Adefovir currently in clinical use is a precursor of adefovir, which is hydrolyzed in vivo to adefovir for antiviral action. Adefovir is an acyclic analogue of deoxyadenosine 5′-monophosphate. A randomized double-blind placebo-controlled clinical trial showed that oral adefovir significantly inhibited HBV DNA replication in HBeAg-positive patients with chronic hepatitis B. The rates of HBV DNA conversion (<1000 copies/ml) were 28%, 45% and 56% at 1, 2 and 3 years of application, respectively, and the rates of HBeAg serological conversion were 12%, 29% and 43%, respectively; the incidence of drug resistance The incidence of drug resistance was 0%, 1.6% and 3.1% respectively; the incidence of drug resistance in HBeAg-negative patients at 1, 2 and 3 years of treatment was 0%, 3.0% and 5.9%-11% respectively. The drug is effective in both compensated and decompensated cirrhotic patients with lamivudine resistance variants. At higher doses, there is some nephrotoxicity, mainly in the form of increased serum creatinine and decreased blood phosphorus, but the effect on renal function is less at a dose of 10 mg daily, and at 48-96 weeks of treatment, serum creatinine rises by >0.5 mg/dl (44.2 μmol/L) from baseline in about 2-3% of patients. Therefore, serum creatinine and blood phosphorus should be monitored regularly in patients treated with adefovir. Adefovir has been approved by the SFDA for the treatment of chronic hepatitis B. Its indication is for adult patients with chronic hepatitis B with compensated liver function. This drug is especially suitable for those who need long-term medication or have lamivudine resistance. Pharmacology and Toxicology】 Pharmacology Mechanism of Action: Adefovir is an acyclic nucleoside analogue of adenosine monophosphate, which is phosphorylated into an active metabolite, adefovir diphosphate, by the action of cellular kinase. Adefovir diphosphate inhibits HBV DNA polymutase (reverse transcriptase) in two ways; either by competing with the natural substrate deoxyadenosine triphosphate, or by causing DNA strand lengthening and termination upon integration into viral DNA. The inhibition constant (Ki) of adefovir diphosphate against HBV DNA polymutase was 0.1 μM, but the inhibition of human DNA polymutase α and γ was weaker with Ki values of 1.18 μM and 0.97 μM, respectively. Antiviral activity: In human hepatoma cell lines transfected with HBV, the concentration of adefovir that inhibited 50% viral DNA replication (IC50) was 0.2 to 2.5 uM. Drug resistance: Long-term resistance analysis (96 to 144 weeks) was performed in patients with detectable serum HBV DNA despite treatment with adefovir, and rtN236T and rtA181V variants were determined to be associated with adefovir resistance. In vitro studies found that the rtN236T variant resulted in a 4- to 14-fold reduction in HBV susceptibility to adefovir, with rebound of serum HBV DNA in 6/6 patients who developed this variant. rtA181V variant resulted in a 2.5 to 3-fold reduction in HBV susceptibility to adefovir, with rebound occurring in 2/3 patients who developed this variant. The incidence of variants associated with adefovir resistance was 0% (0/629) at weeks 0-48, 2% (6/293) at weeks 49-96, 1.8% (3/163) at weeks 97-144, and a cumulative incidence of 3.9% over 3 years. Cross-resistance: Recombinant HBV variants containing lamivudine resistance-associated mutations (rtL_180M, rtM204I, rtM204V, rtL180M + rtM204V, rtV173L) on the HBV DNA polymutase gene were sensitive to adefovir in vitro. Adefovir also showed anti-HBV effects in patients containing lamivudine-resistant-associated mutant HBV with a median decrease in serum HBV DNA of 4.3 log10 copies/mL. HBV variants containing DNA polymutations (rtT128N and rtR153Q or rtW153Q, associated with hepatitis B immunoglobulin resistance) were sensitive to adefovir in vitro. In vitro studies showed that HBV expressing the rtN236T mutation associated with adefovir resistance was 2- to 3-fold less susceptible to lamivudine, while HBV with the rtA181V mutation associated with adefovir resistance was 3-fold less susceptible to lamivudine. Toxicological studies: Chronic toxicity: In animal studies, renal tubular nephropathy, characterized by histological changes and/or elevated urea nitrogen and serum creatinine, was the primary dose-limiting toxic response to adefovir. The exposure observed in animal studies where nephrotoxicity occurred was approximately 3 to 10 times greater than that at the recommended human therapeutic dose (10 mg/day). Genotoxicity: Adefovir was mutagenic in an in vitro mouse lymphocytoma assay (with or without metabolic activation). In human peripheral blood lymphocyte assays without metabolic activation, adefovir induced chromosomal aberrations. Adefovir mice had negative micronucleus test results and adefovir had negative Ames test results in the presence or absence of metabolic activation. Reproductive toxicity: No effect on fertility was seen in rats when exposure was approximately 19 times the exposure at the human therapeutic dose. No embryotoxic or teratogenic effects were seen in rats and rabbits given adefovir orally (at exposures approximately 23 and 40 times the human therapeutic dose of 10 mg/day, respectively). In pregnant rats given adefovir intravenously, the incidence of embryotoxicity and fetal malformations (generalized edema, eye vesicle depression, umbilical hernia and tail kink) was increased at doses that produced significant maternal toxicity (equivalent to 38 times human exposure). No adverse effects were seen at intravenous doses equal to 12 times the human exposure. Carcinogenicity: No carcinogenic effects were observed in mice and rats given adefovir orally at doses equivalent to 10 and 4 times the human exposure at therapeutic doses, respectively.