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研究生:辛宜臻
研究生(外文):Yi-Chen Hsin
論文名稱:人類免疫缺乏病毒合併伺機感染的抗反轉錄病毒治療使用時機--系統回顧與統合分析
論文名稱(外文):Timing of Antiretroviral Therapy in HIV patients withOpportunistic Infections -- a Systematic Review andMeta-analysis
指導教授:方啟泰方啟泰引用關係
指導教授(外文):Chi-Tai Fang
口試委員:盛望徽王振源林先和
口試委員(外文):Wang-Huei ShengJann-Yuan WangHsien-Ho Lin
口試日期:2016-07-28
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:流行病學與預防醫學研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:英文
論文頁數:33
中文關鍵詞:人類免疫缺乏病毒抗反轉錄病毒藥物結核病隱球菌腦膜炎免疫重建症候群
外文關鍵詞:human immunodeficiency virus(HIV)tuberculosis(TB)cryptococcal meningitisantiretroviral therapy (ART)immune reconstitution inflammatory syndrome(IRIS)
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當人類免疫缺乏病毒(human immunodeficiency virus, HIV)感染的病患罹患伺機感染時,同時併用抗反轉錄病毒藥物治療(antiretroviral therapy, ART)已證實可以降低死亡延長存活。但抗反轉錄病毒藥物的使用時機仍是臨床上難題。因此,我們希望透過系統回顧跟統合分析來回答此問題,伺機感染將著重在結核病(tuberculosis, TB)跟隱球菌腦膜炎(cryptococcal meningitis)。
自 Pubmed、Embase、ISRCTN registry、AIDSinfo、ClinicalTrial.gov 等資料庫進行文獻搜尋,從1996 至2015 年,納入相關的隨機分派臨床試驗,篩選符合的研究並進行偏差風險的評估。統合分析以風險比(risk ratio)作基準,在HIV 合併結核病的部分採用隨機效應模型,在HIV 合併隱球菌腦膜炎的部分採用固定效應模型,比較死亡跟免疫重建症候群的發生風險。
在 HIV 合併TB 感染的部分,透過系統性文獻回顧後,有七個隨機分派臨床試驗納入統合分析。其中兩個研究著墨在整合治療(integrated ART:在結核治療的六個月內開始ART)跟接續治療(sequential ART:在結核治療的六個月後開始ART)的比較。從存活結果來看,整合治療未明顯比接續治療佔優勢(pooled RR=0.79, 95% CI: 0.28-2.25)。分群分析發現患者CD4 細胞數低於200 cells/mm3 此族群接受整合治療會降低死亡。有六個研究比較時間點為早用(在結核治療的前四週開始ART)跟晚用(結核治療八週後開始ART): 早用或晚用 ART 對死亡風險沒有顯著影響(pooled RR=0.86, 95% CI: 0.67-1.11, I2:23%)。分群分析發現對於初始CD4 細胞數低於50 cells/mm3 患者,早用抗反轉錄病毒藥物可降低死亡風險。此外,早用抗反轉錄病毒藥物治療與免疫重建症候群(IRIS)的發生有關(pooled RR=2.16, 95%CI:1.67-2.80, I2:20%)。
關於 HIV 合併隱球菌腦膜炎感染,經系統性文獻回顧後,共四個隨機分派臨床試驗,共293 參加者,納入統合分析。提早使用ART(抗黴菌治療的前兩週開始ART)比延後使用ART(抗黴菌治療的四週後開始ART)明顯增加死亡風險至1.4 倍(pooled RR=1.41, 95% CI: 1.06-1.89, I2: 34.5%)。其中有兩篇涉及免疫重建症候群(IRIS),發現提早使用ART 發生IRIS 風險為延後使用的2.6 倍(pooled RR=2.64, 95%CI: 1.31-5.31, I2: 57%)。
結論
當人類免疫缺乏病毒感染的病患合併新發結核病感染時,整合及早用抗反轉錄病毒藥物(ART)未顯著降低死亡風險,但在結核治療前四週內使用ART 發生免疫重建症候群(IRIS)之風險為八週後的兩倍。分群分析發現,只有初始CD4 細胞數低於200 cells/mm3 的患者在結核治療六個月內使用ART 比六個月後死亡風險降低,在初始CD4 細胞數低於50 cells/mm3 的患者,ART 在結核治療前四週內使用比八週後死亡風險下降。考量IRIS 風險,初始CD4 細胞數高於50 cells/mm3 的患者,是否早用ART 有斟酌空間。
當人類免疫缺乏病毒感染的病患合併隱球菌腦膜炎感染時,提早使用抗反轉錄病毒藥物會增加死亡跟免疫重建症候群風險。特別是在醫藥資源貧乏的地區,建議延後使用抗反轉錄病毒藥物。


Background
Although antiretroviral therapy is essential for survival in HIV patients with acute opportunistic infections (OIs), the timing to start antiretroviral therapy (ART) remains a clinical challenge. Thus, we performed a systematic review and meta-analysis to investigate the optimal timing of ART initiation in HIV patients with acute OIs, focus on tuberculosis (TB) and cryptococcal meningitis(CM).
Methods
We searches the PubMed, Embase, ISRCTN registry, AIDSinfo and ClinicalTrial.gov for randomized controlled trials regarding these issue published from 1996 to 2015. We used the risk ratio (RR) as the effect measure, which was pooled by random effects models in part of HIV/TB and by fixed effects in part of HIV/CM. Evens of death and immune reconstitution inflammatory syndrome(IRIS) were recorded. Risk of bias was also assessed.
Results
Seven randomized controlled trials regarding timing of initiating ART in HIV/TB co-infected patients were included. Two trials compared outcome of integrated ART(within 6 months of TB treatment) with sequential ART(after 6 months of TB treatment). Integrated ART is not superior to sequential ART in survival (pooled RR=0.79, 95% CI: 0.28-2.25). SAPiT trial showed integrated ART conferred survival benefit over sequential ART in subgroup whose baseline CD4 cell count bellow 200 cells/mm3. Six trials examined the impact between early (within 4 weeks of TB treatment) and late initiation of ART (after 8 weeks of TB treatment). Early versus late initiation of ART was not associated with mortality risk (pooled RR=0.86, 95% CI: 0.67-1.11, I2:23%). Early ART reduced mortality risk in the subgroup whose baseline CD4 cell counts bellow 50 cells/mm3. Early initiation of ART increased risk of IRIS (pooled RR=2.16, 95% CI:1.67-2.80, I2:20%).
We enrolled four randomized controlled trials, total 293 participants, into systematic review regarding timing of ART initiation in HIV patients with cryptococcal meningitis. The mortality risk of earlier ART initiation (within 2 weeks of antifungal treatment) is higher than that of deferred ART initiation (after 4 weeks of antifungal treatment) (pooled RR=1.41, 95% CI: 1.06-1.89, I2: 34.5%). Two trials included CM-IRIS. Earlier initiating ART was associated with the increased risk of CM-IRIS (pooled RR=2.64, 95% CI: 1.31-5.31, I2: 57%).
Conclusion
Our findings reveal that integrated ART and early ART did not pose a significant impact on overall mortality in HIV/TB co-infected patients. Integrated ART conferred survival benefit in those with baseline CD4 cell count bellow 200 cells/mm3 and early ART reduced deaths in those whose baseline CD4 cell count bellow 50 cells/mm3. However, early ART bore a higher risk of IRIS compared with late ART. As consideration of IRIS risk, early ART within 4 weeks of TB treatment might be reconsidered in HIV/TB co-infected patients whose baseline CD4 cell counts above 50 cells/mm3. In HIV patients with cryptococcal meningitis, earlier initiation of ART was associated with increased risk of mortality and IRIS. Deferred ART will be suggested in HIV patients with cryptococcal meningitis, particularly in source-limited settings.

Acknowledgments ii
Chinese Abstract iii
Abstract v
Tables of Contents vii
List of Tables viii
List of Figures ix

Chpater 1. Timing of Antiretroviral Therapy Initiation in HIV Patients with Tuberculosis 1
1.1. Introduction 1
1.2. Methods 2
1.2.1. Inclusion and exclusion criteria 2
1.2.2. Search strategies and study selection 2
1.2.3. Data extraction 3
1.2.4. Assessment of quality of included studies 3
1.2.5. Data synthesis and statistical analysis 3
1.3. Results 4
1.4. Discussion 6
1.5. Conclusion 9
1.6. References 10
Chpater 2. Timing of Antiretroviral Therapy Initiation in HIV Patients with Cryptococcal Meningitis 22
2.1. Introduction 22
2.2. Methods 23
2.2.1. Inclusion and exclusion criteria 23
2.2.2. Search strategies and study selection 23
2.2.3. Data extraction 24
2.2.4. Assessment of quality of included studies 24
2.2.5. Data synthesis and statistical analysis 24
2.3. Results 25
2.4. Discussion 26
2.5. Conclusions 28
2.6. References 29

Chapter 1 References
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3.World Health Organization. WHO policy on collaborative TB/HIV activities: Guidelines for national programmes and other stakeholders. Geneva: World Health Organization 2012.

4.World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach: 2010 Revision. Geneva: World Health Organization 2010.

5.World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach - Second edition. Geneva: World Health Organization 2016.

6.Naidoo K, Baxter C, Abdool Karim SS. When to start antiretroviral therapy during tuberculosis treatment? Curr Opin Infect Dis 2013;26:35-42.

7.Uthman OA, Okwundu C, Gbenga K, Volmink J, Dowdy D, Zumla A, et al. Optimal timing of antiretroviral therapy initiation for HIV-infected adults with newly diagnosed pulmonary tuberculosis: a systematic review and meta-analysis. Ann Intern Med 2015;163:32-39.

8.Abay SM, Deribe K, Reda AA, Biadgilign S, Datiko D, Assefa T, et al.. The effect of early initiation of antiretroviral therapy in TB/HIV-coinfected patients: a systematic review and meta-analysis. J Int Assoc Provid AIDS Care. 2015;14:560-70

9.Yan S, Chen L, Wu W, Fu Z, Zhang H, Li Z, et al. Early versus delayed antiretroviral therapy for HIV and tuberculosis co-infected patients: a systematic review and meta-analysis of randomized controlled trials. PLoS One. 2015;10:e0127645

10.Mfinanga SG, Kirenga BJ, Chanda DM, Mutayoba B, Mthiyane T, Yimer G, et al. Early versus delayed initiation of highly active antiretroviral therapy for HIV-positive adults with newly diagnosed pulmonary tuberculosis (TB-HAART): a prospective, international, randomised, placebo-controlled trial. Lancet. Infect Dis 2014;14:563-571.

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12.Abdool Karim SS, Naidoo K, Grobler A, Padayatchi N, Baxter C, Gray AL, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Eng J Med 2010; 362(8): 697-706.

13.Abdool Karim SS, Naidoo K, Grobler A, Padayatchi N, Baxter C, Gray AL, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Eng J Med 2011;365:1492-1501.

14.Blanc FX, Sok T, Laureillard D, Borand L, Rekacewicz C, Nerrienet E, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Eng J Med 2011;365:1471-1481.

15.Havlir DV, Kendall MA, Ive P, Kumwenda J, Swindells S, Qasba SS, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Eng J Med 2011;365:1482-1491.

16.Manosuthi W, Mankatitham W, Lueangniyomkul A, Thongyen S, Likanonsakul S, Suwanvattana P, et al. Time to initiate antiretroviral therapy between 4 weeks and 12 weeks of tuberculosis treatment in HIV-infected patients: results from the TIME study. J Acquir Immune Defic Syndr 2012;60:377-383.

17.Sinha S, Shekhar RC, Singh G, Shah N, Ahmad H, Kumar N, et al. Early versus delayed initiation of antiretroviral therapy for Indian HIV-Infected individuals with tuberculosis on antituberculosis treatment. BMC Infect Dis 2012;12:168.

18.Amogne W, Aderaye G, Habtewold A, Yimer G, Makonnen E, Worku A, et al. Efficacy and Safety of Antiretroviral Therapy Initiated One Week after Tuberculosis Therapy in Patients with CD4 Counts < 200 Cells/muL: TB-HAART Study, a Randomized Clinical Trial. PLoS One. 2015;10:e0122587.

19.Lai RP, Nakiwala JK, Meintjes G, Wilkinson RJ. The immunopathogenesis of the HIV tuberculosis immune reconstitution inflammatory syndrome. Eur J Immunol 2013;43:1995-2002.

20.Yang CH, Chen KJ, Tsai JJ, Lin YH, Cheng SH, Wang KF, et al. The impact of HAART initiation timing on HIV-TB co-infected patients, a retrospective cohort study. BMC Infect Dis. 2014; 4:304.

Chapter 2 References
1.Park BJ, Wannemuehler KA, Marston BJ, GovenderN, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 2009; 23:525–30.

2.French N, Gray K, Watera C, et al. Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults. AIDS. 2002;16:1031–8

3.Djawe K, Buchacz K, Hsu L, Chen MJ, Selik RM, Rose C, Williams T, Brooks JT, Schwarcz S. Mortality Risk After AIDS-Defining Opportunistic Illness Among HIV-Infected Persons--San Francisco, 1981-2012. J Infect Dis. 2015; 212:1366-75.

4.Kambugu A, Meya DB, Rhein J, et al. Outcomes of cryptococcal meningitis in Uganda before and after the availability of highly active antiretroviral therapy. Clinical Infectious Diseases. 2008;46:1694-1701.

5.Bisson GP, Nthobatsong R, Thakur R, et al. The use of HAART is associated with decreased risk of death during initial treatment of cryptococcal meningitis in adults in Botswana. Journal of Acquired Immune Deficiency Syndromes. 2008;49:227-229.

6.Chottanapund S, Singhasivanon P, Kaewkungwal J, Chamroonswasdi K, Manosuthi W. Survival time of HIV-infected patients with cryptococcal meningitis. Journal of the Medical Association of Thailand. 2007;90:2104-2111.

7.National Institutes of Health. Prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Updated Guidelines from the Centers for Disease Control and Prevention. Clin Infect Dis. 2014;58:1308-11.

8.World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach - Second edition. 2016

9.Torok ME, Yen NT, Chau TT, et al. Timing of initiation of antiretroviral therapy in human immunodefi ciency virus (HIV)-associated tuberculous meningitis. Clin Infect Dis 2011; 52: 1374–83.

10.Makadzange AT, Ndhlovu CE, Takarinda K, Reid M, Kurangwa M, Gona P, Hakim JG. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin Infect Dis. 2010;50:1532-8.

11.Boulware DR, Meya DB, Muzoora C, Rolfes MA, Huppler Hullsiek K, Musubire A, Taseera K, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med. 2014;370:2487-98.

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14.Bisson GP, Molefi M, Bellamy S, Thakur R, Steenhoff A, Tamuhla N, et al. Early versus delayed antiretroviral therapy and cerebrospinal fluid fungal clearance in adults with HIV and cryptococcal meningitis. lin Infect Dis. 2013;56: 1165-73.

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16.Scriven JE, Rhein J, Hullsiek KH, von Hohenberg M, Linder G, Rolfes MA, et al. Early ART After Cryptococcal Meningitis Is Associated With Cerebrospinal Fluid Pleocytosis and Macrophage Activation in a Multisite Randomized Trial. J Infect Dis. 2015;212:769-78.

17.Rolfes MA, Hullsiek KH, Rhein J, Nabeta HW, Taseera K, Schutz C, et al. The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin Infect Dis. 2014;59:1607-14.


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