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Pegylated IFN-α2b added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B

World Journal of Gastroenterology 2006年第15期12卷 2417-2422页

作者： Themistoklis Vassiliadis Kalliopi Patsiaoura Konstantinos Tziomalos Theodoros Gkiourtzis Olga Giouleme Nikolaos Grammatikos Despoina Rizopoulou Nikolaos Nikolaidis Panagiotis Katsinelos Eleni Orfanou-Koumerkeridou Nikolaos Eugenidis 2nd Propaedeutic Department of Internal Medicine Aristotle University of Thessaloniki Hippokration General HospitalThessalonikiGreece Department of Pathology Hippokration General Hospital ThessalonikiGreece 4th Department of Internal Medicine Aristotle University of Thessaloniki Hippokration General HospitalThessalonikiGreece

AIM： To investigate the role of pegylated-interferon （IFN）α-2b in the management of patients with lamivudineresistant chronic hepatitis B. METHODS： Twenty consecutive anti-HBe positive patients were treated with pegylated IFN α-2b （100 IJg sc once weekly） for 12 mo. There was no interruption in lamivudine therapy. Hematology, liver biochemistry, serum HBV DNA levels were detected by PCR, and vital signs were also assessed. Liver histology was assessed in some patients at entry and at wk 52 for comparison. RESULTS： Nine patients （45%） had a partial virological end-treatment response; seven patients （35%） showed complete virological end-treatment response. Eight patients （40%） showed biochemical end-treatment response. There was a trend for higher virological response rates in patients who had previously responded to IFN and relapsed compared to IFN non-responders （four out of seven patients vs none out of six patients, respectively; P=0.1）. Patients without virological endtreatment response showed significant worsening of fibrosis [median score 2 （range, 1 to 3） vs median score 3 （range, 1 to 4）], in the first and second biopsy respectively （P=0.014）, whereas necroinflammatory activity was not significantly affected. Patients with complete or partial virological end-treatment response did not show any significant changes in histological findings, possibly due to the small number of patients with paired biopsies （n = 5）. Nevertheless, after 12 mo of follow-up, only onepatient （5%） showed sustained virological response and only 2 patients （10%） showed sustained biochemical response. Two patients （10%） discontinued pegylated ]FN both after 6 mo of treatment due to flu-like symptoms. CONCLUSION： Pegylated IFNα-2b, when added to ongoing lamivudine therapy in patients with lamivudineresistant chronic hepatitis B, induces sustained responses only in a small minority of cases.

关键词： Pegylated interferon lamivudine resistance HBeAg negative chronic hepatitis B Adefovir

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Hepatitis B virus infection and renal transplantation

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World Journal of Gastroenterology 2010年第31期16卷 3878-3887页

作者： Ming-Chao Tsai Yen-Ta Chen Yu-Shu Chien Tsung-Hui Hu Division of Hepato-Gas-troenterology Department of Internal MedicineChang Gung Memorial HospitalKaohsiung Medical CenterChang Gung University College of Medicine123Ta-Pei RoadNiao-Sung HsiangKaohsiung Hsien 833Taiwan China Department of Urology Chang Gung Memorial HospitalKaohsiung Medical CenterChang Gung University College of Medicine123Ta-Pei RoadNiao-Sung HsiangKaohsiung Hsien 833 TaiwanChina Division of Nephrology De-partment of Internal MedicineChang Gung Memorial HospitalKaohsiung Medical CenterChang Gung University College of Medicine123Ta-Pei RoadNiao-Sung HsiangKaohsiung Hsien 833Taiwan China

Although the prevalence of chronic hepatitis B virus (HBV) infection has declined in renal transplant recipients (RTRs), it remains a relevant clinical problem with high morbidity and mortality in long-term follow up. A thorough evaluation, including liver biopsy as well as assessment of HBV replication in serum (i.e. hepatitis B e antigen and/or HBV DNA) is required before transplantation. Interferon should not be used in this setting because of low efficacy and precipitation on acute allograft rejection. The advent of effective antiviral therapies offers the opportunity to prevent the progression of liver disease after renal transplantation. However, as far as we are aware, no studies have compared prophylactic and preemptive strategies. To date, the majority of RTRs with HBV-related liver disease have had a high virological and biochemical response to lamivudine use. However, lamivudine resistance is frequent with a prolonged course of therapy. Considering long-term treatment, antiviral agents with a high genetic barrier to resistance and lack of nephrotoxicity are suggested. The optimal strategy in RTRs with HBV infection remains to be established in the near future.

关键词： Hepatitis B Renal transplantation lamivudine resistance

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Mutations outside the YMDD motif in the P protein can also cause DHBV resistant to lamivudine

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World Journal of Gastroenterology 2005年第27期11卷 4261-4267页

作者： Jin-Yang He Yu-Tong Zhu Rui-Yi Yang Li-Ling Feng Xing-Bo Guo Feng-Xue Zhang Hong-Shan Chen Tropical Medicine Institute of Guangzhou University of Traditional Chinese Medicine Guangzhou 510405 Guangdong Province China Institute of Medical Biotechnology of CAMS and PUMC Beijing 100050 China

AIM: To observe the lamivudine resistance character of a DHBV strain in vitro and in vivo, and to analyze if the lamivudine resistance character is caused by gene mutation or by abnormity of the lamivudine ***: Congenitally DHBV-negative Guangdong brown ducks and duck embryo liver cells were respectively taken as animal and cell model. The lamivudine-susceptive DHBV and lamivudine-resistant DHBV (LRDHBV) were infected and lamivudine was administrated according to the divided groups. The changes of DHBV quantity in the animal and cell model were tested. Three lamivudineresistant and two lamivudine-susceptive DHBV complete genomes were successfully amplified, sequenced and then submitted to GenBank. All the DHBV complete sequences in the GenBank at present were taken to align with the three LRDHBV to analyze the mutational points related to the lamivudine-resistant ***: Both the animal and cell model showed that the large and the small dosage lamivudine have no significant inhibitory effect on the LRDHBV. Five sequences of DHBV complete genomes were successfully cloned. The GenBank accession numbers of the three sequences of LRDHBV are AY521226, AY521227, and AY433937. The two strains of lamivudine-susceptive DHBV are AY392760and AY536371. The correlated mutational points are KorR86Q and AorE591T in the P ***: The lamivudine resistance character of this DHBV strain is caused by genome mutation; the related mutational points are KorR86Q and AorE591T and have no relations with the YMDD motif mutation.

关键词： DHBV lamivudine resistance Mutational points

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Outcome of lamivudine-resistant hepatitis B virus is generally benign except in cirrhotics

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World Journal of Gastroenterology 2005年第28期11卷 4344-4350页

作者： Yock-Young Dan Chun-Tao Wai Yin-Mei Lee Dede Selamat Sutedja Bee-Leng Seer Seng-Gee Lim Division of Gastroenterology National University Hospital Singapore

AIM： We set to determine factors that determine clinical severity after the development of resistance.METHODS： Thirty-five Asian patients with genotypic lamivudine resistance were analyzed in three groups： 13/35 （37%） were non-cirrhotics with normal pre-treatment ALT （Group IA）, 12/35 （34%） were non-cirrhotics with elevated pre-treatment ALT （Group IB）, and 10/35 （29%） were cirrhotics （Group II）. Patients were followed for a median of 98 wk （range 26-220） after the emergence of genotypic resistance.RESULTS： Group IA patients tended to retain normal ALT. Group IB patients showed initial improvement of ALT with lamivudine but 9/12 patients （75%） developed abnormal ALT subsequently. On follow-up however, this persisted in only 33%. Group II patients also showed improvement while on treatment, but they deteriorated with the emergence of resistance with 30% death from decompensated liver disease. Pretreatment ALT levels and CPT score （in the cirrhotic group） were predictive of clinical resistance and correlated with peak ALT levels and CPT score.CONCLUSION： The phenotype of lamivudine-resistant HBV correlated with the pretreatment phenotype. The clinical course was generally benign in non-cirrhotics. However, cirrhotics had a high risk of progression and death （30%） with the development of lamivudine resistance.

关键词： lamivudine resistance YMDD mutants Hepatitis B treatment Nucleoside analog

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YVDD Mutation of Hepatitis B Virus, a Dominant lamivudine-Resistant Type in Guangzhou, South China

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Virologica Sinica 2008年第3期23卷 218-225页

作者： Zhi-ying OU Rong ZHOU Yun-shao HE Guangzhou Children＇s Hospital 318 RenMingZhong Rd Guangzhou 510120 China Daan Gene Diagnostic Center of Sun Yat-sen University 74 Zhongshan Rd 2^nd Guangzhou 510081 China

The epidemiological effects of native and mutated YMDD motif in the HBV genome under the selective pressure of lamivudine were investigated. YMDD wild and mutation motif in HBV genome were detected by flow through reverse dot blots （PT-RDB） with KaiPuTM DNA HybriMax Rapid Hybridization Machine based on the principle of ＂Flow-through hybridization＂ and by the traditional Reverse Dot Blot assay. Sera from 1 021 suspected lamivudine-resistant chronic HBV carriers after more than 8 months of lamivudine therapy and the corresponding archived sera were collected and assayed. We found 35.94% were single type infections with 8.03% YMDD, 7.93% YIDD and 19.98% YVDD. It was also found that 64.06% were mixed infections including 1.96% YMDD and YIDD, 51.62% YMDD and YVDD, 1.96% YIDD and YVDD, 8.52% YMDD, YIDD and YVDD. The levels of infections containing YVDD motif reached 82.08%. The pretreatment infectious status were： YMDD single infection was 36.93%; YIDD single infection was 6.07%; YVDD single infection was 17.04%; YMDD and YIDD mixed infection was 0.97%; YMDD and YVDD mixed infection was 33.99%; YIDD and YVDD mixed infection was 0.98%; YMDD, YIDD and YVDD mixed infection was 4.02%. Infections containing YVDD motif were only 56.03%. The 34.32% mutation rate of YMDD motif to YVDD was significantly higher than the 10.97% of YMDD to YIDD （U=10.98, P〈0.05）, as estimated by Mann-Whitney U-test for non-parametric data. HBV containing YVDD motif might have an evolutionary ascendancy and become the dominant type under the selective pressure of lamivudine.

关键词： HBV lamivudine resistance PT-RDB Mutation Evolution

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