BACKGROUND: Advanced HIV disease (AHD) remains a persistent public health challenge. Data regarding the burden, characteristics and predictors of AHD is scarce specifically for rural settings of sub-Saharan Africa. This study aimed to describe trends in annual CD4 count distribution and to characterise adult persons living with HIV (PLWH) on ART who have AHD in rural KwaZulu-Natal, South Africa. METHODS: A retrospective cohort design of annual CD4 count distribution was conducted among antiretroviral therapy (ART) patients aged 18 years and older. We used routinely collected data from adults receiving ART in Eshowe and Mbongolwane areas in KwaZulu-Natal, South Africa, between January 1, 2008, and June 30, 2021. Fine-Greys competing risks regression with proportional sub-distribution hazard models was used to determine factors associated with time to CD4 recovery. RESULTS: A total of 34,729 patients were included of which 68.5% were females. The median age of the study sample was 33.5 years (interquartile range [IQR] 27-41 years), and the median CD4 count was 277 cells/μL (IQR, 149-452 cells/μL). The proportion of patients entering care with AHD declined over time from 62% in 2008 to 20% in 2021. Across all periods, those entering care with AHD were more likely to be men when compared to women (Relative risk [RR] 1.49
95% 1.33-1.67). In addition, the proportion of patients with AHD who were ART-experienced increased from 4% in 2008 to 63% in 2021. Among ART-experienced, men were more likely to present with AHD compared to women (RR 1.79
95% CI 1.52-2.11). Among those with AHD, the cumulative incidence of CD4 recovery to >
350 cells/μL was 3.21 (95% CI 3.13-3.29) per 100 adult-years follow-up time. CONCLUSION: Over time fewer patients with AHD are entering care in KwaZulu-Natal, South Africa. However, the proportion of PLWH entering care with AHD remains consistently high, affecting 1 in 4 PLWH accessing HIV services. In addition, there is an increasing number of ART-experienced patients with AHD. Implementation of male-friendly services, combined with intensified adherence support and re-engagement initiatives should be considered to reduce mortality risk for PLWH in rural regions in South Africa.