摘要：人類巨細胞病毒感染很常見，在免疫力正常的人其感染常是無症狀或很輕微，但在免疫低下病人可以造成很嚴重的疾病。目前對嚴重巨細胞病毒疾病的治療是以抗病毒藥物ganciclovir 和foscarnet 為主。但是即使用藥物治療，其死亡率仍然很高，同時這些抗病毒藥物的抗藥性也漸漸產生，使治療更為困難。這些抗藥性病毒感染今年來在接受移植的病人越來越多，而且常伴隨快速的臨床惡化及更高的死亡率。pUL97 的突變是巨細胞病毒對ganciclovir 產生抗藥性最主要的機制，在台灣，抗藥性巨細胞病毒的比率，及其對臨床治療及預後的影響從未被研究過。為了闡明以上問題，我們設計了一個三年期研究，將利用對UL97 做基因型分析的方法，針對臨床分離出的巨細胞病毒株、接受血液幹細胞移植且有病毒血症之臨床檢體、及有嚴重侵入型巨細胞病毒疾病者的臨床檢體做偵測，以闡明台灣抗藥性病毒所佔的比率，也將分析抗藥性對臨床病程、預後的影響。同時我們也將致力於尋找和抗藥性有關的新突變基因，在基因型分析中發現的新突變都將嘗試作抗藥性表現型的確認。我們認為此計畫將有助於瞭解巨細胞病毒抗藥性在台灣的現況，更可對巨細胞病毒感染有更適當的治療，改善巨細胞病毒感染者的預後。
Abstract: Most human cytomegalovirus (CMV) infections are asymptomatic or mild inimmunocompentent individuals. However, it may cause serious diseases, especially inimmunocompromised patients. For patients with severe CMV disease, ganciclovir andfoscarnet are the mainstay treatment. However, the mortality remains high even underanti-viral treatment. Not only the treatment response is unsatisfactory, but also serious sideeffects and emerging drug resistance compromise its use.Ganciclovir-resistant CMV infection (GCV-R CMV) had been described years in AIDSpatients and emerged in transplant recipients in recent decade. Those infections may beassociated with aggressive clinical course, organ dysfunction, and mortality. Nowadays, GCVresistance has been described after both prophylaxis and preemptive therapy. Mutations ofpUL97, which converts GCV to its monophosphate form, account for most of the resistance toGCV. The status of drug resistance of CMV remains unclear in Taiwan. To what extent thetreatment failure of CMV disease could be contributed to drug resistance is still unknown. Todelineate the proportion of CMV resistance strains and how these drug resistance CMVcompromising the clinical course, we conduct this 3-year project to elucidate these issues.We will survey the existence of drug resistance genes by genotypic assay from theclinical CMV isolates and from the patient’s specimens in the hematopoietic stem celltransplant recipients with CMV viremia and in the patients with invasive CMV diseases. Wewill also analyze the risk factors, clinical severity, treatment response, and prognosis forpatients with the resistant CMV infection. In addition to the known mutations, we also aim tosearch for novel mutations that account for antiviral drug resistance. If a novel mutation isfound during the study, we will further examine whether this genotypic mutation isresponsible for the phenotypic resistance.In summary, in this 3-year project we will clarify the drug resistance status and itsimpact on clinical settings in Taiwan. The data have never been studied and will providevaluable information. The results can shed the light on the proportion of CMV resistance inTaiwan and the clinical significance of the resistance on treatment response. Moreover, wealso want to identify novel mutations responsible for antiviral drug resistance of CMV inTaiwan. By understanding the extent and the effect of resistance CMV in the clinical settings,optimal treatment guideline could be formulated.