan
authors.forename: Francesco
authors.initials: F
authors.lastname: Castelli
authors.forename: Franco
authors.initials: F
authors.lastname: Maggiolo
authors.forename: Elisa
authors.initials: E
authors.lastname: Di Filippo
authors.forename: Simona
authors.initials: S
authors.lastname: Di Giambenedetto
authors.forename: Roberta
authors.initials: R
authors.lastname: Gagliardini
authors.forename: Annalisa
authors.initials: A
authors.lastname: Saracino
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Pietro
authors.forename: Andrea
authors.initials: A
authors.lastname: Gori
authors.forename: Laura
authors.initials: L
authors.lastname: Sighinolfi
authors.forename: Angelo
authors.initials: A
authors.lastname: Pan
authors.forename: Maria Concetta
authors.initials: MC
authors.lastname: Postorino
authors.forename: Carlo
authors.initials: C
authors.lastname: Torti
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D060085:Coinfection; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy; D006526:Hepatitis C / Q000150:complications* / Q000188:drug therapy; D006801:Humans; D015994:Incidence; D007372:Interferons / Q000008:administration & dosage; D053208:Kaplan-Meier Estimate; D008103:Liver Cirrhosis / Q000401:mortality / Q000821:virology*; D008137:Longitudinal Studies; D008297:Male; D012367:RNA, Viral / Q000032:analysis; D012189:Retrospective Studies; D012254:Ribavirin / Q000008:administration & dosage; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D012367:RNA, Viral; D012254:Ribavirin; D007372:Interferons