Mechanisms underlying enhanced infection prophylaxis for advanced HIV in Africa

非洲晚期艾滋病毒加强感染预防的机制

• 批准号: MR/P022251/1
• 负责人: Andrew Prendergast
• 金额: $ 105.25万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP022251%2F1
• 关键词: Mechanisms; underlying; enhanced; infection; prophylaxis

Around one-quarter of people with HIV in Africa have very advanced disease when they start treatment, and one-in-ten die during the first few months of taking HIV medicines. Deaths occur due to a variety of different infections and from a failing immune system, which is over-active but not efficient at fighting infections (so-called 'immune activation'). In the REALITY clinical trial, which enrolled 1805 children and adults in four African countries, we showed that giving these patients a 'bundle' of 5 different types of anti-infection medicines during the first 3 months of HIV treatment led to a 27% reduction in deaths. This new approach could save 3 lives for every 100 people treated with these extra anti-infection medicines, and has the advantage of being easy to deliver at community-based health clinics in Africa. Before scaling up this new intervention to reach more people with advanced HIV, decision-makers (such as the World Health Organization and National Ministries of Health) need to understand the pros and cons of such an approach. To help inform this process, we now need to understand exactly how this bundle of anti-infection medicines works.In the REALITY study, the 'bundle' reduced tuberculosis and fungal infections, but did not seem to have an effect on the number of worm or bacterial infections that were reported during the study. It is possible, therefore, that we do not need to include the 2 antibiotics (albendazole and azithromycin) that were meant to prevent worm and bacterial infections. If these two medicines are not needed in the 'bundle' this would save costs and reduce the risks of both side effects and developing antibiotic resistance. On the other hand, we may have missed diagnosing bacterial and worm infections in patients who died, because there are few facilities that can test for these infections in Africa and some patients died at home. This study will use blood and stool samples collected from patients who died or survived in the REALITY trial to try and understand how the bundle of anti-infection medicines worked. We will look at using more sensitive methods for detecting these bacteria and worms (by identifying their genetic material in patient samples) to see if azithromycin and albendazole helped to prevent infections in the bloodstream or gut. We will also look to see if these anti-infection medicines helped to reduce the high levels of unhealthy immune activation, which may stop people dying by preventing the immune system from getting exhausted and failing completely. If we find evidence that albendazole and azithromycin are important in reducing deaths, then they clearly need to be included in the bundle of anti-infection medicines. If we find no evidence that they contributed to reducing deaths, then they could be removed from the 'bundle'. Finally, even with this new bundle of care, 11% of patients with advanced HIV died by the end of the first year of HIV treatment, and we clearly need new ways of reducing this high ongoing death rate. It is possible that the 5 anti-infection medicines and the way in which we chose to give them were not enough, and that other approaches to preventing infections, reducing immune activation and improving the health of the gut are needed. The laboratory studies we plan to do will help to understand the reasons people still die, and what the next intervention trial might be to help avoid this.

在非洲，大约四分之一的艾滋病毒携带者在开始治疗时患有非常严重的疾病，十分之一的人在服用艾滋病毒药物的头几个月内死亡。死亡是由于各种不同的感染和免疫系统的失效造成的，免疫系统过度活跃，但在对抗感染方面效率不高(所谓的“免疫激活”)。在四个非洲国家的1805名儿童和成人参加的现实临床试验中，我们表明，在艾滋病毒治疗的前3个月，给这些患者5种不同类型的抗感染药物，可以减少27%的死亡。这种新方法可以挽救每100名接受这些额外抗感染药物治疗的人的3条生命，而且其优点是很容易在非洲的社区卫生诊所提供。在扩大这一新的干预措施以接触到更多晚期艾滋病毒感染者之前，决策者(如世界卫生组织和各国卫生部)需要了解这种方法的利弊。为了帮助了解这一过程，我们现在需要确切地了解这种抗感染药物是如何发挥作用的。在现实研究中，这一捆绑药物减少了结核病和真菌感染，但似乎对研究期间报告的蠕虫或细菌感染的数量没有影响。因此，我们有可能不需要包括用于预防蠕虫和细菌感染的两种抗生素(阿苯达唑和阿奇霉素)。如果这两种药物不需要捆绑在一起，这将节省成本，并降低副作用和产生抗生素耐药性的风险。另一方面，我们可能错过了对死亡患者的细菌和蠕虫感染的诊断，因为在非洲，几乎没有设施可以检测这些感染，一些患者在家中死亡。这项研究将使用从现实试验中死亡或存活的患者身上收集的血液和粪便样本，试图了解抗感染药物束是如何起作用的。我们将研究使用更敏感的方法来检测这些细菌和蠕虫(通过识别患者样本中的遗传物质)，看看阿奇霉素和阿苯达唑是否有助于预防血流或肠道感染。我们还将研究这些抗感染药物是否有助于降低高水平的不健康免疫激活，这种激活可能通过防止免疫系统耗尽和完全失效来阻止人们死亡。如果我们发现阿苯达唑和阿奇霉素在减少死亡方面很重要的证据，那么它们显然需要包括在抗感染药物捆绑包中。如果我们没有发现它们有助于减少死亡的证据，那么它们可以被从“捆绑包”中删除。最后，即使有了这种新的护理组合，11%的晚期艾滋病毒患者在接受艾滋病毒治疗的第一年结束时死亡，我们显然需要新的方法来降低这一持续的高死亡率。可能是5种抗感染药物和我们选择的给药方式不够，还需要其他预防感染、减少免疫激活和改善肠道健康的方法。我们计划进行的实验室研究将有助于了解人们仍然死亡的原因，以及下一次干预试验可能有助于避免这种情况。

项目成果

Effect of ready-to-use supplementary food on mortality in severely immunocompromised HIV-infected individuals in Africa initiating antiretroviral therapy (REALITY): an open-label, parallel-group, randomised controlled trial.

• DOI: 10.1016/s2352-3018(18)30038-9
• 发表时间: 2018-05
• 期刊: The lancet. HIV
• 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

Plasma calprotectin as a biomarker of mortality at antiretroviral treatment initiation in advanced HIV - pilot study.

• DOI: 10.12688/wellcomeopenres.15563.2
• 发表时间: 2020
• 期刊: Wellcome open research
• 作者: Kamau FW;Gwela A;Nyerere AK;Riitho V;Njunge JM;Ngari MM;Prendergast AJ;Berkley JA
• 通讯作者: Berkley JA

Causes and Timing of Mortality and Morbidity Among Late Presenters Starting Antiretroviral Therapy in the REALITY Trial.

• DOI: 10.1093/cid/cix1141
• 发表时间: 2018-03-04
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Post FA;Szubert AJ;Prendergast AJ;Johnston V;Lyall H;Fitzgerald F;Musiime V;Musoro G;Chepkorir P;Agutu C;Mallewa J;Rajapakse C;Wilkes H;Hakim J;Mugyenyi P;Walker AS;Gibb DM;Pett SL;Reduction of EArly mortaLITY in HIV-infected adults and children starting antiretroviral therapy (REALITY) Trial Team
• 通讯作者: Reduction of EArly mortaLITY in HIV-infected adults and children starting antiretroviral therapy (REALITY) Trial Team

Late Presentation With HIV in Africa: Phenotypes, Risk, and Risk Stratification in the REALITY Trial.

• DOI: 10.1093/cid/cix1142
• 发表时间: 2018-03-04
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Siika A;McCabe L;Bwakura-Dangarembizi M;Kityo C;Mallewa J;Berkley J;Maitland K;Griffiths A;Baleeta K;Mudzingwa S;Abach J;Nathoo K;Thomason MJ;Prendergast AJ;Walker AS;Gibb DM;REALITY Trial Team
• 通讯作者: REALITY Trial Team