台灣地區愛滋病毒與B型肝炎病毒共同感染者體內D型肝炎病毒之血清流行病學探討

D型肝炎病毒(HDV)覆加感染會增加人類免疫不全病毒(HIV)與B型肝炎病毒(HBV)共同感染者肝炎發作與慢性肝臟併發症之風險。在台灣地區非靜脈藥物毒癮(IDU)的HIV患者中，約18至20%罹患慢性B型肝炎。在此回溯性觀察研究中，我們調查此一族群中，近期HDV覆加感染之血清流行病學，分析其發生率及相關危險因子，並建立real-time PCR方法定量HDV病毒量，以評估雞尾酒療法(HAART)治療HIV/HBV/HDV共同感染患者的效果。在1992年到2012年間，我們一共收集375位HIV與HBV共同感染者的血清檢體進行分析，其中包含241位男同性戀、49位異性戀、16位雙性戀、34位IDU患者及其它路徑感染患者35人。在HDV抗體篩選部分，我們發現有38位陽性(10.1%)，316位陰性(84.3%)以及2位equivocal(0.5%)。我們進一步用核酸定序分析抗體陽性患者的HDV基因型，發現主要型別為genotype 4(N=19)與genotype 2(N=9)。針對這些病人在不同時間點的基因定序分析，我們發現病人並沒有同時感染兩種病毒基因型的情況發生。接著我們計算HDV感染發生率：從HDV抗體陽性族群中，我們找到16位病人有血清轉陽的時間點，配合337位HDV抗體持續陰性患者，共追蹤1763.63年(PYFU)後，得到1992-2012年HDV感染總發生率為9.07/1000人年；西元1992-2001、2002-2006、2007-2012年的發生率逐年上升，分別為0、3.91、13.26/1000人年(P<0.05)。接著在16個HDV抗體陽轉病人中，排除一位靜脈毒癮者，再導入嵌入型病例對照研究法，分析HDV感染的相關因子。我們發現相較於HDV抗體持續陰性患者，HDV近期感染者的肝功能指數與梅毒指數皆較高，而其它相關因子，包括：HIV感染危險因子、CD4 T細胞數、HIV病毒量、HBV病毒量、使用lamivudine(3TC)或tenofovir(TDF)之治療藥物或者HCV共同感染等，在兩族群間無顯著差異。HIV/HBV/HDV近期感染患者有15位使用HAART抗病毒藥物治療，分析HDV抗體陽轉後病毒標記的分布，顯示HAART對於降低HIV與HBV病毒量有良好的效果，但對於降低HDV病毒量及HBsAg的效果則不明顯。接著，我們進一步比較HDV陽轉患者且有使用HAART的確切時間病人共8個，並配對相同治療時間的HIV/HBV且HDV陰性患者共15位，分析他們體內的病毒標記分布。結果顯示HBsAg在HDV Ab陰性與HDV Ab陽性時間點的分布量在HDV陽性族群較HDV陰性族群高，此外，HBsAg的下降程度在HDV抗體轉揚患者身上較高(P<0.05)，而這樣的現象可能與HDV RNA的升高有關。歸納結果，我們發現在台灣地區HIV與HBV共同感染族群中，HDV感染的盛行率為10.1%。HDV近期感染的發生率為9.07/1000人年，從西元1992-2001到2007-2012年間發生率有顯著增加，此現象與肝炎發作及梅毒指數相關。在HAART治療下，HIV/HBV/HDV共同感染者體內的HIV與HBV病毒量有明顯的治療效果，而對於HDV RNA與HBsAg則沒有明顯的抑制效果。因此，建議公共衛生政策方面應該要加強HIV/HBV共同感染族群間HDV的防治，對於HIV/HBV且非IDU的族群防治的重點在於宣導安全性行為以減少HDV感染的風險。

關鍵字

雞尾酒療法；肝炎；血清感染發生率；梅毒；性行為感染

並列摘要

Super-infection with hepatitis D virus (HDV) in HIV/HBV-coinfected patients may increase risk for hepatitis flares and chronic hepatic complications. In this retrospective observational study, we aimed to determine the incidence of and factors associated with recent HDV super-infection among HIV/HBV-coinfected patients without injection drug use in Taiwan, where the prevalence of chronic HBV infection among HIV-infected patients were 18 to 20%. During the study period, 375 HIV/HBV-coinfected patients were enrolled, including 241 male homosexuals, 49 heterosexuals, 16 bisexuals, 34 injection drug users (IDUs) and 35 infected through other routes. We found 38 were HDV Ab positive(10.1%), 318 HDV Ab negative(84.3%) and 2 equivocal(0.5%). These patients were infected with HDV genotypes 2 (N=9) and 4 (N=19). No superinfected of other HDV genotypes were observed in these patients during follow up. After 1763.63 person-years of follow-up (PYFU), the overall incidence rate of HDV infection was 9.07 per 1000 PY, which increased from 0 in 1992-2001, 3.91 in 2002-2006 to 13.26 per 1000 PY in 2007-2012 (P<0.05). In the nested case-control study, we found that more patients with recent HDV infection had elevated aminotransferase levels and syphilis than those without seroconversion. There were no differences in terms of risk behavior for HIV transmission, CD4 or plasma HIV RNA, plasma HBV DNA, receipt of lamivudine or tenofovir, or anti-HCV seropositivity between the case and control patients. We established a real-time PCR method for quantification of HDV RNA load to assess the effect of HAART. We found HAART reduced HIV and HBV viral load, but not HDV RNA load and HBsAg titer. Eight HDV seroconvertors and 15 HDV negative patients were compared with respect to the distribution of HBV DNA, HBsAg and HDV RNA. HBsAg titer in HDV negative patients was higher than that in HDV seroconvertors when HDV Ab were tested last negative and first positive. Besides, the HBsAg titer decreased in HDV seroconvertors more significantly in HDV negative patients (P<0.05), which was associated with HDV RNA. In the era of HAART, the overall incidence of recent HDV infection in HIV/HBV-coinfected patients was 9.07 per 1,000 PYFU, HDV seroconvertors increased significantly from 1992-2001 to 2007-2012 which was associated with hepatitis flares and syphilis despite treatment with lamivudine or tenofovir. HAART was effective for control of HIV and HBV replication, but ineffective in reducing HDV RNA load and HBsAg titer. We suggested the public health policy should pay attention to HDV prevention. For example, to make widely known the guidance of safety sexual behavior to reduce the risk of HDV infection in HIV/HBV and non-IDU group.

並列關鍵字

highly active antiretroviral therapy ； hepatitis ； seroincidence ； syphilis ； sexually transmitted infection

參考文獻

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台灣地區愛滋病毒與B型肝炎病毒共同感染者體內D型肝炎病毒之血清流行病學探討

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