Mechanisms underlying enhanced infection prophylaxis for advanced HIV in Africa 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. The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world.