人類免疫不全病毒感染者之潛伏性結核感染

Latent Tuberculosis Infection in HIV-infected persons

李欣蓉(Shin-Jung Lee)

指導教授 ： 方啟泰

國立臺灣大學/公共衛生學院/流行病學與預防醫學研究所/博士(2015年)

https://doi.org/10.6342/NTU.2015.01647

摘要

背景: 目前缺乏單一檢驗方法來預測人類免疫病毒(HIV)感染者得到結核病的風險。我們發展和驗證了一個臨床風險評估流程，利用CD4細胞數目，HIV病毒載量 (pVL)，和丙型干擾素釋放檢驗(IGRA)，來辨識在低到中負荷結核病情境，且已接受高效能抗反轉錄酶病毒治療(HAART)之HIV感染者，那些人具有得到結核病的高風險。
方法: 此為前瞻性五年之世代研究，在兩家醫院之HIV感染者進行，研究時間為2006年至2012年。HAART的啟用依據當時的治療準則(CD4細胞數目<=350/μL)。我們使用Cox迴歸分析來找出活動性結核的預測因子並建立評估流程。採用之驗證世代包括1455位已在國際雜誌發表之研究中的HIV感染者。我們計算模式以操作特徵曲線下面積(area under the receiver operating characteristic (ROC)curve)進行。
結論: 總共772位進入研究追蹤中位數為5.21年，其中17位發生活動性結核。CD4細胞數 < 350/μL 或 pVL ≥ 100,000/mL可以預測活動性結核發生(adjusted HR 4.87, 95% CI 1.49-15.90, P=0.009)。在CD4 ≥ 350/μL或 pVL < 100,000/mL (adjusted HR 6.09, 95% CI 1.52-24.40, P=0.01)的條件下，IGRA的結果陽性能正確預測潛伏性結核感染。比起僅使用IGRA的策略，此評估流程可使敏感度增加從37.5%到76.5%，
陰性預測值可增加從98.5%至99.2%。比起全面預防性治療策略，此評估流程可以避免468 (60.6%)人接受到不需要的結核病預防性治療。本研究世代的操作特徵曲線下面積為0.692 (95% CI: 0.587-0.798) ，在兩個驗證世代中分別為0.792 (95% CI: 0.776-0.808) 和0.766。
結論: 一個經過驗證的評估流程，包含CD4細胞數目，HIV病毒載量，和IGRA結果可以應用在低到中度結核病負荷情境，針對有例行接受HAART的HIV感染者，來引導結核病預防性治療的給予。此評估流程的實施將可避免低風險病患曝觸到不需要的藥物毒性，同時減少全面治療造成的醫療系統的負荷。

關鍵字

潛伏性結核 ； 人類免疫缺乏病毒 ； 丙型干擾素釋放檢驗 ； 流程

並列摘要

Background: Predicting the risk of tuberculosis (TB) in people living with HIV (PLHIV) using a single test is currently not possible. We aimed to develop and validate a clinical algorithm, using baseline CD4 cell counts, HIV viral load (pVL), and interferon-gamma release assay (IGRA), to identify PLHIV who are at high risk for incident active TB in low-to-moderate TB burden settings where highly active antiretroviral therapy (HAART) is routinely provided.
Methods: A prospective, 5-year, cohort study of adult PLHIV was conducted from 2006 to 2012 in two hospitals in Taiwan. HAART was initiated based on contemporary guidelines (CD4 count <= 350/μL). Cox regression was used to identify the predictors of active TB and to construct the algorithm. The validation cohorts included 1455 HIV-infected individuals from previous published studies. Area under the receiver operating characteristic (ROC) curve was calculated.
Results: Seventeen of 772 participants developed active TB during a median follow-up period of 5.21 years. Baseline CD4 < 350/μL or pVL ≥ 100,000/mL was a predictor of active TB (adjusted HR 4.87, 95% CI 1.49-15.90, P=0.009). A positive baseline IGRA predicted TB in patients with baseline CD4 ≥ 350/μL and pVL < 100,000/mL (adjusted HR 6.09, 95% CI 1.52-24.40, P=0.01). Compared with an IGRA-alone strategy, the algorithm improved the sensitivity from 37.5% to 76.5%, the negative predictive value from 98.5% to 99.2%. Compared with an untargeted strategy, the algorithm spared 468 (60.6%) from unnecessary TB preventive treatment. Area under the ROC curve was 0.692 (95% CI: 0.587-0.798) for the study cohort and 0.792 (95% CI: 0.776-0.808) and 0.766 in the 2 validation cohorts.
Conclusions: A validated algorithm incorporating the baseline CD4 cell count, HIV viral load, and IGRA status can be used to guide targeted TB preventive treatment in PLHIV in low-to-moderate TB burden settings where HAART is routinely provided to all PLHIV. The implementation of this algorithm will avoid unnecessary exposure of low-risk patients to drug toxicity and simultaneously, reduce the burden of universal treatment on the healthcare system.

並列關鍵字

latent tuberculosis ； HIV ； IGRA ； algorithm

參考文獻

18. Centers for Disease Control R.O.C. (Taiwan). Taiwan Tuberculosis Control Report 2013. Taipei: Taiwan Center for Disease Control,

1. Badri M, Wilson D, Wood R (2002) Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet 359: 2059-2064.

3. Centers for Disease Control and Prevention (2000) Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 161: S221-247.

4. Selwyn PA, Hartel D, Lewis VA, Schoenbaum EE, Vermund SH, Klein RS, et al. (1989) A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 320: 545-550.

5. Suthar AB, Lawn SD, del Amo J, Getahun H, Dye C, Sculier D, et al. (2012) Antiretroviral therapy for prevention of tuberculosis in adults with HIV: a systematic review and meta-analysis. PLoS Med 9: e1001270.