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发表于 2004-10-24 02:49
Lamivudine
Lamivudine, a nucleoside analogue, competitively inhibits reverse transcriptase by competing with deoxycytidine triphosphate for incorporation into DNA chains, resulting in chain termination. The median effective concentration (EC50) of lamivudine for the treatment of HBV infection is 0.01--5.6 mol/L.
Numerous limited and 2 large multicenter, randomized, placebo-controlled trials have established the use of lamivudine for HBeAg-positive and HBeAg-negative individuals with CHB. The rates of HBeAg seroconversion to HBeAb were 16%--17% for subjects who received a 12-month course of lamivudine, 100 mg/day, compared with 4%--6% for subjects who received placebo. Although the rates of seroconversion were low, in a comparison of subjects who received lamivudine with subjects who received placebo, lamivudine (1) effectively suppressed HBV DNA to undetectable levels in 44% of subjects (vs. 16% of subjects), (2) normalized ALT levels in 41% of subjects (vs. 7% of subjects), and (c) improved necroinflammatory scores by >2 points in 49%--56% of subjects (vs. 23%--25% of subjects). The strongest predictor of response was the ALT level noted at baseline before the initiation of therapy. Higher rates of response to lamivudine correlated with higher pretreatment levels of ALT. Seroconversion appears to be durable in 64%--77% of subjects at the end of 3 years of follow-up. The durability of response may be influenced by the continuation of lamivudine therapy after seroconversion. Recent data have suggested that continued treatment for 4--8 months after seroconversion leads to improved durability of response. This is likely related to the clearance of the HBV cccDNA reservoir, as discussed above.
Although the initial rates of response among HBeAg-negative subjects are high, long-term responses are infrequent. "Complete response," which was defined by loss of HBV DNA and ALT normalization, was 63% versus 6% for placebo recipients after 6 months of treatment with lamivudine, 100 mg/day. After 12 months of lamivudine therapy, the rate of complete response was 65%--74%. However, the durability of the responses, similar to the durability of the responses to IFN-α, was much lower. In fact, almost all patients experienced relapse after discontinuation of therapy, and most relapses occurred within the first 5 months after treatment was stopped.
In addition, HBV genotype and subtype appear to influence sustained response and resistance to lamivudine. Patients infected with HBV genotype B appear to have higher rates of response to lamivudine, and patients with HBV subtype ayw tend to have lower mean serum HBV DNA levels and less resistance to lamivudine, compared with patients with HBV subtype adw.
Prolonged lamivudine therapy increases the development of resistance to lamivudine. Mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV RNA--dependent DNA polymerase lead to resistance. Although prolonged therapy appears to increase the rate of HBeAg seroconversion from 17% to 27% among HBeAg-positive patients, resistance emerged in 38% of patients. In the long-term follow-up to the multicenter Asian trial that detected a rate of resistance of 14% at the end of 1 year of therapy, 38%, 49%, 66%, and 69% of subjects developed resistance to lamivudine at 2, 3, 4, and 5 years of therapy, respectively. A total of 19% of the subset of HBeAg-negative patients developed resistance to lamivudine after receiving therapy for 1 year, and resistance was seen among 44% of patients after 2 years of therapy.
Lamivudine is well tolerated, and the rate of associated adverse events was similar to that noted for placebo in randomized trials. The only major adverse event, which is not a drug toxicity per se, appears at the time of withdrawal of lamivudine and results in an increase in the HBV DNA level and the development of a hepatic flare. This syndrome has been best described in individuals with HIV-HBV coinfection, but it can also occur in monoinfected patients as well. Similarly, with the development of resistance and breakthrough viremia, this phenomenon can also occur.
In summary, because of its site of action in the life cycle of HBV, lamivudine does not affect cccDNA, and, consequently, it allows HBV to persist intracellularly until the host cell dies. Therefore, clearance of the infection relies on host defense mechanisms, as evidenced by the influence of baseline ALT levels on outcome. Prolonged therapy with lamivudine appears to improve rates of seroconversion and delay the progression of disease until resistance develops.
Adefovir dipivoxil (numerous adefovir reports of updated data can be found on NATAP website, use search engine)
Adefovir dipivoxil is the prodrug of adefovir, an acyclic phosphonated adenine nucleotide analogue. Intracellularly, adefovir dipivoxil undergoes 2 phosphorylation steps to compete with deoxyadenosine triphosphate to inhibit viral DNA polymerase and HBV reverse transcriptase, resulting in chain termination of DNA synthesis. Its EC50 for HBV is 0.2--2.5 mol/L. It may also have immunomodulatory effects by increasing natural killer cell activity and type I IFN induction.
Two large multicenter, randomized, double-blinded, placebo-controlled trials of adefovir dipivoxil have been reported, leading to approval of the drug by the US Food and Drug Administration in 2002. In a trial involving HBeAg-positive subjects with CHB, a comparison of subjects who received adefovir dipivoxil, 10 mg/day for 48 weeks, with subjects who received placebo revealed HBeAg seroconversion in 12% and 6% of subjects, histologic improvement in 53% and 25% of subjects, and undetectable HBV DNA levels in 21% and 0% of subjects, respectively. In a similarly designed trial involving HBeAg-negative patients with CHB, histologic improvement was noted in 64% of subjects who received adefovir dipivoxil versus 33% of subjects who received placebo, and undetectable serum HBV DNA levels were noted in 51% of subjects who received adefovir dipivoxil versus 0% of subjects who received placebo. In both trials, the long-term response rates while subjects were not receiving therapy were not reported; however, reemergence of viral replication would be expected because of incomplete suppression of the viral reservoir.
In contrast to findings regarding lamivudine therapy, mutations leading to clinical resistance were not detected during 2 years of adefovir dipivoxil therapy, although recent reports have identified mutations associated with virologic rebound after prolonged therapy. As the number and types of HBV therapies expand, adefovir dipivoxil may be useful in several areas. Its use for the treatment of lamivudine-resistant CHB has been promising. In clinical trials involving subjects with decompensated cirrhosis and in subjects after liver transplantation, adefovir dipivoxil was well tolerated, achieved significant reductions in HBV DNA levels, improved results of liver function tests, and improved Child-Pugh scores. Finally, HBV subtype adw appears to be intrinsically less responsive and more likely to develop resistance to lamivudine [61]. On the other hand, adefovir dipivoxil appears to be active for all HBV genotypes.
Adefovir dipivoxil, when administered in the 10-mg daily dose used for the treatment of HBV infection, appears to be relatively safe. In large trials, the adverse events associated with adefovir dipivoxil were similar to those noted in association with administration of placebo, except for the development of headache, asthenia, diarrhea, and abdominal pain. Events requiring discontinuation of therapy included increases in ALT or aspartate aminotransferase levels, weight loss, and rash. Although nephrotoxicity, which is seen in association with the higher doses of adefovir dipivoxil used for the treatment HIV infection, can still occur, it was not seen more frequently among subjects who received adefovir dipivoxil than among subjects who received placebo in pivotal clinical trials. When withdrawn, adefovir dipivoxil, like lamivudine, can also result in the development of a hepatic flare. In summary, although adefovir dipivoxil does not appear to be more potent than lamivudine, its advantages include treatment of infection due to the YMDD mutant, lamivudine-resistant HBV, and HBV genotypes that are less responsive to lamivudine, as well as a lower rate of resistance associated with long-term therapy.
NEW AGENTS UNDER DEVELOPMENT
A large number of agents that are the focus of preclinical and early clinical trials promise to enhance the effectiveness of the treatment options for CHB (table 1). When administered to treatment-naive subjects during phase 2 clinical trials, entecavir and telbivudine, 2 very potent and well-tolerated agents, have resulted in decreases of 5--6 log10 copies/mL in the plasma HBV DNA level after 48 weeks of therapy. Phase 3 trials of these and other promising agents are ongoing. Entecavir phase III studies are ongoing & study results are expected at AASLD in Oct 2004.
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