Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) is a disease deeply intertwined with social and economic inequalities in many developing nations, including South Africa, where it disproportionately impacts individuals in lower socioeconomic strata and impoverished communities (1). Since 2007, the South African government has made significant strides toward ending its AIDS epidemic by 2030, showcasing that combining scientific evidence with political commitment can save lives (2). The country continues to roll out programs that support various HIV and AIDS prevention strategies, including medical male circumcision, prevention of mother-to-child transmission, and accessible antiretroviral treatment (ART), which is provided free of charge to anyone who tests positive, irrespective of their CD4 count. These subsidised initiatives offer a cost-effective solution for the government to meet its public health goals.

KwaZulu-Natal (KZN), the most populous province in South Africa, has the highest HIV prevalence, with 27.6% of adults living with the virus (3, 4). Following the introduction of ART, there has been a decline in mortality, morbidity, and HIV transmission among those living with HIV (5–7). The need for preventative treatment against opportunistic infections is guided by the CD4 count, a key indicator of a patient’s immune status (8). The recovery of CD4 cell counts after starting ART is a promising predictor of clinical outcomes for HIV patients, correlating with a healthier immune system and enhanced life expectancy (9).

During the first 3 months of suppressive antiretroviral therapy (ART), the rate of CD4 cell recovery is low but progressively improves over time (10). If viral suppression through ART is sustained, most individuals will eventually achieve normal CD4 counts (≥500 cells/mm³). However, about 15–20% of those who start ART with very low CD4 counts (around 200 cells/mm³) may continue to experience persistently low CD4 levels (11). This clinical immunological failure to respond to ART is linked to factors such as age, sex, co-infection with viral hepatitis, initial CD4 + T-cell counts, prolonged untreated HIV infection, and heightened morbidity and mortality (12–14). The inability to recover CD4 counts is associated with an elevated risk of non-AIDS-related health issues and mortality, including cardiovascular diseases, pneumonia, osteoporosis and fractures, liver disease, and cancers related to infections (15–17).

Recent studies have used various statistical methods to assess HIV in KwaZulu-Natal. For example, Mchunu et al. (18) used joint modelling of time-to-event data to assess CD4 cell count and mortality among patients who initiated antiretroviral therapy. The analysis showed that CD4 count can be utilised as a measure of immunological failure and is associated with mortality. Dawood et al. (19) used Kaplan–Meier and multivariable proportional risk models to examine factors associated with hepatitis B prevalence and persistence. The authors concluded that the provision of HIV care and treatment in high Hepatitis B Virus (HBV)-burden settings provides a missed opportunity for HBV screening, immunisation and care provision. Another study (20) utilised Kaplan–Meier curves, log-rank tests, and multivariate proportional hazards models to focus on mortality and treatment response in patients aged 50 years and older. The results showed that older HIV-infected patients were associated with higher mortality compared to the younger cohort. Older patients have a risk of developing diabetes and hypertension. Naidoo et al. (21) used Kaplan–Meier and multivariable proportional hazards models to analyse factors associated with male mortality. Results showed men had more advanced HIV disease and a higher mortality rate compared to women. Although the findings from these studies remain valid and relevant, population dynamics and other health indicators may have changed in recent years.

Despite the introduction of universal test and treat (UTT) in South Africa in 2016, a substantial proportion of people living with HIV (PLWH) continue to initiate antiretroviral therapy (ART) at CD4 counts ≤200 cells/mm³, underscoring persistent challenges in early HIV diagnosis and timely linkage to care (22, 23). This pattern highlights a critical disconnect between ART initiation and effective immunological recovery, warranting empirical investigation. Although CD4 count recovery following ART initiation has been extensively studied, evidence remains limited for individuals who begin treatment with advanced immunosuppression, particularly in high-burden, resource-constrained settings. To address this gap, this study applies survival analysis methods to estimate the time to CD4 count recovery and to identify its key determinants among PLWH receiving ART in KwaZulu-Natal, South Africa. The findings are expected to inform resource allocation, clinical management, and policy formulation to improve treatment outcomes.

This study applied time-to-event models to identify factors associated with the timing of CD4 count recovery among people living with HIV who initiated ART with advanced immunosuppression (CD4 < 200 cells/mm³), most commonly classified as late presenters. Late presentation has been consistently associated with impaired immune recovery, opportunistic infections, and increased mortality. The high proportion of patients who did not achieve CD4 recovery in our cohort underscores the long-term immunological consequences of delayed entry into care and highlights the importance of early HIV diagnosis and timely ART initiation (25). Previous studies have similarly demonstrated that baseline CD4 count strongly predicts immune reconstitution and that individuals initiating ART at very low CD4 levels may fail to achieve counts exceeding 500 cells/mm³ (9, 17).

Several demographic and clinical factors were significantly associated with CD4 recovery, including tuberculosis status, geographic location, viral load, gender, age, and baseline CD4 count. The interpretation of the gender effect on CD4 count recovery indicates a clear disparity in immune reconstitution between males and females. The findings showed that males had a significantly lower hazard of CD4 recovery compared to females (HR = 0.584, p < 0.001), indicating slower immunological recovery among men following ART initiation. This result is consistent with previous studies reporting that men experience poorer HIV treatment outcomes, including slower CD4 recovery and higher mortality risk compared to women (26–28). Biological differences in immune function, health-seeking behaviour, later presentation to care, and differences in treatment adherence may contribute to this pattern. Although some evidence suggests that men may demonstrate strong virological responses, women often exhibit stronger early immunological responses to ART. However, this advantage may diminish over time, particularly when accounting for baseline disease severity and other clinical factors (29).

Geographic location was a significant determinant of CD4 count recovery. Patients from rural areas had a significantly higher hazard of CD4 recovery compared to their urban counterparts (HR = 1.307, p = 0.002), indicating a faster rate of immunological recovery among rural patients (42). This finding suggests that, within this cohort, rural patients may have benefited from factors such as earlier treatment response, differences in baseline characteristics, or programmatic variations in care delivery. Although prior studies have reported mixed evidence regarding urban–rural disparities in HIV outcomes (30, 31), with many highlighting structural barriers in rural settings (31, 32), our results suggest that rural residence in this context was associated with improved immunological recovery. Differences across studies may reflect variations in healthcare systems, decentralisation of ART services, population characteristics, and baseline disease severity.

Tuberculosis co-infection was associated with reduced CD4 recovery, underscoring the challenge of managing HIV–TB co-morbidity. Patients with prevalent TB were less likely to achieve CD4 counts ≥500 cells/mm³ (HR = 0.759, p = 0.004), consistent with previous studies reporting impaired immune reconstitution in the presence of TB infection (33–35). TB-related immune activation and systemic inflammation may hinder CD4 restoration despite ART, emphasising the importance of integrated HIV–TB care.

Viral load suppression emerged as a strong predictor of CD4 recovery. Patients with viral loads ≤400 copies/mL experienced significantly faster and more frequent CD4 recovery than those with higher viral loads (HR = 1.467, p < 0.001), highlighting the central role of effective virological control in immune reconstitution (36). Although ART adherence was not directly measured in this study, sustained viral suppression likely reflects effective treatment response and continuity of care rather than behavioural factors alone (37, 38). These findings reinforce viral load as a key biological marker linked to immunological recovery.

Age was negatively associated with CD4 recovery, indicating diminished immune reconstitution among older patients (HR = 0.980, p < 0.001). This finding is consistent with evidence that immune regenerative capacity declines with age, leading to slower and less complete CD4 recovery following ART initiation (19, 29). Early treatment initiation and closer clinical monitoring may therefore be particularly important in older populations.

In contrast, WHO clinical stage and ART regimen type were not significantly associated with CD4 recovery. The lack of regimen effect may reflect the use of standardised first-line therapies across the cohort, suggesting that baseline clinical and demographic characteristics exert a greater influence on immune recovery than regimen choice alone. This finding supports the continued effectiveness of existing treatment protocols and indicates that switching regimens, when clinically indicated, may not compromise immunological outcomes.

Overall, these findings highlight the multifactorial nature of CD4 recovery following ART initiation. Differences by age, gender, co-infection status, viral suppression, and geographic context suggest that immune reconstitution is shaped by both biological and structural factors. Addressing disparities in access to care, ensuring early diagnosis and treatment, and prioritising sustained viral suppression remain central to improving immunological outcomes in HIV treatment programs.

The introduction of dual-drug regimens in antiretroviral therapy seems to be an effective alternative to conventional three-drug combinations, particularly for treatment-experienced and virologically stable patients (39–41). Advantages of dual drug regimens are reduced toxicity, lower treatment burden, and improved long-term tolerability. However, their effectiveness in individuals presenting with advanced HIV disease (WHO stage 4) remains insufficiently studied. Patients with severe immunosuppression often require robust viral suppression to facilitate optimal immune reconstitution.

In conclusion, time-to-event analyses demonstrated significant variability in CD4 recovery following ART initiation. Older age, male sex, urban residence, TB co-infection, and unsuppressed viral load (>400 copies/mL) were independently associated with delayed immune reconstitution. These findings underscore the substantial heterogeneity in immunological response among individuals initiating ART with advanced immunosuppression. Although antiretroviral regimen type was not significantly associated with CD4 recovery in this cohort, delayed or incomplete immune restoration may heighten the risk of HIV-related morbidity and increase the burden on healthcare systems. Targeted interventions and closer monitoring of high-risk subgroups may be warranted to optimise immunologic outcomes and improve long-term prognosis. The identification of baseline clinical and demographic factors associated with slower CD4 recovery may assist in risk stratification and targeted clinical follow-up. Monitoring of viral load levels remains central for assessing virological response to ART, while CD4 count measurements provide complementary information on immunological recovery, particularly among patients initiating treatment with low CD4 counts. While dual antiretroviral therapy (ART) regimens, particularly dolutegravir-based combinations, have demonstrated robust efficacy and durability in maintaining viral suppression across diverse clinical settings, evidence remains limited in individuals presenting late with advanced immunosuppression. Late presenters represent a clinically vulnerable population in whom the dynamics of virologic response, CD4⁺ T-cell recovery, immune reconstitution, and the risk of immune reconstitution inflammatory syndrome may differ from those observed in earlier-stage disease. Future prospective studies and real-world cohort analyses are therefore warranted to specifically evaluate the safety, effectiveness, and immunologic outcomes of two-drug regimens in late presenters, including their impact on long-term immune recovery and clinical endpoints. Such data will be essential to better define the role of dual ART strategies in this high-risk population and to inform individualized treatment approaches.