HBV基因型和准种与阿德福韦酯抗病毒治疗关系的研究
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摘要
第一部分阿德福韦酯治疗一年后HBV基因型变化情况的研究
目的：研究52例阿德福韦酯(adefovir dipivoxil, ADV)治疗1年后的慢性乙型肝炎(chronic hepatitis B, CHB)患者,观察是否有乙型肝炎病毒(hepatitis B virus, HBV)基因型改变。
方法：选择52例CHB患者作为研究对象,口服ADV抗病毒治疗1年,采用多对型特异性引物巢式PCR (polymerase chain reaction, PCR)技术扩增HBV基因并分析治疗前后HBV基因型的变化情况。
结果：52例ADV治疗1年的CHB患者中,有一例患者基因型发生改变,该患者体内HBV基因型由治疗前的B型变为B/C混合型。
结论：阿德福韦酯可使HBV基因型发生改变。
第二部分HBV基因型与阿德福韦酯疗效的关系
目的：探讨CHB患者体内HBV基因型对阿德福韦酯抗病毒疗效的影响。
方法：选择52例CHB患者作为研究对象,口服阿德福韦酯抗病毒治疗1年,采用多对型特异性引物巢式PCR检测HBV基因型,并观察治疗后第3、6、12个月时抗病毒疗效。
结果：52例患者中B基因型39例,C基因型13例,在ADV治疗第3,6,12个时,B基因型与C基因型患者之间的HBV DNA转阴率,丙氨酸氨基转移酶(alanine aminotransferase, ALT)复常率及乙肝病毒e抗原(hepatitis B e antigen, HBeAg)血清转换率均无统计学差异(P>0.05)。
结论：B基因型HBV与C基因型HBV,对ADV的生化应答和病毒学应答无明显差别。
第三部分阿德福韦酯与乙型肝炎病毒准种变异特点的联系
目的：研究阿德福韦酯治疗一年后慢性乙型肝炎患者体内乙型肝炎病毒P区与C区基因序列的准种变化特点。
方法：选择37例口服阿德福酯治疗一年的慢性乙肝患者作为研究对象,其中病毒学应答患者27例,部分应答5例,无应答2例,病毒学突破3例。这些慢性乙肝患者血清中HBV基因型采用多对型特异性引物巢式PCR技术检测均为B型。从这些患者血清中提取HBV DNA,经PCR反应扩增其P区与C区基因后,采用熔点曲线法分析治疗前后准种变化情况。
结果：阿德福韦酯治疗前,病毒学应答组27例患者HBV P区波峰数为4.59±0.57个,部分应答组与无应答组共7例患者HBV P区波峰数为5.80±0.79个病毒学突破组3例患者HBV P区波峰数为6.67±0.58个,3者之间两两比较,均有统计学差异(P<0.05)。其中,部分应答组5例患者HBV P区波峰数为5.50±0.84个,无应答组2例患者HBV P区波峰数为6.50±0.71个
阿德福韦酯治疗1年后,病毒学应答组HBV P区波峰数为4.28±1.19个,部分应答组HBV P区波峰数为5.00±0.71个,无应答组HBV P区波峰数为5.00±0.00个,上述三组分别与治疗前HBV P区波峰数相比,均无统计学差异(P>0.05)。病毒学突破组治疗1年后,HBV P区波峰数为4.00±1.00个,明显少于治疗前HBV P区波峰数(P<0.05)。
HBV C区治疗前波峰数与治疗后相比,各组均无明显差别(P>0.05)。
结论：①HBV P区准种数越多,阿德福韦酯的抗病毒疗效越低,越容易出现阿德福韦酯耐药；②出现阿德福韦酯耐药后,HBV P区准种数明显减少,但可出现优势准种；③阿德福韦酯对HBV C区准种作用不明显。
Part1 Research about HBV genotype switches after one year of adefovir dipivoxil treatment
Objective:To study whether the hepatitis B virus (HBV) genotypes of 52 chronic hepatitis B (CHB)patients, who have been treated with adefovir dipivoxil (ADV)for one year, have changed.
Methods:52 patients with chronic hepatitis B were medicated with ADV for one year. Nested polymerase chain reaction (PCR) with multiple pairs of geno-type-specific primers was performed to investigate whether there were any differ-ences in the patients'HBV genotypes before and after the treatment, Subsequently.
Results:Among the 52 CHB patients, one patient's HBV genotype changed from type B into a B/C mixed genotype after the ADV treatment.
Conclusion:HBV genotype in CHB patients can change after ADV treatment.
Part2 The relationship between HBV genotypes and efficacy of adefovir dipivoxil
Objective:To investigate the effect of HBV genotypes on the antiviral efficacy of ADV in CHB patients.
Methods:Firstly,52 patients with chronic hepatitis B were medicated with ADV for one year, then nested PCR with multiple pairs of genotype-specific primers was carried out to analyse the HBV genotyepe, At last, the antiviral efficacy at the 3rd,6th, 12th maonths after the ADV treatment were observed.
Results:39 of the 52 patients were genotype B and 13 were genotype C. After 12 months'treatment, there were no significant differences in the ratio of HBV DNA negative conversion, alanine aminotransferase (ALT) normalization and HBeAg se-roconversion between patients with B genotype and C genotype HBV (P>0.05).
Conclusions:HBV genotype has no significant effect on virological, biochemi-cal and immunological response to ADV.
Part3 The relationship between adefovir dipivoxil and hepatitis B virus quasispecies mutation
Objective:To study the quasispecies mutation of HBV P region and C region from CHB patients after one year of ADV treatment.
Methods:37 CHB patients who had taken ADV orally for one year were se-lected as research objects, among whom 27 cases were completely virological re-sponse,5 were partial response,2 cases were non-response and 3 cases had virologi-cal breakthrough. All of them were HBV B genotype confirmed by nested PCR with multiple pairs of genotype-specific primers. First, HBV DNAs were extracted from all these 37 patients. Subsequently, PCR were adopted to amplify the P region and C region of HBV DNA. Lastly, melting curve were employed to analyse the quasispe-cies variance before and after ADV treatment.
Results:Before the treatment of ADV, the virological response group had 4.59±0.57 peaks in HBV P region, while the partial and non-response group had 5.80±0.79 peaks, and the virological-breakthrough group had 6.67±0.58 peaks. Staticstics showed significant differences among each group(P<0.05).Among them, the virological response group had 5.50±0.84 peaks in HBV P region, the non-response group had 6.50±0.71 peaks in HBV P region.
After one year of ADV treatment, the virological response group had 4.28±1.19 peaks in HBV P region, the partial response group had 5.00±0.71 peaks, while the non- response group had 5.00±0.00 peaks. Compared with that before treatment, there were no significant differences in HBV P region peaks of each group(P>0.05, respctively). Nevertheless, the virological-breakthrough group had 4.00±1.00 peaks in HBV P region peaks, apparently less than that before ADV treatment (P<0.05).
Meanwhile, the count of HBV C region peaks in each group were not significant different pre- and post- ADV treatment (P>0.05).
Conclusion:①The more quasispecies HBV P region has, the lower antiviral ef-ficacy ADV shows, and the the more likely to be resistant to ADV treatment; case of ADV resistance, the number of HBV P region quasispecies reduces signifi-cantly, however, perdominant quasispecies may appear at the same time;①The effct of ADV on the count of HBV C region quasispecies is not significant.
目的：研究52例阿德福韦酯(adefovir dipivoxil, ADV)治疗1年后的慢性乙型肝炎(chronic hepatitis B, CHB)患者,观察是否有乙型肝炎病毒(hepatitis B virus, HBV)基因型改变。
方法：选择52例CHB患者作为研究对象,口服ADV抗病毒治疗1年,采用多对型特异性引物巢式PCR (polymerase chain reaction, PCR)技术扩增HBV基因并分析治疗前后HBV基因型的变化情况。
结果：52例ADV治疗1年的CHB患者中,有一例患者基因型发生改变,该患者体内HBV基因型由治疗前的B型变为B/C混合型。
结论：阿德福韦酯可使HBV基因型发生改变。
第二部分HBV基因型与阿德福韦酯疗效的关系
目的：探讨CHB患者体内HBV基因型对阿德福韦酯抗病毒疗效的影响。
方法：选择52例CHB患者作为研究对象,口服阿德福韦酯抗病毒治疗1年,采用多对型特异性引物巢式PCR检测HBV基因型,并观察治疗后第3、6、12个月时抗病毒疗效。
结果：52例患者中B基因型39例,C基因型13例,在ADV治疗第3,6,12个时,B基因型与C基因型患者之间的HBV DNA转阴率,丙氨酸氨基转移酶(alanine aminotransferase, ALT)复常率及乙肝病毒e抗原(hepatitis B e antigen, HBeAg)血清转换率均无统计学差异(P>0.05)。
结论：B基因型HBV与C基因型HBV,对ADV的生化应答和病毒学应答无明显差别。
第三部分阿德福韦酯与乙型肝炎病毒准种变异特点的联系
目的：研究阿德福韦酯治疗一年后慢性乙型肝炎患者体内乙型肝炎病毒P区与C区基因序列的准种变化特点。
方法：选择37例口服阿德福酯治疗一年的慢性乙肝患者作为研究对象,其中病毒学应答患者27例,部分应答5例,无应答2例,病毒学突破3例。这些慢性乙肝患者血清中HBV基因型采用多对型特异性引物巢式PCR技术检测均为B型。从这些患者血清中提取HBV DNA,经PCR反应扩增其P区与C区基因后,采用熔点曲线法分析治疗前后准种变化情况。
结果：阿德福韦酯治疗前,病毒学应答组27例患者HBV P区波峰数为4.59±0.57个,部分应答组与无应答组共7例患者HBV P区波峰数为5.80±0.79个病毒学突破组3例患者HBV P区波峰数为6.67±0.58个,3者之间两两比较,均有统计学差异(P<0.05)。其中,部分应答组5例患者HBV P区波峰数为5.50±0.84个,无应答组2例患者HBV P区波峰数为6.50±0.71个
阿德福韦酯治疗1年后,病毒学应答组HBV P区波峰数为4.28±1.19个,部分应答组HBV P区波峰数为5.00±0.71个,无应答组HBV P区波峰数为5.00±0.00个,上述三组分别与治疗前HBV P区波峰数相比,均无统计学差异(P>0.05)。病毒学突破组治疗1年后,HBV P区波峰数为4.00±1.00个,明显少于治疗前HBV P区波峰数(P<0.05)。
HBV C区治疗前波峰数与治疗后相比,各组均无明显差别(P>0.05)。
结论：①HBV P区准种数越多,阿德福韦酯的抗病毒疗效越低,越容易出现阿德福韦酯耐药；②出现阿德福韦酯耐药后,HBV P区准种数明显减少,但可出现优势准种；③阿德福韦酯对HBV C区准种作用不明显。
Part1 Research about HBV genotype switches after one year of adefovir dipivoxil treatment
Objective:To study whether the hepatitis B virus (HBV) genotypes of 52 chronic hepatitis B (CHB)patients, who have been treated with adefovir dipivoxil (ADV)for one year, have changed.
Methods:52 patients with chronic hepatitis B were medicated with ADV for one year. Nested polymerase chain reaction (PCR) with multiple pairs of geno-type-specific primers was performed to investigate whether there were any differ-ences in the patients'HBV genotypes before and after the treatment, Subsequently.
Results:Among the 52 CHB patients, one patient's HBV genotype changed from type B into a B/C mixed genotype after the ADV treatment.
Conclusion:HBV genotype in CHB patients can change after ADV treatment.
Part2 The relationship between HBV genotypes and efficacy of adefovir dipivoxil
Objective:To investigate the effect of HBV genotypes on the antiviral efficacy of ADV in CHB patients.
Methods:Firstly,52 patients with chronic hepatitis B were medicated with ADV for one year, then nested PCR with multiple pairs of genotype-specific primers was carried out to analyse the HBV genotyepe, At last, the antiviral efficacy at the 3rd,6th, 12th maonths after the ADV treatment were observed.
Results:39 of the 52 patients were genotype B and 13 were genotype C. After 12 months'treatment, there were no significant differences in the ratio of HBV DNA negative conversion, alanine aminotransferase (ALT) normalization and HBeAg se-roconversion between patients with B genotype and C genotype HBV (P>0.05).
Conclusions:HBV genotype has no significant effect on virological, biochemi-cal and immunological response to ADV.
Part3 The relationship between adefovir dipivoxil and hepatitis B virus quasispecies mutation
Objective:To study the quasispecies mutation of HBV P region and C region from CHB patients after one year of ADV treatment.
Methods:37 CHB patients who had taken ADV orally for one year were se-lected as research objects, among whom 27 cases were completely virological re-sponse,5 were partial response,2 cases were non-response and 3 cases had virologi-cal breakthrough. All of them were HBV B genotype confirmed by nested PCR with multiple pairs of genotype-specific primers. First, HBV DNAs were extracted from all these 37 patients. Subsequently, PCR were adopted to amplify the P region and C region of HBV DNA. Lastly, melting curve were employed to analyse the quasispe-cies variance before and after ADV treatment.
Results:Before the treatment of ADV, the virological response group had 4.59±0.57 peaks in HBV P region, while the partial and non-response group had 5.80±0.79 peaks, and the virological-breakthrough group had 6.67±0.58 peaks. Staticstics showed significant differences among each group(P<0.05).Among them, the virological response group had 5.50±0.84 peaks in HBV P region, the non-response group had 6.50±0.71 peaks in HBV P region.
After one year of ADV treatment, the virological response group had 4.28±1.19 peaks in HBV P region, the partial response group had 5.00±0.71 peaks, while the non- response group had 5.00±0.00 peaks. Compared with that before treatment, there were no significant differences in HBV P region peaks of each group(P>0.05, respctively). Nevertheless, the virological-breakthrough group had 4.00±1.00 peaks in HBV P region peaks, apparently less than that before ADV treatment (P<0.05).
Meanwhile, the count of HBV C region peaks in each group were not significant different pre- and post- ADV treatment (P>0.05).
Conclusion:①The more quasispecies HBV P region has, the lower antiviral ef-ficacy ADV shows, and the the more likely to be resistant to ADV treatment; case of ADV resistance, the number of HBV P region quasispecies reduces signifi-cantly, however, perdominant quasispecies may appear at the same time;①The effct of ADV on the count of HBV C region quasispecies is not significant.
引文
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[1]Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B:special emphasis on disease progression and prognostic factors. J Hepatol,2008;48(2):335-352
[2]Liang TJ, et al. Hepatitis B:the virus and the disease. Hepatology,2009;49:S13-S21
[3]Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, management and treatment of hepati-tis C:an update. Hepatology,2009;49(4):1335-1374
[4]European Association for the Study of the Liver. EASL clinical practiceguidelines:manage-ment of chronic hepatitis B. Journal of Hepatology,2009;50(1):227-242
[5]Mason WS, Burrell CJ, Casey J, et al. Virus taxonomy. Eighth report of the international committee on taxonomy of viruses. Amsterdam:Elsevier; 2005
[6]Chu CJ, Lok AS, et al. Clinical significance of hepatitis B virus genotypes. Hepatology, 2002;35(5):1274-1276.
[7]Schaefer S. Hepatitis B virus taxonomy and hepatitis B virus genotypes. World Journal of Gastroenterology,2007; 13(1):14-21
[8]Hannoun C, Krogsgaard K, Horal P, et al. Genotype mixtures of hepatitis B virus in patients treated with interferon. Journal of Infection Diseases,2002;186(6):752-759
[9]Kao JH, Chen PJ, Lai MY, Chen DS, et al. Acute exacerbations of chronic hepatitis B are rarely associated with superinfection of hepatitis B virus. Hepatology,2001;34(4):817-823
[10]Sugauchi F, Orito E, Ichida T, et al. Hepatitis B virus of genotype B with or without recom-bination with genotype C over the precore region plus the core gene. Journal of Virology, 2002;76(12):5985-5992
[11]Kao JH, Chen PJ, Lai MY, et al. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology,2000; 118(3):554-559
[12]Fujie H, Moriya K, Shintani Y, et al. Hepatitis B virus genotypes and hepatocellular carci-noma in Japan. Gastroenterology,2001; 120(6):1564-1565
[13]Taylor Brent C, Yuan Jian-Min, Shamliyan Tatyana A, et al. Clinical outcomes in adults with chronic hepatitis B in association with patient and viral characteristics:a systematic review of evidence. Hepatology,2009;49:S85-S95
[14]Yu MW, Yeh SH, Chen PJ, et al. Genotype and DNA levels of hepatitis B virus and the risk of hepatocellular carcinoma. Journal of National Cancer Insitute,2005;97(4):265-272
[15]Livingston SE, Simonetti JP, McMahon BJ,et al. Hepatitis B virus genotypes in Alaska Na-tive people with hepatocellular carcinoma:preponderance of genotype F. Journal of Infection Diseases,2007; 195(1):5-11
[16]Sorrell Michael F, Belongia Edward A, Costa Jose, et al. National Institutes of Health con-sensus development conference statement:management of hepatitis B. Hepatology, 2009;49:S4-S12
[17]Flink HJ, van Zonneveld M, Hansen BE, et al. Treatment with Peg-interferon a-2b for HBeAg-positive chronic hepatitis B:HBsAg loss is associated with HBV genotype. The
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