Project Overview
Despite widespread roll-out of antiretroviral treatment, approximately 630,000 people died of HIV-related diseases in 2024. 60% of these deaths occurred in African countries, a consequence of the high proportion of people with advanced HIV disease (AHD, defined as a CD4 count below 200 cells/µL). People with AHD are particularly susceptible to developing severe infections, leading to death in approximately 20% of inpatients. However, the true burden and causes of infections among inpatients living with HIV remains unknown, leading to gaps in guidelines published by the World Health Organization. ADVANCE GERMS-SA aims to determine the burden, aetiology of, and risk factors for severe infections among hospitalised adults living with HIV in South Africa.
The Problem
Paucity of data on causes of illness and death in hospitalised people with AHD
Although the burden of tuberculosis and cryptococcal meningitis is well described, accounting for more than half of HIV-related deaths, the contribution and aetiology of other severe infections, including antimicrobial-resistant (AMR) infections, to hospitalisation and death among patients with AHD remain poorly defined.
Evidence from cohort and autopsy studies of hospitalised patients indicate that severe bacterial infections (including sepsis, meningitis, and pneumonia) account for a large proportion of HIV-related deaths in African countries. However, the exact proportion is likely higher than current estimates as bacterial infections are often difficult to diagnose and determine as a cause of death. Evidence from autopsy studies demonstrates that most pathogens are not identified by routine testing prior to death, emphasising the limitations of culture-based diagnostics in patients with sepsis. Although HIV is a known risk factor, the true burden of severe fungal infections among people with AHD also remains unknown due to limited diagnostic tools and under-investigation of clinical syndromes attributed to other opportunistic infections.
The risk of AMR infections among people living with HIV is likely greatest among those with AHD due to frequent hospital admissions and antibiotic prescriptions. However, national and facility-level surveillance programmes to identify AMR patterns in countries with high burdens of AHD are scarce. The gaps in data on the burden, aetiology of, and risk factors for infections among people with AHD lead to a lack of evidence-based preventative and curative interventions.
The Impact
ADVANCE GERMS-SA will use a vast network of laboratory-based data from patients living with HIV across South Africa, an established national surveillance platform, GERMS-SA, and facility-level cohort studies to investigate severe infections among hospitalised people living with HIV. A three-tiered approach will generate different levels of surveillance, and a rich sample repository will yield an unprecedented opportunity to investigate the causes of severe infections in patients with AHD that are frequently missed by routine care diagnostics.
Further evidence on the burden, aetiology of, and risk factors for severe infections among adults with AHD will inform guidance for preventing and treating infections in outpatient and inpatient settings, including antimicrobial prophylaxis, targeted pre-emptive treatment, expanded vaccination, screening, diagnostic, and treatment packages, and post-discharge care.
The findings of ADVANCE GERMS-SA will be highly relevant to other African countries, providing the evidence required to guide future trials and guidelines on how to prevent and screen for severe infections, investigate and manage patients when they seek care at hospital level, and provide optimal follow-up. Targeted interventions aiming to reduce the impact of severe infections in people with AHD could significantly reduce the number of HIV-related deaths worldwide.
Study Design
Population-level Retrospective Record-Linkage Cohort study
A national cohort of patients with AHD (CD4 <200 cells/μL) and without AHD (CD4 >350 cells/μL) will be created using data from the National Health Laboratory Service (NHLS). All adult patients with at least one CD4 test result between 2018 and 2023 will be included. NHLS Pathology data and GERMS-SA surveillance datasets from the National Institute for Communicable Diseases (NICD) will be linked to the cohort to estimate the incidence and aetiology of laboratory-confirmed bloodstream infections, meningitis, tuberculosis and cryptococcal meningitis among patients with AHD. Modelling will be used to assess the effect of AHD (compared to non-AHD) on the risk of severe infections. The epidemiology and spatial distribution of infections and AMR in patients with and without AHD will be determined.
Facility-level Surveillance Cohort Study
Surveillance data will be collected from the clinical notes of adult people living with HIV who are admitted to hospital under study-associated medical units at two tertiary hospitals in Johannesburg. Isolates of pathogens identified to cause bloodstream infections or meningitis during admission will be analysed for phenotypic and genotypic AMR. Remnant blood, cerebrospinal fluid, urine, and stool samples from patients with AHD will undergo additional testing after all routine care analyses to elucidate infective causes of illness not captured by routine tests.
Facility-level Prospective Cohort Study
Prospective data and additional samples will be collected from a cohort of patients with AHD who are admitted to the same hospitals in Johannesburg and provide personal or proxy informed consent. Additional samples (blood, mycobacterial blood cultures, urine, nasopharyngeal/skin/oral/rectal swabs, oral wash samples and mask inserts) will be analysed for infectious causes of illness not captured by routine tests. Participants will be followed up by phone call to ascertain morbidity and mortality during a 6-month period.
Patient Population
Project Outcome Measures
All tiers: Incidence of severe bacterial and fungal infections and AMR infections in patients with AHD admitted to hospital
Timeline
Recruitment
Team Members
Media
Tier 2 Launch
Tier 3 Launch
Wake R. Fungal Sepsis and Advanced HIV Disease. (Invited talk) TIMM, Bilbao, Spain. 2025
Publications and Abstracts
mGem: Sepsis and antimicrobial resistance in the context of advanced HIV disease
Authors: Rachel M. Wake, Nelesh P. Govender
Sepsis triggered by bloodstream infections (BSI) is a significant driver of HIV-related mortality, particularly among in-patients with advanced HIV disease (AHD). Currently, the incidence, etiology, and outcomes of BSI in this population are poorly defined…
Missed opportunities for HIV testing among medical admissions in South Africa
Juliet Vimbai Rundogo, Emily Prendergast, Nonhlanhla Phume, Jeremy Nel, Lauren Richards, Merika Tsitsi, Lior Chernick, Nelesh Govender, and Rachel Wake
Juliet presented at SAHIV 2025: Missed opportunities for HIV testing among medical admissions in South Africa- ADVANCE GERMS. Rundogo JV, Prendergast E , Phume N, et al. SAHCS 2025 Conference Abstract # 46
Antimicrobial Chemotherapy Conference 2026
Session six: Oral poster presentations-Investigating the aetiology and contribution of antimicrobial-resistant infections to illness and death among hospitalised adults with advanced HIV disease: observations from a retrospective cohort in South Africa.
Dr Emily Prendergast, University of the Witwatersrand, Johannesburg