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Background: Hepatitis B virus (HBV) infection is a major global health problem leading to severe liver diseases such as cirrhosis and hepatocellular carcinoma. Tenofovir Disoproxil Fumarate (TDF) is an orally bioavailable prodrug of Tenofovir. This study aimed to evaluate the efficacy and safety of long-term TDF therapy in Egyptian Chronic Hepatitis B patients, Objective: Assessment of effectiveness and safety of TDF therapy in Egyptian HBV patients. Materials and Methods: HBV was confirmed by detection of both HBsAg and HBV DNA. All patients were given antiviral drug (300 mg TDF, oral, once a day for 3 months). Results: Before treatment; HBV Patients showed significant elevation in Ferritin, Albumin, S. Creatinine, AST, ALT, PO4, INR, and PT compared to the healthy volunteers’ group. Additionally showed a decrease in AFP, DB, TB, PC, PLT, and WBCs again in comparison to the control group. After receiving HBV TDF, the same group of patients showed a significant increase in Ferritin, S. Creatinine, TB, PC, WBCs, and Hb% and a significant decrease in PO4, Albumin, INR, and PT compared to pre-treatment conditions. Conclusion: we show clear benefits of TDF therapy in ethnically diverse CHB populations, even among patients with only mild/moderate liver disease at baseline.