Changes in Mitochondrial Toxicity in Peripheral Blood Mononuclear Cells During Four-Year Administration of Entecavir Monotherapy in Chinese Patients with Chronic Hepatitis B

BACKGROUND: This study aimed to assess whether long-term entecavir monotherapy induces mitochondrial toxicity in patients with chronic hepatitis B (CHB). MATERIAL/METHODS: This was a prospective study in 34 antiviral treatment-naïve patients with CHB who received entecavir monotherapy and were followed up for 4 years. Blood samples were collected after 0, 2, 3, and 4 years of entecavir (ETC) monotherapy (ETC0, ETC2, ETC3, and ETC4, respectively). Mitochondrial DNA (mtDNA) contents were determined using real-time quantitative polymerase chain reaction (qRT-PCR) and mtDNA(4977) depletions were detected using nested PCR. Levels of hepatitis B virus (HBV) DNA, alanine aminotransferase, alanine aminotransferase, hepatitis B e antigen (HBeAg), creatine kinase, urea nitrogen, and serum creatinine were recorded. RESULTS: mtDNA contents at ETC0 (9.6±6.3) and ETC4 (10.3±6.2) were markedly higher than at ETC2 (0.8±0.5, P<0.01) and ETC3 (1.3±0.9, P<0.01), but there were no differences between ETC2 and ETC3 or between ETC0 and ETC4. MtDNA(4977) depletion appeared in 79.4% cases at ETC2 and in 70.6% at ETC3, which were much higher than at ETC0 (32.4%, P<0.01) and ETC4 (8.8%, P<0.01), but there were no differences in mtDNA(4977) depletion ratio between ETC2 and ETC3, or between ETC0 and ETC4. mtDNA content was negatively correlated to mtDNA(4977) depletion (partial regression coefficient of −4.555, P<0.001, R(2)=0.315). mtDNA content was positively correlated with age (partial regression coefficient of 0.131, P=0.045). CONCLUSIONS: Results suggest that during 4-year entecavir monotherapy for CHB, the mtDNA contents initially decreased and then increased, while the mtDNA(4977) depletion rates first increased and then decreased.