Background:  Chronic liver disease in HIV⁺ patients is generally associated to chronic hepatitis B or C virus (HBV, HCV) or alcohol abuse. The availability of non-invasive tools to assess liver fibrosis has allowed the identification of individuals in whom liver disease is an unexpected finding.

Methods:  All HIV⁺ patients on follow-up at our institution in 2005 underwent liver fibrosis assessment using elastometry (FibroScan). Advanced liver fibrosis was defined as F2-F4 Metavir score estimates (stiffness >9.5 kPa), being liver cirrhosis (F4) considered for stiffness >14 kPa. Patients with positive serum HCV RNA, HBV DNA, HBsAg, or current or past alcohol abuse were excluded. Likewise, records of patients with iron or copper overload, a1-antitrypsin deficiency or autoimmune diseases or those exposed to known hepatotoxic drugs were discarded.

Results:  A total of 1028 HIV⁺ patients lacking any known risk factor for liver disease were identified (72% men who have sex with men [MSM], 16% injecting drug users [IDU], 12% heterosexual). Overall, 24 (2.3%) showed advanced liver fibrosis ; and half of them (1.2%) were diagnosed as cirrhotic. In fact, 10 (0.9%) of these patients had already developed symptomatic liver disease, including ascites, gastrointestinal bleeding, and encephalopathy. Patients with advanced liver fibrosis were MSM (73%), IDU (13%), and persons infected by heterosexual contacts (14%). In univariate analysis, values for patients with and without advanced liver fibrosis were as follows:  age (49 vs 45 years, p = ns), female gender (27% vs 10%, p = 0.05), prior episodes of alanine aminotransferase (ALT) >100 IU/mL (16 vs 14%, p = ns), mean CD4 counts (533 vs 611 cells/mL, p = ns), peak glucose levels (131 vs 117 mg/dL, p = 0.008), and peak triglyceride levels (233 vs 188 mg/dL, p = ns). The effect of ART exposure was assessed in a subset of 136 randomly selected HIV⁺ individuals; a total of 935 patient-years of ART exposure were examined. Overall, exposure to nevirapine (NVP), efavirenz (EFV), and protease inhibitor (PI) was 56%, 43%, and 70%, respectively. Mean overall ART exposure was 7.3 vs 6.8 years in patients with and without advanced liver fibrosis, respectively (p = ns). However, a significant correlation was found between length of didanosine (ddI) exposure and liver fibrosis staging (ρ: 0.16; p = 0.04). An even stronger association was found for length of exposure to ddI plus stavudine (d4T) (ρ: 0.19; p = 0.02). No such association was found for other nucleoside reverse transcriptase inhibitor (NRTI), nor for NVP, EFV, or PI.

Conclusions:  Advanced liver fibrosis of unknown etiology can be seen in nearly 2% of HIV⁺ individuals, mostly MSM and heterosexual women. Prolonged exposure to ddI±d4T and high glucose levels, but not ALT elevations, might play a major role.