Steroids and enhanced antibiotics for the treatment of patients in africa with refractory sepsis: STARS trial

The National Institute of Allergy and Infectious Diseases awarded the University of Virginia a $993,962 Cooperative Agreement (U01AI192033) on September 20, 2025, to conduct a randomized 2×2 factorial clinical trial testing hydrocortisone and enhanced antimicrobial therapy for treatment of sepsis in HIV-positive patients in sub-Saharan Africa, running through August 31, 2030.

The STARS trial (Steroids and Enhanced Antibiotics for the Treatment of Patients in Africa with Refractory Sepsis) will test two primary hypotheses: that seven-day hydrocortisone therapy followed by a seven-day taper improves 28-day mortality compared to standard care without corticosteroids, and that a 14-day enhanced antimicrobial regimen targeting tuberculosis and drug-resistant bacteria (rifampin, isoniazid, levofloxacin, and linezolid) improves 28-day mortality compared to ceftriaxone monotherapy. The trial responds to documented tuberculosis-driven sepsis mortality of 20–50 percent within the first 4–5 days of admission in sub-Saharan Africa and observed corticosteroid insufficiency in critically ill patients, particularly those with concurrent HIV and TB.

Place of performance is Charlottesville, Virginia.

Sub-recipients include Mbarara University of Science and Technology Faculty of Medicine (Uganda), awarded January 29, 2026, to lead completion of clinical trial registration, local team hiring, regulatory protocol submission, manual development, drug procurement, pharmacy and laboratory planning, and site activation in Mbarara; Kibong'oto Infectious Diseases Hospital (Tanzania), awarded February 12, 2026, to execute parallel milestones in Tanzania; and the Regents of the University of Minnesota, awarded January 19, 2026, to provide regulatory and trial-design expertise, protocol and consent document editing, and weekly oversight calls led by Dr. Boulware, drawing on his prior experience with COVID-19, cryptococcal meningitis, TB meningitis, and Ebola clinical trials.

This award falls under CFDA 93.855 (Allergy and Infectious Diseases Research).

Abstract

Sepsis is defined as life-threatening organ dysfunction due to a dysregulated host response to infection and is the leading cause of global mortality. The world health organization has declared sepsis a global priority. Yet, little is known about sepsis in the global south and specifica LLY sub-saharan africa where there are an estimated 17 million cases and 3.5 million attributable deaths per year. The majority of these patients are living with human immunodeficiency virus (HIV). We have determined the leading cause of sepsis in this region is tuberculosis (TB) which is responsible for 25-30% of bloodstream infections in septic patients. TB sepsis is associated with 20-50% mortality rates with the majority of deaths occurring within the first 4-5 days of admission. Other causative pathogens include bacteria commonly or intrinsically resistant to third-generation cephalosporins which are the standard antimicrobial treatment for sepsis adopted from the global north. We have also studied anti-TB pharmacokinetics/ pharmacodynamics in septic patients and discovered considerably low circulating drug concentrations that are suboptimal for microbial kill. Concurrently, we have also found a high burden of corticosteroid insufficiency in people with critical illness at our study sites in uganda and tanzania. HIV and TB, independently and in combination, contribute to adrenal infection and endogenous steroid insufficiency. In further observational study, adults with sepsis at our study sites treated with corticosteroids have significantly improved survival from septic shock in-line with some, but not all, trials of adjunctive steroids in infection associated critical illness. Therefore, our hypotheses are that immediate hydrocortisone administered over 7 days followed by a 7-day taper will improve 28 day mortality compared to the standard of care where corticosteroids are not administered, and that an enhanced antimicrobial regimen with optimized sepsis-specific dosing for 14 days to target TB and other drug-resistant bacteria of sepsis (rifampin, isoniazid, levofloxacin and linezolid) will improve 28 day mortality compared to the standard of care of ceftriaxone alone. We will test these hypotheses through a randomized 2X2 factorial clinical trial where participants hospitalized with HIV and sepsis will be randomized to 1) hydrocortisone or the standard care without hydrocortisone, and 2) the enhanced antimicrobial regimen plus ceftriaxone or the standard care with ceftriaxone alone. This randomized 2X2 factorial clinical trial is strongly endorsed by tanzanian and ugandan stakeholders, utilizes drugs that are available within national formularies and regional pharmacies, and if successful will be scalable for adults with sepsis in HIV endemic regions of sub-saharan africa.