HIV has had a major impact in low- and middle-income countries, causing serious illness and many deaths. HIV treatment has greatly improved survival and people whose HIV is well controlled can now live almost as long as people without HIV.

However, people who start treatment late or whose treatment has not worked well may have very weak immune systems, shown by very low CD4 counts. These patients are said to have advanced HIV disease and are still at high risk of serious infections. Common infections include pneumonia and bloodstream infections caused by bacteria, which often lead to hospital admission or death.

A previous study showed that giving extra preventive antibiotics when starting HIV treatment reduced illness and death. The REVIVE study aims to find out whether a short course of a widely available antibiotic, azithromycin, is safe, reduces hospital stays, and lowers the risk of death in people with advanced HIV disease.

The study plans to enroll 300 adults in Kenya from two hospitals: Kenyatta National Hospital and Jaramogi Oginga Odinga Teaching and Referral Hospital. The participants will be adults aged 18 years and older with very low CD4 counts (of less than 100) from the outpatient clinics, or referrals from nearby clinics, or admitted in the three hospitals. People in the study will be put into one of two groups by chance. One group will take azithromycin once a day for four weeks, and the other group will take a look-alike pill with no medicine in it. Everyone in the study will continue to receive their usual HIV treatment as recommended in the national guidelines.

The main outcome being studied is death from any cause within 24 weeks. The study will also look at whether the treatment works differently depending on factors such as sex, body weight, tuberculosis status, use of other preventive medicines, and CD4 count.

Background

Low- and middle-income countries have been profoundly impacted by HIV disease, where the disease perpetuates significant morbidity and mortality. Efficacious antiretroviral therapy (ART) has drastically improved prognosis, with the life expectancy of those who achieve virologic suppression approaching that of the general population. However, patients with low CD4 cell count and advanced HIV disease (AHD), either at baseline due to late patient presentation or suboptimal treatment secondary to myriad possible factors remain at great risk of opportunistic infections. Bacterial pneumonia and bacteraemia are leading causes of hospitalisation and mortality in patients with AHD, and frequently identified pathogens include Streptococcus pneumoniae, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae and non-typhoidal Salmonella. The REALITY trial demonstrated benefit from enhanced antimicrobial prophylaxis at time of ART initiation. Azithromycin, a relatively safe, broad-spectrum macrolide antibiotic which is widely accessible was part of the package intervention in the REALITY trial. REVIVE trial will hypothesise that short course azithromycin is safe, effective, reduces hospitalisation and has independent mortality benefit to patients with AHD.

Methods

This is a multi-centre, randomised, placebo-controlled, double-blinded, parallel group, event-driven trial coordinated through Population Health Research Institute (PHRI), a joint institute of Hamilton Health Sciences and McMaster University, Hamilton, Canada.

The trial will target to competitively enrol 300 participants in Kenya at The Kenyatta National hospital and Jaramogi Oginga Odinga Teaching and Referral Hospital. Patients above 18 years of age with CD4 cell count <100 cells/mm3 will be screened for enrolment. Screening will include participants on outpatient follow up at the primary sites, participants referred from facilities in the catchment areas of the primary centers as well as inpatients at the two facilities. Participants will be randomised 1:1 at time of study entry to receive 250mg azithromycin once daily for 4 weeks or identical placebo. Concomitant standard of care per the national guidelines will continue for all participants.

The primary analysis will use time-to-event methods Cox proportional hazards regression, censoring at 24 weeks. We will explore treatment effects in pre-specified subgroup defined by sex, weight, active TB at randomization, concurrent cotrimoxazole and isoniazid prescription and CD4 count. The primary outcome that will be evaluated will be all-cause mortality over first 24 weeks after randomisation. The trial will also evaluate all-cause mortality at 12 weeks, hospitalisation at 24 weeks, adverse drug reactions, quality of life of participants and cost effectiveness.

Conclusion

REVIVE trial will evaluate the efficacy, benefits, safety and cost effectiveness of addition of azithromycin to the standard of care in in patients with AHD.