丙型肝炎直接抗病毒药物（DAAs）预存耐药及丙型肝炎流行和治疗情况分析

发布时间：2018-05-04 01:28

本文选题：丙型肝炎病毒 + 直接抗病毒药物　；参考：《重庆医科大学》2017年硕士论文

【摘要】：目的:近日,世界卫生组织(World Health Organization,WHO)提出了“到2030年消除病毒性肝炎作为公共健康威胁”的全球肝炎防治策略。直接抗病毒药物(Direct-acting antiviral agents,DAAs)的问世使得丙型肝炎病毒(Hepatitis C Virus,HCV)感染的防治似乎更容易达到目标。但DAAs耐药相关变异(Resistance-associated variants,RAVs)的出现会降低DAAs治疗的效果,甚至导致治疗失败。然而全球HCV DAAs的预存耐药流行情况还不清楚。此外,我国作为肝炎大国,目前HCV感染的流行和治疗情况也不清楚。因此,了解清楚上述问题对早日实现WHO提出的宏伟目标来说是很有必要的。方法:1.全球HCV直接抗病毒药物预存耐药突变流行情况分析:首先从NCBI Gen Bank核酸数据库提取所有的HCV全长序列。其次,查阅文献,总结出所有已知的DAAs耐药突变位点(包括临床相关的耐药位点)。再用MEGA 5.0软件比对所得序列,分析其耐药突变位点的流行情况。最后用SPSS 20.0软件统计结果。2.中国西部HCV感染的流行及治疗情况分析:我们回顾性的分析了2013-2015年在我院检测HCV抗体(Antibody,Ab)的病人的电子病历。分析了HCV-Ab的阳性率以及HCV-RNA阳性病人的治疗情况。用SPSS 20.0软件统计结果。结果:1.总的来说,全球HCV DAAs预存耐药突变流行率是很高的(58.7%,854/1455)。在各大洲中,DAAs预存耐药突变流行率最高的是亚洲(74.1%),其次是非洲(71.9%),美洲(53.5%)和欧洲(51.4%)。在各个基因型中,基因6型的预存耐药突变率是最高的(99%),接下来是基因4型,基因1a型,基因3型和基因1b型(分别是85.5%,56%,50%和34.3%)。对于不同种类的DAAs而言,我们发现有40.0%的序列含有针对NS5A抑制剂的RAVs;29.6%的序列含有针对NS3蛋白酶抑制剂的RAVs。值得注意的是,针对NS5B核苷酸抑制剂(Nucleotide inhibitor,NI)的RAVs是罕见的(4%的序列)。同时正如我们预期的那样,对于目前各大指南推荐的无干扰素治疗方案的联合耐药突变率是非常低的(0.2-2.0%)。2.总的来说,HCV-Ab的阳性率是1.44%(1616/112576)。男性的HCV-Ab阳性率要高于女性(1.96%比1.06%,p0.01)。35-44年龄组的HCV-Ab阳性率是最高的(3.24%,591/18254)。而非感染科来源的病人的HCV-Ab阳性率是0.64%(634/99061)。此外,在1616个HCV-Ab阳性的患者中,有1278(79.08%)名患者接受了HCV-RNA检测,其中有951(74.41%)名患者是HCV-RNA阳性。值得注意的是,在这些HCV-RNA阳性的患者中,只有45.64%(434/951)的患者接受了标准的聚乙二醇干扰素联合利巴韦林(Peg-IFN/Ribavirin,P/R)治疗。但是接受治疗的HCV感染患者的治愈率还是很高的(73.51%,272/370)。此外,有10.96%(32/292)的HCV-RNA阳性患者同时也检测到了HBs Ag阳性。这32名患者的HCV治愈率比HBs Ag阴性患者低,但没有统计学差异。结论:1.全球HCV DAAs预存耐药突变的流行率是很高的,无论是在各大洲还是各基因型。但是,以NI为基础的DAAs联合方案的耐药突变流行率是很低的,提示我们这些治疗方案可能是治疗慢性丙型肝炎较好的策略。2.我国的HCV感染患者可能自2006年HCV感染人口普查以来有所增加。P/R治疗方案在我国的治愈率还是很高的,但是仍有一半以上的患者没有接受治疗。因此,更加科学、全面、合理的HCV感染防治策略的制定和实施是很有必要的。
[Abstract]:Objective: Recently, the WHO (World Health Organization, WHO) proposed a global hepatitis control strategy to eliminate viral hepatitis as a public health threat. The advent of the direct antiviral drug (Direct-acting antiviral agents, DAAs) makes the prevention and control of hepatitis C virus (Hepatitis C Virus, HCV) infection more likely. It is easy to achieve the goal. However, the emergence of DAAs resistance related variants (Resistance-associated variants, RAVs) can reduce the effect of DAAs treatment and even lead to treatment failure. However, the prevalence of HCV DAAs in the global HCV DAAs is not clear. In addition, our country is a major hepatitis, and the prevalence and treatment of HCV infection is not clear. Therefore, it is not clear that the prevalence and treatment of HCV infection are not clear. It is necessary to clear the above problems for the early realization of the grand goal of WHO. Method: analysis of the epidemic situation of the 1. global HCV direct antiviral drugs. First, all HCV full-length sequences are extracted from the NCBI Gen Bank nucleic acid database. Secondly, all the known DAAs mutation sites (package) are summarized. MEGA 5 software alignment was used to analyze the prevalence of drug-resistant mutation sites. Finally, SPSS 20 software was used to analyze the prevalence and treatment of HCV infection in Western China: a retrospective analysis of 2013-2015 years in our hospital for the detection of HCV antibody (Antibody, Ab) patients in our hospital. The positive rate of HCV-Ab and the treatment of HCV-RNA positive patients were analyzed. The results of SPSS 20 software were used. Results: 1. overall, the global HCV DAAs preexisting resistance mutation prevalence rate was very high (58.7%, 854/1455). Among the continents, the highest prevalence rate of DAAs preexisting mutation was Asia (74.1%), followed by Africa (71.9%), beauty. Chau (53.5%) and Europe (51.4%). In various genotypes, the preexisting resistance mutation rate of gene 6 is the highest (99%), followed by gene 4, gene 1a, gene 3, and gene 1B (85.5%, 56%, 50% and 34.3% respectively). For different types of DAAs, we found that 40% sequences contain RAVs for NS5A inhibitors; 29.6% sequence It is noteworthy that the RAVs. for NS3 protease inhibitors is that the RAVs of the NS5B nucleotide inhibitor (Nucleotide inhibitor, NI) is a rare (4% sequence). And as we expected, the combined resistance mutation rate for interferon free treatments recommended by the major guidelines is very low (0.2-2.0%).2. total. The positive rate of HCV-Ab was 1.44% (1616/112576). The positive rate of HCV-Ab in men was higher than that in women (1.96% to 1.06%, P0.01) in.35-44 age group (3.24%, 591/18254). The HCV-Ab positive rate in non infectious patients was 0.64% (634/ 99061). In addition, among 1616 HCV-Ab positive patients, there were 1278 (79.08%) names. The patients received a HCV-RNA test, of which 951 (74.41%) were HCV-RNA positive. It is worth noting that only 45.64% (434/951) of the HCV-RNA positive patients received the standard peginterferon combined with Leigh Bhave Lin (Peg-IFN/Ribavirin, P/ R) treatment. But the cure rate of HCV infected patients received treatment was still still It was very high (73.51%, 272/370). In addition, 10.96% (32/292) HCV-RNA positive patients also detected HBs Ag positive. The HCV cure rate of these 32 patients was lower than that of HBs Ag negative patients, but there was no statistical difference. Conclusion: the prevalence rate of 1. global HCV DAAs predeposited mutations is very high, whether in all continents or genotypes. It is, the NI based DAAs combination regimen is very low in resistance mutation prevalence, suggesting that these treatments may be a better strategy for the treatment of chronic hepatitis C.2., our HCV infected patients may have increased the cure rate in our country since the 2006 HCV infection population census, but the cure rate in our country is still high, but still there is a high rate of cure in China. More than half of the patients did not receive treatment. Therefore, it is necessary to formulate and implement a more scientific, comprehensive and rational strategy for the prevention and treatment of HCV infection.

【学位授予单位】：重庆医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R512.63

【参考文献】