Enhanced Liver Fibrosis Marker as a Noninvasive Predictor of Mortality in HIV/Hepatitis C Virus-coinfected Women From a Multicenter Study of Women With or at Risk for HIV

Marion G. Peters; Peter Bacchetti; Ross Boylan; Audrey L. French; Phyllis C. Tien; Michael W. Plankey; Marshall J. Glesby; Michael Augenbraun; Elizabeth T. Golub; Roksana Karim; Julie Parkes; William Rosenberg


AIDS. 2016;30(5):723-729. 

In This Article

Abstract and Introduction


Objective: Coinfection with hepatitis C virus (HCV) is a major cause of morbidity and mortality among individuals with HIV. Our objective was to assess the prognostic performance of noninvasive measures of liver fibrosis in predicting all-cause mortality in women with HIV/HCV coinfection.

Design: We studied HCV/HIV coinfected women enrolled in the prospective, multicenter Women's Interagency HIV Study. Aspartate aminotransferase to platelet ratio and FIB-4 were used to identify women without fibrosis at all visits and women who progressed to severe fibrosis.

Methods: Enhanced liver fibrosis (ELF), which utilizes direct measures of fibrosis, hyaluronic acid, procollagen III aminoterminal peptide and tissue inhibitor of matrix metalloproteinase was performed.

Results: Included were 381 women with 2296 ELF measurements, with mean follow-up 8.3 ± 3.3 years. There were 134 deaths (60% with severe liver fibrosis). Receiver operator characteristic curves at fixed time windows prior to death or at end of follow-up showed that ELF was best at predicting mortality when tested within a year of death (area under the curve for ELF 0.85 vs. APRI 0.69, P < 0.0001 and vs. FIB-4 0.75, P = 0.0036); and 1–3 years prior (ELF 0.71 vs. APRI 0.61, P = 0.005 and vs. FIB-4 0.65, P = 0.06). Use of all three measures did not improve on ELF alone. In multivariate logistic regression models controlling for CD4+ cell count, HIV viral load, antiretroviral use and age, ELF continued to perform better than APRI and FIB-4.

Conclusion: ELF predicted all-cause mortality and was superior to APRI and FIB-4 in HIV/HCV coinfected women.


Coinfection with hepatitis C virus (HCV) leads to significant morbidity and mortality in HIV-infected individuals.[1] Assessment of liver disease severity, including the degree of hepatic fibrosis, is important in counseling patients with HCV and determining the need for treatment. Efforts have focused on the identification of noninvasive methods of assessing fibrosis that avoid the limitations of liver biopsy, which is costly, invasive and does not always stage fibrosis accurately.[2,3] Noninvasive methods include serum markers and transient elastography. Transient elastography has been shown to predict mortality in HIV/HCV-coinfected patients but cannot be studied retrospectively.[4,5] We have previously found that both aspartate aminotransferase (AST) to platelet ratio (APRI) and FIB-4 are independently associated with all-cause mortality in HIV/HCV-coinfected women in Women's Interagency HIV Study (WIHS).[6] Although both tests are readily available, they are less sensitive and not specific as they lack biological plausibility as they measure markers of inflammation [alanine aminotransferase (ALT), AST] and platelets rather than so-called 'direct markers' of fibrosis, components of liver matrix and mediators of matrix remodeling. These latter components are incorporated in the enhanced liver fibrosis test, which uses hyaluronic acid, procollagen III aminoterminal peptide (PIIINP) and tissue inhibitor of matrix metalloproteinase (TIMP-1).[7,8] The aim of this study was to assess the performance of enhanced liver fibrosis (ELF) relative to other noninvasive markers in predicting all-cause mortality in women with HIV and HCV coinfection. We chose ELF as it has been validated in HCV monoinfection and other chronic liver diseases; it utilizes direct measures of extra cellular matrix components as noted above; and it has not yet been studied in HIV-infected individuals.[7,9] Accurate serum markers of fibrosis in HIV and HCV coinfection would allow for more frequent measurements without requiring invasive and costly procedures. We chose all-cause mortality as prior work noted that death certificates have significant limitations and liver disease may have been the underlying or contributing cause of septic death, renal death or multisystem organ failure.[6]