Raltegravir-intensified initial antiretroviral therapy in advanced HIV disease in Africa: A randomised controlled trial.
Raltegravir-intensified initial antiretroviral therapy in advanced HIV disease in Africa: A randomised controlled trial.
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DOI：
10.1371/journal.pmed.1002706
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发表时间：
2018-12
期刊：
影响因子：
15.8
通讯作者：
REALITY trial team
中科院分区：
文献类型：
--
作者：
Kityo C;Szubert AJ;Siika A;Heyderman R;Bwakura-Dangarembizi M;Lugemwa A;Mwaringa S;Griffiths A;Nkanya I;Kabahenda S;Wachira S;Musoro G;Rajapakse C;Etyang T;Abach J;Spyer MJ;Wavamunno P;Nyondo-Mipando L;Chidziva E;Nathoo K;Klein N;Hakim J;Gibb DM;Walker AS;Pett SL;REALITY trial team
在撒哈拉以南非洲，严重免疫功能低下的艾滋病毒感染者在开始抗逆转录病毒治疗（ART）后不久死亡率很高（约10%）。这一组也有最大的发病率和死亡率与免疫重建炎症综合征（IRIS），一个矛盾的反应，成功的ART。整合酶抑制剂导致显着更快的下降HIV病毒载量（VL）比所有其他ART类。我们假设，用整合酶抑制剂雷特格韦加强标准三联药物ART，将更快地降低HIV VL，从而降低早期死亡率，尽管这种策略也可能导致更多的IRIS事件。在一项2 × 2 × 2析因开放标签平行组试验中，来自肯尼亚、马拉维、乌干达和津巴布韦地区医院的8个城市/城郊艾滋病诊所的感染艾滋病病毒的初治成人、青少年和5岁以上儿童，分化簇4（CD4）<100个细胞/mm3，以1：1的比例随机接受标准三联药物ART治疗，伴或不伴12周的雷特格韦强化治疗，随访48周。主要结局是24周死亡率，按意向治疗进行分析。在2，356名筛选合格的个体中，1，805名在2013年6月18日至2015年4月10日期间随机分配。在1，805例受试者中，961例（53.2%）为男性，72例（4.0%）为儿童/青少年，中位年龄为36岁，CD4计数为37个细胞/mm3，血浆病毒血症为249，770拷贝/mL。五十六例受试者（3.1%）在48周时失访。到24周时，97/902（10.9%）雷特格韦强化ART vs 91/903（10.2%）标准ART参与者死亡（调整后的风险比[aHR]= 1.10 [95% CI 0.82 - 1.46]，p = 0.53），没有证据表明与其他随机化相互作用（p异质性> 0.7），尽管4周时雷特格韦强化ART对VL的抑制显著更大，（标准ART组343/836 [41.0%] vs 113/841 [13.4%]，p <0.001）和12周（标准ART组567/789 [71.9%] vs 415/803 [51.7%]，p <0.001）。在48周内，没有证据表明死亡率存在差异（aHR = 0.98 [95% CI 0.76 - 1.28]，p = 0.91）;严重（aHR = 0.99 [0.81 - 1.21]，p = 0.88），4级（aHR = 0.88 [0.71 - 1.09]，p = 0.29）或ART修饰（aHR = 0.90 [0.63 - 1.27]，p = 0.54）不良事件（后者发生在59例[6.5%]接受雷特格韦强化ART的受试者中，而66例[7.3%]接受标准ART的受试者中）;在判断为与IRIS兼容的事件中（发生于89例[9.9%]接受雷特格韦强化ART的受试者vs 86例[9.5%]接受标准ART的受试者，p = 0.79）或住院期间（aHR = 0.94 [95% CI 0.76 - 1.17]，p = 0.59）。在12周时，1名和2名强化雷特格韦的参与者分别预测了中等水平和高水平的雷特格韦耐药。在48周时，核苷逆转录酶抑制剂（NRTI）突变K219E/Q（p = 0.004）和非核苷逆转录酶抑制剂（NNRTI）突变K101 E/P（p = 0.03）和P225 H（p = 0.007）在雷特格韦强化ART参与者的病毒中不太常见，对替诺福韦（p = 0.06）、阿巴卡韦（p = 0.08）和利匹韦林（p = 0.07）的中等或高水平耐药的证据较弱。该研究的局限性包括一些参与者的临床、放射学和/或微生物学信息有限，反映了中心的可用服务，以及缺乏基线基因型。尽管12周的雷特格韦强化治疗耐受性良好，并且在早期死亡风险最大的时间内比标准三联药物ART更快地降低HIV病毒血症，但该策略并未降低该组的死亡率或临床事件，因此没有必要。没有过多的IRIS相容性事件，表明整合酶抑制剂可以安全地用作严重免疫功能低下个体的标准三联药物一线治疗的一部分。ClinicalTrials.gov 国际标准随机对照试验编号ISRCTN 43622374。在因子随机现实试验中，Sarah步行者和同事记录了晚期艾滋病患者强化初始抗逆转录病毒治疗的结果。在非洲，艾滋病毒阳性并开始接受严重免疫抑制治疗（CD4 <100个细胞/mm3）的人在开始治疗后不久死亡的风险很高。预计在标准的三联抗逆转录病毒治疗中加入整合酶抑制剂（雷特格韦）12周将更快地降低HIV病毒载量：我们想知道这是否会降低早期高死亡率。我们随机分配了1，805名成年人，青少年和年龄较大的儿童接受标准抗逆转录病毒治疗，有或没有12周的连续性雷特格韦。我们发现，接受12周连续性雷特格韦治疗的患者HIV病毒载量下降速度明显更快。然而，我们发现，在开始治疗后24周内，接受抗拉替拉韦治疗的患者（97/902 [10.9%]）与未接受抗拉替拉韦治疗的患者（91/903 [10.2%]）之间的死亡率无显著差异;在临床疾病进展、免疫重建、炎症综合征或不良事件方面也无差异。在这项研究中，我们发现，加强初始抗逆转录病毒治疗的效力并没有降低治疗的早期死亡率，也没有为在严重免疫抑制的情况下开始治疗的个体中广泛使用提供支持。然而，它也没有增加临床重要的免疫重建炎症综合征的发生率，这表明整合酶抑制剂可以安全地取代标准一线抗逆转录病毒治疗的其他组分。
In sub-Saharan Africa, individuals infected with HIV who are severely immunocompromised have high mortality (about 10%) shortly after starting antiretroviral therapy (ART). This group also has the greatest risk of morbidity and mortality associated with immune reconstitution inflammatory syndrome (IRIS), a paradoxical response to successful ART. Integrase inhibitors lead to significantly more rapid declines in HIV viral load (VL) than all other ART classes. We hypothesised that intensifying standard triple-drug ART with the integrase inhibitor, raltegravir, would reduce HIV VL faster and hence reduce early mortality, although this strategy could also risk more IRIS events. In a 2×2×2 factorial open-label parallel-group trial, treatment-naive adults, adolescents, and children >5 years old infected with HIV, with cluster of differentiation 4 (CD4) <100 cells/mm3, from eight urban/peri-urban HIV clinics at regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe were randomised 1:1 to initiate standard triple-drug ART, with or without 12-week raltegravir intensification, and followed for 48 weeks. The primary outcome was 24-week mortality, analysed by intention to treat. Of 2,356 individuals screened for eligibility, 1,805 were randomised between 18 June 2013 and 10 April 2015. Of the 1,805 participants, 961 (53.2%) were male, 72 (4.0%) were children/adolescents, median age was 36 years, CD4 count was 37 cells/mm3, and plasma viraemia was 249,770 copies/mL. Fifty-six participants (3.1%) were lost to follow-up at 48 weeks. By 24 weeks, 97/902 (10.9%) raltegravir-intensified ART versus 91/903 (10.2%) standard ART participants had died (adjusted hazard ratio [aHR] = 1.10 [95% CI 0.82–1.46], p = 0.53), with no evidence of interaction with other randomisations (pheterogeneity > 0.7) and despite significantly greater VL suppression with raltegravir-intensified ART at 4 weeks (343/836 [41.0%] versus 113/841 [13.4%] with standard ART, p < 0.001) and 12 weeks (567/789 [71.9%] versus 415/803 [51.7%] with standard ART, p < 0.001). Through 48 weeks, there was no evidence of differences in mortality (aHR = 0.98 [95% CI 0.76–1.28], p = 0.91); in serious (aHR = 0.99 [0.81–1.21], p = 0.88), grade-4 (aHR = 0.88 [0.71–1.09], p = 0.29), or ART-modifying (aHR = 0.90 [0.63–1.27], p = 0.54) adverse events (the latter occurring in 59 [6.5%] participants with raltegravir-intensified ART versus 66 [7.3%] with standard ART); in events judged compatible with IRIS (occurring in 89 [9.9%] participants with raltegravir-intensified ART versus 86 [9.5%] with standard ART, p = 0.79) or in hospitalisations (aHR = 0.94 [95% CI 0.76–1.17], p = 0.59). At 12 weeks, one and two raltegravir-intensified participants had predicted intermediate-level and high-level raltegravir resistance, respectively. At 48 weeks, the nucleoside reverse transcriptase inhibitor (NRTI) mutation K219E/Q (p = 0.004) and the non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E/P (p = 0.03) and P225H (p = 0.007) were less common in virus from participants with raltegravir-intensified ART, with weak evidence of less intermediate- or high-level resistance to tenofovir (p = 0.06), abacavir (p = 0.08), and rilpivirine (p = 0.07). Limitations of the study include limited clinical, radiological, and/or microbiological information for some participants, reflecting available services at the centres, and lack of baseline genotypes. Although 12 weeks of raltegravir intensification was well tolerated and reduced HIV viraemia significantly faster than standard triple-drug ART during the time of greatest risk for early death, this strategy did not reduce mortality or clinical events in this group and is not warranted. There was no excess of IRIS-compatible events, suggesting that integrase inhibitors can be used safely as part of standard triple-drug first-line therapy in severely immunocompromised individuals. ClinicalTrials.gov NCT01825031. International Standard Randomised Controlled Trials Number ISRCTN 43622374. In the factorial randomised REALITY trial, Sarah Walker and colleagues document outcomes of intensified initial antiretroviral treatment for people with advanced HIV disease. Individuals in Africa who are HIV positive and initiating treatment with severe immunosuppression (CD4 < 100 cells/mm3) have high risks of dying shortly after starting treatment. It would be expected that adding an integrase inhibitor (raltegravir) to standard triple-drug antiretroviral therapy for 12 weeks would reduce HIV viral load faster: we wanted to find out whether this would reduce high early mortality. We randomly allocated 1,805 adults, adolescents, and older children to receive standard antiretroviral therapy with or without 12 weeks of adjunctive raltegravir. We found that the group receiving 12 weeks of adjunctive raltegravir had significantly faster declines in HIV viral load. However, we found no significant difference in deaths within 24 weeks of starting treatment between those receiving adjunctive raltegravir (97/902 [10.9%]) or not (91/903 [10.2%]); nor were there differences in clinical disease progression, immune reconstitution, inflammatory syndrome, or adverse events. In this study, we found that intensifying the potency of initial antiretroviral therapy did not reduce early mortality on treatment, providing no support for its widespread use in individuals initiating treatment with severe immunosuppression. However, it also did not increase the rates of clinically important immune reconstitution inflammatory syndrome, suggesting that integrase inhibitors could replace other components of standard first-line antiretroviral therapy safely.
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DOI：
10.1016/s2352-3018(18)30038-9
发表时间：
2018-05
期刊：
The lancet. HIV
影响因子：
--
作者：
Mallewa J;Szubert AJ;Mugyenyi P;Chidziva E;Thomason MJ;Chepkorir P;Abongomera G;Baleeta K;Etyang A;Warambwa C;Melly B;Mudzingwa S;Kelly C;Agutu C;Wilkes H;Nkomani S;Musiime V;Lugemwa A;Pett SL;Bwakura-Dangarembizi M;Prendergast AJ;Gibb DM;Walker AS;Berkley JA;REALITY trial team
通讯作者：
REALITY trial team
影响因子：
3
作者：
Lake JE;McComsey GA;Hulgan T;Wanke CA;Mangili A;Walmsley SL;Stramotas SA;Tracy R;Currier JS
通讯作者：
Currier JS
DOI：
10.1097/qad.0b013e32833d45c5
发表时间：
2010-09-10
期刊：
AIDS (London, England)
影响因子：
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作者：
Cornell M;Grimsrud A;Fairall L;Fox MP;van Cutsem G;Giddy J;Wood R;Prozesky H;Mohapi L;Graber C;Egger M;Boulle A;Myer L;International Epidemiologic Databases to Evaluate AIDS Southern Africa (IeDEA-SA) Collaboration
通讯作者：
International Epidemiologic Databases to Evaluate AIDS Southern Africa (IeDEA-SA) Collaboration
影响因子：
3.7
作者：
Gupta A;Nadkarni G;Yang WT;Chandrasekhar A;Gupte N;Bisson GP;Hosseinipour M;Gummadi N
通讯作者：
Gummadi N
影响因子：
3.8
作者：
Asmuth, David M.;Ma, Zhong-Min;Pollard, Richard B.
通讯作者：
Pollard, Richard B.