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

Abstract

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.