Emergence of predominant adefovir resistant mutation during additive lamivudine therapy for adefovir resistance in chronic hepatitis B patients with prior resistance to laminudine

Abstract

Background and Aim : Lamivudine(LAM) is commonly used for the treatment of chronic hepatitis B(CHB) as a first-line antiviral agent. Adefovirdipivoxil(ADV) therapy is effective, but viral resistance is common in LAM resistant patients. It has been reported that sequential treatment of antiviral agents may increase the risk of viral resistance to multiple agents. Antiviral efficacy of additive LAM treatment for ADV resistance in patients with prior LAM resistance is uncertain. We investigated virologic response and emerging pattern of resistant mutations during administration of additive LAM therapy for ADV resistance in chronic hepatitis B patients with prior resistance to LAM.

Patients and Methods: Ten patients of CHB with an additive LAM therapy for at least 6 months in addition to ongoing ADV treatment were included (M/F:9/1, mean age 47.8 yrs, HBeAg7 cases , HBeAg-3 cases). All of them have received LMV and ADV monotherapy sequentially. Laboratory tests including HBV-DNA level (real-time PCR) and ADV-resistant mutation(RFMP) were performed in stored sera at the start of ADV and every 3 months thereafter. Virologic response was defined as HBV-DNA <5log10 copies/ml or decrease in HBV-DNA by >2log10 copies/ml, and viral breakthrough as an increase in HBV-DNA level >1 log10 from the nadir in virologic responders.

Results : All the patients except one had liver cirrhosis, and two of them had hepatocellular carcinoma. All of them revealed YMDD mutation(5 YIDD cases, 3 YVDD cases, and 1 mixed case) during prior LAM therapy. After commencement of ADV monotherapy for the LAM resistance, YMDD mutations were not detected by RFMP. The patients showed viral resistance to ADV with emergence of ADV resistant mutations(rtA181V/T in 7 cases, rtN236T in 1 case) as a mixed pattern of mutant and wild type. LAM was started in addition to ongoing ADV therapy. Mean follow up period of the additive LAM therapy was 9.6 months. Two HBeAg-negative patients showed viral response with ALT normalization. However, 8 patients did not achieve viral response at all. ADV resistant mutations persisted as a predominant pattern in 6 patients among the 8 non-responders. ALT level was increasing during the additive LAM treatment in non-responders, 2 of them showed ALT flare (>5 times UNL) with clinical deterioration. Three patients were switched to tenofovir/LAM for salvage therapy.

Conclusion: Additive LAM therapy for ADV resistance may potentiate pre-existing ADV resistant mutation which developed during the sequential treatment of ADV monotherapy for LMV resistance. ADV resistant mutation might be selected as a predominant pattern during the sequential antiviral treatment.