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'25 at 25': Reducing deaths among people starting HIV treatment with advanced disease

18 Oct 2024

Huge progress has been made in the last two decades at improving access to treatment for people living with HIV around the world. But around 15-30% of people starting HIV treatment have advanced disease, and are at high risk of dying within in the first few weeks of treatment. In this part of our ‘25 at 25’ series, we look back at the REALITY trial, which found a way to prevent deaths among people starting HIV treatment with advanced disease. 

HIV affects the immune system, making it vulnerable to infections. Antiretroviral therapy can control the virus, allowing the immune system to do its job, keeping people living with HIV healthy. We know from the START trial that starting treatment as early as possible after infection is best. But not everyone does start treatment soon after infection. If the virus has already caused lots of damage to the immune system by the time antiretroviral therapy is started, people can be at high risk of death in the first few weeks of treatment. Most of these deaths are due to invasive bacterial infections, tuberculosis or cryptococcal meningitis. 

The REALITY trial looked at ways to reduce these deaths in the early stages of treatment. It tested three strategies, in addition to standard HIV treatment, for the first 12 weeks of treatment: 

  • A bundle of medicines (enhanced prophylaxis) to prevent infections 
  • Increasing the potency of ART by adding the anti-HIV drug raltegravir to reduce the amount of virus in the blood faster 
  • Ready-to-Use Supplementary Food to improve nutritional status 

1,805 adults and children over 5 years of age from Kenya, Malawi, Uganda and Zimbabwe took part in the REALITY trial. All had advanced HIV disease, with CD4 counts (a measure of the health of the immune system) under 100 cells/mm3 and were starting Antiretroviral medicines (ARVs). People who took part in the trial were followed up for 48 weeks. 

In the enhanced prophylaxis comparison, people were randomised to immediately receive either cotrimoxazole prophylaxis (an antibiotic that can be used to prevent bacterial infections) which is standard care, or a package that also included additional drugs: 

  • Isoniazid for 12 weeks to prevent tuberculosis (in a new single pill with cotrimoxazole) 
  • Fluconazole for 12 weeks to prevent cryptococcal disease and candida  
  • Azithromycin for 5 days to prevent bacterial and protozoal diseases 
  • Albendazole (single dose) to treat worms 

REALITY found there were three fewer deaths for every hundred people treated in the group who had the enhanced prophylaxis than the group who had standard cotrimoxazole prophylaxis. Or, putting this another way, enhanced prophylaxis reduced the risk of death by 27%. People in the enhanced prophylaxis group were also less likely to have severe AIDS illnesses, abnormal test results or require admission to hospital. 

The drugs used in the enhanced prophylaxis package are all relatively low cost, costing less than $5 more than standard cotrimoxazole, per patient. Health economic analysis has found that the package was cost-effective in all the countries where the trial was carried out. 

The researchers estimate that around 300,000 people could benefit from the enhanced prophylaxis package each year. If implemented, it could save the lives of around 10,000 people each year, and protect many others from infections. 

The results of the comparison that tested adding an extra ARV drug (raltegravir) to standard ART showed adding raltegravir decreased the amount of HIV virus in the blood much faster than standard ART. But this rapid reduction in viral load did not lead to a reduction in deaths or severe AIDS illnesses. The ready-to-use supplementary food did not decrease deaths. 

Implementing the results of the REALITY trial depends on being able to identify people with advanced disease who need this additional support, through CD4 testing. At the time REALITY was carried out, there had been a move away from routine CD4 testing. Since the results of the REALITY trial have been published, there has been increased interest in identifying people with advanced disease. Recent WHO guidelines support the use of CD4 testing people who are starting HIV treatment, in order to identify who needs additional support.  

Implementing all parts of the package (and changing WHO guidelines) has been rather patchy, as there were different views about the need for diagnostic testing for these diseases which still is not widely available. However all parts of this trial have been included as a recommended option in WHO guidelines for people presenting with advanced HIV disease where diagnostics are not available.  

Further information