Antiretroviral Therapy and Risk of Stroke in People with HIV in Zambia

Antiretroviral Therapy and Risk of Stroke in People with HIV in Zambia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Antiretroviral Therapy and Risk of Stroke in People with HIV in Zambia Stanley ZIMBA, Owen NGALAMIKA, Emmanuel MUKAMBO, Theresa SHANKANGA, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6945551/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Sep, 2025 Read the published version in AIDS Research and Therapy → Version 1 posted 7 You are reading this latest preprint version Abstract Background People with HIV (PWH) are at increased risk of stroke likely due to many factors including antiretroviral therapy (ART). We sought to evaluate the association between ARTand risk of stroke in PWH. Methods We conducted a prospective case-control study at the University Teaching Hospital in Lusaka, Zambia between March 2022 and October 2024 in PWH comparing those with stroke (cases) and without (controls) matched (1:2) for age, sex and race. Standardized data collection instruments were used to collect demographic, clinical, laboratory and imaging information. Comparisons were made between the cases and controls, and subgroup analysis by ART duration was done for the cases. Results We analyzed results for 205 cases and 410 controls. Compared to controls, cases were more likely to have hypertension (71% vs. 18%, p =0.001), lower CD4 counts [293(163-592) cells/µl vs. 533 (376-688) cells/µl, p =0.0001] and to be on second line ART (23% vs. 4%, p =0.001). Hypertension (aOR 19.7, 95% CI 3.1-126.4, p =0.002) and Tenofovir Disoproxil Fumarate (TDF) use (aOR 85.3, 95% CI 5.3-1380.7, p =0.002) were associated with increased odds of stroke, whereas Dolutegravir (aOR 0.03, 95% CI 0.001-0.58, p =0.02) and alcohol use (aOR 0.24, 95% CI 0.06-0.95) were associated with reduced odds of stroke. The majority of stroke patients on long-term ART were using Dolutegravir (80% vs. 35%, p =0.001) and TDF (72% vs. 42%, p =0.01). Conclusion In PWH, TDF associates with higher odds of stroke. Although Dolutegravir associates with reduced odds of stroke, stroke patients on long-term ART are more likely to be on it. Antiretroviral therapy HIV infection stroke Sub-Saharan Africa Zambia Figures Figure 1 1. Introduction Sub-Saharan Africa (SSA) shoulders a disproportionate burden of stroke and HIV. 1 – 3 These two epidemics are often intertwined and affect young adults aged less than 50 years without traditional stroke risk factors. 4 , 5 This presents a socioeconomic and public health crisis in SSA as the most affected individuals are productive members of society who are expected to propel economic development. HIV is increasingly recognized as an independent stroke risk factor. 6 – 8 The exact mechanisms by which HIV increases the risk of stroke are not well-defined. Most of what is known about HIV-associated stroke comes from high-income settings where traditional stroke risk factors such as diabetes, hypertension, hyperlipidemia and smoking are more common. HIV has an effect on vascular biology leading to an increased risk of cardiovascular and cerebrovascular diseases. This may occur as HIV-associated vasculopathy, indirectly through opportunistic infections, 9 , 10 or as a consequence of antiretroviral therapy (ART) drugs. Nucleoside reverse-transcriptase inhibitors such as Didanosine and Abacavir have been associated with increased cardiovascular risk whereas Tenofovir Disoproxil Fumarate (TDF) has consistently not demonstrated any such association in multiple cohort studies. 11 – 13 Boosted protease inhibitors (PIs), which are the cornerstone of second line ART in many SSA countries such as Zambia, are associated with an increased risk of metabolic syndromes with longer exposure, which may worsen an underlying atherosclerotic process. 14 All these drugs could increase the risk of cerebrovascular disease and stroke, but evidence linking them with such an association is lacking especially in SSA which is most affected by the HIV pandemic. Sub-Saharan Africa has a diverse and genetically different population which requires further investigation of ART and its contribution to stroke risk. Additionally, integrase inhibitors which form the backbone of first line ART in most African countries could potentially increase the risk of stroke within six months of ART initiation, as they rapidly suppress HIV which may possibly lead to an immune reconstitution inflammatory syndrome (IRIS)-like process. 10 , 15 , 16 While the relationship between HIV and stroke has been explored, the specific role of ART – particularly with the widespread adoption of Dolutegravir (DTG) by World Health Organization (WHO) as the first-line ART backbone since 2016 – remains poorly understood. 17 – 19 This matched case-control study aimed to investigate the association between ART, duration of use, and stroke risk among people with HIV (PWH). We hypothesized that DTG-based regimens would be associated with increased stroke risk within one year (recent) of ART initiation due to DTG’s rapid virological suppression and potential for IRIS stroke. We also hypothesized that PIs would be associated with increased stroke risk with long-term (≥ 1 year) use due to their increased risk for metabolic syndrome with long-term use. 2. Methods 2.1 Study Setting The study was conducted at the University Teaching Hospital (UTH) in Lusaka, the largest and national referral tertiary care centre in Zambia. The hospital has neurodiagnostic assessments tools including magnetic resonance imaging (MRI), computed tomography (CT), and electroencephalography (EEG). The hospital has a neurology division with a functional stroke unit and a large adult centre for infectious diseases which attends to more than 20,000 PWH every year. Admission to UTH, physician consultations and medications stocked in the hospital pharmacy are free of charge for patients, but patients may pay out of pocket for all investigations if they do not have health insurance. As such, incomplete workups are common because of financial limitations or unavailability of reagents. In addition, investigations, which would not significantly alter patient management are usually not undertaken. However, UTH's status as a national referral centre with advanced neurodiagnostic tools and a high volume of PWH makes it an ideal setting for investigating HIV-associated stroke. 2.2 Study Design and Period We conducted a prospective case control study from March 2022 to October 2024 on PWH with (cases) and without (controls) stroke matched (1:2) for age, sex and race. Controls were consecutive patients accessing routine UTH outpatient HIV care services who were confirmed to be stroke-free after a neurological assessment. Cases were further stratified by ART use duration [recent ( 1 year)]. 2.3 Participants All cases were adults ( > 18 years) either admitted to the inpatient neurology service or seen at the neurology clinic at UTH with a clinical diagnosis of stroke in PWH on ART, with symptom onset of less than 2 months. All paper charts during the study period were reviewed to confirm the diagnosis of stroke. Of note, all patients admitted to UTH are routinely offered voluntary HIV testing and counseling upon admission. Patients with neuroimaging-confirmed ischemic stroke or intracerebral hemorrhage (ICH) were categorized accordingly; those seen with clinically suspected stroke who did not undergo neuroimaging due to financial constraints or scanner malfunction were categorized as “unknown stroke” (US). Exclusion criteria included transient ischemic attack (TIA) (symptom duration less than 24 hours), subdural or epidural hematoma, non-stroke neurological diagnoses, and stroke occurring secondary to surgery or traumatic injury. 2.4 Recruitment Process and Measurements We leveraged the national electronic medical records for PWH (SMART Care), chart reviews and patient interviews to obtain data for cases and pre-enrolment data for controls including blood pressure, ART regimen and duration, CD4 count, and HIV viral load as well as socio-economic and clinical related factors. Routine stroke workup, including CT and MRI scans, lipid panel, electrocardiogram and echocardiogram, were also recorded if obtained as part of routine clinical care. All patients were assessed and examined by a neurologist (SZ). Stroke severity was graded according to the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS). 20, 21 Hypertension and diabetes mellitus were defined per World Health Organization (WHO) guidelines 22, 23 and atrial fibrillation was defined by self-reported history or ECG or Echo confirming atrial fibrillation. Hyperlipidaemia was defined by self-report, statin use or standard laboratory cutoffs including low density lipoprotein (LDL) greater than 3.36 mmol/l, high-density lipoprotein (HDL) less than 1.29 mmol/l, total cholesterol more than 5.17 mmol/l or triglycerides greater than 3.88 mmol/l. 24 Cigarette smoking was classified as active smoker (current or former smoker for less than 1 year), passive smoker (household member or coworker who regularly smoked in his/her presence for more than 1 year during the last 10 years) or nonsmoker, and alcohol intake (ex-drinker for less than 1 year or current alcohol intake). 2.5 Stroke Classification A radiologist (MC) interpreted all brain imaging, and stroke classification was done independently by two study investigators (SZ and MA) with a third neurologist (DS) adjudicating when there was disagreement between the first two reviewers. Due to limited diagnostics, ischemic stroke cases were further classified using the Bamford classification: total anterior circulation infarction (TACI), partial anterior circulation infarction (PACI), posterior circulation infarction (POCI) and lacunar infarction (LACI). 25 2.6 Sample Size No pre-determined sample size was calculated for this exploratory study, but consecutive sampling was continued for a pre-defined period of one year. Based on our clinical registry, 5 we had estimated to recruit 200 PWH with stroke during this recruitment period. The recruitment period was extended from one to two years due to disruptions caused by the COVID-19 pandemic. 2.7 Statistical Analysis All data were entered into a secure REDCap database hosted by the Zambian Ministry of Health Infectious Diseases Directorate and analysed using SPSS version 27. 26, 27 Demographic and clinical characteristics were summarized with descriptive statistics. Chi square test was used to determine the association between categorical variables. Student t-test was used to compare normally-distributed continuous variables between cases and controls, while the Mann-Whitney U-test was used if the continuous variables were not normally-distributed. P values of less than 0.05 were taken as statistically significant. A multivariable conditional logistic regression model was then used to adjust for confounders and to identify factors independently associated with stroke in PWH. Only variables statistically significant at bivariate analysis were included in the multivariable conditional logistic regression model. Different models were run and the best predictive model was selected based on one with the largest area under the Receiver-operating characteristic (ROC) curve, lowest Akaike information criterion (AIC) and Bayesian information criterion (BIC), and the highest likelihood ratio. We checked fitness of the model using Hosmer-Lame-Show goodness of fit test and confirmed that there was no multicollinearity using variance inflation factor (VIF) values. 2.8 Ethical Approval Ethical approval was obtained from the University of Zambia Biomedical Research Ethics Committee (No. 1945-2021) and National Health Research Authority (REF: NHREB00008/30/09/2021), while permission was obtained from UTH management to conduct the study at UTH. Written informed consent to participate in the study as well as for publication was obtained from each of the study participants. For participants with altered mental status, informed consent was obtained from a surrogate, defined as a caregiver or close relative. 3. Results 3.1 Demographics In total, 205 cases and 410 controls were enrolled (Figure 1). The cases presented with a median NIHSS score of 9 (5-16) and mRS score of 4 (2-5). Ninety-one percent of the cases were identified as either ischemic or intracerebral hemorrhage and the rest were unknown as they did not get neuroimaging. For ischemic stroke, the majority (67%) of cases had anterior circulation infarction followed by lacunar infarction using Bamford classification (Table 1). 3.2 Risk Factors and Comorbidities Compared to controls, cases were more likely to have traditional risk factors for stroke such as hypertension, diabetes, hyperlipidemia and atrial fibrillation. They also had lower CD4 counts and advanced WHO HIV clinical stage. Although 87% of cases were on long-term ART, they were significantly less compared to controls, and they were more likely to be on second line ART (Table 1). Table 1: Comparison of demographic, clinical characteristics and ART factors between PWH with and without stroke Characteristics Cases (n=205) Controls (n=410) p-value Demographic/Clinical Female n (%) 114 (56) 229 (56) 0.95 Age, mean (SD) 52 (±12) 52(±12) 0.95 Secondary school or higher n (%) 136 (66) 278 (68) 0.72 Married/cohabiting n (%) 107 (52) 212 (52) 0.91 Alcohol intake n (%) 59 (29) 264 (64) 0.001 Smoking n (%) 25 (12) 20 (5) 0.001 BMI (Kg/m 2 ), median (IQR) 26.7 (22.9-32.2) 26.1 (23.5-29.2) 0.74 Systolic BP, mean (SD) 139(±29) 135(±13) 0.04 Diastolic BP, mean (SD) 89(±17) 79(±13) 0.0001 NIHSS, median (IQR) 9 (5-16) NA mRS, median (IQR) 4 (2-5) NA Stroke Type Stroke type n (%) Ischemic Intracerebral hemorrhage Unknown stroke 129 (63) 58 (28) 18 (9) NA ¥ Bamford Classification of Ischemic Strokes, n (%): LACI PACI TACI POCI 51/129 (39) 36/129 (28) 28/129 (22) 14/129 (11) NA Comorbid Conditions Hypertension n (%) 145 (71) 73 (18) 0.001 Diabetes mellitus n (%) 24 (12) 15 (4) 0.001 Hyperlipidemia n (%) 37 (18) 1 (0) 0.001 Previous stroke n (%) 56 (27) NA Atrial fibrillation n (%) 5 (2) 1 (0) 0.01 HIV-associated Factors CD4 count (cells/µl), median (IQR) 293 (163-592) 533 (376-688) 0.0001 CD4 count ≥200cells/µl, n (%) 53/79 (67) 311/334 (93) 0.001 HIV viral load (copies/ml), median (IQR) 20 (0-241) 0 (0-29) 0.13 ART use, n (%) 200 (98) 404 (99) 0.39 ART duration, ≥ 1 year, n (%) 174/200 (87) 394/404 (99) 0.001 Second line ART n (%) 46/200 (23) 17/404 (4) 0.001 Dolutegravir n (%) 148/200 (74) 389/404 (95) 0.001 Tenofovir Disoproxil Fumarate n (%) 136/200 (68) 119/404 (29) 0.001 Protease Inhibitors n (%) 14/200 (7) 10/404 (2) 0.01 WHO HIV Clinical Stage n (%) 0.001 Stage 1 132 (64) 380 (93) Stage 2 37 (18) 21 (5) Stage 3 20 (10) 9 (2) Stage 4 16 (8) 0 (0) Bolded text signifies p < 0.05. ¥ Bamford classification pertains to those with confirmed ischemic strokes only, not the total sample Abbreviations: ART=antiretroviral therapy; BMI=body mass index; BP=blood pressure; LACI=lacunar anterior circulatory infarct; mRS=modified Rankin Scale; NIHSS=national institute of health stroke scale; PACI=partial anterior circulatory infarct; POCI=posterior circulatory infarct; TACI=total anterior circulatory infarct; WHO=world health organization 3.3 Independent Predictors of stroke Hypertension (aOR 19.7, 95% CI 3.1-126.4, p =0.002) and Tenofovir Disoproxil Fumarate (TDF) use (aOR 85.3, 95% CI 5.3-1380.7, p =0.002) were independently associated with increased odds of stroke, while Dolutegravir (DTG) use (aOR 0.03, 95% CI 0.001-0.58, p =0.02) and alcohol intake (aOR 0.24, 95% CI 0.06-0.95) were associated with reduced odds of stroke (Table 2). The prediction model used had area under ROC curve of 82% (Supplemental Figure 1). Table 2: Multivariable conditional logistic regression analysis of factors associated with stroke in PWH Variables Adjusted OR (95% CI) p–value (Adj. OR) Alcohol intake n (%) 0.24 (0.06-0.95) 0.04 Hypertension n (%) 19.7 (3.1-126.4) 0.0 1 CD4 count (cells/µl), median (IQR) 1.000 (0.996-1.001) 0.24 Dolutegravir n (%) 0.03 (0.001-0.58) 0.02 Tenofovir Disoproxil Fumarate n (%) 85.3 (5.3-1380.7) 0.0 1 Second line ART n (%) 17.7 (0.9-353.9) 0.06 3.4 PWH with Stroke and ART Use Duration Of the 200 PWH and stroke taking ART, 174 (87%) were on long-term ART use. Those on long-term ART were less likely to be on second line ART, but more likely to be on TDF and DTG compared with their counterparts with recent ART use. Additionally, they were less likely to be on PIs compared with recent ART use, but the difference was not statistically significant (Table 3). Table 3 . PWH presenting with stroke stratified by duration of ART use Characteristics ART ≥ 1 year (n=174) ART < 1 year (n=26) p-value Second line ART n (%) 31 (18) 15 (58) 0.001 Dolutegravir n (%) 139 (80) 9 (35) 0.001 Tenofovir Disoproxil Fumarate n (%) 125 (72) 11 (42) 0.01 Protease Inhibitors n (%) 11 (6) 3 (12) 0.40 4. Discussion This case-control study showed that stroke risk in PWH is associated with many factors including ART use. Notably, we found that TDF was associated with increased odds (aOR 85.3) of stroke in PWH. Protease inhibitors only showed increased odds of stroke at univariate analysis. Dolutegravir use was independently associated with reduced odds of stroke, but significantly more PWH and stroke were likely to be on DTG long-term use on subgroup analysis. Our findings add a new dimension to the existing body of knowledge. For instance, TDF is known to be associated with better lipid profiles and potentially reduced cardiovascular risk, while its association with stroke risk has not previously been reported. 28 Treatment with TDF has consistently been associated with lower lipid levels, a decline in renal function and reduced bone mineral density. 12, 29 The mechanism by which it would be implicated in stroke risk is unclear, although its effect on renal function and its interaction with other ART drugs could provide a possible explanation for our findings, which need further research. In addition, the immunological and virological status of patients taking TDF may be important, as poorly-controlled HIV-infection can increase the risk of stroke. 8, 30 As for DTG, it has been associated with increased risk of stroke within the first few months of its initiation due to its rapid virological suppression leading to a potential IRIS. 15, 16, 31, 32 Our findings suggest an overall reduced odds of stroke with DTG use which could be explained by its beneficial effects on metabolic and inflammatory markers compared to other ART drugs. 33 However, our findings showed that a higher proportion of long-term ART users with stroke were on DTG. This could suggest that long-term instead of recent DTG use is an important factor in stroke risk. Recent studies have demonstrated that DTG is associated with hypertension, 34 hence its role in increasing stroke risk could also be indirectly through hypertension with prolonged use. We found a modest association between boosted protease inhibitors (PIs) and increased odds of stroke which was not sustained on multivariable analysis. PIs are used in second line ART, and have been shown to increase cardiovascular disease risk by promoting metabolic syndrome with prolonged use. 35 Our modest findings can be explained by the small numbers of recruited participants on PIs. Even on subgroup analysis of the cases, we observed that PWH and stroke were less likely to be on long-term use of PIs, but the difference was not statistically significant compared. It is important to emphasize that long-term ART use for our study was defined as 12 months or more whereas other studies which have looked at prolonged PIs use have considered more than 24 months. 36 This timeframe difference could also have a bearing on our findings. What is clear from our results is that both traditional and HIV-associated factors are important risk factors of stroke in this population of PWH. Hypertension was an independent risk factor of stroke in our study, with almost 20 times higher odds of stroke. However, we found the opposite for alcohol intake as it was noted to reduce the odds of stroke, although we did not properly quantify its use in our cohort. Several studies have shown that alcohol intake is an important risk factor for stroke with a direct relationship depending on quantities consumed, with some studies suggesting that alcohol intake in moderation is actually protective. 37-39 Our findings ultimately support the current consensus that the actual mechanism of stroke in PWH is multifactorial, and ART may be a co-factor. Our study has several limitations, including being a single-centre study at a national referral hospital, which might make the generalizability of these results difficult. As this was an exploratory study, we did not correct for multiple comparisons so that some of the associations found here may be due to chance alone. We did not thoroughly assess the contribution of the other ART drugs such as Abacavir, Zidovudine, Emtricitabine and Tenofovir Alafenamide which some of the participants may have been taking. Similarly, we did not compare for multiple ART combinations (e.g. some on the participants were taking both TDF and DTG) or the influence of the previous ART regimen for those who were recruited on second line ART. Nevertheless, our expectation is that these results are likely generalizable and they provide preliminary data that can be used to guide the development of interventions to reduce stroke risk in PWH. Some findings were based on information from the routine care available at the hospital during the study. The BMI for a few patients could not be calculated because of lack of a proper weighing scale for bedridden patients. Resource limitations also meant that not every participant was thoroughly evaluated for stroke risk factors such as hyperlipidaemia and diabetes (Supplemental Table 1). However, a strength of this study is the relatively large sample size and that all participants received a thorough clinical evaluation by trained neurologists making the clinical characterizations of this cohort more reliable than in many other SSA populations in which participants are assessed by non-neurologist healthcare workers. In conclusion, PWH are at increased risk of stroke due to multiple factors including traditional risk factors such as hypertension and HIV-associated factors such as ART use. Tenofovir Disoproxil Fumarate increases the odds of stroke. Although Dolutegravir associates with reduced odds of stroke, stroke patients on long-term ART are more likely to be on it. We found a modest association between PIs use and increased stroke risk. Future research designed to focus on multiple combinations of the different ART drugs and their contribution to stroke risk is needed to provide better insight into these findings in order to allow for the development of targeted and effective interventions for both primary and secondary stroke prevention for PWH. Declarations The authors have nothing to disclose. Funding: NIH K01 TW011771-01, D43 TW010543 and 2D43TW009744. Author Contribution SZ made substantial contribution to conception and design of the study and data collection and drafted and revised the manuscript. ON was integral in study conceptualization, analysis and also revised the manuscript. EM participated in data collection and revision of the manuscript. TS participated in data collection and revision of the manuscript. TM participated in data collection and revision of the manuscript. DM participated in data collection and revision of the manuscript. BM participated in data collection and analysis. MC participated in data interpretation and revision of the manuscript. MaC participated in research design and revision of the manuscript. MeA participated in data collection and revision of the manuscript. LC participated in data collection and revision of the manuscript. VK was involved in revising the manuscript critically for important intellectual content. LM was integral in study conceptualization, study design and also revised the manuscript. OS was integral in study conceptualization, study design and also revised the manuscript. OR was involved in the design and revision of the manuscript. MA revised the manuscript for intellectual content. DS made substantial contributions to study conception, study design and revision of the manuscript. All authors read and approved the final manuscript. Acknowledgements We thank the Department of Internal Medicine and the Adult Infectious Diseases Centre at UTH for supporting this study. This study received funding from the NIH Office of AIDS Research, NIH K01 TW011771-01, the Fogarty International Center and National Institute of Mental Health, of the National Institutes of Health under Award Number D43 TW010543 and the Fogarty International Centre of the US National Institutes of Health under Award Number 2D43TW009744. References Organization WH. HIV: fact sheet on Sustainable Development Goals (SDGs): health targets: World Health Organization. Regional Office for Europe, 2017. Kengne AP, Anderson CS. The neglected burden of stroke in Sub-Saharan Africa. International Journal of Stroke 2006;1:180-190. Uthman OA. Global, regional, and national disability‐adjusted life years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990‐2015: a systematic analysis for the Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2015 Study. Lancet 2016;388:1603-1658. Tipping B, de Villiers L, Wainwright H, Candy S, Bryer A. Stroke in patients with human immunodeficiency virus infection. Journal of Neurology, Neurosurgery & Psychiatry 2007;78:1320-1324. Zimba S, Nutakki A, Chishimba L, et al. Risk factors and outcomes of HIV-associated stroke in Zambia. Aids 2021;35:2149-2155. Chow FC, Regan S, Feske S, Meigs JB, Grinspoon SK, Triant VA. Comparison of ischemic stroke incidence in HIV-infected and non–HIV-infected patients in a US health care system. JAIDS Journal of Acquired Immune Deficiency Syndromes 2012;60:351-358. Benjamin LA, Bryer A, Emsley HC, Khoo S, Solomon T, Connor MD. HIV infection and stroke: current perspectives and future directions. The Lancet Neurology 2012;11:878-890. Harding BN, Avoundjian T, Heckbert SR, et al. HIV viremia and risk of stroke among people living with HIV who are using antiretroviral therapy. Epidemiology 2021;32:457-464. Connor M. Stroke in patients with human immunodeficiency virus infection. BMJ Publishing Group Ltd, 2007: 1291-1291. Benjamin LA, Allain TJ, Mzinganjira H, et al. The role of human immunodeficiency virus–associated vasculopathy in the etiology of stroke. The Journal of infectious diseases 2017;216:545-553. Friis-Møller N, Thiebaut R, Reiss P, et al. Predicting the risk of cardiovascular disease in HIV-infected patients: the data collection on adverse effects of anti-HIV drugs study. European journal of cardiovascular prevention & rehabilitation 2010;17:491-501. Santos JR, Saumoy M, Curran A, et al. The lipid-lowering effect of tenofovir/emtricitabine: a randomized, crossover, double-blind, placebo-controlled trial. Clinical Infectious Diseases 2015;61:403-408. Huhn GD, Shamblaw DJ, Baril J-G, et al. Atherosclerotic cardiovascular disease risk profile of tenofovir alafenamide versus tenofovir disoproxil fumarate. Open forum infectious diseases; 2020: Oxford University Press US: ofz472. Group DS. Class of antiretroviral drugs and the risk of myocardial infarction. New England Journal of Medicine 2007;356:1723-1735. Benjamin LA, Corbett EL, Connor MD, et al. HIV, antiretroviral treatment, hypertension, and stroke in Malawian adults: a case-control study. Neurology 2016;86:324-333. Zimba S, Mbewe N, Chishimba L, Chomba M, Saylor D. Immune reconstitution inflammatory syndrome: a report of TB-IRIS after switching from efavirenz to dolutegravir. Tropical Doctor 2021;51:216-218. Walmsley S, Berenguer J, Khuong-Josses M, Kilby J, Lutz T, Podzamczer D. Dolutegravir regimen statistically superior to efavirenz/tenofovir/emtricitabine: 96-week results from the SINGLE study (ING114467). Conference on Retrovirues and Opportunistic Infections; 2014. Raffi F, Rachlis A, Brinson C, et al. Dolutegravir efficacy at 48 weeks in key subgroups of treatment-naive HIV-infected individuals in three randomized trials. Aids 2015;29:167-174. Jiang J, Xu X, Guo W, et al. Dolutegravir (DTG, S/GSK1349572) combined with other ARTs is superior to RAL-or EFV-based regimens for treatment of HIV-1 infection: a meta-analysis of randomized controlled trials. AIDS research and therapy 2016;13:1-10. Lyden P, Brott T, Tilley B, et al. Improved reliability of the NIH Stroke Scale using video training. NINDS TPA Stroke Study Group. Stroke 1994;25:2220-2226. Scale S. Modified Rankin Scale. http://www strokecenter org/trials/scales/rankin html 2008. Whitworth J. World Health Organization, International Society of Hypertension Writing Group. J Hypertens 2003;21:1983-1992. Alberti KGMM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabetic medicine 1998;15:539-553. Nelson RH. Hyperlipidemia as a risk factor for cardiovascular disease. Primary care 2012;40:195. Bamford J, Sandercock P, Dennis M, Warlow C, Burn J. Classification and natural history of clinically identifiable subtypes of cerebral infarction. The Lancet 1991;337:1521-1526. Harris PA, Taylor R, Minor BL, et al. The REDCap consortium: building an international community of software platform partners. Journal of biomedical informatics 2019;95:103208. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. Journal of biomedical informatics 2009;42:377-381. Dorjee K, Desai M, Choden T, Baxi SM, Hubbard AE, Reingold AL. Acute myocardial infarction associated with abacavir and tenofovir based antiretroviral drug combinations in the United States. AIDS research and therapy 2021;18:1-10. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. Jama 2004;292:191-201. Nweke M, Mshunqane N. Characterization and stratification of risk factors of stroke in people living with HIV: A theory-informed systematic review. BMC Cardiovascular Disorders 2025;25:1-34. Wijting I, Rokx C, Wit F, Postma A, Hoepelman A, van der Ende M. Integrase Inhibitors are an Independent Risk Factor for IRIS: an ATHENA-Cohort Study. Conference on Retroviruses and Opportunistic Infections; 2017: 13-16. Psichogiou M, Poulakou G, Basoulis D, Paraskevis D, Markogiannakis A, L. Daikos G. Recent advances in antiretroviral agents: potent integrase inhibitors. Current pharmaceutical design 2017;23:2552-2567. Roux CG, Mason S, du Toit LD, Nel J-G, Rossouw TM, Steel HC. Comparative Effects of Efavirenz and Dolutegravir on Metabolomic and Inflammatory Profiles, and Platelet Activation of People Living with HIV: A Pilot Study. Viruses 2024;16:1462. Byonanebye DM, Polizzotto MN, Maltez F, et al. Associations between change in BMI and the risk of hypertension and dyslipidaemia in people receiving integrase strand-transfer inhibitors, tenofovir alafenamide, or both compared with other contemporary antiretroviral regimens: a multicentre, prospective observational study from the RESPOND consortium cohorts. The Lancet HIV 2024;11:e321-e332. Echecopar-Sabogal J, D’Angelo-Piaggio L, Chanamé-Baca DM, Ugarte-Gil C. Association between the use of protease inhibitors in highly active antiretroviral therapy and incidence of diabetes mellitus and/or metabolic syndrome in HIV-infected patients: A systematic review and meta-analysis. International journal of STD & AIDS 2018;29:443-452. Parra-Rodriguez L, Sahrmann JM, Butler AM, Olsen MA, Powderly WG, O’Halloran JA. Antiretroviral Therapy and Cardiovascular Risk in People With HIV in the United States—An Updated Analysis. Open Forum Infectious Diseases; 2024: Oxford University Press US: ofae485. Smyth A, O'Donnell M, Rangarajan S, et al. Alcohol intake as a risk factor for acute stroke: the INTERSTROKE study. Neurology 2023;100:e142-e153. Reynolds K, Lewis B, Nolen JDL, Kinney GL, Sathya B, He J. Alcohol consumption and risk of stroke: a meta-analysis. Jama 2003;289:579-588. Zhang C, Qin Y-Y, Chen Q, et al. Alcohol intake and risk of stroke: a dose–response meta-analysis of prospective studies. International journal of cardiology 2014;174:669-677. Additional Declarations No competing interests reported. Supplementary Files SupplementarymaterialAIDSResearch.doc Cite Share Download PDF Status: Published Journal Publication published 29 Sep, 2025 Read the published version in AIDS Research and Therapy → Version 1 posted Editorial decision: Revision requested 11 Aug, 2025 Reviews received at journal 14 Jul, 2025 Reviewers agreed at journal 26 Jun, 2025 Reviewers invited by journal 26 Jun, 2025 Editor assigned by journal 23 Jun, 2025 Submission checks completed at journal 23 Jun, 2025 First submitted to journal 21 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6945551","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":476807181,"identity":"37f95f34-f66b-4f80-90f2-1fe39113f33f","order_by":0,"name":"Stanley ZIMBA","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABD0lEQVRIiWNgGAWjYBADGQZmBjYGhgoGBgOYkAQutWwQigei5QxJWkBMxjYitMjPb372uKDmMI98O3fag5/zDsubszcfYPhRwZA4swG7FoNjbObGM44d5mFs5t1u2LvtsOHOnmMJjD1nGBJn47DFgI3BTJqH7TAPMzPvNgnebYcZN9zIMWAGujBxHi6HtbF/k+b5d5iHDahF8u+cw/YEtTAc4zGT5m07zMMD1CLN23A4Ea4Fp8OO5ZRJz+xL55Fg5t1uLHMsPXnDmWMJB3vOSBjj8r588/Ft0gXfrOXk+89ue/imxtp2w/Hmgw9+VNjIzjiAy2UMwEhEgGYweQBPRGJoqcOrchSMglEwCkYmAAAGklWcHY9ezgAAAABJRU5ErkJggg==","orcid":"","institution":"University Teaching Hospital","correspondingAuthor":true,"prefix":"","firstName":"Stanley","middleName":"","lastName":"ZIMBA","suffix":""},{"id":476807182,"identity":"bd2cdb47-30be-4f43-8871-f09a19857853","order_by":1,"name":"Owen NGALAMIKA","email":"","orcid":"","institution":"University of Zambia School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Owen","middleName":"","lastName":"NGALAMIKA","suffix":""},{"id":476807183,"identity":"b840c5b6-d152-4541-9994-7d8dff271a12","order_by":2,"name":"Emmanuel MUKAMBO","email":"","orcid":"","institution":"University Teaching Hospital","correspondingAuthor":false,"prefix":"","firstName":"Emmanuel","middleName":"","lastName":"MUKAMBO","suffix":""},{"id":476807184,"identity":"071a9299-d92a-4bab-9ad5-c6d3fd6eda6f","order_by":3,"name":"Theresa SHANKANGA","email":"","orcid":"","institution":"University Teaching Hospital","correspondingAuthor":false,"prefix":"","firstName":"Theresa","middleName":"","lastName":"SHANKANGA","suffix":""},{"id":476807185,"identity":"20e3d3b4-d999-4838-98de-649b5e2529cb","order_by":4,"name":"Taonga MSIMUKO","email":"","orcid":"","institution":"University Teaching Hospital","correspondingAuthor":false,"prefix":"","firstName":"Taonga","middleName":"","lastName":"MSIMUKO","suffix":""},{"id":476807186,"identity":"15645d76-e180-4412-8157-dbb61b853088","order_by":5,"name":"Diwell MWANSA","email":"","orcid":"","institution":"University Teaching Hospital","correspondingAuthor":false,"prefix":"","firstName":"Diwell","middleName":"","lastName":"MWANSA","suffix":""},{"id":476807187,"identity":"5b978154-620d-4a9a-82ae-fd5deff3e9a2","order_by":6,"name":"Bwalya MULENGA","email":"","orcid":"","institution":"University Teaching Hospital","correspondingAuthor":false,"prefix":"","firstName":"Bwalya","middleName":"","lastName":"MULENGA","suffix":""},{"id":476807188,"identity":"080c4614-32fa-41fa-b21f-97ac50c863af","order_by":7,"name":"Mike CHISHA","email":"","orcid":"","institution":"University Teaching Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mike","middleName":"","lastName":"CHISHA","suffix":""},{"id":476807189,"identity":"fa17bb95-eac2-4952-aea3-57b22afe1297","order_by":8,"name":"Mashina CHOMBA","email":"","orcid":"","institution":"University of Zambia School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Mashina","middleName":"","lastName":"CHOMBA","suffix":""},{"id":476807190,"identity":"bc1ad050-53a4-4d04-a9b9-e19f2b0fcad7","order_by":9,"name":"Melody ASUKILE","email":"","orcid":"","institution":"University Teaching Hospital","correspondingAuthor":false,"prefix":"","firstName":"Melody","middleName":"","lastName":"ASUKILE","suffix":""},{"id":476807191,"identity":"0bc24537-0428-47f6-8bef-4c4ba6e95c1b","order_by":10,"name":"Lorraine CHISHIMBA","email":"","orcid":"","institution":"University Teaching Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lorraine","middleName":"","lastName":"CHISHIMBA","suffix":""},{"id":476807192,"identity":"5f436e59-536a-4494-9923-744e4ca39939","order_by":11,"name":"Violet KAYAMBA","email":"","orcid":"","institution":"University of Zambia School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Violet","middleName":"","lastName":"KAYAMBA","suffix":""},{"id":476807193,"identity":"d298f20f-5c98-4278-8b18-93b2088055a5","order_by":12,"name":"Lloyd MULENGA","email":"","orcid":"","institution":"University Teaching Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lloyd","middleName":"","lastName":"MULENGA","suffix":""},{"id":476807194,"identity":"f57b253b-5bb0-4061-bb0c-b24de4ad0f9d","order_by":13,"name":"Omar SIDDIQI","email":"","orcid":"","institution":"Beth Israel Deaconess Medical Center, Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Omar","middleName":"","lastName":"SIDDIQI","suffix":""},{"id":476807195,"identity":"037c8ebd-d6aa-4279-940b-ffa46aa0e254","order_by":14,"name":"Owen A. ROSS","email":"","orcid":"","institution":"Mayo Clinic College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Owen","middleName":"A.","lastName":"ROSS","suffix":""},{"id":476807196,"identity":"61d9d5e8-d655-4567-a968-f1c8f76e40cf","order_by":15,"name":"Masharip ATADZHANOV","email":"","orcid":"","institution":"University Teaching Hospital","correspondingAuthor":false,"prefix":"","firstName":"Masharip","middleName":"","lastName":"ATADZHANOV","suffix":""},{"id":476807197,"identity":"062038b7-6190-422d-8c10-b049847bb99a","order_by":16,"name":"Deanna SAYLOR","email":"","orcid":"","institution":"University Teaching Hospital","correspondingAuthor":false,"prefix":"","firstName":"Deanna","middleName":"","lastName":"SAYLOR","suffix":""}],"badges":[],"createdAt":"2025-06-21 14:38:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6945551/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6945551/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12981-025-00799-5","type":"published","date":"2025-09-29T15:57:25+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85756225,"identity":"c64caa07-8614-4b3d-b3aa-b67d416daf51","added_by":"auto","created_at":"2025-07-01 10:48:09","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":58634,"visible":true,"origin":"","legend":"\u003cp\u003eRecruitment process\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6945551/v1/3f2767b494b8274ace5290c8.jpg"},{"id":92883950,"identity":"d4622ae3-3527-4d59-b8cd-34b4da156dbb","added_by":"auto","created_at":"2025-10-06 16:11:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":759824,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6945551/v1/01bc88e6-6fda-4d42-b2ee-94713af1ccd8.pdf"},{"id":85756229,"identity":"fd7028cc-704a-4936-bd3e-faf381f88bb0","added_by":"auto","created_at":"2025-07-01 10:48:09","extension":"doc","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":163840,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementarymaterialAIDSResearch.doc","url":"https://assets-eu.researchsquare.com/files/rs-6945551/v1/5b10be93f6de73a902f05486.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Antiretroviral Therapy and Risk of Stroke in People with HIV in Zambia","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eSub-Saharan Africa (SSA) shoulders a disproportionate burden of stroke and HIV.\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e These two epidemics are often intertwined and affect young adults aged less than 50 years without traditional stroke risk factors.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e This presents a socioeconomic and public health crisis in SSA as the most affected individuals are productive members of society who are expected to propel economic development. HIV is increasingly recognized as an independent stroke risk factor.\u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e The exact mechanisms by which HIV increases the risk of stroke are not well-defined. Most of what is known about HIV-associated stroke comes from high-income settings where traditional stroke risk factors such as diabetes, hypertension, hyperlipidemia and smoking are more common.\u003c/p\u003e \u003cp\u003eHIV has an effect on vascular biology leading to an increased risk of cardiovascular and cerebrovascular diseases. This may occur as HIV-associated vasculopathy, indirectly through opportunistic infections,\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e or as a consequence of antiretroviral therapy (ART) drugs. Nucleoside reverse-transcriptase inhibitors such as Didanosine and Abacavir have been associated with increased cardiovascular risk whereas Tenofovir Disoproxil Fumarate (TDF) has consistently not demonstrated any such association in multiple cohort studies.\u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Boosted protease inhibitors (PIs), which are the cornerstone of second line ART in many SSA countries such as Zambia, are associated with an increased risk of metabolic syndromes with longer exposure, which may worsen an underlying atherosclerotic process.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e All these drugs could increase the risk of cerebrovascular disease and stroke, but evidence linking them with such an association is lacking especially in SSA which is most affected by the HIV pandemic. Sub-Saharan Africa has a diverse and genetically different population which requires further investigation of ART and its contribution to stroke risk. Additionally, integrase inhibitors which form the backbone of first line ART in most African countries could potentially increase the risk of stroke within six months of ART initiation, as they rapidly suppress HIV which may possibly lead to an immune reconstitution inflammatory syndrome (IRIS)-like process.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWhile the relationship between HIV and stroke has been explored, the specific role of ART \u0026ndash; particularly with the widespread adoption of Dolutegravir (DTG) by World Health Organization (WHO) as the first-line ART backbone since 2016 \u0026ndash; remains poorly understood.\u003csup\u003e\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e This matched case-control study aimed to investigate the association between ART, duration of use, and stroke risk among people with HIV (PWH). We hypothesized that DTG-based regimens would be associated with increased stroke risk within one year (recent) of ART initiation due to DTG\u0026rsquo;s rapid virological suppression and potential for IRIS stroke. We also hypothesized that PIs would be associated with increased stroke risk with long-term (\u0026ge;\u0026thinsp;1 year) use due to their increased risk for metabolic syndrome with long-term use.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003e2.1 Study Setting\u003c/p\u003e\n\u003cp\u003eThe study was conducted at the University Teaching Hospital (UTH) in Lusaka, the largest and national referral tertiary care centre in Zambia. The hospital has neurodiagnostic assessments tools including magnetic resonance imaging (MRI), computed tomography (CT), and electroencephalography (EEG). The hospital has a neurology division with a functional stroke unit and a large adult centre for infectious diseases which attends to more than 20,000 PWH every year. Admission to UTH, physician consultations and medications stocked in the hospital pharmacy are free of charge for patients, but patients may pay out of pocket for all investigations if they do not have health insurance. As such, incomplete workups are common because of financial limitations or unavailability of reagents. In addition, investigations, which would not significantly alter patient management are usually not undertaken. However, UTH's status as a national referral centre with advanced neurodiagnostic tools and a high volume of PWH makes it an ideal setting for investigating HIV-associated stroke.\u003c/p\u003e\n\u003cp\u003e2.2 Study Design and Period\u003c/p\u003e\n\u003cp\u003eWe conducted a prospective case control study from March 2022 to October 2024 on PWH with (cases) and without (controls) stroke matched (1:2) for age, sex and race. Controls were consecutive patients accessing routine UTH outpatient HIV care services who were confirmed to be stroke-free after a neurological assessment. Cases were further stratified by ART use duration [recent (\u0026lt; 1 year) and long-term (\u003cu\u003e\u0026gt;\u003c/u\u003e 1 year)].\u003c/p\u003e\n\u003cp\u003e2.3 Participants\u003c/p\u003e\n\u003cp\u003eAll cases were adults (\u003cu\u003e\u0026gt;\u003c/u\u003e18 years) either admitted to the inpatient neurology service or seen at the neurology clinic at UTH with a clinical diagnosis of stroke in PWH on ART, with symptom onset of less than 2 months. All paper charts during the study period were reviewed to confirm the diagnosis of stroke. Of note, all patients admitted to UTH are routinely offered voluntary HIV testing and counseling upon admission. Patients with neuroimaging-confirmed ischemic stroke or intracerebral hemorrhage (ICH) were categorized accordingly; those seen with clinically suspected stroke who did not undergo neuroimaging due to financial constraints or scanner malfunction were categorized as “unknown stroke” (US). Exclusion criteria included transient ischemic attack (TIA) (symptom duration less than 24 hours), subdural or epidural hematoma, non-stroke neurological diagnoses, and stroke occurring secondary to surgery or traumatic injury.\u003c/p\u003e\n\u003cp\u003e2.4 Recruitment Process and Measurements\u003c/p\u003e\n\u003cp\u003eWe leveraged the national electronic medical records for PWH (SMART Care), chart reviews and patient interviews to obtain data for cases and pre-enrolment data for controls including blood pressure, ART regimen and duration, CD4 count, and HIV viral load as well as socio-economic and clinical related factors. Routine stroke workup, including CT and MRI scans, lipid panel, electrocardiogram and echocardiogram, were also recorded if obtained as part of routine clinical care. All patients were assessed and examined by a neurologist (SZ). Stroke severity was graded according to the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS).\u003csup\u003e20, 21\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHypertension and diabetes mellitus were defined per World Health Organization (WHO) guidelines\u003csup\u003e22, 23\u003c/sup\u003e and atrial fibrillation was defined by self-reported history or ECG or Echo confirming atrial fibrillation. Hyperlipidaemia was defined by self-report, statin use or standard laboratory cutoffs including low density lipoprotein (LDL) greater than 3.36 mmol/l, high-density lipoprotein (HDL) less than 1.29 mmol/l, total cholesterol more than 5.17 mmol/l or triglycerides greater than 3.88 mmol/l.\u003csup\u003e24\u003c/sup\u003e Cigarette smoking was classified as active smoker (current or former smoker for less than 1 year), passive smoker (household member or coworker who regularly smoked in his/her presence for more than 1 year during the last 10 years) or nonsmoker, and alcohol intake (ex-drinker for less than 1 year or current alcohol intake).\u003c/p\u003e\n\u003cp\u003e2.5 Stroke Classification\u003c/p\u003e\n\u003cp\u003eA radiologist (MC) interpreted all brain imaging, and stroke classification was done independently by two study investigators (SZ and MA) with a third neurologist (DS) adjudicating when there was disagreement between the first two reviewers. Due to limited diagnostics, ischemic stroke cases were further classified using the Bamford classification: total anterior circulation infarction (TACI), partial anterior circulation infarction (PACI), posterior circulation infarction (POCI) and lacunar infarction (LACI).\u003csup\u003e25\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e2.6 Sample Size\u003c/p\u003e\n\u003cp\u003eNo pre-determined sample size was calculated for this exploratory study, but consecutive sampling was continued for a pre-defined period of one year. Based on our clinical registry,\u003csup\u003e5\u003c/sup\u003e we had estimated to recruit 200 PWH with stroke during this recruitment period. The recruitment period was extended from one to two years due to disruptions caused by the COVID-19 pandemic.\u003c/p\u003e\n\u003cp\u003e2.7 Statistical Analysis\u003c/p\u003e\n\u003cp\u003eAll data were entered into a secure REDCap database hosted by the Zambian Ministry of Health Infectious Diseases Directorate and analysed using SPSS version 27.\u003csup\u003e26, 27\u003c/sup\u003e Demographic and clinical characteristics were summarized with descriptive statistics. Chi square test was used to determine the association between categorical variables. Student t-test was used to compare normally-distributed continuous variables between cases and controls, while the Mann-Whitney U-test was used if the continuous variables were not normally-distributed. \u003cem\u003eP\u003c/em\u003e values of less than 0.05 were taken as statistically significant.\u003c/p\u003e\n\u003cp\u003eA multivariable conditional logistic regression model was then used to adjust for confounders and to identify factors independently associated with stroke in PWH. Only variables statistically significant at bivariate analysis were included in the multivariable conditional logistic regression model. Different models were run and the best predictive model was selected based on one with the largest area under the Receiver-operating characteristic (ROC) curve, lowest Akaike information criterion (AIC) and Bayesian information criterion (BIC), and the highest likelihood ratio. We checked fitness of the model using Hosmer-Lame-Show goodness of fit test and confirmed that there was no multicollinearity using variance inflation factor (VIF) values.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2.8 Ethical Approval\u003c/p\u003e\n\u003cp\u003eEthical approval was obtained from the University of Zambia Biomedical Research Ethics Committee (No. 1945-2021) and National Health Research Authority (REF: NHREB00008/30/09/2021), while permission was obtained from UTH management to conduct the study at UTH. Written informed consent to participate in the study as well as for publication was obtained from each of the study participants. For participants with altered mental status, informed consent was obtained from a surrogate, defined as a caregiver or close relative.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003e3.1 Demographics\u003c/p\u003e\n\u003cp\u003eIn total, 205 cases and 410 controls were enrolled (Figure 1). The cases presented with a median NIHSS score of 9 (5-16) and mRS score of 4 (2-5). Ninety-one percent of the cases were identified as either ischemic or intracerebral hemorrhage and the rest were unknown as they did not get neuroimaging. For ischemic stroke, the majority (67%) of cases had anterior circulation infarction followed by lacunar infarction using Bamford classification (Table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3.2 Risk Factors and Comorbidities\u003c/p\u003e\n\u003cp\u003eCompared to controls, cases were more likely to have traditional risk factors for stroke such as hypertension, diabetes, hyperlipidemia and atrial fibrillation. They also had lower CD4 counts and advanced WHO HIV clinical stage. Although 87% of cases were on long-term ART, they were significantly less compared to controls, and they were more likely to be on second line ART (Table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1:\u003c/strong\u003e Comparison of demographic, clinical characteristics and ART factors between PWH with and without stroke\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCases (n=205)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControls (n=410)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 562px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDemographic/Clinical\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eFemale n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e114 (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e229 (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eAge, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e52 (\u0026plusmn;12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e52(\u0026plusmn;12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eSecondary school or higher n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e136 (66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e278 (68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eMarried/cohabiting n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e107 (52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e212 (52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eAlcohol intake n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e59 (29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e264 (64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eSmoking n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e25 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e20 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eBMI (Kg/m\u003csup\u003e2\u003c/sup\u003e), median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e26.7 (22.9-32.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e26.1 (23.5-29.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eSystolic BP, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e139(\u0026plusmn;29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e135(\u0026plusmn;13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.04\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eDiastolic BP, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e89(\u0026plusmn;17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e79(\u0026plusmn;13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eNIHSS, median (IQR)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e9 (5-16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003emRS, median (IQR)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e4 (2-5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 562px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStroke Type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eStroke type n (%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Ischemic\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Intracerebral hemorrhage\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Unknown stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e129 (63)\u003c/p\u003e\n \u003cp\u003e58 (28)\u003c/p\u003e\n \u003cp\u003e18 (9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003csup\u003e\u0026yen;\u003c/sup\u003e\u003c/strong\u003eBamford Classification of Ischemic Strokes, n (%):\u003c/p\u003e\n \u003cp\u003eLACI\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ePACI\u003c/p\u003e\n \u003cp\u003eTACI\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ePOCI\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e51/129 (39)\u003c/p\u003e\n \u003cp\u003e36/129 (28)\u003c/p\u003e\n \u003cp\u003e28/129 (22)\u003c/p\u003e\n \u003cp\u003e14/129 (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 562px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eComorbid Conditions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eHypertension n (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e145 (71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e73 (18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eDiabetes mellitus n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e24 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e15 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eHyperlipidemia n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e37 (18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003ePrevious stroke n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e56 (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eAtrial fibrillation n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e5 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHIV-associated Factors\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eCD4 count (cells/\u0026micro;l), median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e293 (163-592)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e533 (376-688)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eCD4 count \u0026ge;200cells/\u0026micro;l, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e53/79 (67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e311/334 (93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eHIV viral load (copies/ml), median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e20 (0-241)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0 (0-29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eART use, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e200 (98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e404 (99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eART duration, \u0026ge; 1 year, n (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e174/200 (87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e394/404 (99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eSecond line ART n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e46/200 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e17/404 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eDolutegravir n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e148/200 (74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e389/404 (95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eTenofovir Disoproxil Fumarate n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e136/200 (68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e119/404 (29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eProtease Inhibitors n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e14/200 (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e10/404 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eWHO HIV Clinical Stage n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eStage 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e132 (64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e380 (93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eStage 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e37 (18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e21 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eStage 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e20 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e9 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 264px;\"\u003e\n \u003cp\u003eStage 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e16 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eBolded text signifies p \u0026lt; 0.05.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026yen;\u003c/strong\u003e Bamford classification pertains to those with confirmed ischemic strokes only, not the total sample\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e ART=antiretroviral therapy; BMI=body mass index; BP=blood pressure; LACI=lacunar anterior circulatory infarct; mRS=modified Rankin Scale; NIHSS=national institute of health stroke scale; PACI=partial anterior circulatory infarct; POCI=posterior circulatory infarct; TACI=total anterior circulatory infarct; WHO=world health organization\u003c/p\u003e\n\u003cp\u003e3.3 Independent Predictors of stroke\u003c/p\u003e\n\u003cp\u003eHypertension (aOR 19.7, 95% CI 3.1-126.4, \u003cem\u003ep\u003c/em\u003e=0.002) and Tenofovir Disoproxil Fumarate (TDF) use (aOR 85.3, 95% CI 5.3-1380.7, \u003cem\u003ep\u003c/em\u003e=0.002) were independently associated with increased odds of stroke, while Dolutegravir (DTG) use (aOR 0.03, 95% CI 0.001-0.58, \u003cem\u003ep\u003c/em\u003e=0.02) and alcohol intake (aOR 0.24, 95% CI 0.06-0.95) were associated with reduced odds of stroke (Table 2). The prediction model used had area under ROC curve of 82% (Supplemental Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2:\u003c/strong\u003e Multivariable conditional logistic regression analysis of factors associated with stroke in PWH\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdjusted OR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026ndash;value (Adj. OR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eAlcohol intake n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0.24 (0.06-0.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.04\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eHypertension n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e19.7 (3.1-126.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0\u003c/strong\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eCD4 count (cells/\u0026micro;l), median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e1.000 (0.996-1.001)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eDolutegravir n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0.03 (0.001-0.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eTenofovir Disoproxil Fumarate n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e85.3 (5.3-1380.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0\u003c/strong\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eSecond line ART n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e17.7 (0.9-353.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e3.4 PWH with Stroke and ART Use Duration\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOf the 200 PWH and stroke taking ART, 174 (87%) were on long-term ART use. Those on long-term ART were less likely to be on second line ART, but more likely to be on TDF and DTG compared with their counterparts with recent ART use. Additionally, they were less likely to be on PIs compared with recent ART use, but the difference was not statistically significant (Table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e. PWH presenting with stroke stratified by duration of ART use\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eART \u0026ge; 1 year (n=174)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eART \u0026lt; 1 year (n=26)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003eSecond line ART n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e31 (18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e15 (58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003eDolutegravir n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e139 (80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e9 (35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003eTenofovir Disoproxil Fumarate n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e125 (72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e11 (42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003eProtease Inhibitors n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e11 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e3 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.40\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis case-control study showed that stroke risk in PWH is associated with many factors including ART use. Notably, we found that TDF was associated with increased odds (aOR 85.3) of stroke in PWH. \u0026nbsp; Protease inhibitors only showed increased odds of stroke at univariate analysis. Dolutegravir use was independently associated with reduced odds of stroke, but significantly more PWH and stroke were likely to be on DTG long-term use on subgroup analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur findings add a new dimension to the existing body of knowledge. For instance, TDF is known to be associated with better lipid profiles and potentially reduced cardiovascular risk, while its association with stroke risk has not previously been reported.\u003csup\u003e28\u003c/sup\u003e Treatment with TDF has consistently been associated with lower lipid levels, a decline in renal function and reduced bone mineral density.\u003csup\u003e12, 29\u003c/sup\u003e The mechanism by which it would be implicated in stroke risk is unclear, although its effect on renal function and its interaction with other ART drugs could provide a possible explanation for our findings, which need further research. In addition, the immunological and virological status of patients taking TDF may be important, as poorly-controlled HIV-infection can increase the risk of stroke.\u003csup\u003e8, 30\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAs for DTG, it has been associated with increased risk of stroke within the first few months of its initiation due to its rapid virological suppression leading to a potential IRIS.\u003csup\u003e15, 16, 31, 32\u003c/sup\u003eOur findings suggest an overall reduced odds of stroke with DTG use which could be explained by its beneficial effects on metabolic and inflammatory markers compared to other ART drugs.\u003csup\u003e33\u003c/sup\u003e However, our findings showed that a higher proportion of long-term ART users with stroke were on DTG. This could suggest that long-term instead of recent DTG use is an important factor in stroke risk. Recent studies have demonstrated that DTG is associated with hypertension,\u003csup\u003e34\u003c/sup\u003e hence its role in increasing stroke risk could also be indirectly through hypertension with prolonged use.\u003c/p\u003e\n\u003cp\u003eWe found a modest association between boosted protease inhibitors (PIs) and increased odds of stroke which was not sustained on multivariable analysis. PIs are used in second line ART, and have been shown to increase cardiovascular disease risk by promoting metabolic syndrome with prolonged use.\u003csup\u003e35\u003c/sup\u003e Our modest findings can be explained by the small numbers of recruited participants on PIs. Even on subgroup analysis of the cases, we observed that PWH and stroke were less likely to be on long-term use of PIs, but the difference was not statistically significant compared. It is important to emphasize that long-term ART use for our study was defined as 12 months or more whereas other studies which have looked at prolonged PIs use have considered more than 24 months.\u003csup\u003e36\u003c/sup\u003e This timeframe difference could also have a bearing on our findings.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhat is clear from our results is that both traditional and HIV-associated factors are important risk factors of stroke in this population of PWH. Hypertension was an independent risk factor of stroke in our study, with almost 20 times higher odds of stroke. However, we found the opposite for alcohol intake as it was noted to reduce the odds of stroke, although we did not properly quantify its use in our cohort. Several studies have shown that alcohol intake is an important risk factor for stroke with a direct relationship depending on quantities consumed, with some studies suggesting that alcohol intake in moderation is actually protective.\u003csup\u003e37-39\u003c/sup\u003e Our findings ultimately support the current consensus that the actual mechanism of stroke in PWH is multifactorial, and ART may be a co-factor.\u003c/p\u003e\n\u003cp\u003eOur study has several limitations, including being a single-centre study at a national referral hospital, which might make the generalizability of these results difficult. As this was an exploratory study, we did not correct for multiple comparisons so that some of the associations found here may be due to chance alone. We did not thoroughly assess the contribution of the other ART drugs such as Abacavir, Zidovudine, Emtricitabine and Tenofovir Alafenamide which some of the participants may have been taking. Similarly, we did not compare for multiple ART combinations (e.g. some on the participants were taking both TDF and DTG) or the influence of the previous ART regimen for those who were recruited on second line ART. Nevertheless, our expectation is that these results are likely generalizable and they provide preliminary data that can be used to guide the development of interventions to reduce stroke risk in PWH. Some findings were based on information from the routine care available at the hospital during the study. The BMI for a few patients could not be calculated because of lack of a proper weighing scale for bedridden patients. Resource limitations also meant that not every participant was thoroughly evaluated for stroke risk factors such as hyperlipidaemia and diabetes (Supplemental Table 1). However, a strength of this study is the relatively large sample size and that all participants received a thorough clinical evaluation by trained neurologists making the clinical characterizations of this cohort more reliable than in many other SSA populations in which participants are assessed by non-neurologist healthcare workers.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn conclusion, PWH are at increased risk of stroke due to multiple factors including traditional risk factors such as hypertension and HIV-associated factors such as ART use. Tenofovir Disoproxil Fumarate increases the odds of stroke. Although Dolutegravir associates with reduced odds of stroke, stroke patients on long-term ART are more likely to be on it. We found a modest association between PIs use and increased stroke risk. Future research designed to focus on multiple combinations of the different ART drugs and their contribution to stroke risk is needed to provide better insight into these findings in order to allow for the development of targeted and effective interventions for both primary and secondary stroke prevention for PWH.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe authors have nothing to disclose.\u003c/p\u003e\n\u003ch2\u003eFunding:\u003c/h2\u003e\n\u003cp\u003eNIH K01 TW011771-01, D43 TW010543 and 2D43TW009744.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eSZ made substantial contribution to conception and design of the study and data collection and drafted and revised the manuscript. ON was integral in study conceptualization, analysis and also revised the manuscript. EM participated in data collection and revision of the manuscript. TS participated in data collection and revision of the manuscript. TM participated in data collection and revision of the manuscript. DM participated in data collection and revision of the manuscript. BM participated in data collection and analysis. MC participated in data interpretation and revision of the manuscript. MaC participated in research design and revision of the manuscript. MeA participated in data collection and revision of the manuscript. LC participated in data collection and revision of the manuscript. VK was involved in revising the manuscript critically for important intellectual content. LM was integral in study conceptualization, study design and also revised the manuscript. OS was integral in study conceptualization, study design and also revised the manuscript. OR was involved in the design and revision of the manuscript. MA revised the manuscript for intellectual content. DS made substantial contributions to study conception, study design and revision of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eWe thank the Department of Internal Medicine and the Adult Infectious Diseases Centre at UTH for supporting this study. This study received funding from the NIH Office of AIDS Research, NIH K01 TW011771-01, the Fogarty International Center and National Institute of Mental Health, of the National Institutes of Health under Award Number D43 TW010543 and the Fogarty International Centre of the US National Institutes of Health under Award Number 2D43TW009744.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eOrganization WH. HIV: fact sheet on Sustainable Development Goals (SDGs): health targets: World Health Organization. Regional Office for Europe, 2017.\u003c/li\u003e\n\u003cli\u003eKengne AP, Anderson CS. The neglected burden of stroke in Sub-Saharan Africa. International Journal of Stroke 2006;1:180-190.\u003c/li\u003e\n\u003cli\u003eUthman OA. Global, regional, and national disability‐adjusted life years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990‐2015: a systematic analysis for the Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2015 Study. Lancet 2016;388:1603-1658.\u003c/li\u003e\n\u003cli\u003eTipping B, de Villiers L, Wainwright H, Candy S, Bryer A. Stroke in patients with human immunodeficiency virus infection. Journal of Neurology, Neurosurgery \u0026amp; Psychiatry 2007;78:1320-1324.\u003c/li\u003e\n\u003cli\u003eZimba S, Nutakki A, Chishimba L, et al. Risk factors and outcomes of HIV-associated stroke in Zambia. Aids 2021;35:2149-2155.\u003c/li\u003e\n\u003cli\u003eChow FC, Regan S, Feske S, Meigs JB, Grinspoon SK, Triant VA. Comparison of ischemic stroke incidence in HIV-infected and non\u0026ndash;HIV-infected patients in a US health care system. JAIDS Journal of Acquired Immune Deficiency Syndromes 2012;60:351-358.\u003c/li\u003e\n\u003cli\u003eBenjamin LA, Bryer A, Emsley HC, Khoo S, Solomon T, Connor MD. HIV infection and stroke: current perspectives and future directions. The Lancet Neurology 2012;11:878-890.\u003c/li\u003e\n\u003cli\u003eHarding BN, Avoundjian T, Heckbert SR, et al. HIV viremia and risk of stroke among people living with HIV who are using antiretroviral therapy. Epidemiology 2021;32:457-464.\u003c/li\u003e\n\u003cli\u003eConnor M. Stroke in patients with human immunodeficiency virus infection. BMJ Publishing Group Ltd, 2007: 1291-1291.\u003c/li\u003e\n\u003cli\u003eBenjamin LA, Allain TJ, Mzinganjira H, et al. The role of human immunodeficiency virus\u0026ndash;associated vasculopathy in the etiology of stroke. The Journal of infectious diseases 2017;216:545-553.\u003c/li\u003e\n\u003cli\u003eFriis-M\u0026oslash;ller N, Thiebaut R, Reiss P, et al. Predicting the risk of cardiovascular disease in HIV-infected patients: the data collection on adverse effects of anti-HIV drugs study. European journal of cardiovascular prevention \u0026amp; rehabilitation 2010;17:491-501.\u003c/li\u003e\n\u003cli\u003eSantos JR, Saumoy M, Curran A, et al. The lipid-lowering effect of tenofovir/emtricitabine: a randomized, crossover, double-blind, placebo-controlled trial. Clinical Infectious Diseases 2015;61:403-408.\u003c/li\u003e\n\u003cli\u003eHuhn GD, Shamblaw DJ, Baril J-G, et al. Atherosclerotic cardiovascular disease risk profile of tenofovir alafenamide versus tenofovir disoproxil fumarate. Open forum infectious diseases; 2020: Oxford University Press US: ofz472.\u003c/li\u003e\n\u003cli\u003eGroup DS. Class of antiretroviral drugs and the risk of myocardial infarction. New England Journal of Medicine 2007;356:1723-1735.\u003c/li\u003e\n\u003cli\u003eBenjamin LA, Corbett EL, Connor MD, et al. HIV, antiretroviral treatment, hypertension, and stroke in Malawian adults: a case-control study. Neurology 2016;86:324-333.\u003c/li\u003e\n\u003cli\u003eZimba S, Mbewe N, Chishimba L, Chomba M, Saylor D. Immune reconstitution inflammatory syndrome: a report of TB-IRIS after switching from efavirenz to dolutegravir. Tropical Doctor 2021;51:216-218.\u003c/li\u003e\n\u003cli\u003eWalmsley S, Berenguer J, Khuong-Josses M, Kilby J, Lutz T, Podzamczer D. Dolutegravir regimen statistically superior to efavirenz/tenofovir/emtricitabine: 96-week results from the SINGLE study (ING114467). Conference on Retrovirues and Opportunistic Infections; 2014.\u003c/li\u003e\n\u003cli\u003eRaffi F, Rachlis A, Brinson C, et al. Dolutegravir efficacy at 48 weeks in key subgroups of treatment-naive HIV-infected individuals in three randomized trials. Aids 2015;29:167-174.\u003c/li\u003e\n\u003cli\u003eJiang J, Xu X, Guo W, et al. Dolutegravir (DTG, S/GSK1349572) combined with other ARTs is superior to RAL-or EFV-based regimens for treatment of HIV-1 infection: a meta-analysis of randomized controlled trials. AIDS research and therapy 2016;13:1-10.\u003c/li\u003e\n\u003cli\u003eLyden P, Brott T, Tilley B, et al. Improved reliability of the NIH Stroke Scale using video training. NINDS TPA Stroke Study Group. Stroke 1994;25:2220-2226.\u003c/li\u003e\n\u003cli\u003eScale S. Modified Rankin Scale. http://www strokecenter org/trials/scales/rankin html 2008.\u003c/li\u003e\n\u003cli\u003eWhitworth J. World Health Organization, International Society of Hypertension Writing Group. J Hypertens 2003;21:1983-1992.\u003c/li\u003e\n\u003cli\u003eAlberti KGMM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabetic medicine 1998;15:539-553.\u003c/li\u003e\n\u003cli\u003eNelson RH. Hyperlipidemia as a risk factor for cardiovascular disease. Primary care 2012;40:195.\u003c/li\u003e\n\u003cli\u003eBamford J, Sandercock P, Dennis M, Warlow C, Burn J. Classification and natural history of clinically identifiable subtypes of cerebral infarction. The Lancet 1991;337:1521-1526.\u003c/li\u003e\n\u003cli\u003eHarris PA, Taylor R, Minor BL, et al. The REDCap consortium: building an international community of software platform partners. Journal of biomedical informatics 2019;95:103208.\u003c/li\u003e\n\u003cli\u003eHarris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)\u0026mdash;a metadata-driven methodology and workflow process for providing translational research informatics support. Journal of biomedical informatics 2009;42:377-381.\u003c/li\u003e\n\u003cli\u003eDorjee K, Desai M, Choden T, Baxi SM, Hubbard AE, Reingold AL. Acute myocardial infarction associated with abacavir and tenofovir based antiretroviral drug combinations in the United States. AIDS research and therapy 2021;18:1-10.\u003c/li\u003e\n\u003cli\u003eGallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. Jama 2004;292:191-201.\u003c/li\u003e\n\u003cli\u003eNweke M, Mshunqane N. Characterization and stratification of risk factors of stroke in people living with HIV: A theory-informed systematic review. BMC Cardiovascular Disorders 2025;25:1-34.\u003c/li\u003e\n\u003cli\u003eWijting I, Rokx C, Wit F, Postma A, Hoepelman A, van der Ende M. Integrase Inhibitors are an Independent Risk Factor for IRIS: an ATHENA-Cohort Study. Conference on Retroviruses and Opportunistic Infections; 2017: 13-16.\u003c/li\u003e\n\u003cli\u003ePsichogiou M, Poulakou G, Basoulis D, Paraskevis D, Markogiannakis A, L. Daikos G. Recent advances in antiretroviral agents: potent integrase inhibitors. Current pharmaceutical design 2017;23:2552-2567.\u003c/li\u003e\n\u003cli\u003eRoux CG, Mason S, du Toit LD, Nel J-G, Rossouw TM, Steel HC. Comparative Effects of Efavirenz and Dolutegravir on Metabolomic and Inflammatory Profiles, and Platelet Activation of People Living with HIV: A Pilot Study. Viruses 2024;16:1462.\u003c/li\u003e\n\u003cli\u003eByonanebye DM, Polizzotto MN, Maltez F, et al. Associations between change in BMI and the risk of hypertension and dyslipidaemia in people receiving integrase strand-transfer inhibitors, tenofovir alafenamide, or both compared with other contemporary antiretroviral regimens: a multicentre, prospective observational study from the RESPOND consortium cohorts. The Lancet HIV 2024;11:e321-e332.\u003c/li\u003e\n\u003cli\u003eEchecopar-Sabogal J, D\u0026rsquo;Angelo-Piaggio L, Chanam\u0026eacute;-Baca DM, Ugarte-Gil C. Association between the use of protease inhibitors in highly active antiretroviral therapy and incidence of diabetes mellitus and/or metabolic syndrome in HIV-infected patients: A systematic review and meta-analysis. International journal of STD \u0026amp; AIDS 2018;29:443-452.\u003c/li\u003e\n\u003cli\u003eParra-Rodriguez L, Sahrmann JM, Butler AM, Olsen MA, Powderly WG, O\u0026rsquo;Halloran JA. Antiretroviral Therapy and Cardiovascular Risk in People With HIV in the United States\u0026mdash;An Updated Analysis. Open Forum Infectious Diseases; 2024: Oxford University Press US: ofae485.\u003c/li\u003e\n\u003cli\u003eSmyth A, O\u0026apos;Donnell M, Rangarajan S, et al. Alcohol intake as a risk factor for acute stroke: the INTERSTROKE study. Neurology 2023;100:e142-e153.\u003c/li\u003e\n\u003cli\u003eReynolds K, Lewis B, Nolen JDL, Kinney GL, Sathya B, He J. Alcohol consumption and risk of stroke: a meta-analysis. Jama 2003;289:579-588.\u003c/li\u003e\n\u003cli\u003eZhang C, Qin Y-Y, Chen Q, et al. Alcohol intake and risk of stroke: a dose\u0026ndash;response meta-analysis of prospective studies. International journal of cardiology 2014;174:669-677.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"aids-research-and-therapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arty","sideBox":"Learn more about [AIDS Research and Therapy](http://aidsrestherapy.biomedcentral.com/)","snPcode":"12981","submissionUrl":"https://submission.nature.com/new-submission/12981/3","title":"AIDS Research and Therapy","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Antiretroviral therapy, HIV infection, stroke, Sub-Saharan Africa, Zambia ","lastPublishedDoi":"10.21203/rs.3.rs-6945551/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6945551/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePeople with HIV (PWH) are at increased risk of stroke likely due to many factors including antiretroviral therapy (ART). We sought to evaluate the association between ARTand risk of stroke in PWH.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted a prospective case-control study at the University Teaching Hospital in Lusaka, Zambia between March 2022 and October 2024 in PWH comparing those with stroke (cases) and without (controls) matched (1:2) for age, sex and race. Standardized data collection instruments were used to collect demographic, clinical, laboratory and imaging information. Comparisons were made between the cases and controls, and subgroup analysis by ART duration was done for the cases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe analyzed results for 205 cases and 410 controls. Compared to controls, cases were more likely to have hypertension (71% vs. 18%, \u003cem\u003ep\u003c/em\u003e=0.001), lower CD4 counts [293(163-592) cells/µl vs. 533 (376-688) cells/µl, \u003cem\u003ep\u003c/em\u003e=0.0001] and to be on second line ART (23% vs. 4%, \u003cem\u003ep\u003c/em\u003e=0.001). Hypertension (aOR 19.7, 95% CI 3.1-126.4, \u003cem\u003ep\u003c/em\u003e=0.002) and Tenofovir Disoproxil Fumarate (TDF) use (aOR 85.3, 95% CI 5.3-1380.7, \u003cem\u003ep\u003c/em\u003e=0.002) were associated with increased odds of stroke, whereas Dolutegravir (aOR 0.03, 95% CI 0.001-0.58, \u003cem\u003ep\u003c/em\u003e=0.02) and alcohol use (aOR 0.24, 95% CI 0.06-0.95) were associated with reduced odds of stroke. The majority of stroke patients on long-term ART were using Dolutegravir (80% vs. 35%, \u003cem\u003ep\u003c/em\u003e=0.001) and TDF (72% vs. 42%, \u003cem\u003ep\u003c/em\u003e=0.01).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn PWH, TDF associates with higher odds of stroke. Although Dolutegravir associates with reduced odds of stroke, stroke patients on long-term ART are more likely to be on it.\u003c/p\u003e","manuscriptTitle":"Antiretroviral Therapy and Risk of Stroke in People with HIV in Zambia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-01 10:48:04","doi":"10.21203/rs.3.rs-6945551/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-11T11:45:15+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-14T07:16:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"141272357822444355009542497606289281376","date":"2025-06-26T10:27:39+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-26T09:30:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-23T14:24:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-23T12:48:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"AIDS Research and Therapy","date":"2025-06-21T14:28:54+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"aids-research-and-therapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arty","sideBox":"Learn more about [AIDS Research and Therapy](http://aidsrestherapy.biomedcentral.com/)","snPcode":"12981","submissionUrl":"https://submission.nature.com/new-submission/12981/3","title":"AIDS Research and Therapy","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c9cc27f4-589e-4948-b2c2-b3a3c2519c51","owner":[],"postedDate":"July 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-06T16:05:55+00:00","versionOfRecord":{"articleIdentity":"rs-6945551","link":"https://doi.org/10.1186/s12981-025-00799-5","journal":{"identity":"aids-research-and-therapy","isVorOnly":false,"title":"AIDS Research and Therapy"},"publishedOn":"2025-09-29 15:57:25","publishedOnDateReadable":"September 29th, 2025"},"versionCreatedAt":"2025-07-01 10:48:04","video":"","vorDoi":"10.1186/s12981-025-00799-5","vorDoiUrl":"https://doi.org/10.1186/s12981-025-00799-5","workflowStages":[]},"version":"v1","identity":"rs-6945551","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6945551","identity":"rs-6945551","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}