Mechanisms underlying enhanced infection prophylaxis for advanced HIV in Africa

在非洲，大约四分之一的艾滋病毒感染者在开始治疗时病情已经非常严重，十分之一的人在服用艾滋病毒药物的头几个月死亡。死亡是由于各种不同的感染和免疫系统的衰竭造成的，免疫系统过度活跃，但在对抗感染方面效率低下（所谓的“免疫激活”）。在REALITY临床试验中，我们在四个非洲国家招募了1805名儿童和成人，结果表明，在艾滋病毒治疗的前三个月，给这些患者“捆绑”5种不同类型的抗感染药物，导致死亡率降低了27%。每100名接受这些额外抗感染药物治疗的患者中，这种新方法可挽救3人的生命，并且具有易于在非洲社区卫生诊所提供的优势。在扩大这一新的干预措施以覆盖更多的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一束抗感染药物是如何起作用的。在REALITY研究中，“捆绑”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两种抗生素（阿苯达唑和阿奇霉素），这两种抗生素旨在预防蠕虫和细菌感染。如果“捆绑”中不需要这两种药物，这将节省成本，减少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能够检测这些感染的设施，而且一些患者死在家里。这项研究将使用从在REALITY试验中死亡或幸存的患者身上收集的血液和粪便样本，试图了解抗感染药物是如何起作用的。我们将考虑使用更灵敏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），以确定阿奇霉素和阿苯达唑是否有助于预防血液或肠道感染。我们还将研究这些抗感染药物是否有助于降低不健康的免疫激活水平，这可能会通过防止免疫系统耗尽和完全失效来阻止人们死亡。如果我们发现证据表明阿苯达唑和阿奇霉素在减少死亡方面很重要，那么它们显然需要被纳入抗感染药物包中。如果我们没有发现任何证据表明它们有助于减少死亡，那么它们就可以从“捆绑”中移除。最后，即使有了这种新的一揽子护理，11%的晚期艾滋病患者在艾滋病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种持续的高死亡率。可能这5种抗感染药物和我们选择的给药方式还不够，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，以及下一个干预试验可能有助于避免这种情况。

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.