Human immunodeficiency virus (HIV) infection is an established risk factor for vascular disease.¹ Chronic limb-threatening ischaemia (CLTI) signifies the severe phase of the peripheral artery disease (PAD) spectrum and is associated with major morbidity, limb loss and mortality.² Chronic limb-threatening ischaemia is defined as ischaemic rest pain, tissue loss or gangrene of the lower extremities.² In 2015, over 230 million adults worldwide were estimated to have PAD, 72.9% of whom were in low- and middle-income countries,³ with prevalence still increasing globally.⁴ South Africa, with the greatest absolute number of people living with human immunodeficiency virus (PLHIV) in the world,⁵ faces a significant burden of PAD.⁶ The interplay of HIV and traditional cardiometabolic risk factors is complex, particularly so with the transformation of HIV into a chronic disease as a result of improved roll-out of antiretroviral treatment (ART): ART exposure in PLHIV has improved from 26% in 2010 to 74% in 2021.^5,7 Current data on PLHIV presenting with CLTI, especially in the ART era, remain limited.¹

There is increasing evidence that PLHIV develop vascular disease at a younger age with fewer traditional cardiovascular risk factors than HIV-negative individuals do.^8,9,10 This fact has been corroborated by African studies.^11,12

The optimal management of CLTI in PLHIV remains uncertain. Some studies found PLHIV with CLTI were more likely to undergo lower extremity amputation compared to HIV-seronegative patients and had worse surgical outcomes, with higher rates of bypass failure and mortality.^13,14 Similarly, South African data, prior to modern ART, showed poor limb-salvage rates for occlusive disease (31.6%¹⁵ and 36.1%¹⁶), with subsequent longer hospital admissions and amputation rates.^15,16 It is important to note that these studies were limited by small sample sizes and conducted prior to the modern ART era. Consequently, drawing definitive conclusions regarding the efficacy of modern endovascular and surgical interventions in this population remains challenging. Conversely, others found no worse outcomes with endovascular revascularisation⁸ and no increased risk of amputation or mortality after surgical revascularisation.^8,17

Our study focused on CLTI in the South African context, a population with a high burden of HIV and an increasing burden of non-communicable diseases. Our primary aim was to establish the period prevalence of HIV among patients with index CLTI at Tygerberg Hospital, a tertiary care facility in Cape Town, South Africa. Secondary aims included describing the HIV-specific characteristics of PLHIV with CLTI, as well as comparing the age distribution, cardiovascular risk factors, comorbidities and management outcomes of PLHIV presenting with CLTI to their HIV-negative counterparts.

Our study found a minimum HIV prevalence of 3.5% (95% CI: 2.5% – 4.7%) among index CLTI patients admitted over a 7-year period in a high HIV-burden population during the ART era. People living with human immunodeficiency virus presented more than a decade younger and were less likely to have hypertension, diabetes, hypercholesterolaemia, IHD and stroke although multivariable analysis suggested these differences were largely age related. Importantly, no significant differences were observed in endovascular or OSR success, complication rates or in-hospital mortality in PLHIV compared to their HIV-seronegative counterparts; these findings are qualified by the small number of PLHIV in the treatment subgroups. Consequently, these results should be interpreted as observational trends rather than definitive clinical outcomes, particularly regarding the comparative efficacy of surgical versus endovascular interventions.

Notably, 26% of PLHIV were newly diagnosed during their admission, and one-third were ART naïve. This finding suggests that CLTI often serves as the sentinel presentation of untreated HIV in younger patients. These findings highlight a critical opportunity for vascular units to implement routine HIV screening and initiate ART early, which may be vital in mitigating the systemic inflammation and accelerated vascular ageing that drive progression to limb-threatening ischaemia.

Our estimated prevalence is lower than the latest reported HIV prevalence of 5.6% of the adults aged 50 years and older in the Western Cape.¹⁹ Although our prevalence calculation is conservative, there lies a possibility that PLHIV present at an unsalvageable stage in their CLTI disease at their base hospitals and therefore undergo primary amputation without tertiary referral. Tran et al. found that symptomatic PLHIV were more likely to present with advanced disease of PAD than their seronegative counterparts.¹³ People living with human immunodeficiency virus in our study were almost three times more likely to be down-referred for amputation, which may suggest that more PLHIV are being referred in from our district hospitals than those presenting within our own drainage area.

The mechanisms promoting earlier CLTI in PLHIV remain multifactorial, likely involving cytokine-driven endothelial dysfunction and accelerated atherosclerosis that persists despite viral suppression.²⁰ Our finding that PLHIV presented with a lower prevalence of traditional risk factors like hypertension and diabetes mirrors previous research,^8,13,17,21 although our multivariable analysis suggests that this is largely a function of their younger age. This result suggests that while HIV may accelerate vascular ageing, this paucity of comorbidities did not differ when stratified by CD4+, viral load or ART status.

The high rate of amputation observed in our study confirms that CLTI remains a morbid end stage of PAD in the South African context, aligning with pre-modern ART studies by Van Marle and Paruk.^16,22 This outcome suggests that despite advances in HIV care, many patients still present with unsalvageable disease. Furthermore, while PLHIV were less likely to undergo ET, this situation reflects international trends in which HIV-related lesions are often more complex, advanced (Rutherford ≥ 4) and less amenable to percutaneous intervention.¹³ Notably, the absence of revascularisation in patients with CD4+ counts < 200 cells/µL may suggest that severely immunocompromised PLHIV present later or with more aggressive disease, potentially precluding limb-salvage efforts.

We found no increased likelihood of worse perioperative outcomes – specifically regarding major amputation, complications or mortality – in PLHIV compared to HIV-negative patients. These findings align with recent large retrospective cohorts showing no significant difference in perioperative success among procedure-matched patients regardless of HIV status.¹⁷ Our success rates for OSR are consistent with international literature, including outcomes from major randomised controlled trials such as Farber et al.²³ While pre-modern ART studies in South Africa reported lower salvage rates,²² contemporary data suggest that revascularisation is increasingly effective, though regional variations in disease severity and healthcare infrastructure continue to influence individual outcomes.

We recognise that the limitations of our study lie initially in the retrospective nature thereof. We were reliant on the quality of existing EMRs, and certain health determinants could not be determined retrospectively, such as socioeconomic status, obesity or healthcare access. This was a public healthcare single-centre study, and inter-hospital HIV prevalence may vary. Almost half of the cohort (47.7%) had an unknown HIV status, which we conservatively assumed to be HIV-negative, potentially underestimating HIV prevalence. People living with human immunodeficiency virus numbers were marginally less than expected, which may have limited the power to detect significant differences in certain outcomes or subgroups. We did not stratify patients on their clinical presentation or prognostication tools such as the Wound, Ischaemia and Foot Infection (WIfI) score, which may affect outcomes.²⁴ We are a resource-limited setting, and hence, poor surgical candidates would not be selected for revascularisation. We further assumed that all down-referred patients underwent amputation, as revascularisation is unavailable outside tertiary facilities; however, some patients may have been deemed terminal and received palliation instead. Furthermore, as outcomes and complications were recorded only during the index hospital admission, this study does not capture long-term limb-salvage rates, late-onset complications or readmissions for recurrent symptoms, which may lead to an underestimation of the total disease burden. Down-referral may thus underestimate in-hospital mortality. Surgical decisions, such as primary ablation versus revascularisation, were assumed to rely on established patient prognostic factors, such as age, comorbidities, extent of tissue loss, sepsis, venous conduit availability, adequate target vessels, mobility and patient preferences – rather than HIV status alone. The lack of post-discharge follow-up is a significant methodological limitation, compounded by the well-documented challenges of patient retention and fragmented referral pathways within the South African public healthcare system. Consequently, while our in-hospital outcomes are robust, the reliability of our conclusions regarding long-term limb salvage and mortality remains restricted, as we cannot account for late-stage complications or deaths occurring after discharge. We did not track patients after discharge from the index intervention, preventing identification of post-discharge complications or surgical failures.

Future research could focus on revascularisation outcomes in age-matched prospective studies, addressing aspects such as socioeconomic factors, WIfI scores and post-discharge follow-up. Furthermore, the number of down-referred PLHIV prompts consideration of the burden of HIV with CLTI in district hospitals, including whether more PLHIV are undergoing primary amputation than HIV-negative individuals, without referral for revascularisation work-up.

In conclusion, we found a minimum HIV prevalence of 3.5% in patients admitted for index CLTI to Tygerberg Hospital from 2016 to 2022. People living with human immunodeficiency virus were 12 years younger, with fewer risk factors than their HIV-negative counterparts, yet revascularisation outcomes, complication rates and in-hospital mortality were similar. Chronic limb-threatening ischaemia remains a significant consequence of the double-burden of HIV and non-communicable diseases in resource-limited settings. Our results suggest that revascularisation may be a viable strategy in managing these patients; such observational trends, if confirmed in larger cohorts, could support more equitable treatment approaches. Early diagnosis, timely referral and prevention strategies, such as risk factor reduction and consistent ART adherence, may be essential to improving outcomes in PLHIV with CLTI. Frontline clinicians should recognise CLTI in younger PLHIV with fewer risk factors to enable early intervention. Further research is required to better understand the challenges faced by PLHIV with CLTI.