Entecavir resistance

Colonno RJ, Rose R, Baldick CJ, Levine S, Pokomowski K, Yu CF, Walsh A, Fang J, Hsu M, Mazzucco C, Eggers B, Zhang S, Plym M, Klesczewski K, Tenney DJ (2006) Entecavir resistance is rare in nucleoside naive patients with hepatitis B, Hepatology 44 1656-1665... 

Lamivudine resistance Adefovir resistance Entecavir resistance Telbivudine resistance... 

Patients who develop resistance to lamivudine have significant improvement in histology while receiving entecavir, but higher doses (1 mg daily) are required. Additionally, 19% of lamivudine-resistant patients had undetectable HBV DNA levels compared to 1% of those who continued treatment with lamivudine.36 At present, no resistance has been associated with entecavir in patients treated for 1 year, but the data beyond 1 year of therapy are unknown. Entecavir resistance has only been seen in patients who already had lamivudine resistance.37... 

The 5 -triphosphate metabolite of entecavir has been shown to accumulate in-tracellularly at concentrations that are inhibitory to 3TC-resistant HBV DNA polymerase (Levine et al. 2002). This would imply that entecavir should be active against HBV infections that have become resistant to treatment with lamivudine. Yet, it should be taken into account that treatment with lamivudine leads to the same... 

Although lamivudine results in rapid and potent virus suppression, chronic therapy may ultimately be limited by the emergence of lamivudine-resistant HBV isolates (eg, L180M or M204I/V), estimated at 15-30% at 1 year and 70% at 5 years of therapy. Resistance has been associated with flares of hepatitis and progressive liver disease. Cross-resistance between lamivudine and emtricitabine or entecavir may occur however, adefovir maintains activity against lamivudine-resistant strains of HBV. 

Entecavir is a guanosine nucleoside with strong antiviral activity. It is also effective in lamivudine-resistant patients. After 48 weeks of treatment comprising a daily dose of 0.5 or 1.0 mg, there was elimination of HBV DNA in 25 — 30% and normalization of the transaminases in 60—70% of lamivudine-resistant patients. Tolerance is good. Entecavir-induced mutants were not detected. (173)... 

The therapeutic armementarium in this field is enlarging with promising results but at the expense of viral resistance and cost.The drugs used in HBV treatment are mainly interferons (mostly pegylated), and nucleos(t)ide analogs (Lamivudine, Adefovir and the more recent ones Telbivudine, Entecavir and Tenofovir). Different... 

MECHANISMS OE ACTION AND RESISTANCE Lamivudine triphosphate potently inhibits the DNA polymerase/reverse transcriptase of HBV. Lamivudine has enhanced antiviral activity against hepadnaviruses when combined with adefovir or penciclovir. Point mutations in the HBV DNA polymerase markedly reduce sensitivity. Lamivudine resistance confers cross-resistance to agents such as emtricitabine and is often associated with an additional mutation that confers cross-resistance to famciclovir. Lamivudine-resistant HBV retains susceptibility to adefovir and partially to entecavir. Viruses bearing certain mutations are less replication competent than wild-type HBV, but lamivudine resistance is associated with elevated HBV DNA levels, decreased likelihood of HbeAg loss or seroconversion, hepatitis exacerbations, and progressive fibrosis and graft loss in transplant recipients. 

The approval of the nncleotide and nucleoside analogs 1-5 marked a significant advance in the treatment of chronic hepatitis B. In comparison to compounds 2-5, entecavir (1) is a novel carbocychc nucleoside analog with potent and highly selective activity against HBV, as well as a low rate of resistance. In this chapter, the pharmacological profile and syntheses of entecavir (1) will be profiled in detail. 

Entecavir (1) is a potent inhibitor of HBV replication. It is active against lamivudine (2)-resistant HBV and also offers the convenience of once daily dosing and a favorable safety profile. 

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