Background:  Few data exist on liver histology and mitochondrial function in HIV-infected patients with chronic alanine aminotransferase/aspartate aminotransferase (ALT/AST) elevation of unknown origin.

Methods:  We investigated prospectively mitochondrial function and mitochondrial DNA (mtDNA) content in liver biopsies from HIV-infected patients with ALT elevation >upper limit of the normal range (ULN) for >6 months and treated with cART. Patients with chronic alcohol abuse, hepatitis C virus (HCV) or hepatitis B virus (HBV) co-infection, or autoimmune or genetic liver diseases were excluded. In a subgroup of 16 patients with available liver biopsies, mitochondrial respiratory chain (complexes I, II, and IV) and citrate synthase activities were evaluated in liver homogenates using spectrophotometric assays while the mtDNA was quantified by real-time polymerase chain reaction (RT-PCR).

Results:  We included 30 patients with a median age of 46 years (31 to 67), a median body mass ndex of 23 kg/m² (22 to 24), a viral load <200 copies/mL (200 to 94600) in 19 (63%) patients, and a median CD4 of 365/mm³ (204 to 921) at time of biopsy. The median duration of HIV infection was 13 years (9 to 15). The median exposure time to combination ART (cART) was:  118 months (83 to 133) for NRTI, 41 months (22 to 46) for NNRTI, and 53 months (36 to 90) for protease inhibitors (PI). The median ALT level was 80 U/L (68 to 135). Histologic abnormalities were found in 20 of 30 (67%) patients. Steatosis was present in 18 of 30 (60%) patients (mild [6% to 30%] in 9 patients and severe [>30%] in 9 patients) and was associated with concomitant lobular inflammation and/or hepatocellular ballooning in 16 of 18 patients consistent with the diagnosis of NASH according to the NAS score. Liver fibrosis was found in 18 of 30 patients:  13 patients as F1 and 5 patients as ≥F2, including 3 patients with cirrhosis (Metavir score). Compared to patients without NASH, patients with NASH had significantly higher fasting glucose levels (median 5.2 [5 to 5.5] mM/L NASH vs 4.9 [4.4 to 5.3]mM/L, p = 0.01) and fasting insulin levels (median 19.4 [14.7 to 32.8]mU/L vs 10.9 [8.7 to 14.4]mU/L, p = 0.007). In the subgroup of sixteen patients, 9 were classified as NASH. Between patients with and without NASH, respectively, no significant difference in mitochondrial function (complex IV activity:  94 [43 to 136] vs 76 [26 to 92]nM/min·mg of protein) and liver mtDNA amount (median 6920 [3684 to 19,893] vs 5584 [4113 to 27,472] copies/cells) was observed.

Conclusions:  HIV-infected patients on cART with chronic ALT elevation have a high rate of liver lesions with predominant histologic patterns of NASH related to insulin resistance. Despite long exposure to cART, in our population, the liver abnormalities may not account to mitochondrial dysfunction.