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回复 乙肝人1949 的帖子
许多年前，科学家们研究了如何预测PegIFN治疗的成功或失败. 不幸的是，他们并不是很成功.
2.1 Baseline predictors of Peg‐IFN response
Baseline predictors of response in HBeAg‐positive patients are low viral load, high serum ALT levels, i.e. >2‐5 times x upper limit of normal (ULN), younger age, female gender, HBV genotype and high activity scores on liver biopsy. HBV genotypes A and B have been associated with higher rates of HBeAg seroconversion and HBsAg loss than genotypes C and D. A baseline score system (from 0 to 8) including 5 factors: female gender, quantitative HBsAg (qHBsAg), HBV genotype, ALT, HBV DNA predicted the patients with higher chance of response to Peg‐IFNα2a. Out of 443 treated patients, 134 (30%), 164 (37%), and 110 (25%) had HBV DNA ≤2000 IU/mL, HBeAg seroconversion, and a combined response (HBV DNA ≤2000 IU/mL and HBeAg seroconversion 1‐year post‐treatment), respectively. In patients with baseline scores ≥5, 63% (40/63) and 43% (27/63) had HBeAg seroconversion and a combined response, respectively, compared to a very low rate (5%, 2/43) in patients with scores of 0‐1 (95% negative predictive value [NPV]).8 High baseline ALT, low serum HBV DNA, younger age, female gender and HBV genotype were independent predictors of response in HBeAg‐negative patients. Patients with genotypes B or C infection had a better chance of response than those with genotype D. A baseline score system (from 0 to 7) that combined five variables: HBV genotype, HBV DNA, ALT, qHBsAg and age identified patients with a high and low likelihood of response. HBV DNA<2000 IU/mL and HBV DNA<2000 IU/mL plus normal ALT 48 weeks after EOT were achieved in 61% and 45% of patients with baseline scores ≥4, respectively, but in only 11% and 8% of patients with scores 0‐1 with a 89% and 92% NPV, respectively.9
Unfortunately, the fluctuating pattern of serum HBV DNA and ALT tends to make the prediction of response using these variables difficult. Thus, other pretreatment predictors of response to IFN‐based treatment were searched for using a genome‐wide association (GWAS) analysis of SNPs rs12979860 and rs8099917 mapping in the genomic region 3 kb upstream of the gene codifying for IL28B on chromosome 19, now renamed IFN lambda 4 (IFNλ4). However, the preliminary observations of an association between favorable IFNλ4 polymorphisms and increased chances of a sustained virological and serological response in both HBeAg‐positive and ‐negative patients were not confirmed in subsequent studies.10 Recently, IFNλ4 rs368234815 and rs117648444 variants were reported to strongly predict HBsAg clearance in 126 HBeAg‐negative patients treated with IFN and followed up for a median of 11 1-23 years.11 This study reported that the 15‐year cumulative probability of HBsAg loss in the 62 carriers of the rs368234815 TT/TT genotype, which abolishes IFNλ4 protein production and in the 19 patients carrying the rs117648444 T allele, which produces an impaired IFNλ4‐S70 protein, was significantly higher than in the 45 subjects who encoded only the fully functional IFNλ4‐P70 (42% vs 11%, P = .003). On multivariate analysis, a combination of the rs368234815 and rs117648444 genotypes strongly predicted HBsAg clearance (HR 5.90, 95% CI 1.70‐20.9, P = .006) together with pretreatment serum HBV DNA levels (HR 0.57, 95% CI 0.39‐0.83, P = .003). However, until further studies confirm these results in large cohorts of homogeneous ethnic and virological groups, baseline host genetic testing to prioritize CHB patients for Peg‐IFN therapy is not recommended in clinical practice.12
2.1 Peg-IFN反应的基线预测因子
HBeAg阳性患者反应的基线预测指标是低病毒载量，高血清ALT水平，即> 2-5倍x正常上限（ULN），年轻，女性，HBV基因型和肝活检活动评分高。 HBV基因型A和B与基因型C和D相比具有更高的HBeAg血清转化率和HBsAg丢失率。基线评分系统（从0到8）包括5个因素：女性，女性，定量HBsAg（qHBsAg），HBV基因型，ALT ，HBV DNA预测患者对Peg‐IFNα2a有更高的反应机会。在443例接受治疗的患者中，134（30％），164（37％）和110（25％）的HBV DNA≤2000 IU / mL，HBeAg血清转化以及合并反应（HBV DNA≤2000 IU / mL和HBeAg血清转化1年后）。在基线评分≥5的患者中，分别有63％（40/63）和43％（27/63）的患者发生HBeAg血清转化和合并反应，而在HBsAg评分较低的患者中（5％，2/43）评分为0-1（95％阴性预测值[NPV]）。8高基线ALT，低血清HBV DNA，年龄，女性性别和HBV基因型是HBeAg阴性患者反应的独立预测因子。基因型为B或C的患者比基因型为D的患者有更好的反应机会。基线评分系统（从0到7）结合了五个变量：HBV基因型，HBV DNA，ALT，qHBsAg和年龄高的患者且回应可能性低。 EOT后48周，HBV DNA <2000 IU / mL和HBV DNA <2000 IU / mL以及正常ALT分别达到基线评分≥4的患者的61％和45％，但分别只有11％和8％的患者得分0-1分别具有89％和92％的净现值9。
不幸的是，血清HBV DNA和ALT的波动模式往往使使用这些变量预测反应变得困难。因此，使用在19号染色体上编码IL28B的基因上游3 kb的基因组区域中映射的SNP rs12979860和rs8099917的SNP rs12979860和rs8099917的全基因组关联（GWAS）分析，寻找了对基于IFN的治疗反应的其他预处理预测因子，现已更名为IFNλ4（IFNλ4）。但是，在随后的研究中，尚未证实在良好的IFNλ4多态性与HBeAg阳性和阴性患者中持续的病毒学和血清学应答之间存在关联的初步观察结果。10最近，据报道，IFNλ4rs368234815和rs117648444变体强烈可以预测126名接受IFN治疗的HBeAg阴性患者的HBsAg清除率，中位随访时间为11 1-23年。11该研究报告说，rs368234815 TT / TT基因型的62名携带者中15年累积HBsAg消失的可能性，它消除了IFNλ4蛋白的产生，在19名携带rs117648444 T等位基因的患者中产生了IFNλ4-S70蛋白受损，明显高于仅编码全功能IFNλ4-P70的45名受试者（42％比11％， P = 0.003）。在多变量分析中，rs368234815和rs117648444基因型的组合强烈预测了HBsAg清除率（HR 5.90，95％CI 1.70-20.9，P = .006）以及治疗前血清HBV DNA水平（HR 0.57，95％CI 0.39-0.83， P = 0.003）。但是，直到进一步的研究证实了在同质种族和病毒学人群中的大量研究结果之前，临床实践中不建议使用基线宿主基因检测将CHB患者优先用于Peg-IFN治疗。 |
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楼主: StephenW
发表于 2020-12-12 21:27
