高效能抗病毒療法時代HBV共同感染對HIV病人在長期臨床預後的影響：世代研究

Effect of HBV Coinfection on the Clinical Outcome of HIV-Infected Patients in the Highly Active Antiretroviral Therapy (HAART) Era: A Cohort Study

邱國瑋(Kuo-Wei Chiu)

指導教授 ： 方啟泰

共同指導教授 ： 溫在弘(Tzai-Hung Wen)

國立臺灣大學/公共衛生學院/流行病學研究所/碩士(2010年)

https://doi.org/10.6342/NTU.2010.00852

摘要

背景：因為相似的病毒傳播途徑(包括不安全的性行為，輸血，共用針具以及垂直感染) B型肝炎病毒共同感染在人類免疫缺乏病毒感染病人中相當常見。在高效能抗病毒療法出現之前的時代，人類免疫缺乏病毒感染者的存活時間很短，絕大多數患者都死於後天免疫缺乏症候群相關的伺機性感染或腫瘤等併發症，是否合併感染慢性B型肝炎對人類免疫缺乏病毒感染者預後影響很小。但情況在1997年高效能抗病毒療法全面應用後完全改觀。高效能抗病毒療法降低了人類免疫缺乏病毒感染者的伺機性感染發病率，大幅延長存活時間。人類免疫缺乏病毒感染者因後天免疫缺乏症候群相關伺機性感染死亡比例大幅下降，慢性肝炎相關死亡的比例上升。但使情況更複雜的是：高效能抗病毒療法處方中一項重要的組成藥物為Lamivudine（台灣進入高效能抗病毒療法的人類免疫缺乏病毒感染者約有90% 以上使用此藥物），它可以同時抑制人類免疫缺乏病毒和B型肝炎病毒，理論上應可抵銷慢性B型肝炎合併感染對人類免疫缺乏病毒感染者預後的不利影響。由於上述兩項因素對慢性肝炎相關死亡的效果係一正一反，難以僅憑學理預測其綜合效果。因而在高效能抗病毒療法時代，必須以實證研究探討慢性B型肝炎合併感染是否成為人類免疫缺乏病毒感染重要預後因子此一重要議題。

目標：本研究的目的即欲探討在高效能抗病毒療法時代人類免疫缺乏病毒和B型肝炎病毒共同感染的病患在不同B型肝炎病毒標記(B型肝炎s抗原，B型肝炎e抗原)下存活狀態的差異性。

方法：本研究屬於觀察性世代研究，以從1997年以來在台大醫院以及台北市立性病防治所(現為台北市立聯合醫院昆明院區)進行高效能抗病毒療法的人類免疫缺乏病毒感染者為收案對象，一共為592人納入分析，分做3組：(1) B型肝炎s抗原陰性；(2) B型肝炎s抗原陽性，B型肝炎e抗原陰性：(3) B型肝炎s抗原陽性，B型肝炎e抗原陽性，並以固定世代的方式來分析。經由病人之身分證號碼與國家死亡登記資料庫交叉比對來檢查病人全死因死亡、後天免疫缺乏症候群相關死亡以及肝臟相關疾病死亡的情形，以世代研究法追蹤至2008年12月31日，追蹤時間中位數為10.25年。運用Kaplan-Meier方法來繪製存活曲線並用log-rank檢定比較三組之間的差異。使用Cox proportional hazard model來控制可能的干擾因子。

結果：B型肝炎病毒s抗原盛行率大約為21%。存活分析的結果顯示不管在單變項或是多變項分析中，B型肝炎病毒感染對於人類免疫缺乏病毒感染者有增加死亡風險(包括全死因死亡、後天免疫缺乏症候群相關死亡以及肝臟相關疾病死亡)。在共同感染的病人中，B型肝炎病毒e抗原陽性的病人較B型肝炎病毒e抗原陰性者有更高的死亡風險但未達到統計上的顯著差異。

結論：在此高效能抗病毒療法的世代中，雖然有90%的人類免疫缺乏病毒感染者服用含有Lamivudine的處方，B型肝炎病毒s抗原仍然為肝臟相關疾病死亡的一項顯著預測因子。未來需要進一步探討是否需要以合併使用兩種或以上能有效抑制人類免疫缺乏病毒和B型肝炎毒的藥物處方來治療HIV-HBV共同感染病人。

關鍵字

HBV-HIV共同感染 ； 干安能 ； 肝臟相關疾病死亡

並列摘要

Introduction: Due to a shared route of viral transmission (including unprotected sex, blood transfusions, contaminated needles and vertical transmission), hepatitis B virus (HBV) infection is common among human immunodeficiency virus (HIV)-infected patients. Since 1997, the advance of highly active antiretroviral therapy (HAART) has greatly decreased the incidence of acquired immunodeficiency syndrome (AIDS) and prolonged patient survival, which allows a longer time for the development of HBV-associated liver disease. In the HAART era, liver-related deaths (LRD) now account for greater proportion of deaths among HIV-infected patients. Interestingly, lamivudine (3TC), an important component of HAART, can directly inhibit HBV replication, and theoretically, it might decrease the rate of liver-related deaths. Therefore, empirical studies are required to clarify the net results of these dual effects on the prognosis of HIV-HBV coinfected patients in the HAART era.

Objectives: This study aimed to investigate the differences in survival between the HBV-HIV coinfected patients with different HBV serological markers.

Methods: Six hundred and eleven HIV-infected patients who began the HAART program at the National Taiwan University Hospital (NTUH) or the Taipei Municipal Venereal Disease Control Institution (now Taipei City Hospital, KunMing Branch) (TCHKM) since 1997 were enrolled in this observational cohort study, and 592 patients were analyzed. The patients were divided into three groups: (1) HBsAg-negative; (2) HBsAg-positive, HBeAg-negative, (3) HBsAg-positive, HBeAg-positive. These patients were analyzed as fixed cohorts. To determine the endpoint (all-cause death, AIDS-related death and liver-related death), we used the Taiwan ID number of each patient to perform a cross-reference with the National Death Certificate database. The survival curves of each cohort were analyzed using the mortality rates of AIDS- and liver-related diseases, documented up to Dec 31, 2008. The median follow-up time was 10.25 years. The survival curves were generated using the Kaplan-Meier method, and a log-rank test was used to compare differences between three groups. To adjust for other potential confounding factors, a Cox proportional hazard model was used.

Results: The HBsAg prevalence was 21%. Our results revealed that HIV-infected patients with HBV infection had an increased risk for death (including all-cause death, AIDS-related death and liver-related death) in univariate and multivariate analyses. Among the coinfected patients, HBeAg-positive patients demonstrated a higher risk for death (HR>1) but the risk was not statistically significant.

Conclusions: Although 90% of the HIV-infected patients received 3TC-containing regimens in this HAART cohort, the HBsAg-positive status remained a significant predictor for LRD. Further studies are required to clarify whether a combination of drugs that effectively inhibit both HIV and HBV is needed for all HIV-HBV-coinfected patients on HAART in areas with a high HBV prevalence.

並列關鍵字

HIV-HBV coinfection ； Lamivudine ； Liver-related death

參考文獻

1. Rustgi VK, Hoofnagle JH, Gerin JL, et al.: Hepatitis B virus infection in the acquired immunodeficiency syndrome. Ann Intern Med 1984; 101(6): 795-7.

2. World Heath Organization. http://www.who.int/topics/hiv_aids/en/

3. Sun HY, Ko WC, Tsai JJ, et al.: Seroprevalence of chronic hepatitis B virus infection among taiwanese human immunodeficiency virus type 1-positive persons in the era of nationwide hepatitis B vaccination. Am J Gastroenterol 2009; 104(4): 877-84.

4. Scharschmidt BF, Held MJ, Hollander HH, et al.: Hepatitis B in patients with HIV infection: relationship to AIDS and patient survival. Ann Intern Med 1992; 117(10): 837-8.

5. Sinicco A, Raiteri R, Sciandra M, et al.: Coinfection and superinfection of hepatitis B virus in patients infected with human immunodeficiency virus: no evidence of faster progression to AIDS. Scand J Infect Dis 1997; 29(2): 111-5.